14 – 17 April, 2024 ● Hybrid Meeting
Copyright: Modified and published with permission from https://www.ebmt.org/annual-meeting
Sponsorship Statement: Publication of this supplement is sponsored by the European Society for Blood and Marrow Transplantation. All content was reviewed and approved by the EBMT Committee, which held full responsibility for the abstract selections.
19: Acute Leukaemia
P001 AUTOLOGOUS VERSUS HAPLOIDENTICAL DONOR STEM CELL TRANSPLANTATION FOR FAVORABLE-AND INTERMEDIATE-RISK ACUTE MYELOID LEUKEMIA IN FIRST REMISSION AND UNDETECTABLE MINIMAL RESIDUAL DISEASE: A MULTI-CENTER, PROSPECTIVE STUDY
Yiyang Ding1, Yuhua Ru1, Jinjin Zhu1, Xi Zhang2, Lin Liu3, Erlie Jiang4, He Huang5, Jishi Wang6, Jiong Hu7, Yanming Zhang8, Yajing Xu9, Mingzhen Yang10, Jia Chen 1, Depei Wu1
1National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China, 2Xinqiao Hospital, Third Military Medical University, Chongqing, China, 3The First Affiliated Hospital of Chongqing Medical University, Chongqing, China, 4Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China, 5Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, 6Affiliated Hospital of Guizhou Medical University, Guiyang, China, 7Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 8Huai’an Hospital Affiliated to Xuzhou Medical College and Huai’an Second People’s Hospital, Huai’an, China, 9XiangYa Hospital, Central South University, Changsha, China, 10the First Affiliated Hospital of Anhui Medical University, Hefei, China
Background: In the absence of HLA-matched donor, HLA-haploidentical donor stem cell transplantation (haplo-SCT) and autologous SCT (ASCT) are both valid postremission therapy with well-documented effects in patients with favorable-and intermediate-risk acute myeloid leukemia (AML). Our previous retrospective study has suggested similar survival following ASCT compared to haplo-SCT for favorable- and intermediate-risk AML patients in the first complete remission (CR1). Hence, we designed a prospective, multi-center study to further confirm this conclusion.
Methods: A prospective study was conducted in 10 Chinese centers. The main inclusion criteria were: 1) adult patients >=18 years old; 2) diagnosis as AML with intermediate-risk according to ELN 2010 or 2017; 3) ASCT or haplo-SCT underwent between 2014-2019; 4) in CR1 and MRD negative before transplant. The Primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), cumulative incidence of relapse (CIR), treatment-related mortality (TRM), and graft-versus-host disease-free and relapse-free survival (GRFS).
Results: A total of 368 patients diagnosed with favorable-and intermediate-risk AML were included from 10 institutions between January 2014 and December 2019, in accordance with the European Leukemia Net criteria (Table 1). Of these, 184 patients underwent ASCT, and 184 underwent haplo-SCT. In the overall cohort analysis, the CIR in the ASCT group was offset by reduced TRM when compared with the haplo-SCT group, resulting in similar PFS (70.5% versus 74.9%, P = 0.880) and improved OS (83.0% versus 77.0%, P = 0.044). Furthermore, ASCT patients exhibited a higher GRFS (70.5% versus 57.4%, P<0.001) attributed to the absence of GVHD. The OS trend was accentuated in the favorable-risk cohort, while comparable OS was observed in the intermediate-risk cohort. Multivariate analyses indicated that haplo-SCT, advanced age, MLL-AF9 rearrangement, graft cell dosage, and hematopoietic engraftment time independently impacted outcomes.
Table 1. Patient Characteristics.
Auto (n = 184) | Haplo (n = 184) | P | ||
---|---|---|---|---|
Median age (range) | 36 (18-64) | 35 (18-60) | 0.078 | |
Gender | Male | 104 | 95 | 0.346 |
Female | 80 | 89 | ||
Risk stratification | Favorable | 94 | 85 | 0.348 |
Intermediate | 90 | 99 | ||
WBC at diagnosis (median, 109/L) | 8.83 | 15.42 | 0.003 | |
Abnormal karyotype at diagnosis | 51 | 81 | 0.013 | |
Abnormal molecular at diagnosis | FLT3-ITD | 4 | 11 | 0.065 |
MLL-AF9 | 3 | 5 | 0.475 | |
Induction courses | 1 | 134 | 133 | 0.907 |
>1 | 50 | 51 | ||
Consolidation courses | ≤2 | 67 | 139 | <0.001 |
>2 | 117 | 45 | ||
HiDAC before transplant | 91 | 18 | <0.001 |
Conclusions: In conclusion, both ASCT and haplo-SCT proved to be viable approaches for the post-remission treatment of patients with favorable-and intermediate-risk AML. Notably, ASCT demonstrated superior outcomes in the favorable-risk cohort.
Clinical Trial Registry: Haplo-SCT vs ASCT With or Without Decitabine in AML CR1 - Full Text View - ClinicalTrials.gov (ClinicalTrails.gov Identifier: NCT02059720)
Disclosure: Nothing to declare
19: Acute Leukaemia
P002 OUTCOME OF ALLOGRAFTED ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS TREATED WITH THE PEDIATRIC-INSPIRED, MRD-ORIENTED GIMEMA LAL 1913 PROTOCOL IN THE REAL-LIFE: A CAMPUS ALL STUDY
Gianluca Cavallaro 1, Davide Lazzarotto2, Chiara Pavoni1, Francesca Valsecchi1, Cristina Papayannidis3, Marco Cerrano4, Sabina Chiaretti5, Nicola Fracchiolla6, Fabio Giglio7, Michelina Dargenio8, Monia Lunghi9, Silvia Imbergamo10, Maria Ilaria Del Principe11, Silvia Trappolini12, Monica Fumagalli13, Patrizia Zappasodi14, Prassede Salutari15, Mario Delia16, Crescenza Pasciolla17, Federico Mosna18, Barbara Scappini19, Fabio Forghieri20, Patrizia Chiusolo21, Cristina Skert22, Benedetta Cambò23, Marzia Defina24, Giuseppe Lanzarone25, Mauro Endri26, Massimiliano Bonifacio27, Carla Mazzone28, Lidia Santoro29, Antonino Mulè30, Valentina Mancini31, Paola Minetto32, Giorgia Battipaglia33, Alessandro Cignetti34, Lara Aprile35, Robin Foà5, Anna Candoni2,20, Federico Lussana1,36
1ASST Papa Giovanni XXIII, Bergamo, Italy, 2Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy, 3IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy, 4AOU Città della Salute e della Scienza – Presidio Molinette, Torino, Italy, 5Sapienza University, Roma, Italy, 6IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milano, Italy, 7IRCCS Ospedale San Raffaele, Milano, Italy, 8Ospedale Vito Fazzi, Lecce, Italy, 9University of Eastern Piedmont, Novara, Italy, 10Azienda Ospedale Università di Padova, Padova, Italy, 11University of Rome Tor Vergata, Roma, Italy, 12Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I, Ancona, Italy, 13Ospedale San Gerardo, Monza, Italy, 14Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, 15Azienda USL di Pescara, Pescara, Italy, 16Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Bari, Italy, 17IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy, 18Azienda Sanitaria dell’Alto Adige, Bolzano, Italy, 19Azienda Ospedaliera Universitaria Careggi, Firenze, Italy, 20Azienda Ospedaliero Universitaria di Modena, Modena, Italy, 21Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy, 22Ospedale dell’Angelo, Venezia, Italy, 23University of Parma, Parma, Italy, 24Azienda Ospedaliero Universitaria Senese, Siena, Italy, 25A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy, 26Ospedale Cà Foncello, Treviso, Italy, 27Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy, 28St. Eugenio Hospital, Roma, Italy, 29Azienda Ospedaliera San Giuseppe Moscati, Avellino, Italy, 30A.O. Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy, 31ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy, 32IRCCS Ospedale Policlinico San Martino, Genova, Italy, 33Azienda Ospedaliero-Universitaria Federico II, Napoli, Italy, 34Azienda Ospedaliera Ordine Mauriziano, Torino, Italy, 35Ospedale San Giuseppe Moscati, Taranto, Italy, 36University of Milan, Milano, Italy
Background: The GIMEMA LAL 1913 was a pediatric-inspired and minimal residual disease (MRD)-oriented phase 2 chemotherapy protocol that included peg-asparaginase for the frontline treatment of adult Philadelphia-negative acute lymphoblastic leukemia (Ph- ALL) patients (Bassan et al, Blood Advances, 2023). This protocol represents the standard treatment for adult Ph- ALL in Italy. The outcome of patients treated with the same protocol in the real-life setting and who underwent an allogeneic stem cell transplant (SCT) was the aim of this study.
Methods: Within the framework of the Campus ALL network in Italy, we analyzed the post-transplant data of newly diagnosed adult Ph- ALL patients treated according to the LAL 1913 protocol and who underwent a SCT between August 2016 and January 2023 in 35 Italian centers. Patients in 1st remission (CR1) were considered eligible for a SCT as consolidation based on the joint assessment of the disease risk profile at diagnosis (high white blood cell, immunophenotype or adverse cytogenetics/molecular biology) and post-consolidation MRD status. We also included relapsed patients in 2nd CR (CR2). Endpoints were the 2-year overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM) and cumulative incidence of relapse (CIR). Outcomes were analyzed from the day of SCT.
Results: Among 322 consecutive newly diagnosed Ph- ALL, 201 patients who underwent a SCT were included in this analysis (Table 1). The median age at diagnosis was 38 years (18-66). Median follow-up was 28 months. Patients allografted in CR1 were associated with a significantly superior 2-year OS (77% vs 32%, p<0.001), DFS (67% vs 35%, p = 0.003) and CIR (24% vs 47%, p = 0.006) compared to patients transplanted in CR2. Pre-transplant MRD negativity was strongly associated with a superior OS (81% vs 50%, p<0.001), DFS (71% vs 44%, p = 0.003) and CIR (21% vs 43%, p = 0.006). MRD negativity also impacted favorably on the prognosis of patients transplanted in 2nd CR in terms of OS and disease-free survival (Fig. 1). The outcome was similar between B- and T-lineage ALL, patients’ age (< or > 55 years) and baseline risk class. A myeloablative conditioning was adopted in 156 (79%) patients and total-body irradiation (TBI) in 125 (66%). There was no significant difference when using TBI 800 cGy vs TBI 1200 cGy and TBI-fludarabine vs TBI-alkylating agents. The use of ATG in sibling and unrelated donors did not affect CIR. The 2-year NRM was 11% and it was not significantly affected by pre- and post-transplant factors.
Table 1.
Patients’ characteristics | N = 201 | |
---|---|---|
Age at diagnosis, n(%) | <55 | 163 (81.1) |
>=55 | 38 (18.9) | |
Cell lineage, n(%) | B-ALL | 97 (48.3) |
T-ALL | 104 (51.7) | |
Baseline risk, n(%) | Standard Risk | 55 (27.4) |
High Risk | 25 (12.4) | |
Very High Risk | 121 (60.2) | |
Disease status at transplant, n(%) | CR1 | 171 (85.1) |
CR2 | 29 (14.4) | |
Pre transplant MRD, n(%) | Negative | 130 (68.8) |
Positive | 58 (30.7) | |
Donor, n(%) | Sibling | 61 (30.7) |
Matched unrelated donor | 68 (34.2) | |
Aploidentical | 37 (18.6) | |
Mismatched unrelated donor | 33 (16.6) | |
Conditioning regimen, n(%) | Myeloablative | 156 (78.8) |
Reduced intensity | 42 (21.2) | |
TBI, n(%) | No | 64 (33.9) |
Yes | 125 (66.1) |
Figure 1: 2-years DFS
Conclusions: Our study on a series of patients treated with a modern therapeutic strategy confirms the higher risk of relapse in patients with pre-transplant MRD positivity. Given the availability of pre-transplant immunotherapies, all efforts should be made to eradicate MRD prior to undergoing the SCT, or with post-transplant pre-emptive treatment. An advantage in survival was observed when transplant was performed in CR1 compared to CR2, highlighting the importance of an early identification of high-risk patients candidate to transplant consolidation. Importantly, a significant improvement in NRM outcome was recorded.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P003 FREQUENCY AND IMPACT OF SOMATIC MUTATIONS ON OUTCOMES OF ACUTE MYELOID LEUKEMIA PATIENTS RECEIVING ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION: FROM THE EBMT ACUTE LEUKEMIA WORKING PARTY
Ali Bazarbachi 1, Jacques-Emmanuel Galimard2, Myriam Labopin2, Iman Abou Dalle1, Jaime Sanz3, Huang He4, Jiri Mayer5, Carlos Solano6, Celestine Simand7, Laimonas Griskevicius8, Johan Maertens9, Maija Itäla-Remes10, Ain Kaare11, Maria-Pilar Gallego-Hernanz12, Gesine Bug13, Josep-Maria Ribera14, Alain Gadisseur15, Christoph Schmid16, Mi Kwon17, Xavier Poiré18, Paola Coccia19, Manuel Jurado Chacón20, Frédéric Baron21, Eolia Brissot22, Arnon Nagler23, Fabio Ciceri24, Mohamad Mohty25
1American University of Beirut Medical Center, Beirut, Lebanon, 2EBMT Statistical Unit, Sorbonne University, Saint-Antoine Hospital, Paris, France, 3University Hospital La Fe, Valencia, Spain, 4First Affiliated Hospital of Zhejiang University School of Medicine, Kunming, China, 5University Hospital Brno, Brno, Czech Republic, 6Hospital Clínico Universitario. University of Valencia, Valencia, Spain, 7ICANS, Strasbourg, France, 8Hôpitaux Universitaires Strasbourg, Strasbourg, France, 9University Hospital Gasthuisberg, Leuven, Belgium, 10Turku University Hospital, Turku, Turkey, 11Tartu University Hospital, Tartu, Estonia, 12Hopital La Miletrie, Poitiers, France, 13Goethe-Universitaet, Frankfurt Main, Germany, 14ICO-Hospital Universitari Germans Trias i Pujol, Josep Carreras Research Institute, Badalona, Spain, 15Antwerp University Hospital (UZA), Antwerp E, Belgium, 16University Hospital and Medical Faculty, University of Augsburg, Augsburg, Germany, 17Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain, 18Cliniques Universitaires St. Luc, Brussels, Belgium, 19Azienda Ospedali Riuniti di Ancona, Ancona, Italy, 20Hospital Univ. Virgen de las Nieves, Granada, Grenada, 21University of Liege, Liege, Belgium, 22Sorbonne University, Paris, France, 23Hematology Division, Chaim Sheba Medical Center, Tel-Hashomer, Israel, 24IRCCS Ospedale San Raffaele, Milano, Italy, 25Sorbonne University, Saint-Antoine Hospital, Paris, France
Background: Acute myeloid leukemia (AML) is a very heterogeneous hematological malignancy, which includes numerous genetically defined subsets. In the context of allogeneic hematopoietic cell transplantation (allo-HCT), the frequency and prognostic value of different gene-gene interactions has not been studied and may differ from that of patients treated with chemotherapy alone.
Methods: This is a registry-based analysis from the EBMT with the approval of the EBMT Acute Leukemia Working Party. Adult patients aged more than 18 years with a diagnosis of AML who received an allo-HCT between 2013-2022, with an available genetic profile determined at diagnosis by next generation sequencing (NGS) were included.
Results: We identified 836 allografted AML patients who had NGS performed at diagnosis. Most of these patients had de novo AML (88%), with a median age of 53 years (range: 18-78 years). Karyotype was favorable in 7%, intermediate in 69% and adverse in 24% of patients. At transplant, 74% of patients were in first remission (CR1) and 13% in CR2. The most frequent detectable mutations by frequency were DNMT3A (33%), FLT3 (29%), NPM1 (29%), TET2 (28%), NRAS (23%), RUNX1 (22%), WT1 (22%), BCOR (19%), ASXL1 (17%), IDH2 (17%), IDH1 (15%), SRSF2 (13%), STAG2 (12%), CEBPA (11%), TP53 (10%), KRAS (10%), and PTPN11 (10%). By multiple correspondence analysis, two independent groups of co-occurring mutations were identified, the first group included DNMT3A, NPM1 and FLT3, the second group included ASXL1, SRSF2 and RUNX1. Outcome analysis was performed on the subset of 298 patients allografted in CR1 with available data for DNMT3A, NPM1, FLT3, ASXL1, SRSF2 and RUNX1. Most of these patients had de novo AML (90%), with a median age of 53 years (range: 19-75 years). Seventy percent had intermediate-risk cytogenetics, while 27% were adverse-risk. Median follow up was 2.5 years. When outcome analysis was performed according to the presence of single mutations, none of the six mutations significantly affected RI or LFS. The 2-year OS was positively affected by the presence of NPM1 mutation (78% vs 66%; p = 0.02) and FLT3 (79% vs 65%, p = 0.01) but not significantly affected by the other 4 mutations. When mutations were investigated in groups, the 2-year RI, LFS and OS were 24%, 70% and 78%, respectively, for patients with NPM1 mutation regardless of other co-mutations, 35%, 56% and 69% for patients with FLT3-ITD and/or DNMT3A mutation, wild type NPM1, regardless of other co-mutations, 17%, 70% and 74% for patients with RUNX1 and/or ASXL1 and/or SRSF2 mutation without FLT3-ITD and with wild type NPM1 and wild type DNMT3A, and 20%, 56% and 61% for patients with all six genes unmutated.
Conclusions: NGS at diagnosis can be extremely useful in risk stratification of AML patients undergoing allo-HSCT, potentially allowing adequate post-transplant interventions. Notably, the 2-year LFS of 70% for patients harboring RUNX1 and/or ASXL1 and/or SRSF2 mutation indicates that allo-HSCT can overcome the adverse risk associated with these somatic mutations at diagnosis.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P004 ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ELDERLY ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS: A STUDY FROM THE SOCIÉTÉ FRANCOPHONE DE GREFFE DE MOELLE ET THÉRAPIE CELLULAIRE (SFGM-TC)
Yves Chalandon 1, Raynier Devillier2, Ariane Boumendil3, Stephanie Nguyen4, Claude-Eric Bulabois5, Patrice Ceballos6, Eolia Brissot7, Marie-Thérèse Rubio8, Hélène Labussière-Wallet9, Johan Maertens10, Patrice Chevallier11, Natacha Maillard12, Xavier Poiré13, Cristina Castilla-Llorente14, Yves Beguin15, Jérôme Cornillon16, Sébastien Maury17, Tony Marchand18, Etienne Daguindau19, Jacques-Olivier Bay20, Pascal Turlure21, Amandine Charbonnier22, Anne-Lise Menard23, Karin Bilger24, Gaelle Guillerm25, Sylvie François26, Ali Bazarbachi27, Sylvain Chantepie28, Philippe Lewalle29, Ambroise Marçais30, Michael Loschi31, Malek Benakli32, Paul Chauvet33, Edouard Forcade34, Anne Huynh35, Marie Robin36, Stavroula Masouridi-Levrat1
1Hôpitaux Universitaire Genève (HUG) and Faculty of Medicine, Geneva, Switzerland, 2Institut Paoli-Calmettes, Marseille, France, 3SFGM-TC, Paris, France, 4Hôpital de la Pitié Salpêtrière, AP-HP, Paris, France, 5CHU Grenoble-Alpes, Grenoble, France, 6CHU de Montpellier, Montpellier, France, 7Hôpital Saint-Antoine, AP-HP, Paris, France, 8CHRU de Nancy-Brabois, Nancy, France, 9Hôpital Lyon Sud, Lyon, France, 10UZ Leuven, Leuven, Belgium, 11CHU Nantes, Nantes, France, 12CHU Poitiers, Poitiers, France, 13Cliniques Universitaires Saint-Luc, Brussels, Belgium, 14Gustave Roussy Cancer Campus, Villejuif, France, 15CHU de Liège, Liège, Belgium, 16CHU St-Etienne, Saint-Etienne, France, 17Hôpital Henri-Mondor, AP-HP, Créteil, France, 18CHU Rennes, Rennes, France, 19CHU de Besançon, Besançon, France, 20CHU de Clermont-Ferrand, Clermont-Ferrand, France, 21Limoges University Hospital, Limoges, France, 22CHU Amiens, Amiens, France, 23Centre Henri Becquerel, Rouen, France, 24CHRU de Strasbourg, Strasbourg, France, 25CHRU de Brest, Brest, France, 26CHU Angers, Angers, France, 27American University of Beirut, Beirut, Lebanon, 28CHU de Caen, Caen, France, 29Hôpital Universitaire de Bruxelles (HUB), Institut Jules Bordet, Brussels, Belgium, 30Hôpital Necker, AP-HP, Paris, France, 31CHU de Nice, Nice, France, 32CPMC d’Alger, Alger, Algeria, 33CHU de Lille, Université de Lille, Lille, France, 34CHU Bordeaux, Bordeaux, France, 35CHU Toulouse, Toulouse, France, 36Hôpital Saint-Louis, AP-HP, Paris, France
Background: There are very scarce data regarding the outcome of elderly patients with ALL who received alloHSCT as consolidation therapy in CR. Thus, the optimal conditioning regimen still need to be determined. We here present the outcome of ALL patients older than 59 years from the SFGM-TC.
Methods: The primary outcome of this registry study was OS. Secondary outcomes were PFS, NRM, RI, aGvHD grade II-IV, cGvHD, engraftment and GRFS. Competing risks analyses were performed to analyze NRM, aGvHD grade II-IV, cGvHD and neutrophil engraftment. Univariable analyses were performed using the log-rang test for OS and PFS, while Gray’s test was used for CI. Multivariable analyses were performed using the Cox proportional hazards regression model including age, ALL subtype, time from diagnosis to alloHSCT, disease status at alloHSCT, donor to patient CMV status, donor to patient sex, ATG use, MAC, TBI use.
Results: A total of 316 patients ≥ 60 years old transplanted for ALL from 2012 to 2022 in 36 participating centers were included. Patient’s characteristics are described in Table 1.
With a median follow up of 34.5 months (IQR 29.5-38.8), 3-year OS was 46% (95% CI 40-53%) with disease status at transplant impacting negatively OS, 53% in CR1, 32% in CR2, 29% in advanced disease, p = 0.002 and ALL subtype, 59% in Ph+ ALL, 40% in Ph- ALL, 34% in T-ALL, 20% in other/NA, p<0.001.
3-year PFS was 41% (95% CI 35-48%) with disease status at transplant impacting negatively, 49% in CR1, 26% in CR2, 22% in advanced disease, p<0.001, ALL subtype, 51% in Ph+ ALL, 41% in Ph- ALL, 21% in T-ALL, 21% in other/NA, p<0.001, year of HSCT worse < 2018, p = 0.007, CMV -/- worse, p = 0.033, absence of TBI worse, p = 0.018. 3-year NRM was 23% (95% CI 18-28%). 3-year RI was 36% (95% CI 31-42%) with disease status at transplant impacting negatively, 29% in CR1, 50% in CR2, 56 in advanced disease, p = 0.0042, ALL subtype, 26% in Ph+ ALL, 43% in Ph- ALL, 57% in T-ALL, 42% in other/NA, p = 0.0064, year of HSCT worse < 2018, p = 0.0216, CMV -/- worse, p<0.001, absence of TBI worse, p = 0.0069, MRD worse, p = 0.0111. 3-year GRFS was 30% (95% CI 25-37%) with disease status at transplant impacting negatively, 35% in CR1, 22% in CR2, 23% in advanced disease, p = 0.029, ALL subtype, 37% in Ph+ ALL, 33% in Ph- ALL, 15% in T-ALL, 17% in other/NA, p = 0.0029, year of HSCT worse < 2018, p<0.001.
CI of aGVHD grade II-IV was 33% (95% CI 28-38%), grade III-IV 11% (95% CI 8-15%), cGVHD 35% (95% CI30-41%), extensive cGVHD 21% (95% CI 16-26%).
Multivariable analyses confirmed a worse OS and PFS for advanced disease, with a HR of 1.79 (95% CI 1.22-2.64), p = 0.00322 and ALL subtype with a HR for other than Ph+ ALL of 1.99 (95%CI 1.42-2.79).
Characteristics | N = 316 |
---|---|
Age at HSCT median (IQR) | 63.82 (61.8-66.5) |
Age at diagnosis median (IQR) | 63.02 (61-65.4) |
Time from diagnosis to HSCT median (IQR) months | 7.05 (5.7-10.3) |
Year of HSCT median (IQR) | 2017.5 (2015-2020) |
ALL subtype | |
B-ALL Ph- | 81 (25.9%) |
B-ALL Ph+ | 156 (49.8%) |
T-ALL | 42 (13.4%) |
Other/unknown | 37 (11.7%) |
Patient’s sex | |
Female | 156 (49.4%) |
Male | 160 (50.6%) |
Disease status at HSCT | |
CR1 | 224 (70.9%) |
CR2 and + | 74 (23.4%) |
Not in CR | 18 (5.7%) |
Molecular CR | |
Yes | 121 (38.3%) |
No | 79 (25%) |
Missing | 116 (36.7%) |
Type of donor | |
Haploidentical | 56 (17.7%) |
MSD | 83 (26.3%) |
MUD | 142 (44.9%) |
MMUD | 23 (7.2%) |
Missing | 12 (3.8%) |
Source of stem cell | |
BM | 22 (7%) |
PBSC | 294 (93%) |
Donor to patient’s sex | |
Female to male | 44 (14%) |
Other | 271 (86%) |
Missing | 1 |
CMV donor/patient | |
Neg/Neg | 84 (26.8%) |
Neg/Pos | 93 (29.7%) |
Pos/Neg | 24 (7.7%) |
Pos/Pos | 112 (35.8%) |
Missing | 3 |
ATG | |
Yes | 220 (69.6) |
No | 96 (30.4%) |
Conditioning | |
RIC | 204 (64.6%) |
MAC | 112 (35.4%) |
TBI | |
No | 203 (64.2%) |
Yes | 113 (35.8%) |
TBI & Dose | |
No TBI | 203 (64.4%) |
TBI < 8 Gy | 43 (13.7%) |
TBI 8 Gy | 69 (21.9%) |
Missing | 1 |
Disease Risk Index | |
Intermediate | 224 (71.3%) |
High | 72 (22.9%) |
Very high | 18 (5.7%) |
Missing | 2 |
Comorbidity index (Sorror) | |
>=3 | 76 (32.5%) |
1-2 | 53 (22.6%) |
105 (44.9%) | |
Missing | 82 |
Conclusions: This study suggests that alloHSCT is a reasonable option for elderly ALL patients without any impact of age but advanced disease and ALL subtype other than Ph+ ALL negatively influenced the outcome.
Disclosure: YC: Y.C. has received consulting fees for advisory board from MSD, Novartis, Incyte, BMS, Pfizer, Abbvie, Roche, Jazz, Gilead, Amgen, Astra-Zeneca, Servier; Travel support from MSD, Roche, Gilead, Amgen, Incyte, Abbvie, Janssen, Astra-Zeneca, Jazz, Sanofi all via the institution.
EF: EF received funding for congress participation from Alexion, Gilead, Jazz, MSD, Novartis; and also honoraria for boards and speaker bureau participation from Alexion, GSK, Novartis, Gilead, Astellas.
ML: honorari : Alexion, Astra Zeneca, BMS Celgene, Gilead, GSK, Jazz, Kartos, Medac, MSD, Novartis, Pfizer, Sanofi, Sobi, Telios
TM: Consulting fees : Servier, Jazz Pharmaceutical, Sobi, Astellas. Travel support from Servier, Jazz Pharmaceutical
AH : AH has received consulting fees advisory board from Jazz, Pfizer, Servier, Novartis, Astellas; Travel support from Medac, Jazz, Neovii all via the Institution.
All the others do not have any conflict of interest.
19: Acute Leukaemia
P005 ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION FOR OLDER PATIENTS WITH PHILADELPHIA-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA. A SURVEY BY THE ACUTE LEUKEMIA WORKING PARTY OF THE EBMT
Sebastian Giebel 1, Myriam Labopin2, Ryszard Swoboda1, Didier Blaise3, Ibrahim Yakoub-Agha4, Stephanie Nguyen5, Eva Maria Wagner-Drouet6, Cristina Castilla-Llorente7, Panagiotis Kottaridis8, Thomas Schroeder9, Renato Fanin10, Jakob Passweg11, Jurjen Versluis12, Charles Crawley13, Ludovic Gabellier14, Stephan Mielke15, Xavier Poiré16, Erfan Nur17, Carlos Pinho Vaz18, Matthias Eder19, Riccardo Saccardi20, Peter Dreger21, Zinaida Peric22, Mohamad Mohty2, Fabio Ciceri23
1Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland, 2EBMT Unit, Sorbonne Universités, UPMC University of Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA), AP-HP, Saint Antoine Hospital, Paris, France, 3Programme de Transplantation & Therapie Cellulaire, Marseille, France, 4CHU de Lille, University of Lille, INSERM U1286, Infinite, Lille, France, 5Universite Paris IV, Hopital la Pitié-Salpêtrière, Paris, France, 6University Medical Center Mainz, Meinz, Germany, 7Gustave Roussy Cancer Campus, Villejuif, France, 8University College London Hospital, London, United Kingdom, 9University Hospital Essen, Essen, Germany, 10Azienda Ospedaliero Universitaria di Udine, Udine, Italy, 11University Hospital | Basel, Basel, Switzerland, 12Erasmus University Medical Center Cancer Institute, Rotterdam, Netherlands, 13Addenbrookes Hospital Cambridge, Cambridge, United Kingdom, 14University Hospital of Montpellier, Montpellier, France, 15Karolinska University Hospital, Stockholm, Sweden, 16Cliniques Universitaires St. Luc, Brussels, Belgium, 17Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands, 18Inst. Português de Oncologia do Porto, Porto, Portugal, 19Hannover Medical School, Hannover, Germany, 20Azienda Ospedaliera Universitaria Careggi, Firenze, Italy, 21University of Heidelberg, Heidelberg, Germany, 22University Hospital Center Rijeka and School of Medicine, University of Rijeka, Rijeka, Croatia, 23Ospedale San Raffaele s.r.l., Haematology and BMT, Milano, Italy
Background: Tyrosine kinase inhibitors (TKIs) with or without chemotherapy, followed by allogeneic hematopoietic cell transplantation (allo-HCT) are the standard of care for patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). In older patients, intensity of the conditioning regimens is frequently reduced, which may result in increased risk of relapse. However, introduction of alternative approaches using 2nd or 3rd generation TKIs in combination with blinatumomab may restrict the role of allo-HCT. The goal of this study was to evaluate results of recent allo-HCTs for patients aged ≥55 years, and to identify prognostic factors.
Methods: This was a retrospective analysis based on data from the EBMT registry, including 566 patients with Ph+ ALL treated with allo-HCT in first complete remission between the years 2016 and 2022.
Results: Median recipient age was 60 (range, 55-76) years. Allo-HCT was performed using either a matched sibling (n = 138, 24%), unrelated (n = 343, 61%) or haploidentical (n = 85, 15%) donor. Conditioning regimen was myeloablative in 47% of cases and based on total body irradiation (TBI) in 49% of patients. Status of measurable residual disease was reported as negative in 59.5% of patients.
The probability of overall survival (OS) and leukemia-free survival (LFS) at 2 years was 71% and 59.5%, respectively. The incidence of relapse (RI) and non-relapse mortality (NRM) was 18% and 22.5%, respectively. The rate of graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) was 50%. The incidence of grade 3-4 acute GVHD was 9% while that of extensive chronic GVHD it was 15%.
In univariate analysis the use of TBI-based as compared to chemotherapy-based regimens was associated with reduced RI (15% vs. 20.5%, p = 0.04), improved LFS (67% vs. 53%, p = 0.002) and OS (77% vs. 66%, p = 0.01), as well as a tendency toward reduced incidence of NRM (18% vs. 27%, p = 0.1). On the other hand, it was also associated with increased incidence of both overall and extensive chronic GVHD (46% vs. 27.5%, p = 0.001 and 21% vs. 10%, p = 0.001, respectively). In a multivariant model, the use of TBI was the only factor affecting outcomes, being associated with reduced risk of NRM (hazard ratio, [HR] = 0.46, p = 0.004), improved LFS (HR = 0.53, p<0.001) and OS (HR = 0.47, p<0.001) as well as increased risk of chronic GVHD (HR = 1.68, p = 0.009) and extensive chronic GVHD (HR = 1.84, p = 0.04).
Conclusions: Based on this large-scale analysis we conclude that results of allo-HCT for patients with Ph+ ALL aged ≥55 years in the last few years are very encouraging with approximately 60% LFS at 2 years. TBI-based conditioning appears preferable in this patient population. Our data can serve as reference for results of prospective trials.
Clinical Trial Registry: Not applicable
Disclosure: SG received honoraria from Angelini and Novartis
19: Acute Leukaemia
P006 OUTCOME OF PATIENTS WITH IDH-MUTATED AML FOLLOWING ALLOGENEIC STEM CELL TRANSPLANTATION
Thomas Schroeder 1, Sarah Flossdorf1, Caroline Pabst2, Michael Stadler3, Johannes Schetelig4, Claudia Wehr5, Claudia Schuh6, Matthias Stelljes7, Elisa Sala8, Andreas Burchert9, Jennifer Kaivers1, Christian Reinhardt1, Nicolaus Kroeger10, Katharina Fleischhauer1, Christina Rautenberg1
1University Hospital Essen, Essen, Germany, 2University Hospital Heidelberg, Heidelberg, Germany, 3MHH Hannover, Hannover, Germany, 4University Hospital Dresden, Dresden, Germany, 5University Hospital Freiburg, Freiburg, Germany, 6DRST, Ulm, Germany, 7University Hospital Muenster, Muenster, Germany, 8University Hospital Ulm, Ulm, Germany, 9University Hospital Marburg, Marburg, Germany, 10University Hospital Hamburg, Hamburg, Germany
Background: Somatic mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are found in about 15% to 20% of patients with acute myeloid leukemia (AML). While the prognostic impact of these mutations is still controversial, IDH inhibitors have been developed and introduced as targeted treatment for patients with IDH-mutated AML. They are currently under investigation also as maintenance therapy after allogeneic transplantation (allo-SCT), although outcomes of IDH1- and IDH2-mutated (IDHmut) AML patients after allo-SCT have not been well described.
Methods: To address this, we retrospectively analyzed the outcome of IDHmut patients, who were allografted between 2014 and 2021, had available data collected within the German Registry for hematopoetic Stem Cell Transplantation and cellular therapy (DRST) and a follow-up of at least 6 months. Overall (OS) and event-free survival (EFS) were estimated by Kaplan–Meier method and logrank tests were applied for univariable comparisons. Relapse incidence and non-relapse mortality (NRM) were considered as competing risks and calculated using cumulative incidence (CI) estimates employing Gray test for univariable comparisons.
Results: Overall, 356 IDH-mutated AML patients (IDH1 n = 142 40%, IDH2 n = 214 60%) with a median age of 60 (18 to 76) received a first allo-SCT from a related (30%) or unrelated (70%) donor following myeloablative (50%) or reduced intensity (50%) conditioning. According to ELN 2016 genetic risk stratification 21% belonged to the favorable, 42% to intermediate and 27% to adverse category (missing 10%), with 71% of patients being in CR at transplant. Of 262 patients with available information 10 (4%) had received an IDH inhibitor outside clinical trials prior transplantation. After a median follow-up of 24 months, IDH1mut and IDH2mut patients had similar estimated 3-year probabilities of overall survival (78% vs 70%, p = .64). Non-relapse mortlity was comparable (10% vs 14%, p= .48). Three-year probabilities of relapse were numerically higher for IDH1mut compared with IHD2mut patients (34% vs 24%, p= .18) without reaching statistical significance, and concomitantly a numerically lower 3-year event-free survival (56% vs 62% respectively; p= .14).
Conclusions: Taken together, these data from a large multicenter cohort provide benchmarks for analysis and interpretation of results emerging from clinical trials evaluating maintenance IDH1 and IDH2 inhibitor therapy for AML patients after allo-SCT
Clinical Trial Registry: not applicable
Disclosure: Thomas Schroeder: Advisory Boards:BMS; lecture fees BMS, research funding: BMS
Elisa Sala: honoraria for consultancy or travel support from Gilead, Novartis, BMS, Jazz, Neovii, Therakos/Mallinckrodt, MSD, Priothera.
Johannes Schetelig: Advisory Boards: Abbvie, AstraZeneca, BeiGene, BMS, Janssen, and MSD und Lecture Fees: Astellas, AstraZeneca, BeiGene, BMS, Novartis, Eurocept, Medac and Janssen
Claudia Wehr: Travel support/honoraria from Takeda, Jazz Pharmaceuticals.
Christian Reinhardt: consulting and lecture fees from AbbVie, AstraZeneca, Roche, Janssen-Cilag, Novartis, Vertex and Merck. H.C.R. received research funding from Gilead and AstraZeneca. H.C.R. is a co-founder of CDL Therapeutics GmbH.
19: Acute Leukaemia
P007 CD22-TARGETED IMMUNOTHERAPY FOR ADULT PATIENTS WITH RELAPSED OR REFRACTORY B-ALL WHO PREVIOUSLY EXPOSED TO CD19-TARGETED IMMUNOTHERAPY
Mingming Zhang1,2, Yongxian Hu1,2, Peihua Lu3,4, Liang Huang5, Shan Fu1,2, Jingjing Feng1,2, Ruimin Hong1,2, Alex H. Chang6, He Huang 1,2
1Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, 2Liangzhu Laboratory, Hangzhou, China, 3Hebei Yanda Lu Daopei Hospital, Langfang, China, 4Lu Daopei Institute of Hematology, Beijing, China, 5Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, 6Shanghai YaKe Biotechnology, Shanghai, China
Background: CD19-targeted immunotherapy effectively induce remission in relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Patients who fail or relapse after CD19-targeted immunotherapy have an extremely poor prognosis, and immunotherapy targeting CD22 is one of the few possible therapeutic options, but there is currently limited data.
Methods: We conducted a multicenter, retrospective study of CD22-targeted immunotherapy for adult patients with r/r B-ALL who previously exposed to CD19-targeted immunotherapy. Primary objective was complete remission (CR) rate at 1 month.
Results: A total of 30 patients were included, and the median age was 32 (18-67) years old. Four (13.3%) patients were Ph-positive, 10 (33.3%) patients were primary refractory and 10 (33.3%) patients relapsed after allogeneic stem cell transplantation. Six (20.0%) patients were exposed to blinatumomab only, 20 (66.7%) patients were exposed to CD19 CAR-T cell therapy only, and 4 (13.3%) patients were exposed to both. 20 (66.7%) patients received CD22 CAR-T cell therapy, and 10 (33.3%) patients received inotuzumab ozogamicin. In the target expression analysis before CD22-targeted immunotherapy, all patients had CD22-positive expression except one patient was CD22-dim. As for the expression of CD19, 13 (43.3%) patients were CD19-positive, 12 (40.0%) patients were CD19-negative, and 5 (16.7%) patients were CD19-dim or partially expression. Totally 17 (56.7%) patients achieved CR at 1 month after CD22-targeted immunotherapy. The CR rate was 55.0% (11/20) in the CD22 CAR-T group, and 60.0% (6/10) in the inotuzumab ozogamicin group. There was no significant difference between the two groups (P = 0.79). The CR rate for patients exposed to both blinatumomab and CD19 CAR-T seemed to be low and was 25% (1/4). Other factors including primary refractory, post-transplantation relapse, and CD19 expression status had no effect on CR rate. Of the 17 patients who achieved CR, 10 had subsequent relapses, 2 lost to follow-up, 1 died of a post-CAR-T infection, and 1 died of complications of transplantation. As of December 15, 2023, excluding the 2 patients lost to follow-up, only 7 patients remained in MRD negative CR.
Conclusions: CD22-targeted immunotherapy is an effective treatment option for patients with r/r B-ALL who previously exposed to CD19-targeted immunotherapy. However, the relapse rate post CD22-targeted immunotherapy remains high. Therefore, new strategies are still needed to improve the prognosis of this group of patients.
Disclosure: Alex H. Chang is an employee of Shanghai YaKe Biotechnology Ltd., the other authors declare no conflict of interest.
19: Acute Leukaemia
P008 COMPARISON OF THE PROGNOSTIC IMPACT BETWEEN ELN2022 AND ELN2017 RISK CLASSIFICATION IN ALLOGENIC HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS WITH AML
Weihao Chen1, Yeqian Zhao1,2,3,4, Jimin Shi1,2,3,4, Yi Luo1,2,3,4, Jian Yu1,2,3,4, Yamin Tan5,6, Xiaoyu Lai1,2,3,4, Lizhen Liu1,2,3,4, Huarui Fu1,2,3,4, Yishan Ye1,2,3,4, Luxin Yang1,2,3,4, Congxiao Zhang1,2,3,4, He Huang1,2,3,4, Yanmin Zhao 1,2,3,4
1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, 2Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China, 3Institute of Hematology, Zhejiang University, Hangzhou, China, 4Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, China, 5Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China, 6Institute of Cancer and Basic Medicine(IBMC), Chinese Academy of Sciences, Hangzhou, China
Background: Risk classification based on genetic aberrations plays a pivotal role in predicting prognosis and guiding treatment decisions in patients with acute myeloid leukemia (AML). In 2022, the European LeukemiaNet (ELN) issued an updated recommendations for diagnosis and risk classification, building upon the ELN2017 guidelines. While many studies have validated and compared the two versions of ELN risk classifications in chemotherapy cohorts, there remains a scarcity of research comparing the prognostic impact of ELN2017 and ELN2022 criteria in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Methods: We conducted a retrospective study which compared the the prognostic impact between the 2017 and 2022 ELN risk classifications in a real-life cohort of de novo AML patients who underwent allo-HSCT (n = 641) in our center from January 2015 to January 2022. We enrolled patients who had sufficient clinical and genetic information available for ELN risk classification. Patients diagnosed with acute promyelocytic leukemia or whose who received a second transplantation were excluded. Gene mutations or fusion genes detection were performed using polymerase chain reaction before 2017 and next-generation sequencing after 2017.
Results: 623 patients were included in this retrospective study, with a median follow-up time of 2.8 years after allo-HSCT. The median age at allo-HSCT was 40 years (range 10-67). According to ELN2017 risk categories, 32% (n = 202) patients at diagnosis were classified into ELN2017 favorable group, 43% (n = 264) into ELN2017 intermediate group, and 25% (n = 157) into ELN2017 adverse group. In ELN2022, the classification was 32% (n = 202) in favorable, 45% (n = 277) in intermediate, and 23% (n = 144) in adverse group. Patients in adverse group had significantly lower RFS (relapse-free survival) and OS (overall survival) after allo-HSCT compared to those in favorable and intermediate group, regardless in ELN2017 or ELN2022. Nonetheless, RFS of ELN2022 intermediate patients was worse than favorable patients (68.8 vs 82.3%, P = 0.015), and we did not obverse this statistic difference in ELN2017. The c-statistic (area under the curves [AUC]) from ELN2022 for RFS after allo-HSCT was not obviously better compared to ELN2017 (AUCELN22 = 0.637 vs AUCELN17 = 0.616, P = 0.096). The univariate analysis indicated that adverse ELN classification, NR status at allo-HSCT, and CR patients with MRD positivity at allo-HSCT might be associated with worse RFS and OS after allo-HSCT. Therefore, we further refined the ELN2022 system into four categories by incorporating the remission and MRD status at allo-HSCT (favorable: ELN2022 favorable with MRDneg, intermediate: ELN2022 favorable with MRDpos and ELN2022 intermediate with MRDneg, adverse: ELN2022 intermediate with MRDpos and ELN2022 adverse with MRDneg, and very adverse: NR patients at allo-HSCT and ELN2022 adverse with MRDpos). The refined ELN risk classification showed that there was statistical significance between groups for RFS after allo-HSCT, and the AUCRefined ELN22 was significantly better than AUCELN22 (0.703 VS 0.637, P<0.001).
Table 1. Univariate analysis of clinical characteristics in RFS and OS
Variables | RFS | OS | ||
---|---|---|---|---|
HR (95% CI) | P Value | HR (95% CI) | P Value | |
Patient age at HSCT | 1.01(1.00-1.02) | 0.150 | 1.01(1.00-1.03) | 0.066 |
WBC at diagnosis | 1.00(0.99-1.00) | 0.734 | 1.00(0.99-1.00) | 0.981 |
ELN2017 risk classification | <0.001 | <0.001 | ||
Favorable | 1.00[Reference] | 1.00[Reference] | ||
Intermediate | 1.22(0.83-1.80) | 0.316 | 1.31(0.84-2.03) | 0.232 |
Adverse | 2.52(1.71-3.70) | <0.001 | 2.63(1.70-4.07) | <0.001 |
ELN2022 risk classification | <0.001 | <0.001 | ||
Favorable | 1.00[Reference] | 1.00[Reference] | ||
Intermediate | 1.64(0.98-2.74) | 0.058 | 1.45(0.82-2.59) | 0.205 |
Adverse | 4.58(2.90-7.23) | <0.001 | 4.40(2.65-7.28) | <0.001 |
Remission status at time of HSCT | <0.001 | <0.001 | ||
CR1 | 1.00[Reference] | 1.00[Reference] | ||
≥CR2 | 1.05(0.70-1.57) | 0.826 | 1.25(0.81-1.94) | 0.312 |
NR | 2.91(2.02-4.20) | <0.001 | 3.44(2.31-5.11) | <0.001 |
Pretransplant MRD status in CR patents | <0.001 | <0.001 | ||
Negative | 1.00[Reference] | 1.00[Reference] | ||
Positive | 2.88(1.95-4.26) | 2.70(1.74-4.19) | ||
HLA match, n (%) | 0.053 | 0.127 | ||
HLA-identical sibling transplant | 1.00[Reference] | 1.00[Reference] | ||
Haploidentical transplant | 0.85(0.56-1.29) | 0.455 | 0.90(0.56-1.44) | 0.669 |
Unrelated transplant | 1.45(0.84-2.49) | 0.185 | 1.48(0.80-2.74) | 0.185 |
Conclusions: The updated ELN2022 risk classification did not demonstrate improved predictive performance for outcomes after allo-HSCT compared to ELN2017. We refined the stratification system into four groups by incorporating disease status at transplant, aiming to more accurately identify patients with different outcomes following allo-HSCT.
Disclosure: Nothing to declare
19: Acute Leukaemia
P009 EFFICACY AND SAFETY OF THE THIRD-GENERATION TKI OLVEREMBATINIB IN ADULT PH + ACUTE LYMPHOBLASTIC LEUKEMIA WITH RELAPSED DISEASE OR PERSISTENT MRD BRIDGING TO ALLO-HSCT
XiaoYu Zhang 1, Yanhong Zhao1, Rongli Zhang1, Erlie Jiang1
1Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Background: To investigate the efficacy and safety of an olverembatinib regimen in adult Ph/BCR-ABL1 + ALL patients with relapsed disease or persistent MRD prior to allo-HSCT.
Methods: We retrospectively enrolled Ph+ ALL patients with relapsed disease or persistent MRD who were treated with an olverembatinib-based regimen before bridging to HSCT between February 2022 and February 2023.
Results: Seventeen Ph+ ALL patients were treated with olverematinib because of disease recurrence (n = 3) and persistent molecular positivity (n = 14). BCR: ABL1 p190 and p210 fusions were found in nine and eight patients, respectively. Six patients harbored a T315I mutation. In all, 13 patients achieved CMR, and the overall CMR rate by PCR was 76.47%, whereas the MRD neg rate by flow cytometry was 100%. All patients successfully underwent bridging allo-HSCT. With a median follow-up time of 342 (60-509) days post-HSCT, the one-year overall survival rate and recurrence-free survival rate were 94.1±5.71% (95 % CI 83.6~100%) and 88.2±7.81% (95% CI 74.2~100%), respectively. Only one patient experienced extramedullary relapse on day 129. One patient died due to CNS complications.
Conclusions: The findings of this study suggest that in Ph+ ALL patients with disease recurrence and persistent MRD positivity, olverembatinib showed a profound molecular response rate and was well-tolerated in MRD clearance prior to allo-HSCT
Disclosure: The authors declare that they have no competing interests.
19: Acute Leukaemia
P010 INTRACELLULAR CYTOKINE ASSAYS IN COMBINATION WITH DEGRANULATION ASSAY CONTRIBUTE SIGNIFICANTLY TO DETECT AND QUANTIFY LEUKEMIA SPECIFIC IMMUNE CELLS IN AML PATIENTS’ BLOOD OR CULTURE SETTINGS
Olga Schutti1, Lara Klauer2,1, Tobias Baudrexler2,1, Christoph Schmid3, Andreas Rank3, Joerg Schmohl4, Markus Hentrich5, Doris Kraemer6, Helga Schmetzer 1
1Klinikum Grosshadern, Ludwig-Maximilians-University, Working-Group Immune-Modulation, Munich, Germany, 2Contributed Equally, Munich, Germany, 3University Hospital of Augsburg, Augsburg, Germany, 4University Hospital of Tuebingen, Tuebingen, Germany, 5Red Cross Hospital of Munich, Munich, Germany, 6University Hospital of Oldenburg, Oldenburg, Germany
Background: Novel (immune) therapies are needed to stabilize remissions or the disease in AML. Leukemia derived dendritic cells (DCleu) can be generated ex vivo from AML patients’ blasts in whole blood using approved drugs (GM-CSF and PGE-1 (Kit-M)). After T cell enriched, mixed lymphocyte culture (MLC) with Kit-M pretreated (vs. untreated WB) antileukemically directed immune cells of the adaptive and innate immune system were already shown to be significantly increased.
Aims: To evaluate the use of leukemiaspecific assays intracellular cytokine production (INFy, TNFa) INCYT, degranulation (CD107a) DEG for a detailed quantification of leukemiaspecific cells in correlation with functional cytotoxicity and patients’ clinical data.
Methods: Whole blood (WB) samples were collected from 26 AML patients at first diagnosis, during persisting disease, or at relapse after allogeneic stem cell transplantation (SCT), and from 18 healthy volunteers. WB samples were treated with vs. without Kit-M to generate DC/DCleu. After MLC with Kit-M treated vs. untreated WB antigenspecific/ anti-leukemic effects were assessed through INCYT, DEG and a cytotoxicity fluorolysis assay. Quantification of cell subtypes was performed via flowcytometry.
Results: We generated significantly higher frequencies of (mature) DCleu without induction of blast proliferation in Kit-M treated vs. untreated samples. After MLC with Kit-M treated vs. untreated WB, frequencies of immunoreactive cells (e.g. non-naive T-cells, Tprol) as well as in INCYT/DEG ASSAYS leukemiaspecific adaptive - (e.g. B, T(memory)) or innate immune cells (e.g. NK, CIK) were significantly increased. The results of the intracellular production of INFy and TNFa were comparable. The cytotoxicity fluorolysis assay revealed a significantly enhanced blast lysis in Kit-M treated vs. untreated WB. Significant correlations could be shown between induced leukemiaspecific cells of several lines and improved blast lysis.
Conclusions: We successfully detected and quantified immunoreactive cells at a single-cell level using the functional assays (DEG, INCYT, and CTX) ex vivo, allowing us to evaluate the impact of Kit-M pretreated (DC/DCleu containing) WB on the provision of leukemia specific immune cells. Kit-M pretreatment (vs no pretreatment) was shown to significantly increase leukemia-specific IFNγ and TNFɑ producing, degranulating cells and to improve blast-cytotoxicity after MLC.
In vivo treatment of AML patients with Kit-M may lead to anti-leukemic effects and contribute to stabilize the disease or remissions. INCYT and DEG assays qualify to quantify potentially leukemia specific cells on a single cell level and to predict the clinical course of patients under treatment.
Disclosure: Conflict of interest: Modiblast Pharma GmbH (Oberhaching, Germany) holds the European Patent 15 801 987.7-1118 and US Patent 15-517627 ‘Use of immunomodulatory effective compositions for the immunotherapeutic treatment of patients suffering from myeloid leukemias’, with whom H.M.S. is involved with.
19: Acute Leukaemia
P011 TOTAL MARROW AND LYMPHOID IRRADIATION IN COMBINATION WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE-BASED GRAFT VERSUS HOST DISEASE PROPHYLAXIS CONFERS FAVORABLE GVHD-FREE/RELAPSE-FREE SURVIVAL IN PATIENTS WITH ACUTE MYELOID LEUKEMIA
Anthony Stein 1, Monzr Al Malki1, Dongyun Yang1, Joycelynne Palmer1, Ni-Chun Tsai1, Ibrahim Aldoss1, Haris Ali1, Ahmed Aribi1, Andrew Artz1, Savita Dandapani1, Len Farol1,2, Susanta Hui1, An Liu1, Ryotaro Nakamura1, Vinod Pullarkat1, Eric Radany1, Amandeep Salhotra1, James Sanchez1, Ricardo Spielberger1,2, Guido Marcucci1, Stephen Forman1, Jeffrey Wong1
1City of Hope, Duarte, United States, 2Southern California Permanente Medical Group, Los Angeles, United States
Background: We have conducted a phase 2 study of a conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 2000cGy, together with post-transplant cyclophosphamide (PTCy) for patients with acute myeloid leukemia in first or second complete remission (CR). This approach employs PTCy to attenuate the risk of chronic graft-versus-host-disease (GVHD), while using escalated targeted radiation conditioning before allografting to offset the possible increased risk of relapse.
Methods: We evaluated to date the first 25 patients with a median follow-up of ≥1yr (Table) who enrolled between 2018–2023. Key criteria: ages 18–60, first or second CR, minimal residual disease negative by multi-color flow cytometry, and normal organ function. TMLI was administered on days -4 to 0 without addition of chemotherapy. The radiation dose for all patients (n = 25) was 2000cGy, delivered in 200cGy fractions twice daily. The radiation dose delivered to the liver and brain was kept at 1200cGy. Remaining organs were considered non-targeted. All patients received peripheral blood stem cells on day 0. Cyclophosphamide was given on days +3 and +4, 50mg/kg each day for GVHD prevention. Tacrolimus, 1mg continuous infusion adjusted to maintain levels from 5–10ng/mL, was given from day +5 to day +90, and G-CSF 5µg/kg daily was administered at day +5 until recovery of neutrophil counts.
Endpoints included toxicity, engraftment, overall survival (OS), non-relapse mortality (NRM), and GVHD/relapse-free survival (GRFS) at 1yr. Toxicities were defined according to the Bearman and CTCAE 4.03 scales, the latter for hematologic toxicity. A patient safety lead-in segment (n = 6) was conducted to ensure there were no unexpected toxicities. GRFS was defined as the absence of grade 3-4 acute GvHD, chronic GvHD requiring systemic treatment, relapse, or death (from any cause).
Results:
Variable | Median (range) or N (%) |
---|---|
Age at transplant (yrs) | 39 (19-56) |
Cytogenetic risk (ELN criteria) | |
favorable | 1 (4%) |
intermediate | 9 (36%) |
unfavorable | 8 (32%) |
missing | 7 (28%) |
KPS at HSCT | |
80 | 3 (12%) |
90 | 17 (68%) |
100 | 5 (20%) |
HCT-CI | |
16 (64%) | |
1 | 6 (24%) |
≥2 | 3 (12%) |
Donor source | |
MSD | 11 (44%) |
MUD | 14 (56%) |
Female donor to male recipient | |
Yes | 4 (16%) |
No | 21 (84%) |
CMV | |
Negative | 8 (32%) |
Positive | 17 (68%) |
- Patient characteristics. Abbreviations: ELN, European LeukemiaNet; HCT-CI, Hematopoietic Cell Transplantation-specific Comorbidity Index; KPS, Karnofsky Performance Score; MSD, matched sibling donor; MUD, matched unrelated donor; CMV, cytomegalovirus.
The median follow up was 47.1 months (range: 5.9-59.9) for surviving patients (n = 22). Bearman toxicity data are available for all patients. Among these patients, grade 2 toxicities were bladder toxicity and stomatitis. No grade 3-4 toxicities or toxicity-related deaths were observed. All patients engrafted. Median times to neutrophil and platelet recovery were 14 days (range: 13-32) and 20 days (range: 11-49), respectively.
Acute GVHD (aGVHD) developed in 2 patients (100-day Grade II-IV aGVHD: 8.0%, 95%CI: 1.3-22.9); of those, only 1 patient developed Grades III-IV (100-day Grade III-IV aGVHD: 4.0%, 95%CI: 0.3-17.4). Six patients developed chronic GVHD (2-year cGVHD rate: 27%, 95%CI: 11%-47%), which was mild in 5 patients and moderate/severe in 1 patient.
Two-year estimates of OS and leukemia-free survival were 89% (95%CI: 62-97) and 84% (95%CI: 62-94). Disease relapse at 2yrs was 16% (95%CI: 4.9-33). The estimate of NRM at 2yrs was 0%. Relapsed disease after transplant occurred in 5 patients, which led to 3 deaths from relapsed disease. The GRFS rate at 2yrs was 61% (95%CI: 37-78).
Conclusions: 1) This chemotherapy-free conditioning regimen, together with PTCy and tacrolimus, is safe and feasible, with no NRM. 2) All patients achieved engraftment. 3) Participants with ≥1yr follow-up have discontinued immunosuppressive therapy, reducing financial burden and leading to improved quality of life. The results to date suggest a favorable GRFS rate.
Clinical Trial Registry: clinicaltrials.gov, NCT#03467386
Disclosure: Anthony Stein: Sanofi: Current Employment, Current holder of stock options.
19: Acute Leukaemia
P012 INCREASED MESENCHYMAL STROMAL CELLS SENESCENCE AND HIGH CXCL14 LEVELS IN BONE MARROW ARE LINKED WITH THE OCCURRENCE OF GVHD AFTER HEMATOPOIETIC STEM CELLS TRANSPLANTATION
Alexandra Guelton 1, Meriem El Ouafy1, Romain Perouf1, Naceur Charif1, Simona Pagliuca1, Marie-Thérèse Rubio1, Natalia de Isla1
1University of Lorraine, Vandoeuvre-les-Nancy, France
Background: The acute myeloid leukemia (AML) is an hematological malignancy with a bad pronostic with an estimated survival of 50% at 1 year, and 27% at 5 years. The allogenic hematopoietic stem cells transplantation (allo-HSCT) is the only curative treatment of AML, marked by two major adverse effects: graft versus host disease and relapse. Although medullary microenvironment is composed of many cellular actors, mescenchymal stromal stem cells (MSC) constitute key players, both for their role in hematopoiesis and for their immunomodulatory capacities, particulary toward T cells. The aim of our work was to study the link between medullary microenvironment (MSC, cytokines…) in pre-transplantation, and the occurrence of GVHD.
Methods: We conducted a prospective, single-center study at the Nancy University Hospital, involving HSC allograft patients with AML. Inclusion criteria were: graft conditioning including a combination of fludarabine and busulfan, homogeneous graft-versus-host disease (GVHD) prophylaxis (anti-lymphocytic serum, cyclosporin and mycophenolate mofetil. Medullary MSC from bone marrow of patients before HSCT were isolated and cultured. MSC used as control provided from patients without AML, and were obtained after surgical hip arthroplasty. MSC were characterized based on the International Society of Cellular Therapie (ISCT) criteria as their adhesion to plastic, their surface phenotype (CD73 + , CD90+, HLA-DR−, CD45−, CD34−) and their self-renewal capacity.
Then, MSC senescence was studied thanks to β-galactosidase test coupled with EdU proliferation test (5-Methyl-2′-deoxycytidine), to distinguish senescents and proliferative cells, and avoid false positives. Moreover, proteins involved in cell senescence (p16, p21, p53, p38) were evaluated by Western-Blot. Then, many cytokines involved in cell senescence (IL10, IL6, IL1, IL13…) and in immune surveillance (CXCL14) were quantified by CBA and ELISA method. In parallel, MSC immunomodulatory properties were determined by coculture experiments between MSC and T cells from healthy donnors.
T statistical tests and Pearson correlation tests was performed thanks to GraphPad Prism. Principal component analysis (PCA) was performed thanks to XLSTAT.
Results: Our results showed that high levels of medullary MSC senescence from AML patients before HSCT, correlated with a decrease of MSC immunomodulatory properties toward T cells, was associated with the occurrence of GVHD, three months after HSCT. Moreover, a positive correlation between the level of medullary MSC senescence and the medullary concentration of CXCL14 was observed. Among the other cytokines studied, no correlation was shown between their concentration and medullary MSC senescence.
Conclusions: Our results showed that a pro inflammatory microenvironment before HSCT, characterized by the presence of senescent MSC with disturbed immunomodulatory properties, and the presence of CXCL14, would be favorable to the occurrence of GVHD after HSCT.
Disclosure: Nothing to declare
19: Acute Leukaemia
P013 CORRELATION OF THE OVERALL SURVIVAL IN MIXED-PHENOTYPE ACUTE LEUKAEMIA AND ACUTE LYMPHOBLASTIC LYMPHOMA WITH THE REFINED DISEASE RISK INDEX APPLIED IN AN UPPER-MIDDLE INCOME COUNTRY
Naty López-Córdova 1, Jessica Meza-Liviapoma1, Jule Vasquez-Chavez1, Claudio Flores-Flores2, Shirley Quintana-Truyenque1
1Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Peru, 2Universidad Peruana San Juan Bautista, Lima, Peru
Background: The Refined Disease Risk Index (R-DRI; 4 risk groups: low [LR], intermediate [IR], high [HR] and very high [V-HR]) is a score used to estimate overall survival after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in patients with haematological malignancies, however, both in its original version and in the R-DRI does not consider certain diagnoses, such as mixed-phenotype acute leukaemia (MPAL) and acute lymphoblastic lymphomas (LBL). These diagnoses constitute an important population since they have a very aggressive course and fatal outcomes in most cases. The objective of the study is to determine the correlation of overall survival in patients with MPAL and LBL after Allo-HSCT, in relation to R-DRI. These results will allow these patients to be assigned to one of the existing risk groups in order to have an estimate of their post HSCT prognosis.
Methods: We reviewed retrospectively the data of 166 patients who had an Allo-HSCT between 2012 and 2023 in the Bone Marrow Transplant (BMT) unit of the National Institute of Neoplastic Diseases (INEN). The information was extracted from the unit registry and was completed through the electronic medical records. Patients diagnosed and transplanted for MPAL and LBL were subjected to the analysis and their overall survival was evaluated, which was compared with the data of patients with acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Survival was estimated using the Kaplan-Meier method and comparisons were made using the Log-Rank test.
Results: The median age at HSCT was 26 years (range: 15 to 63), 84 patients were men (50.6%). 85 patients had ALL; 41, AML; 11, Chronic myeloid leukaemia (CML); 13, MPAL; and 16, others (Myelodysplastic syndrome: 8, LBL: 6, Hodgkin lymphoma: 1, aggressive T/NK cell leukaemia: 1). According to the R-DRI classification (does not include MPAL and LBL), 4.8% of patients were LR, 38.1% IR, 35.4% HR, and 21.8% V-HR. Median follow-up was 3.9 years and median overall survival (OS) was not reached for the entire cohort. According to R-DRI, the 4-year OS rate was 100% in LR, 57.4% in IR, 53.5% in HR, and 38.3% in V-HR, respectively. The 4-year OS in patients with MPAL was 76.9%, and in LBL 44.4%. The OS of patients with MPAL was superior to those with IR, presenting a significant difference in relation to the HR group (p = 0.015).
Conclusions: The OS of patients with MPAL is superior to those with IR, presenting a significant difference in relation to those with V-HR. These results suggest that there would be a group that is similar to that of IR, but with a better prognosis than that described in the R-DRI and that could give rise to a new “low-intermediate” group in which the MPAL could be included.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P014 SIGNIFICANT IMPROVEMENT OF SURVIVAL AFTER ALLOGENEIC STEM CELL TRANSPLANTATION IN ACUTE LYMPHOBLASTIC LEUKEMIA OVER TWO DECADES – A SINGLE CENTER RETROSPECTIVE ANALYSIS
Ben-Niklas Baermann1, Paula Kessler 1, Astrid Tautges2, Paul Sebastian Jäger1, Mustafa Kondakci3, Kathrin Nachtkamp1, Sascha Dietrich1, Guido Kobbe1
1Medical Faculty and University Hospital Düsseldorf, Düsseldorf, Germany, 2Office for general practice Dirk Röhlich, Trier, Germany, 3Lukas Hospital Solingen, Solingen, Germany
Background: Acute lymphoblastic leukemia (ALL) treatment landscape has dramatically changed within the last two decades. Especially tyrosine kinase inhibitors in Philadelphia positive (BCR-ABL) ALL as well as Blinatumomab, Inotuzumab and chimeric antigen receptor t-cell therapy for B-cell precursor ALL (B-ALL) were the most prominent pharmacologic milestones. Moreover the german multicenter ALL study group (GMALL) made strong efforts to improve conventional and transplant strategies to reduce non relapse mortality.
Methods: We retrospectively analyzed clinical outcome of 146 patients (61% male, 39% female, median age at transplant 36 years, range 17-74) with acute lymphoblastic leukemia (B-ALL 76%, T-ALL 24%) receiving allogeneic stem cell transplantation (alloHSCT) at the UKD, Heinrich Heine University of Düsseldorf between 1989 and 2022. Of Patients with B-ALL 33% were Philadelphia chromosome positive.
The majority of patients (92%) received myeloablative conditioning almost all containing total body irradiation (TBI) with at least 8 Gy. Matched related donors were used in 32%, 40% had matched unrelated donors and 27% mismatched or haploidentical donors. Median time from diagnosis to alloHSCT was 6 months (range 2-80). Haematologic remission could be achieved in 95% prior to transplant.
Results: Median follow up after alloHSCT was 5.6 years for surviving patients. Median overall survival (OS) from transplant for all patients was 2.8 years (95% CI 0.0-6.1 years). OS after two and five years were 51% (95% CI 43-59) and 47% (95% CI 39-55). For T-ALL median OS was not reached, for B-ALL median OS was 1.3 years (95% CI 0-2.9 years).
For patients with first diagnosis from 2000 to 2010, median OS from alloHSCT was 1.2 years, whereas after 2010 median OS is not reached with a significant difference between these subgroups (p<0.05). OS after two and five years for patients with first diagnosis after 2010 were 66 % (95% CI 55-78) and 64 % (95% CI 52-76). These findings can be reproduced for BCR-ABL positive as well as negative B-ALL subgroups but not for patients with T-ALL.
MRD persistence before alloHSCT was associated with significant worse OS even in haematologic complete remission (median OS 1.4 years vs. not reached, p < 0.05), not significantly differing for patients with first diagnosis before or after 2010.
Median OS after alloHSCT could not be improved by application of higher doses of TBI (12Gy vs. 8Gy, median OS 2.9 years vs. not reached, p = 0.5).
Conclusions: Prognosis of B-lineage acute lymphoblastic leukemia after alloHSCT significantly improved over time and reducing TBI toxicity by dose reduction did not negatively influence OS. Achieving MRD negativity before alloHSCT especially with new targeted therapies seems to play an important role. Nevertheless worse OS in patients with MRD persistence could not be overcome in recent years.
Disclosure: Ben-Niklas Baermann: Travel support: Medac, Kite-Gilead; Advisory Role or Speaker Honoraria: Kite-Gilead, Incyte
Paula Kessler: Nothing to declare.
Astrid Tautges: Nothing to declare
Paul Sebastian Jäger: Nothing to declare
Mustafa Kondakci: Nothing to declare
Sascha Dietrich: Nothing to declare
Kathrin Nachtkamp: Nothing to declare.
Guido Kobbe: Advisory Role or Speaker Honoraria: MSD, Pfizer, Amgen, Novartis, Gilead, BMS-Celgene, Abbvie, Biotest, Takeda, Eurocept; Financing of Scientific Research: BMS-Celgene, Amgen, Abbvie, Eurocept, Medac.
19: Acute Leukaemia
P015 OUTCOMES OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOLLOWING BLINATUMOMAB IN CHILDREN AND YOUNG ADULTS WITH B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
Mattia Algeri 1, Michele Massa2, Federica Galaverna2, Daria Pagliara2, Ilaria Pili2, Francesca Del Bufalo2, Marco Becilli2, Emilia Boccieri2, Roberto Carta2, Francesco Quagliarella2, Chiara Rosignoli2, Carmen Dolores De Luca2, Barbarella Lucarelli2, Pietro Merli2, Franco Locatelli3
1IRCCS Bambino Gesù Children’s Hospital - Magna Graecia University, Rome - Catanzaro, Italy, 2IRCCS Bambino Gesù Children’s Hospital, Rome, Italy, 3IRCCS, Bambino Gesù Children’s Hospital, Catholic University of the Sacred Heart, Rome, Italy
Background: Blinatumomab, a CD3-CD19 bispecific T-cell engager, demonstrated high efficacy in inducing and consolidating remission in relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Available evidence suggests that r/r B-ALL patients have a better outcome if they received allogeneic hematopoietic stem cell transplantation (HSCT) after blinatumomab. However, the effect of blinatumomab on HSCT outcomes in children and young adults (YA) remains to be fully elucidated.
Methods: We retrospectively analyzed 78 children and YA with B-ALL who underwent allogeneic HSCT at our Institution, from February 2016 to June 2023, after receiving blinatumomab as last therapy before transplant either as part of reinduction/consolidation or as MRD-clearing strategy. Most patients (n = 55) received a single 28-day course. Median interval from blinatumomab discontinuation to HSCT was 23 days (IQR 19-31.75).
Median age at HSCT was 5 years (range 1-24). Patients received unmanipulated grafts from HLA-identical related (MFD, n = 13) or matched unrelated donors (MUD, n = 33), or αβT-cell depleted HSCT from HLA-haploidentical relatives (TCD-Haplo, n = 32) after TBI- (n = 72, 92.3%) or chemo-based myeloablative conditioning regimen (n = 6, 7.7%). All subjects were in complete remission (CR) at time of HSCT, associated with MRD-negativity (<10^-4) in 94% of cases. Thirty-one (39.7%) patients harbored at least one very high-risk (VHR) disease feature (Table 1). Further patient and transplant characteristics are reported in Table 1.
Sex (female/male) | 31 (40)/47(60) |
---|---|
CR number at Blinatumomab2 | |
• CR1 | 15 (19.2) |
• CR2 | 58 (74.4) |
• CR3 | 5 (6.4) |
Age group | |
• ≤ 4 years | 17 (21.8) |
• 5-11 years | 38 (48.7) |
• ≥12 year | 23 (29.5) |
Very high-risk disease features | |
• TCF3-Rearranged | 2 (2.6) |
• Hypodiploidy | 2 (2.6) |
• KMT2A/AF4 | 5 (6.4) |
• IKZF1plus and poor MRD response after induction | 4 (5.1) |
• No CR at Day33 without cytogenetic abnormalities | 2 (2.6) |
• Very early relapse (<18 months from diagnosis) for CR2 patients | 21 (26.9) |
Therapy before HSCT: | |
• Chemotherapy + Blinatumomab | 49 (62.9) |
• Chemotherapy + Inotuzumab + Blinatumomab | 14 (17.9) |
• Chemo-free treatment of relapse (Inotuzumab OR TKI + Blinatumomab) | 15 (19.2) |
Results: All patients achieved sustained donor engraftment, median time to neutrophil and platelet recovery being 17 (IQR 14-19) and 15 (IQR 11-20) days, respectively. After a median follow-up of 26 months, disease-free survival (DFS) of the whole cohort was 74.2% (95%CI 63.3-85.1), overall survival (OS) 84.3% (95%CI 74.5-94.1) and non-relapse mortality (NRM) 2.6% (95%CI 0-6.2). Cumulative incidence (CI) of grade II-IV acute graft-versus-host disease (aGvHD) was 17.9% (95%CI 9.08-26.6), with only two cases of grade III; CI of extensive chronic GvHD (cGvHD) was 4.6% (95%CI 0-9.7). No unexpected toxicities were observed. Patients aged ≤4 years had significantly lower DFS as compared to those aged 5-11 years or ≥12 years (45.6% 95%CI 20.1-71.1, 82% 95%CI 70-100 and 85.6% 95%CI 68.8-95.5, respectively, p = 0.02), due to a higher cumulative incidence of relapse (CIR 51.5% 95%CI 24-79.1, 18% 95%CI 4.9-31.1, 18.6 95%CI 8.6-28.9, respectively, p = 0.05). Neither the use a specific conditioning, nor MRD status and presence of VHR features influenced the probability of DFS. A trend toward better DFS was observed in CR1 patients (94.1%, 95%CI 82.95-100) versus CR2-3 (69.5%, 95CI 57-83.04, p = 0.18) and in those receiving unmanipulated matched grafts (80.1% 95%CI 64.6-95.6) versus TCD-Haplos (64.9%, 95%CI 48.2-81.5, p = 0.058).
Sixteen patients relapsed after HSCT, all with CD19-positive recurrence, after a median time of 9 months following transplantation (range 1-23). Of them, 10 received anti-CD19 CAR-T cells while 2 received inotuzumab, the 2-year OS after relapse being 52.7% (95%CI 27.1-78,3).
Conclusions: HSCT following blinatumomab in children/YA with r/r B-ALL is safe and highly effective, with remarkably low NRM (only 2 patients died for NRM) and absence of unexpected toxicities. These findings indicate that blinatumomab represents a suitable strategy to achieve long-term disease eradication and that it doesn’t preclude successful salvage with CAR-T cells in case of relapse.
Disclosure: Mattia Algeri: Vertex: Membership on an entity’s Board of Directors or advisory committees; Neovii: Speakers Bureau.
Pietro Merli: Sobi: Membership on an entity’s Board of Directors or advisory committees; Jazz: Membership on an entity’s Board of Directors or advisory committees; Miltenyi: Speakers Bureau; Amgen: Speakers Bureau.
Franco Locatelli: Miltenyi, Jazz Pharm, Medac, Sobi, Gilead, BluebirdBio: Speakers Bureau; Sanofi, Vertex: Membership on an entity’s Board of Directors or advisory committees; Bellicum, Amgen, Neovii, Novartis. Sanofi, SOBI, Vertex: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau
19: Acute Leukaemia
P016 THE ROLE OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN CONSOLIDATION OF MINIMAL RESIDUAL DISEASE-NEGATIVE REMISSION IN RELAPSED/REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA IN ADULTS AFTER PHARMACOLOGIC IMMUNOTHERAPY
Kseniia Afanaseva1, Ivan Moiseev 1, Bella Ayubova1, Elena Babenko1, Ildar Barkhatov1, Tatiana Gindina1, Anna Smirnova1, Olesya Smykova1, Yulia Vlasova1, Sergey Bondarenko1, Alexander Kulagin1
1RM Gorbacheva Research Institute, Pavlov University, St. Petersburg, Russian Federation
Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is a standard consolidation strategy for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients with relapsed/refractory (r/r) disease and persistent minimal residual disease (MRD). Long-term outcomes of pharmacologic immunotherapy in r/r BCP-ALL is relatively modest, but MRD-negative patients have better prognosis, which was not directly compared to the results of allo-HCT in large studies.
Methods: The study included 101 BCP-ALL patients who achieved MRD-negative complete remission (CR) with two consecutive evaluations after either blinatumomab or inotuzumab ozogamicin treatment from November 2014 to September 2023 (Table 1). Median age was 22 years (range, 18 - 67 years). MRD response was assessed both by flow cytometry and molecular analysis for patients with known molecular markers. Median blinatumomab courses were 1 (range, 1-7), inotuzumab ozogamicin – 1 (range, 1-3). Consolidation with allo-HCT was performed in 62 patients, not performed in 39 patients within the frame of the routine clinical practice. Long-term outcomes after immunotherapy according to allo-HCT consolidation were estimated by landmark analysis.
Table 1. Patients’ characteristics of the study group
Characteristics | Immunotherapy followed by allo-HCT N = 62 | Immunotherapy only N = 39 | P-value |
---|---|---|---|
Blinatumomab/Inotuzumab ozogamicin | 40 (65%)/22 (35%) | 32 (82%)/7 (18%) | 0,06 |
High cytogenetic risk (yes/no) | 23 (37%)/39 (63%) | 11 (28%)/28 (72%) | 0,36 |
Extramedullary disease in r/r (yes/no) | 17 (27%)/45 (73%) | 3 (8%)/36 (92%) | 0,02 |
Indication to immunotherapy (MRD/r/r*) | 16 (26%)/46 (74%) | 19 (49%)/20 (51%) | 0,02 |
*R/R status (refractory/1st relapse/>1 relapse) | 5 (11%)/24 (52%)/17 (37%) | 0 (0%)/8 (40%)/12 (60%) | 0,12 |
Previous allo-HCT (yes/no) | 4 (6%)/58 (94%) | 15 (38%)/24 (62%) | 0,001 |
Subsequent immunotherapy (yes/no) | 10 (16%)/52 (84%) | 8 (21%)/31 (79%) | 0,58 |
Donor (Haploidentical/other) | 21 (34%)/41 (66%) | - | - |
Results: Median follow-up time in the group of patients who received allo-HCT after immunotherapy was 55 months (range, 2-95), in immunotherapy without allo-HCT group – 56 months (range, 5 - 101) for those who survived by follow-up. Median time from achievement of MRD-negative CR to allo-HCT was 2 months (range, 2 - 27). Median time from achievement of MRD-negative CR to relapse was 12 months (range, 2 - 72) in immunotherapy followed by allo-HCT group and 13 months (range, 2 – 61) in immunotherapy without HCT group. In a landmark analysis of 5-year overall survival (OS) and relapse-free survival (RFS) by allo-HCT at 2 months after MRD-negative CR establishment no difference between outcomes in two groups was demonstrated: OS was 44,1% (95% CI 29,3 – 66,3) in allo-HCT group and 49,6% (95% CI 38,4 – 64,1) in immunotherapy without allo-HCT group, p = 0,19; RFS was 31% (95% CI 17,9 – 53,7) and 36,1% (95% CI 25,3 – 51,5), p = 0,25, respectively. Results were similar when assessed for 4-months (p = 0,46 for OS and p = 0,67 for RFS) and 6-months landmark points (p = 0,61 for OS and p = 0,83 for RFS). Subgroup univariate analysis showed no influence of any predictors (blinatumomab versus inotuzumab ozogamicin, high cytogenetic risk, extramedullary disease in relapse, MRD or relapse as an indication to immunotherapy, previous allo-HCT) for RFS in immunotherapy without subsequent allo-HCT group, while extramedullary disease in relapse and haploidentical donor increased risk of RFS after allo-HCT, which was confirmed in a multivariate model (HR 2,8 (95% CI 1,38 – 5,6), p = 0,004 and HR 2,3 (95% CI 1,06 – 4,9), p = 0,03).
Conclusions: The study demonstrated that responders to pharmacologic immunotherapy with r/r BCP-ALL with sustainable MRD-negative status have no benefit from all-HCT consolidation in the general group. Nonetheless, heterogeneity in allo-HCT outcomes indicates that further cooperative studies and consolidation of multicenter data is required to define the group which will benefit from allo-HCT in MRD-negative CR.
Disclosure: Nothing to declare
19: Acute Leukaemia
P017 FLAG-IDA/VENETOCLAX IS ASSOCIATED WITH HIGHER REMISSION RATES AND IMPROVED POST-TRANSPLANT SURVIVAL COMPARED TO VENETOCLAX/AZACITIDINE IN RELAPSED/REFRACTORY AML PATIENTS
Evgeny Klyuchnikov1, Anita Badbaran1, Radwan Massoud 1, Normann Steiner1, Petra Freiberger1, Franziska Modemann1, Martin Schönrock1, Sophia Cichutek1, Walter Fiedler1, Micha Peeck2, Nico Gagelmann1, Christine Wolschke1, Francis Ayuk1, Ulrike Bacher3, Nicolaus Kröger1
1University Cancer Center of Hamburg, Hamburg, Germany, 2Agaplesion Diakonie Clinic, Rotenburg, Germany, 3Bern University Hospital, Bern, Switzerland
Background: Patients (pts) with relapsed/refractory (R/R) AML experience poor remission rates and short durations of response. Combinations of BCL2 inhibition have proven to be synergistic with low intensity and intensive chemotherapy, leading to high remissions. In this monocentric study, we compared post-transplant outcomes in R/R AML pts who received low (azacitidine [AZA]) or intensive (FLAG-Ida) regimen combined with venetoclax [VEN] as “bridging” strategies before allogeneic stem cell transplantation (allo-SCT).
Methods: 90 pts (male, n = 53; median, 59 years [range, 19-75]) with R/R AML who received allo-SCT (related, n = 58) between 2019-2023 at the Department of Stem Cell Transplantation (University Medical Centre Hamburg) were included if they received VEN-based “bridging” strategies. The measurable residual disease (MRD) detection was performed by flow cytometry (“different from normal”; ELN guidelines). Primary endpoint was the difference in overall survival (OS) from allo-SCT. Secondary endpoints were differences in leukaemia-free survival (LFS), relapses and non-relapse mortality (NRM) from allo-SCT.
Results: The majority of allografts were performed after myeloablative conditioning (n = 57, 63%) with ATG as GvHD prophylaxis (n = 65, 72%). 62 pts underwent 1st whereas 26 (29%) 2nd and two 3rd allo-SCT. At allo-SCT,62 pts (69%) were in complete remission (CR). Bridging therapy consisted of AZA-VEN (one or two cycles) in 41 pts or FLAG-Ida-VEN in 49 pts. Pre-transplant MRD data were available in 49 pts. The rate of MRDnegCR (16/27, 59% vs 11/27, 41%) and MRDpos CR (16/22, 73% vs 6/22, 27%) was higher in the FLAG-Ida-VEN group. The rate of non-CR (17/28, 61% vs 11/28, 39%, p = 0.055) was higher in the AZA-VEN group.
During a median follow up of 13 months (2-140), there were 34 mortalities, 27 relapses and 13 NRM events. The 2-year OS (61%, 43-77% vs 46%, 29-64%, p = 0.089) and LFS (46%, 27-66% vs 39%, 24-52%, p = 0.045) were better in FLAG-Ida-VEN. The relapse and NRM rates were similar between two groups. Other factors, significant in univariate analysis included remission status and donor type. In the multivariate analysis, CR at allo-SCT had significant independent impact on OS (HR 0.17, 0.08-0.35, p<0.0001), LFS (HR 0.18, 0.1-0.35, p<0.0001) and relapses (HR 0.19, 0.08-0.43, p<0.0001).
In addition, we performed an analysis (n = 77) focusing on remission status augmented by MRD. The 1 y OS for MRDneg CR, MRDpos CR and pts with non-CR was 93% (77-98%), 63% (40-81%) and 30% (16-49%, p<0.001), respectively. The 1-y LFS for MRDneg CR, MRDpos CR and pts with non-CR was 92% (76-98%), 59% (37-78%) and 21% (11-51%, p<0.001), respectively. The relapse rate at 1 y for MRDneg CR, MRDpos CR and pts with non-CR was 9% (2-39%), 21% (8-44%) and 55% (36-72%, p<0.001), respectively. In multivariate analysis, MRDposCR and non-CR had adverse impact on OS (HR 5.2, 1.1-24.4, p = 0.035; HR 11.5, 2.7-49.9, p = 0.001; Wald test, p = 0.002), LFS (HR 2.9, 0.9-9.2, p = 0.076; HR 8.6, 2.9-25, p<0.001; Wald test, p<0.001) and relapses (HR 2.6, 0.5-14.2, p = 0.24; HR 10.1, 2.5-39.8, p<0.001; Wald test, p<0.001) compared to MRDnegCR, respectively.
Conclusions: Intensive venetoclax-based “bridging” regimen with FLAG-Ida is associated with higher CR rates than AZA-VEN, leading to overall better outcomes.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P018 COMPARISON OF OUTCOMES OF HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION USING POST-TRANSPLANTATION CYCLOPHOSPHAMIDE AND EX-VIVO TCRΑΒ + CD19 DOUBLE-NEGATIVE SELECTED GRAFT IN ACUTE MYELOID LEUKEMIA
László Gopcsa 1, Hajnalka Andrikovics1, Alexandra Balogh1, Anikó Barta1, Judit Bogyó2, Zoltán Csukly1, Katalin Dobos1, János Dolgos1, Apor Hardi1, János Fábián1, Laura Giba-Kiss1, József Harasztdombi1, Kinga Kerner1, Ágnes Király1, Gergely Lakatos1, Viktor Lakatos1, Lilla Lengyel1, Nóra Meggyesi1, Noémi Németh1, Melinda Paksi1, Laura Regáli1, Marienn Réti1, János Sinkó1, Bálint Szabó1, Anikó Szilvási2, Éva Torbágyi1, Andrea Várkonyi1, Nikolett Wohner1, István Vályi-Nagy1, Péter Reményi1
1Central Hospital of Southern-Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary, 2The Hungarian National Blood Transfusion Service, Budapest, Hungary
Background: Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) represents a curative therapeutic option for the treatment of patients suffering from acute leukemia. Moreover, the incidence of severe acute and extensive chronic GVHD in the case of Haplo-HSCT has proven to be more favorable compared to the other donor types. Currently, Haplo-HSCT with post-transplantation cyclophosphamide (PTCY) GVHD prophylaxis is considered the “gold standard” procedure. However, a less common approach to performing Haplo-HSCT involves ex-vivo T-cell depletion, employing various methods, with the most recognized being the use of a graft produced through TCRαβ + CD19 double-negative depletion (TCDαβ + CD19). Experiencies with pediatric HSCT using haploidentical grafts generated through TCDαβ + CD19 have been notable for their compelling outcomes. There is limited clinical experience in adult HSCT practice with this method.
Methods: In our retrospective analysis, we compared the outcomes of Haplo-HSCT performed between 2015 and 2022 for AML using PTCY (N = 60) and TCDαβ + CD19 (N = 28).
Results: In the PTCY group, 37 males (62%) and 23 females (38%) were included, with a median age of 50.5 years, while in the TCDαβ + CD19 group, there were 15 males (54%) and 13 females (46%) with a median age of 50 years. Mostly myeloablative conditioning regimens were used in both groups, primarily involving Thiotepa-Busulfan-Fludarabine and Thiotepa-Treosulfan-Fludarabine. All patients in the PTCY group received PTCY+tacrolimus+MMF GVHD prophylaxis. In the TCDαβ + CD19 group, 64% of patients did not received post-graft immunosuppression, however, GVHD prophylaxis was administered in 36% of cases (18% with MMF, 11% with tacrolimus, and 7% with ruxolitinib). The incidence of acute GVHD in the PTCY and TCDαβ + CD19 groups was 39% and 25%, respectively, with severe cases being 7% and 4%. The majority of acute GVHD cases were grade 2 and responded well to steroid treatment. The incidence of chronic GVHD in the PTCY and TCDαβ + CD19 groups was 31% and 21%, respectively. The extensive chronic GVHD was similar in the two groups (14% versus 10,5%). The relapse rates were low in both groups: 13% and 11%. Prolonged poor graft function was observed in 22% of patients receiving PTCY. Non-relapse mortality (NRM) was identical in both groups: PTCY and TCDαβ + CD19 34% and 28%, respectively. The overall survival (OS), disease-free survival (DFS), and refined GVHD-free and relapse-free survival (rGRFS) were more favorable in the TCDαβ + CD19 group: 61% and 53%, 61% and 51%, 53% and 46%.
Conclusions: The presented results are unique in terms of comparing both PTCY and TCDαβ + CD19 methods within one center. The OS, DFS, and GRFS were favorable with the TCDαβ + CD19 method, but larger studies are necessary for confirmation. Unlike in ALL, the occurrence of rejection with the TCDαβ + CD19 method does not significantly impact long-term outcomes. Therefore, the use of TCDαβ + CD19 method in AML can be safely employed, resulting in faster engraftment, shorter hospital stays, and a clearly lower incidence of poor graft function. The relapse rate was low in both patient groups, indicating a significant graft-versus-leukemia effect. The incidence of severe acute GVHD was low. Moreover, the use of post-graft maintenance therapeutic strategies in AML can further enhance long-term patient survival.
Disclosure: Disclosure of conflict of interest: None.
19: Acute Leukaemia
P019 AZACITIDINE AND VENETOCLAX WITH OR WITHOUT DLI IN RELAPSED MYELOID MALIGNANCIES AFTER ALLOGENIC HEMATOPOIETIC STEM CELL TRANSPLANTATION – A RETROSPECTIVE MULTICENTER STUDY OF THE SFGM-TC
Turot Mélanie 1, Loschi Michael2, Chantepie Sylvain3, Arnautou Pierre4, Poire Xavier5, Maillard Natacha6, Chalandon Yves7, El-Cheikh Jean8, Ceballos Patrice9, Devillier Raynier10, Alani Mustafa11, Fatrara Thomas12, Rubio Thérèse13, Daguindau Etienne14, Klemencie Marion15, Beauvais David16, Huynh Anne17, Marchand Tony18, Volpari Victoria19, Barette Lauren19, Pivert Cécile20, Maury Sébastien21, Suarez Felipe22, Fuseau Charline23, Lauron Sandrine24, Uzunov Madalina25, Castilla Cristina26, Forcade Edouard27, Bay Jacques-Olivier1, Ravinet Aurélie1
1Clermont-Ferrand University Hospital, Clermont-Ferrand, France, 2Nice University Hospital, Nice, France, 3Basse-Normandie Institute of Hematology, Caen, France, 4Percy Army Training Hospital, Clamart, France, 5Saint-Luc University Clinic, Uclouvain Bruxelles Woluwe, Belgium, 6Poitiers University Hospital, Poitiers, France, 7Geneva University Hospitals, Geneva, Switzerland, 8AUB Medical Center, Beyrouth, Lebanon, 9Montpellier University Hospital, Montpellier, France, 10Paoli-Calmettes Institute, Marseille, France, 11Henri Becquerel Center, Rouen, France, 12Saint-Etienne University Hospital, Saint-Etienne, France, 13Nancy Regional and University Hospital, Nancy, France, 14Besançon University Hospital, Besançon, France, 15Anger University Hospital, Anger, France, 16Lille University Hospital, Lille, France, 17Toulouse Cancer University Institute, Toulouse, France, 18Rennes University Hospital, Rennes, France, 19Grenoble Alpes University Hospital, Grenoble, France, 20Public Assistance - Paris Hospitals, Paris, France, 21Henri-Mondor Hospital Public Assistance - Paris Hospitals, Créteil, France, 22Necker Hospital Public Assistance - Paris Hospitals, Paris, France, 23Strasbourg Europe Cancer Institute, Strasbourg, France, 24Edouard Herriot Hospital-Lyon Civil Hospices, Lyon, France, 25La Pitié Salpêtrière Hospital Public Assistance - Paris Hospitals, Paris, France, 26Gustave Roussy, Villejuif, France, 27Bordeaux University Hospital, Bordeaux, France
Background: Despite the recent therapeutic progress, between 30 to 40 % patients relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) for acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). While Azacitidine and Venetoclax (VenAza) combination has been approved in previously untreated patients with AML ineligible for intensive induction therapy, VenAza associated with donor lymphocyte infusion (DLI) is also considered post-transplant as salvage therapy. However, limited data are available regarding outcomes with this specific setting.
Methods: To evaluate efficiency and safety of VenAza with/without DLI in relapsed myeloid malignancies after alloHSCT, we retrospectively collected data from January 1, 2016 to September 1, 2022 in 29 centers from the Société Francophone de Greffe de Moelle et Thérapie Cellulaire (SFGM-TC). We included 173 patients aged 18 years or older treated with the association of VenAza as salvage therapy for AML or MDS after one or more alloHSCT. The data were extracted from the ProMISe database, an international registry coordinated in part by the SFGM-TC.
Results: The median follow up after the transplant was 14 months. Out of the 173 patients, 152 (87,86%) had an AML including 11 cases of secondary acute myeloid leukemia, and 21 (12,14%) had a MDS. The median age at transplant was 53,78 (17,9 – 74,86). DLI was administered to 43 patients (24,86%) who relapsed after alloHSCT.76 patients (44,19%) experienced a relapse within 6 months after alloHSCT (defined as “early relapse”) and 96 patients (55,8%) relapsed more than 6 months after alloHSCT (“late relapse”).117 patients were treated with VenAza after their 1st relapse,39 after their 2nd and 6 after 3 or more relapses. The median number of VenAza cycles per patient was 2 (1-13) (Table 1). The median overall survival time estimate was 18,99 months with a 1-year overall survival (OS) of 62,45% (95% CI 55,52 - 70,23%) and a 2-years OS of 40,32 % (95% CI 33,21 – 48,95%). The median survival was longer (p = 0,001) for patients who were treated by VenAza for a late relapse with a 2-years OS of 62,96% (95% CI 53,60 – 73,96%) and 7,17% (95% CI 2,58-19,89%) for early relapses. The OS and EFS (P<0,001) were better in the DLI group. In multivariate analysis, survival remains better in DLI group. (HR = 0,57 (95% CI 0,36 – 0,92)). A total of 82,75 % patients relapsed after post-transplant VenAza and 10,90 % had a complete remission. Additionally, 17 patients (10,43%) developed chronic graft-versus-host disease (GVHC) after alloHCST, including 6 patients after venAza. The main causes of death were relapse or progression of the original disease (61,81%) and infections (21,18%).
Table 1. Patients’ characteristics.
n = 173 | |
---|---|
Patient sex, (n) % | |
Female | 76 (43,96) |
Male | 97 (56,07) |
Median age, years (range) | 53,78 (17,19; 74,86) |
Diagnosis, (n) % | |
AML | 152 (87,86) |
De novo AML | 142 (92,76) |
Secondary AML | 11 (7,23) |
MDS | 21 (12.14) |
Score HCT-CI, (n) % | |
Score > 2 | 34 (21,79) |
Type of transplantation, (n) % | |
Match related donor | 52 (30.06) |
Match unrelated donor | 82 (47.40) |
Haplo identical donor | 39 (22.55) |
Transplantation conditioning, (n) % | |
MAC | 48 (28.24) |
TBI | 10 (5.88) |
ATG | 124 (73.81) |
GVHD prophylaxis, (n) % | 170 (98.27) |
Cyclosporine | 31 (18.24) |
Cyclosporine and Methotrexate | 37 (21.76) |
Cyclosporine and Mycophenolate mofetil | 54 (31.77) |
Cyclosporine, Mycophenolate mofetil and Cyclophosphamide | 34 (20,00) |
Others | 14 (8,24) |
DLI before VenAza, (n) % | 23 (13.30) |
1 | 18 (78,26) |
2 | 4 (17,39) |
3 | 1 (4,35) |
Acute GVHD, (n) % | 79 (45.66) |
Grade >2 | 9 (11,38) |
Chronic GVHD, (n) % | 32 (18,50) |
Score NIH >3 | 5 (10,32) |
Relapses after HSCT, (n) % | |
First relapse | 117 (72,22) |
Second relapse | 39 (24,07) |
Three or more relapse | 6 (3,70) |
Median follow-up after transplant, months (range) | 14,08 (1,74; 65,91) |
VenAza cycles, (n) % (range) | 2 (1;13) |
DLI in association to VenAza, (n) % | 43 (24,86) |
1 | 26 (60,47) |
2 | 7 (16,28) |
3 | 8 (18,60) |
4 | 2 (4,65) |
Relapse after HSCT, (n) % | |
Early relapse < 6 months | 76 (44.19) |
Late relapse > 6 months | 96 (55.81) |
Status post VenAza, (n) % | |
Complete remission | 17 (10,90) |
Relapse | 113 (85,26) |
Conclusions: Notwithstanding the retrospective nature, the results suggest that VenAza is an acceptable salvage therapy after alloHSCT and that the addition of DLI appears to improve survival with superior OS and EFS compared with non-DLI group, according to univariate and multivariate analysis.
Disclosure: Yves Chalandon. has received consulting fees for advisory board from MSD, Novartis, Incyte, BMS, Pfizer, Abbvie, Roche, Jazz, Gilead, Amgen, Astra-Zeneca, Servier; Travel support from MSD, Roche, Gilead, Amgen, Incyte, Abbvie, Janssen, Astra-Zeneca, Jazz, Sanofi all via the institution.
19: Acute Leukaemia
P020 EFFICACY AND SAFETY ANALYSIS OF PROPHYLACTIC BRENTUXIMAB VEDOTIN ADMINISTRATION AFTER PEDIATRIC ACUTE LEUKEMIA HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION
Zhu Huili 1, Cao Xingyu1, Lu Yue1, Zhang Jianping1, Zhao Yanli1, Liu Deyan1, Xiong Min1, Sun Ruijuan1, Liu Hongxing1, Wei Zhijie1
1Hebei Yanda Lu Daopei Hospital, Langfang, China
Background: Acute graft-versus-host disease (aGVHD) is a common complication following allogeneic hematopoietic stem cell transplantation. Currently, the reported incidence of moderate to severe aGVHD in domestic cases is 13%-47%, while the incidence of grade III/IV aGVHD after haploidentical transplantation ranges from 7.9% to 13.8%. This study aims to analyze whether the administration of Brentuximab vedotin after transplantation can reduce the incidence of aGVHD without increasing disease relapse rates and viral infections.
Methods: A retrospective analysis was conducted on 50 pediatric leukemia patients who underwent haploidentical hematopoietic stem cell transplantation at our hospital between June 2017 and July 2022. These patients received prophylactic treatment with Brentuximab vedotin (20mg) on day +1 and day +4 post-transplantation. The median age of the patients was 4.1 years (range: 0.6-16.0 years). Among the cases, 22 were acute lymphoblastic leukemia (ALL), and 28 were acute myeloid leukemia (AML). Before transplantation, 28 patients were in CR1, 14 in CR2, 2 in CR3, and 6 in NR. All patients received myeloablative conditioning regimens, with 33 receiving Bu/Cy, 15 receiving TBI/Cy, 1 receiving Bu/Flu, and 1 receiving TBI/Flu. The median follow-up time was 29.1 months (range: 3.1-70.1 months). Detailed patient data are presented in Table 1.
Results: All 50 patients achieved 100% engraftment of white blood cells, with a median time of 15 days (range: +10 to +21 days). Platelet engraftment occurred in a median time of 9 days (range: +5 to +78 days), except for one patient who did not achieve platelet engraftment. The incidence of aGVHD after transplantation was 44%, with 28% experiencing grade I-II and 16% experiencing grade III-IV aGVHD. The incidence of CMV viremia was 40%, while the incidence of EBV viremia was 8%. During the follow-up period, five patients experienced disease relapse. Seven patients died during the follow-up, including 4 with AML and 3 with ALL. The causes of death were disease relapse in 3 cases, infection in 2 cases, TMA in 1 case, and cGVHD in 1 case. The estimated 5-year overall survival (OS) and leukemia-free survival (LFS) rates were 86%, and the 5-year cumulative relapse rate was 10%. In comparison, a control group of 44 pediatric acute T-cell lymphoblastic leukemia patients who underwent haploidentical transplantation without prophylactic Brentuximab vedotin treatment between January 5, 2021, and June 30, 2022, were analyzed. In the control group, the incidence of aGVHD was 56.8% (P = 0.007), with 36.4% experiencing grade I-II and 20.4% experiencing grade III-IV aGVHD. The incidence of CMV viremia was 68.2% (P = 0.006), and the incidence of EBV viremia was 29.5% (P = 0.007). The relapse rate was 15.9%, and the mortality rate was 27.3%.
Characteristics | Number of Cases |
---|---|
Total Number of Cases | 50 |
Median Age(Range) Years | 4.1 (0.6-16 years old) |
Gender, Male (Number of Cases, %) | 25 (50%) |
Disease Diagnosis | Number of Cases |
ALL (B-cell) | 18 (including 4 cases with CNS involvement) |
ALL (T-cell) | 4 (including 1 case with CNS involvement) |
AML | 28 (including 7 cases of acute megakaryocytic leukemia) |
Pre-transplant Status (Number, %) | |
CR1 | 28 (56%) |
≥CR2 | 16 (32%) |
NR | 6 (12%) |
Pre-conditioning Regimen (Number, %) | |
Bu/Cy | 33 (66%) |
TBI/Cy | 15 (30%) |
Bu/Flu | 1 (2%) |
TBI/Flu | 1 (2%) |
Infusion of MNC (Mean, ×108/kg) | 14.9 |
Infusion of CD34+ (Mean, ×106/kg) | 7.9 |
Infusion of CD3+ (Mean, ×108/kg) | 3.2 |
Conclusions: For pediatric acute leukemia haploidentical HSCT, the administration of Brentuximab vedotin (20mg) on days +1 and +4 after transplantation, in addition to conventional aGVHD prophylaxis (CsA+MMF+sMTX), significantly reduced the overall incidence of aGVHD and grade I-II aGVHD. Administering Brentuximab vedotin on days +1 and +4 did not increase the rates of CMV or EBV infection nor did it increase the risk of disease relapse.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P021 OUTCOMES AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ACUTE LEUKEMIA IN YOUNG ADULTS COMPARED WITH CHILDREN, ADOLESCENTS AND ELDERLY PATIENTS IN GERMANY
Jochen J. Frietsch 1,2, Sarah Flossdorf3,4, Ashrafossadat Ahmadian3,4, Claudia Schuh3, Thomas Schroeder5, Igor-Wolfgang Blau6, Matthias Stelljes7, Nicolaus Kröger3,8, Katharina Egger-Heidrich9, Matthias Eder10, Peter Dreger11, Johanna Tischer12, Eva Wagner-Drouet13, Rita Beier14,15, Peter Bader16, Martin Sauer15, Barbara Meissner14,15, Katharina Fleischhauer3,17, Inken Hilgendorf2
1Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany, 2Klinik für Innere Medizin II, Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Jena, Germany, 3Deutsches Register für hämatopoetische Stammzelltransplantation und Zellherapie e.V., Ulm, Germany, 4Institut für Medizinische Informatik, Biometrie und Epidemiologie, Uniklinikum Essen, Essen, Germany, 5Klinik für Hämatologie und Stammzelltransplantation, Universitätsklinikum Essen, Essen, Germany, 6Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie, Campus Virchow-Klinikum, Berlin, Germany, 7Medizinische Klinik A, Hämatologie, Hämostaseologie, Onkologie und Pneumologie, Universitätsklinikum Münster, Münster, Germany, 8Klinik für Stammzelltransplantation, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany, 9Medizinische Klinik I, Universitätsklinikum Carl Gustav Carus, Dresden, Germany, 10Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation, Medizinische Hochschule Hannover, Hannover, Germany, 11Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany, 12Medizinische Klinik und Poliklinik III, Klinikum der Ludwig-Maximilians-Universität München, München, Germany, 13III. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Germany, 14Pädiatrisches Register für Stammzelltransplantationen und Zelltherapien, Hannover, Germany, 15Klinik für Pädiatrische Hämatologie und Onkologie, Medizinische Hochschule Hannover, Hannover, Germany, 16Klinik für Kinder- und Jugendmedizin, Studienzentralen der Schwerpunkte Onkologie, Hämatologie und Hämostaseologie sowie Stammzelltransplantation, Immunologie und Intensivmedizin, Universitätsklinikum Frankfurt, Frankfurt, Germany, 17Institut für Zelltherapeutische Forschung, Universitätsklinikum Essen, Essen, Germany
Background: The survival after allogeneic hematopoietic SCT is influenced by the patients’ age, diagnosis, donor type and achieved remission. Nevertheless, with a 5-year overall survival (OS) probability of 53%, the outcome of young adults (YA) aged 18 to 39 years is sobering. We sought to provide more detail on outcome by focusing on acute leukemia (AL).
Methods: The German Registry for Hematopoietic Cell Transplantation and Cellular Therapy (DRST) and the German Pediatric Registry for Stem Cell Transplants and Cell Therapies (PRSZT) were screened for patients suffering from AL who received 1st SCT between 2011 and 2019. OS rates were determined by Kaplan-Meier analysis and differences between were evaluated using Score-tests (corresponding to the log-rank test, computed when Hazards are not crossing). Gray’s test was applied to cumulative incidence of NRM using competing risk analysis. To separate relapse from progression, patients not being in complete remission at the time of SCT or within 100 days were excluded from competing risk analysis. A p-value of <0.05 was considered statistically significant.
Results: Altogether 11258 patients were included, with 573, 269, 2158, 4667 and 3591 in the age groups 0-12, 13-17, 18-39, 40-59 and 60-72 years at the time of SCT, respectively. 2424 (21.5%) suffered from acute lymphoblastic leukemia (ALL) and 8834 (78.5%) from acute myeloid leukemia (AML). The majority (89.6%, 10089) of the predominantly male (56.2%, 6331) patients received peripheral blood SCT from a related (28.4%, 3192) or an unrelated (71.6%, 8066) donor with varying degrees of histocompatibility. During the observation period, 4380 (38.9%) patients deceased.
The probability of 5-year OS decreased for AML with increasing patient age: 0-12: 69%; 13-17: 60%; 18-39: 57%; 40-59: 49%; and 60-72 years: 37% and for ALL: 0-12: 73%; 13-17: 71%; 18-39: 53%; 40-59: 51%; and 60-72 years: 37%. Statistically significant differences in the probability of 5-year OS were observed between related and unrelated donors for AML (48% vs. 46%, p = 0.0018), but not for ALL (52% vs. 57%). No statistically significant differences could be observed concerning gender for AML (♀ 49% vs. ♂ 45%, p = 0.0508) and ALL (♀ 57% vs. ♂ 55%).
The 5-year-NRM increased with patient age for both ALL (0-12: 7%; 13-17: 10%; 18-39: 19%; 40-59: 26% and 60-72: 30%; p<0.001) and AML (5%; 14%; 12%; 20% and 30%; p<0.001). The 5-year relapse rate in both entities was lower for 13-17 year old adolescents (AML/ALL 13-17: 26%/18%) than for the other age groups (0-12: 33%/28%, 18-39: 40%/31%, 40-59: 34%/28%, 60-72: 35%/32%).
Conclusions: In this preliminary large retrospective multicenter analysis we show that NRM increases with patient age which also negatively impacts OS. The heterogeneity of the cohort was taken into account by considering diseases separately and age in groups. As differences in patient outcome are being reflected by a distinct disease biology, further investigations are necessary to fully elucidate differences between AML and ALL in age-dependent survival. The increasing NRM with respect to age underlines the relevance of interdisciplinary collaboration between pediatricians and non-pediatricians for the improvement of aftercare concepts, especially for children, adolescents and YA.
Disclosure: IH is chairperson of the board of trustees of the German Foundation for Young Adults with Cancer, received research funding from the H.W. and J. Hector-Foundation and honoraria from AbbVie, Medac, Novartis and Takeda. JF received honoraria from Novartis. All other authors do not declare any conflicts of interest. The Cooperative German Transplant Study group is acknowledged for project development and support.
19: Acute Leukaemia
P022 PHASE I/II STUDY OF CYCLOPHOSPHAMIDE AND BENDAMUSTINE AS POST-TRANSPLANTATION GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS IN REFRACTORY MYELOID NEOPLASMS
Ivan Moiseev 1, Olga Epifanovskaya1, Ksenia Afanasyeva1, Anastasia Beynarovich1, Dmitrii Zhogolev1, Mikhail Kanunnikov1, Yulia Rogacheva1, Tatyana Rudakova1, Nikita Volkov1, Zhamshidbek Khudaiberdiev1, Azamjon Meliboev1, Yulia Vlasova1, Elena Morozova1, Sergei Bondarenko1, Alexander Kulagin1
1RM Gorbacheva Research Institute, Pavlov University, Saint Petersburg, Russian Federation
Background: Efficacy of allogeneic hematopoietic stem cell transplantation (alloHCT) in disease progression of myeloid neoplasms resistant to chemotherapy or targeted therapy is low. Our group recently demonstrated an enhanced graft-versus-leukemia (GVL) effect when replacing cyclophosphamide with bendamustine in a graft-versus-host disease (GVHD) prophylaxis regimen (Moiseev IS et al., TCT, 2021), but there was significant toxicity from this regimen from a poorly controlled cytokine release syndrome (CRS). To reduce toxicity while preserving GVL, we conducted a pilot single-center study of graft-versus-host disease (GVHD) prevention with a combination of cyclophosphamide and bendamustine in refractory myeloid neoplasms.
Methods: Prospective single-center Phase I/II study (NCT04943757) enrolled 50 patients (table 1). Inclusion criteria were myeloid neoplasm, available hematopoietic cell donor, >5% clonal blasts at the start of conditioning, disease refractory to at least one course of induction therapy. Main exclusion criteria: absence of uncontrolled infection and severe concomitant co-morbidities. The protocol included the administration of bendamustine 50 mg/kg/day on days +3, + 4, cyclophosphamide 25 mg/kg/day on days +3, + 4 (PTBC), tacrolimus 0.03 mg/kg from day+5 to day+ 100 day and mycophenolate mofetil 30 mg/kg/day on days 5-35. Patients received FB2 or FB3 conditioning regimen according to their age and performance status.
Characteristics of the study group | N = 50 |
---|---|
Diagnosis | |
Acute myeloid leukemia | 37 |
Myelodysplastic syndrome | 9 |
Chronic myeloid leukemia | 2 |
Chronic myelomonocytic leukemia | 1 |
Atypical chronic myeloid leukemia | 1 |
Age, median years (range) | 48 (18-69) |
Karnofsky index, median (range) | 80% (60-90%) |
Gender | |
Males | 34 |
Females | 16 |
Matched related donor | 10 |
Matched unrelated donor | 26 |
Haploidentical donor | 14 |
Conditioning | |
FB2 conditioning | 33 |
FB3 conditioning | 13 |
Other conditioning | 4 |
Active antimicrobial therapy at the time of HCT | 20 |
Second HCT | 4 |
Co-morbidity index | |
HTC-CI 0 | 24 |
HTC-CI 1 | 17 |
HTC-CI 2 | 6 |
HTC-CI >2 | 3 |
Primary refractory disease | 26 |
Secondary refractory disease | 24 |
Complex karyotype | 10 |
High-risk somatic mutations | 22 |
Median % of blasts at the start of conditioning (range) | 12% (5-86%) |
Results: The cumulative engraftment rate was 86%. Only 1 patient died before engraftment assessment. The median time to recovery of white blood cells was 18 days (range 12-35), platelets - 14 days (range 9-104). Remission was achieved in 88% of patients, with 76% of patients negative for minimal residual disease (MRD). Overall survival (OS) was 33% (95%CI 19-48%), event-free survival (EF) - 21% (95%CI 10-35%). Non-relapse mortality (NRM) was 19% (95%CI 9-31%), cumulative relapse incidence was 60% (95%CI 43-74%). Toxicity included development of CRS in 30% of patients, including 2 patients with grade 4-5 CRS. The most common manifestation of CRS was fever, increased ferritin and abnormal liver function tests (24% of patients). The cumulative incidence of grade II-IV acute GVHD was 20% (95%CI 10-33%), grade III-IV – 18% (95%CI 7-31%), moderate and severe chronic GVHD - 18% (95%CI 8 -31%). Grade II-IV acute GVHD was observed predominantly in patients with CRS grades 2-5 (31% vs. 16%, p = 0.02). Survival subanalysis showed that unrelated or haploidentical donor transplantation was associated with better OS (40% vs 0%, p = 0.008). Unique tolerance mechanisms were revealed with a massive expansion of PD-1L positive monocytes by day +30 (17.7±10.9% of all nucleated cells [NC]) with a decline to 7.1±4.3% and 6.9±6.5% of NC by days +60 and +100 (p<0.001). The level of PD-1L granulocytes was also high: 13.2±10.9%, 8.1±9.4% and 9.0±9.0% of NC on days 30, 60 and 100 (p = 0.4). This was accompanied by rapid expansion of effector T-cells (p<0.001), effector memory T-cells (p<0.001), central memory T-cells (p<0.001), naive T-cells (p<0.0001) and CD197-positive activated T-cells (p<0.0001) early post-transplant. In several patients abnormally high levels of monocytes and lymphocytes persisted for 2 years after HCT.
Conclusions: We developed a promising alloHCT platform for refractory myeloid neoplasms with a unique immunological recovery profile.
Clinical Trial Registry: NCT04943757, clinicaltrials.gov
Disclosure: The study was supported by RSF grant №23-15-00327.
19: Acute Leukaemia
P023 REAL-WORLD OUTCOME OF ACUTE MYELOID LEUKEMIA PATIENTS TREATED WITH ALLOGENEIC STEM CELL TRANSPLANTATION WITHOUT STANDARD INDUCTION CHEMOTHERAPY
Francesca Biavasco 1, Kristina Maas-Bauer1, Jesus Duque-Afonso1, Ralph Waesch1, Michael Luebbert1, Justus Duyster1, Robert Zeiser1, Juergen Finke1, Claudia Wehr1
1University Hospital Freiburg, Freiburg, Germany
Background: Allogeneic hematopoietic cell transplantation (allo-HCT) has become an accessible curative option in elderly patients with acute myeloid leukemia (AML) after development of reduced-intensity conditioning regimen and the introduction of hypomethylating agents (HMA) with venetoclax as induction therapy for elderly unfit patients. While a recent prospective randomised trial showed non-inferior efficacy and better tolerance of HMA over standard chemotherapy in elderly patients, only half of the studied cohort underwent allo-HCT and venetoclax was not included in the study (Luebbert et al., Lancet Haematol. 2023 Nov;10(11):e879-e889). Therefore, real-world data on outcomes of patients not eligible for intensive chemotherapy who received allo-HCT in the venetoclax era are needed.
Methods: We retrospectively analysed data of 106 adult AML patients who underwent allo-HCT without receiving intensive chemotherapy at our center between 2010 and 2023.
Results: Forty-two patients received HMA alone, 24 patients received HMA-venetoclax induction therapy, and 40 patients underwent allo-HCT without previous therapy (upfront) due to personalised clinical decision. Patients who received allo-HCT upfront were younger (median 59.1 years) than HMA (64.9 years) and HMA-venetoclax patients (70.9 years respectively, p<0.0001). The groups did not differ in Karnofsky performance status, ELN risk distribution and time from diagnosis to allo-HCT. Forty-three of the HMA treated (83%) and 15 of the HMA-venetoclax treated patients (62%) did not achieve CR before allo-HCT, resulting in a similar mean blast count before transplantation among groups (41.4 for upfront, 26.5 for HMA and 32.2 for HMA-venetoclax). With a median follow-up of 85.5, 75.4 and 18.9 months in upfront, HMA treated and HMA-venetoclax treated patients, the overall survival at median follow-up time (19 months) was 75.7%, 54.8% and 89.0% respectively, showing a better survival for patients treated with addition of BCL-2 inhibitor. Interestingly, the difference in survival was not reflected in marked difference of progression free survival, which was similar among groups (19-months progression free survival 77.8% upfront, 72.3% HMA and 73.9% HMA-venetoclax). Of note, overall survival benefits for HMA-venetoclax treated patients persisted in the subgroup of patients who did not reach a complete remission before transplant (19-months overall survival for HMA 51.5%, for HMA-venetoclax 82.3%). As expected though, the achievement of a complete remission before allo-HCT was associated with a better survival in both groups (19-months overall survival HMA CR 66.7%, HMA non-CR 51.5% vs. HMA-venetoclax CR 100%, HMA-venetoclax non-CR 82.3%).
Conclusions: These real-world retrospective data on the avoidance of intensive chemotherapy in pre-transplant setting suggest that HMA-venetoclax could be the best therapeutic option for patients with AML. Additionally, the advantage of HMA-venetoclax was independent from achieving CR, even though the achievement of CR is associated with better survival. Confirmatory data of prospective randomised trials are urgently needed to establish the best possible pre-transplant treatment for non-highly proliferating AML patients.
Disclosure: K. M-B is supported by a fellowship of the Faculty of Medicine, Freiburg University (Berta-Ottenstein-Programm) and by the Else-Kröner-Fresenius-Stiftung Nr: 2021_EKEA.131
R.W. received research fundings from Janssen, Sanofi, consultancy: from Amgen, BMS/Celgene, Janssen, Kite/Gilead, Novartis, Pfizer, Sanofi, Takeda, honoraria from Abbvie, Alexion/Astra Zeneca, Amgen, BMS/Celgene, Janssen, Kite/Gilead, Novartis, Pfizer, Sanofi, Takeda and travel support from Janssen, Kite/Gilead, Pfizer, BMS.
C.W. received honoraria/travel grant from Takeda and Jazz Pharmaceuticals.
19: Acute Leukaemia
P024 DURING CB TRANSPLANT IN MRD-POSITIVE AML, RELAPSE IS USUALLY EARLY, IS REDUCED BY ACUTE GVHD AND IS INFLUENCED BY CICLOSPORIN EXPOSURE: A MULTICENTER NATIONAL EXPERIENCE
Srividhya Senthil 1, Abdul Moothedath1, Archana Rauthan2, Ioannis Peppas3, Sandeep Potluri4, Pamela Evans5, Valerie Broderick5, Sarah Lawson4, Emma Barrett6, Caroline Furness7, Kanchan Rao2, Robert Wynn1
1Royal Manchester Children’s Hospital, Manchester, United Kingdom, 2Great Ormond Street Hospital, London, United Kingdom, 3Kings College Hospital NHS Foundation Trust, London, United Kingdom, 4Birmingham Children’s Hospital, Birmingham, United Kingdom, 5Royal Crumlin Hospital, Dublin, Ireland, 6Manchester University Foundation Trust, Manchester, United Kingdom, 7Royal Marsden Hospital, Manchester, United Kingdom
Background: Ciclosporin forms the major GVHD prophylaxis in allogeneic stem cell transplantation. It might be expected to reduce the beneficial graft-versus-leukemia [GVL] effect, and previous studies have reported a relationship between ciclosporin exposure and risk of post-transplant relapse in leukaemia. T cell replete Cord blood (TRCBT) HSCT might be considered the preferred donor cell source in AML with superior GVHD-free, Relapse-free survival (RFS). We report a multicentric experience of the relationship between ciclosporin exposure and time to relapse in a large cohort of paediatric AML patients receiving such a graft.
Methods: It is a retrospective study, data was collected from 5 paediatric transplant centers in the UK on the patients who had a TRCBT for HR AML between 2013 and 2023. Case records were analyzed to get patient, donor, transplant characteristics, GVHD prophylaxis, trough ciclosporin levels in the first 8 weeks and the transplant outcomes including GVHD and its treatment, relapse and transplant related mortality (TRM). The primary endpoint was time to disease relapse, and the relationship between this endpoint and ciclosporin AUC, use of additional immunosuppressive treatment (IST) and its total duration was investigated by Cox regression analysis.
Results:
Demographics and outcomes | No of patients / % |
---|---|
Disease Burden: | |
MRD-positive | 64 (59.25%) |
MRD-negative | 44 (40.7%) |
Severe aGVHD: | |
Skin | 25 (23%) |
Gut | 28 (26%) |
Required systemic IST | 56 (51.8%) |
Mortality in MRD-positive group: | 32 |
Relapse associated | 22(68.7%) |
TRM | 10 (31.2%) |
Mortality in MRD-negative group: | 12 |
Relapse associated | 5 (41.6%) |
TRM | 7 (58.3%) |
GVHD related deaths: | 4 |
MRD-positive group | 2 |
MRD-negative group | 2 |
Relapse: | |
Very early (<6 months) | 21 (61.7%) |
Early (6-12 months) | 11 (32.3%) |
Late (>12 months) | 2 (5.8%) |
The cohort included 108 patients, of whom 64 were MRD-positive pre-transplant, with a median follow up of 737.1 days (range: 24-3540 days). All were given ciclosporin and MMF as GVHD prophylaxis for a variable duration post-transplant according to each centers’ protocol. The severe aGVHD was treated with IST which included steroids in all with or without second agents.
The mortality rate was 40.7% of which nearly three-quarters occurred in the MRD-positive group. Overall, relapse formed the leading cause of death, causing 68.7% of the total deaths in MRD-positive group. It constituted only 41.6% of the deaths in the MRD negative group. The median time to relapse was 180 days (range: 32 to 949) and nearly a third occurred very early within 6 months. TRM was 13% and accounted for the most prominent cause of mortality in MRD-negative group. The GVHD related mortality was very low.
The RFS is significantly greater in MRD-negative group without severe aGVHD than in those without. By comparison, the RFS is significantly lower in the MRD-positive group without severe aGVHD than in those with it. The COX proportional hazards model using 95% CI confirmed a significant inverse relationship of AUC of Ciclosporin in the first 8 weeks on the time to relapse (p<0.02). However, it did not find any effect of IST or the duration of IST on time to relapse (p = 0.579 and p = 0.623 respectively).
Conclusions: This is the largest homogenous cohort of TRCBT in AML investigating the role of ciclosporin prophylaxis on relapse. It confirms the importance of GVL effect and its relation to GVHD in MRD-positive patients as RFS is significantly better in those who experience aGVHD. Most relapse is early and increased ciclosporin exposure in the first 2 months of HSCT reduces the time to relapse in AML. This study supports the development of novel protocols and alternative IS regimens during CBT in the highest risk AML.
Clinical Trial Registry: Not applicable
Disclosure: The authors have no conflict of interest.
19: Acute Leukaemia
P025 IMPACT OF RESPONSE TO THE FIRST INDUCTION COURSE IN AML PATIENTS ON ALLOHSCT OUTCOMES WITH PTCY
Dmitrii Zhogolev1, Bella Aybova1, Anna Smirnova1, Yulia Vlasova1, Daria Chernyshova1, Elena Babenko1, Tatyana Gindina1, Ildar Barkhatov1, Elena Morozova1, Ivan Moiseev 1, Sergey Bondarenko1, Alexander Kulagin1
1RM Gorbacheva Research Institute, St. Petersburg, Russian Federation
Background: For the majority of patients with acute myeloid leukemia (AML), allogeneic hematopoietic stem cell transplantation (alloHSCT) remains as the sole curative option. Recent advancements in transplant technologies, such as post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis, have enhanced the overall outcomes of alloHSCT. It is well-established that patients refractory to 2 induction courses, even with subsequent remission achievement, exhibit poorer outcomes after alloHSCT. However, the impact of refractoriness to the first induction course remains unclear, particularly within the context of PTCy.
Methods: A total of 260 adult patients with AML in first complete remission (CR1), who underwent alloHSCT at RM Gorbacheva Research Institute (CIC 725) from 2013 to 2022 were included in this retro- and prospective study. All participants received the “7 + 3” regimen as their initial induction therapy. Overall survival (OS), leukemia-free survival (LFS), and GVHD-free, relapse-free survival (GRFS) were assessed using the Kaplan-Meier method and log-rank test. Multivariate analysis was conducted utilizing a Cox regression model. To estimate relapse incidence (RI) and non-relapse mortality (NRM) within a competing risk framework, cumulative incidence functions were applied.
Results: Achievement of CR1 occurred after 1 induction course in 158 patients, after 2 induction courses in 68 patients, and after more than 2 induction courses in 34 patients. Groups were balanced on key parameters, with the exception of a higher incidence of secondary AML in the non-refractory group (p = 0.026) and a higher prevalence of unfavorable cytogenetics in the 2 courses refractory group (p = 0.041) (Table 1).
Table 1. Patient, disease and transplant characteristics.
Non-refractory | Refractory to 1 induction course | Refractory to 2 induction courses | p. overall | |
---|---|---|---|---|
N = 158 | N = 68 | N = 34 | ||
Gender, n(%) | 0.332 | |||
Female | 74 (46.8) | 39 (57.4) | 16 (47.1) | |
Male | 84 (53.2) | 29 (42.6) | 18 (52.9) | |
Diagnosis, n(%) | 0.026 | |||
De novo AML | 133 (84.2) | 64 (94.1) | 33 (97.1) | |
Secondary AML | 25 (15.8) | 4 (5.9) | 1 (2.9) | |
Cytogenetics, n(%) | 0.041 | |||
Fav/Int | 138 (87.3) | 59 (86.8) | 24 (70.6) | |
Adv | 20 (12.7) | 9 (13.2) | 10 (29.4) | |
Age at transplant, median (range) | 38 (18-66) | 33 (19-65) | 36 (18-61) | 0.185 |
MRD status at transplant, n(%) | 0.442 | |||
Negative | 101 (63.9) | 43 (63.2) | 19 (55.9) | |
Positive | 38 (24.1) | 21 (30.9) | 10 (29.4) | |
Missing | 19 (12) | 4 (5.9) | 5 (14.7) | |
Donor, n(%) | 0.122 | |||
MRD | 38 (24.1) | 16 (23.5) | 2 (5.8) | |
MUD | 68 (43) | 25 (36.8) | 14 (41.2) | |
MMUD | 27 (17.1) | 18 (26.5) | 9 (26.5) | |
HID | 25 (15.8) | 9 (13.2) | 9 (26.5) | |
Conditioning intensity, n(%) | 0.073 | |||
MAC | 17 (10.8) | 15 (22.1) | 6 (17.6) | |
RIC | 141 (89.2) | 53 (77.9) | 28 (82.4) | |
GVHD prophylaxis, n(%) | 0.105 | |||
CyTxMMF | 116 (73.4) | 51 (75) | 26 (76.5) | |
MonoCy | 32 (20.3) | 12 (17.6) | 2 (5.9) | |
CyRuxo | 10 (6.3) | 5 (7.4) | 6 (17.6) | |
Graft source, n(%) | 0.539 | |||
PBSC | 116 (73.4) | 50 (73.5) | 28 (82.4) | |
BM | 42 (26.6) | 18 (26.5) | 6 (17.6) |
Median follow up after alloHSCT in survivors was 42.3 (3-108.5) months. Engraftment on d28 was attained in 86% (95%CI, 80-91), 90% (95%CI, 79-95), and 88% (95%CI, 70-96) in the non-refractory, refractory to 1, and refractory to 2 courses groups, respectively (p = 0.8). Three-year OS rates were 81.7% (95%CI, 75.7-88.1), 66.5% (95%CI, 55.6-79.5), and 60.1% (95%CI, 44.5-81.2) (p = 0.038), LFS – 78.6% (95%CI, 72.2-85.5), 66.8% (95%CI, 56-79.8), and 40.5% (95%CI, 25.3-64.8) (p<0.001), GRFS – 69.3% (95%CI, 62.2-77.2), 49.5% (95%CI, 38.6-63.6), and 36.5% (95%CI, 22.3-59.8) (p<0.001). The cumulative incidence of NRM at three years was 14% (95%CI, 8.7-19), 16% (95%CI, 8-26), and 19% (95%CI, 7.3-34) (p = 0.8), RI – 7.9% (95%CI, 4.1-13), 17% (95%CI, 9.1-28), and 41% (95%CI, 22-59) (p<0.001). There was no significant statistical difference in aGVHD grades 2-4 (p = 0.22) and grades 3-4 (p = 0.074), cGVHD grades 1-3 (p = 0.93) and grades 2-3 (p = 0.61) incidence.
In the multivariate analysis, failure to achieve remission after one “7 + 3” course was associated with lower OS (HR 1.97, p = 0.02) and GRFS (HR 1.96, p = 0.004) after alloHSCT, with a tendency for lower LFS (HR 1.72, p = 0.056). Age and refractoriness to 2 induction courses were also associated with lower OS, LFS, and GRFS.
Conclusions: This study highlights the failure to respond to one “7 + 3” course as a negative prognostic factor for both OS and GRFS after alloHSCT, when performed with PTCy. The findings underscore the necessity for novel treatment approaches to enhance survival outcomes in these patients. Additionally, there is a crucial need for improved strategies in patients with primary refractory AML and older patients.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P026 POST-TRANSPLANT TYROSINE KINASE INHIBITOR MAINTENANCE IN PH-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA DELIVERS BENEFIT TOWARD IMPROVED OVERALL, RELAPSE-FREE, GVHD/RELAPSE-FREE SURVIVAL AND DECREASED NON-RELAPSE MORTALITY WITHOUT REDUCED RELAPSE
Eshrak Al-Shaibani 1, Carol Chen1, Igor Novitzky-Basso1,2, Ivan Pasic1,2, Auro Viswabandya1,2, Rajat Kumar1,2, Wilson Lam1,2, Arjun Law1,2, Armin Gerbitz1,2, Jonas Mattson1,2, Fotios V. Michelis1,2, José-Mario Capo-chichi3, Dennis D. Kim1,2
1Hans Messner Allogeneic Transplant Program, Division of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Canada, 2University of Toronto, Toronto, Canada, 3University Health Network and University of Toronto, Toronto, Canada
Background: Post-allogenic hematopoietic cell transplantation (HCT) maintenance therapy with tyrosine kinase inhibitor (TKI) in Philadelphia positive acute lymphoblastic leukemia (Ph+ALL) is expected to reduce the risk of relapse. However, clinical benefit from the post-HCT TKIs maintenance (PTM) in Ph+ALL remains still on debate due to conflicting results from the retrospective studies and lack of randomized controlled trial. Herein, we report the long-term outcomes of the patients who received PTM following allogeneic HCT versus not in Ph+ALL.
Methods: We have retrospectively reviewed 80 patients with Ph+ ALL underwent first HCT in complete remission at Princess Margaret Cancer Center from 2000 till 2022. Relapse was defined as morphologic recurrence of ≥5% blasts in bone marrow or by the presence of extramedullary disease. Overall (OS), graft-versus host disease (GVHD)/relapse-free (GRFS) and relapse-free survival (RFS) was calculated by the Kaplan-Meier method and analyzed using a log-rank test, respectively. Cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and chronic GVHD (cGVHD) were calculated considering competing events and analyzed using Fine-Gray model.
Results: Patients’ and disease characteristic are summarized in Table 1. With a median follow-up duration of 26 months among survivors, 16 patients (20%) had progressed following HCT. Fifty-eight patients (72%) did not receive PTM while 22 (28%) patients received PTM. The median time to start PTM was 5.3 months (range; 2.6-9.2) with imatinib (n = 15), dasatinib (n = 5) or ponatinib (n = 4). ABL1 kinase-domain mutation (KDM) was detected in 8 patients: T315I (n = 2), F317L (n = 3), E255K (n = 1), Y253H (n = 1), Q252H (n = 1).
The analysis for OS, GRFS, RFS, NRM, cGVHD and CIR at 2 years showed improved outcomes in favor of PTM: OS, 81% vs 43.4% (p = 0.01); GRFS, 40% vs 5.3% (p = 0.003); RFS, 81% vs 43.4% (p = 0.02); NRM, 4.8% vs 45.8% (p = 0.003); cGVHD 27.7% vs 41.3% (p = 0.54); CIR, 14.3% vs 10.8% (p = 0.19).
Univariate analysis showed PTM improved OS (HR; 0.39 [0.19-0.85], P = 0.02), RFS (HR: 0.54 [0.29-0.99], P = 0.03), GRFS (HR: 0.41 [0.23-0.75], P = 0.004) and NRM (HR: 0.045 [0.003-0.20], P = 0.003). However, it was not associated with relapse risk (HR: 0.143 [0.03-0.33], P = 0.19).
Besides PTM, age >40 was associated with OS (HR: 2.08 [1.11-3.9], P = 0.02), RFS (HR: 1.85 [1.01-3.37], P = 0.05) and NRM (HR: 0.41 [0.27-0.55], P = 0.04). Time -dependent cGVHD found to be associated with improved OS (HR: 0.36 [0.16-0.78], P = 0.009), RFS (HR: 0.31 [0.14-0.68], P = 0.003) and CIR (HR: 0.1522 [0.04-0.54], P = 0.004). Detectable ABL-KDM at ant time prior-HCT increased risk of relapse (HR: 0.38 [0.07-0.69], P = 0.0005).
Multivariable analysis confirmed that PTM improved OS (HR; 0.28 [0.13-0.62], P = 0.02], RFS (HR: 0.32 [0.15- 0.68], P = 0.003), GRFS (HR: 0.41 [0.23-0.75], P = 0.004) and NRM (HR:0.18 [0.06-0.57], P = 0.003). cGVHD also found to improve OS (HR: 0.28 [0.13-0.64], P = 0.002), PFS (HR: 0.23 [0.10-0.51], P = 0.003) and decreased CIR (HR: 0.33 [0.09-1.14], P = 0.08).
Table 1: patients characteristics
Variables | TKI maintenance | No TKI-maintenance | P |
---|---|---|---|
N = 22 | N = 58 | ||
Median age (range) | 54 (19-63) | 44 (19- 65) | 0.2 |
Gender, N (%) | 0.09 | ||
Female | 14 (63.6) | 24 (41.4) | |
Male | 8 (36.4) | 34 (58.6) | |
Disease status, N (%) | 0.04 | ||
CR1 | 15 (68.2) | 52 (89.7) | |
CR2 | 7 (31.8) | 6 (10.3) | |
BCR/ABL pre-HCT, N (%) | 0.57 | ||
MMR | 18 (81.8) | 43 (74.1) | |
No MMR | 4 (18.2) | 15 (25.9) | |
ABL Kinase mutation | 0.03 | ||
Positive | 5 (22.7) | 3 (5.2) | |
Negative | 17 (77.3) | 55 (94.8) | |
Conditioning regimen, N (%) | 0.09 | ||
MAC | 13 (59.1) | 46 (79.3) | |
RIC | 9 (40.9) | 12 (20.7) | |
GVHD prophylaxis, N (%) | 0.005 | ||
Dual T-cell depletion | 8 (36.4) | 5 (8.6) | |
Others | 14 (63.6) | 53 (91.4) | |
PTCY based GVHD, N (%) | <0.001 | ||
Yes | 10 (45.5) | 5 (8.6) | |
No | 12 (54.5) | 53 (91.4) | |
Donor type, N (%) | 0.17 | ||
MRD | 9 (40.9) | 27 (46.6) | |
MUD | 10 (45.5) | 23 (39.7) | |
MMUD | 6 (10.3) | ||
Haploidentical | 3 (13.6) | 2 (3.4) | |
Stem sources | 0.49 | ||
PBSC | 20 (90.9) | 48 (82.8) | |
BMSC | 2 (9.1) | 10 (17.2) | |
OS | 0.02 | ||
Alive | 14 (63.6) | 19 (32.8) | |
Death | 8 (36.4) | 39 (67.2) | |
NRM | 0.005 | ||
Alive | 19 (86.4) | 28 (48.3) | |
Death | 3 (13.6) | 30 (51.7) | |
RFS | 0.04 | ||
No | 13 (59.1) | 18 (31) | |
Yes | 9 (40.9) | 40 (69) | |
Relapse | 0.49 | ||
No | 16 (72.7) | 48 (82.8) | |
Yes | 6 (27.3) | 10 (17.2) | |
Acute GVHD | 0.79 | ||
Yes | 14 (63.6) | 39 (67.2) | |
No | 8 (36.4) | 19 (32.8) | |
Chronic GVHD | 0.79 | ||
Yes | 7 (31.8) | 22 (37.9) | |
No | 15 (68.2) | 36 (62.1) |
- Abbreviation: BM: bone marrow, CR: complete remission, HCT: allogenic hematopoietic cell transplantation, MAC: myeloablative conditioning, MMR: Major molecular response, MRD: matched related donor, MUD: matched unrelated donor, MMUD: mismatch unrelated donor, NRM: non-relapse mortality, OS: overall survival, PBSC: peripheral blood stem cell transplant, PFS: progressive-free survival, PTCY: post-transplant cyclophosphamide, RIC: reduce intensity regimen.
Conclusions: PTM in Ph+ALL delivers a clinical benefit toward better OS, improved RFS, decreased NRM and better GRFS. However, it was not confirmed whether PTM can reduce the risk of relapse.
Disclosure: Nothing to declare
19: Acute Leukaemia
P027 IMPACT OF DONOR AND STEM-CELL SOURCE IN ADULTS WITH HIGH-RISK PHILADELPHIA-NEGATIVE ACUTE LYMPHOBLASTIC LEUKEMIA TRANSPLANTED IN FIRST COMPLETE REMISSION: A STUDY FROM GRAALL AND SFGM-TC
Matthieu Jestin1, Sébastien Maury2, Anne Huynh3, Edouard Forcade4, Ibrahim Yakoubagha5, Cristina Castilla-Llorente6, Jean-Baptiste Mear7, Urs Schanz8, Sylvain Chantepie9, Jakob Passweg10, Nathalie Contentin11, Yves Chalandon12, Nicole Raus13, Véronique Lheritier13, Natacha Maillard14, Marie-Thérèse Rubio15, Raynier Devillier16, Patrice Ceballos17, Sylvie François18, Stéphanie Nguyen-Quoc19, Patrice Chevallier20, Hélène Labussière-Wallet13, Hervé Dombret1, Nicolas Boissel1, Nathalie Dhédin 1
1Hôpital Saint Louis, Paris, France, 2Hôpital Henri Mondor, Créteil, France, 3Institut universitaire du Cancer de Toulouse, Toulouse, France, 4CHU de Bordeaux, Bordeaux, France, 5CRHU Lille, Lille, France, 6Institut Gustave Roussy, Villejuif, France, 7CHU de Rennes, Rennes, France, 8Hôpital Universitaire de Zurich, Zurich, Switzerland, 9CHU de Caen, Caen, France, 10Hôpital Universitaire de Bâle, Bâle, Switzerland, 11Centre Henri Becquerel, Rouen, France, 12Hôpitaux Universitaires de Génève, Génève, Switzerland, 13CHU de Lyon, Lyon, France, 14CHU de Poitiers, Poitiers, France, 15CHRU de Nancy, Nancy, France, 16Institut Paoli-Calmettes, Marseille, France, 17CHU de Montpellier, Montpellier, France, 18CHU d’Angers, Angers, France, 19Hôpital Pitié-Salpétrière, Paris, France, 20CHU de Nantes, Nantes, France
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) stands as a cornerstone in managing high-risk (HR) Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in the first complete remission (CR1). Whereas unrelated donor (UD) has become a standard option in absence of matched sibling donor (MSD), peripheral blood (PB) is mostly used despite a higher incidence of graft-versus-host disease (GVHD). The aim of this study was to evaluate the impact of donor and stem cell source in adults with HR Ph-negative ALL in CR1 prospectively included in the GRAALL-2003 and -2005 trials.
Methods: Between November 2003 and March 2014, 311 patients with HR Ph-negative ALL in CR1 were included in the GRAALL-2003/05 trials and received a HSCT from MSD or UD after a myeloablative conditioning (MAC) regimen. Cord blood (n = 17) or haploidentical transplant (n = 2) were excluded. The primary objective was to assess the impact of donor and stem cell source on acute grade III-IV or chronic extensive GVHD-free relapse-free survival (GRFS). Type of donor (MSD versus UD), use of anti-thymocyte globulin (ATG) and total body irradiation (TBI), stem cell source (PB versus bonne marrow (BM)) and age at transplant were included in univariate and multivariate analyses for GRFS, overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM), incidence of aGVHD grade III-IV and of extensive cGVHD.
Results: Among the 311 patients, 100 had a T-ALL and 211 a Ph-negative BCP-ALL. Median age at transplant was 31.8 years (IQR, 29.7 – 34.5) with 60% of male. All received a MAC regimen, 293 (94%) a TBI-based, 14 (5%) a busulfan-based, and 4 another regimen. Transplant was performed from a MSD in 156 patients (50%) and from a 9/10 or 10/10 matched UD in 155 patients (50%). PB and BM were used in 105 patients (34%) and 206 patients (66%), respectively. ATG was part of the conditioning regimen in 58 patients (19%). In univariate and multivariate analysis for GFRS, after adjustment on age at transplant, use of ATG and TBI, and type of donor, stem cell source (PB vs BM) emerges as the sole variable significantly associated with GRFS (Table). Of note, the type of donor and the use of ATG did not show significant association with GRFS, and also lacked significant correlation with OS, EFS, CIR, TRM, cGVHD and aGVHD. In multivariate analysis using the same covariates, PB was significantly associated with an increased risk of NRM (SHR 2.03, 95%CI(1.19-3.48)), an increased incidence of cGVHD (SHR 3.20, 95%CI(1.79-5.76)) and a decreased CIR (SHR 0.51, 95%CI(0.27-0.96)), but did not correlate with OS and EFS. Interestingly, in sub-groups analysis, GRFS was significantly improved using BM versus PB from UD (HR 2.25, 95%CI(1.46-3.47)) whereas no impact of stem cell source was observed in transplant from MSD.
Variables | Hazard ratio value | 95%CI | p |
---|---|---|---|
Age at HSCT (y) | 1.00 | 0.99-1.01 | 0.95 |
UD vs MSD | 1.11 | 0.79-1.56 | 0.56 |
ATG | 0.68 | 0.43-1.08 | 0.10 |
PB vs BM | 1.54 | 1.11-2.14 | 0.01 |
TBI | 0.95 | 0.60-1.18 | 0.87 |
Conclusions: In adults with HR Ph-negative ALL in CR1, PB and BM are two acceptable options when a MSD is available. Despite the absence of impact of stem cell source on OS, the use of UD BM should be preferred over PB, since it improves long-term quality of life.
Clinical Trial Registry: NCT00327678
Disclosure: Nothing to declare.
19: Acute Leukaemia
P028 HOW DISEASE STATUS IMPACTS ON LONG-TERM SURVIVAL AFTER ALLOGENEIC TRANSPLANT IN ACUTE MYELOID LEUKEMIA: ANALYSIS ON 456 PATIENTS
Alessandro Bruno1, Matteo Giovanni Carrabba1, Simona Piemontese1, Raffaella Greco1, Sarah Marktel1, Sara Mastaglio1, Daniela Clerici1, Francesca Farina1, Elisa Diral1, Luca Vago1, Lorenzo Lazzari1, Edoardo Campodonico1, Giulia Furnari1, Alessandro Criscimanna1, Chiara Secco1, Magda Marcatti1, Consuelo Corti1, Massimo Bernardi1, Jacopo Peccatori1, Fabio Ciceri1,2, Maria Teresa Lupo-Stanghellini 1
1IRCCS Ospedale San Raffaele, Milan, Italy, 2Università Vita-Salute San Raffaele, Milan, Italy
Background: Acute myeloid leukemia (AML) is the most frequent indication for allogeneic hematopoietic stem cell transplant (allo-HSCT). The number of patients undergoing allo-HSCT for AML has steadily increased in the last decades, with improving outcomes. Both the incidence of disease relapse and treatment related mortality (TRM) decrease over time after transplant. While risk factors for disease relapse and TRM in the first years after allo-HSCT are well known, their correlation with long-term survivorship is unclear.
Methods: We retrospectively collected data of 456 consecutive patients (193 females and 263 males) with a diagnosis of AML who received a first allogeneic hematopoietic stem cell transplant in our centre between 2004 and 2019. Ninety-six patients had a matched related donor, 221 a mismatched related donor, 120 an unrelated donor and 19 underwent allo-HSCT from a cord blood unit. Sixty-four (14%) patients had secondary AML. Patients were included regardless of conditioning intensity and graft-versus-host disease (GvHD) prophylaxis. Two hundred and four patients (44%) received allo-HSCT in first complete remission (CR1), 62 patients (14%) in CR>1, and 190 patients (42%) in active disease (AD). Factors impacting on long-term survival after allo-HSCT were evaluated through a multivariate analysis using Cox proportional-hazards model in the whole cohort and subsequently in landmark analysis at 1, 2 and 3 years after allo-HSCT.
Results: Two-hundred and thirty-nine patients (52%) were alive 2 years after allo-HSCT, with a median follow-up of 5.1 years. In this subset, 51 patients died (21%) during subsequent follow-up: 31 of progressive disease (13%), 18 of treatment related complications (8%) and two due to unknown causes (1%), while 15 patients were lost at follow-up (6%). As expected, a better 5-years overall survival (OS) was observed in the overall cohort among patients in CR1 (63%) in comparison to patients in CR>1 (38%) or AD (25%). Nevertheless, in the landmark analysis the impact of disease status on long-term survival was progressively less meaningful: for example, for patients alive at 2 years landmark, the probability of being alive for 3 more years was 86% for patients in CR1, 72% for patients in CR>1 and 79% for patients in AD, with no statistically significant difference between CR>1 and AD. Similar results were found for progression free survival (PFS), TRM and relapse risk. Of note, better long-term outcomes in the overall cohort were associated with younger patient age, allo-HSCT performed after 2013 and using a female donor for a male recipient. Only being younger was still significantly associated with better outcomes in the various landmark analysis. Furthermore, our study confirmed that relapse is still the main cause of death even for long-term survivors: 13% of patients alive at 2 years eventually relapsed.
Conclusions: In conclusion, the negative impact on outcomes of a more advanced disease at allo-HSCT seems to decline progressively after transplant, fostering the importance of strategies that may enhance the anti-leukemic effect of allo-HSCT in the following first months and years.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P029 TLS::ERG FUSION GENE PREDICTS A POOR PROGNOSIS AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN ACUTE MYELOID LEUKEMIA: A SINGLE CENTER STUDY
Gele Tong 1, Yanli Zhao1, Jianping Zhang1, Min Xiong1, Xingyu Cao1, Deyan Liu1, Ruijuan Sun1, Zhijie Wei1, Jiarui Zhou1, Yue Lu1
1Hebei Yanda Lu Daopei Hospital, Langfang, China
Background: Acute myeloid leukemia (AML) patients with the TLS::ERG fusion gene tend to show poor outcomes to traditional chemotherapy. Allogeneic hematologic stem cell transplantation (allo-HSCT) may serve as a potential curative treatment, aiming to enhance the overall survival (OS). However, the long-term safety and efficacy of this treatment for these patients require further exploration.
Methods: A total of 30 AML patients with the TLS::ERG fusion gene were consecutively analyzed, who underwent allo-HSCT in our center between August 2012 and December 2022.
Results: The median age for these patients was 13(2-53) years, with 18 patients 18 years or younger. Before HSCT, the median disease course was 6(3-60) months. Of these patients, 17 (56%) had complex karyotypes, 10(30%) exhibited extramedullary disease, and 10(30%) had additional gene mutations. Prior to HSCT, the disease status was as follows: 18 patients in the first complete remission(CR1),6 in ≥CR2, and 6 in non-remission (NR). In 24 of morphologic CR patients, regular monitoring of TLS::ERG transcript levels before HSCT revealed that 10 patients were TLS::ERG negative, and 14 were TLS::ERG positive. Twenty-seven patients received intensified myeloablative conditioning regimens and the remaining 3 received standard regimens. The transplant donors were haploidentical (n = 23), matched unrelated (n = 5), and matched related (n = 2). In total, eight patients received celluar immutherapy to prophylaxis relapse after transplantation, of them 4 patients received received modified donor lymphocyte infusion (DLI) and another four received IFN-α.eight patients received TLS::ERG positive guided preemptive therapy after transplantation, of them 6 patients received received chemotherapy plus DLI and another two received IFN-α. The median follow-up time for the survivors was 42(12-86)months. The 5-year cumulative incidence of relapse (CIR), and 5-year leukemia-free survival (LFS) and overall survival(OS) after HSCT were 81.6%(95%CI:73.3-89.9),13.2%(95%CI:6.5-19.9), and 13.4%(95%CI:6.4-20.4%), respectively. Relapse occurred in 22 patients with a median relapsed time post-HSCT of 6(3-18) months, among whom 11 simultaneously merged with the extramedullary disease (EMD), among them, twenty patients died from relapse, one patient received therapy and achieved CR, the other one was in relapse status but still alive. Two patients died from treatment-related mortality(TRM). According to disease status (CR/TLS::ERG negative vs. CR/ TLS-ERG positive vs. NR) before allo-HSCT, no significant differences were observed in the 5-year CIR [83.1%(69.8-97.4%) vs. 71.4%(59.3-83.5) vs. 100%), p = 0.602], LFS[15.0%(2.2-27.8%) vs. 21.4%(10.4-32.4) vs 0%), p = 0.548], and OS[18.0%(2.9-33.1%) vs. 16.3%(5.8-26.8%) vs. 16.7%(1.5-31.9%), p = 0.568. Univariate analysis also showed that other factors did not affect the HSCT outcomes.
TABLE1 patient characteristics
Parameters(at diagnosis) n = 30 |
Median age, y(range) 13(2-53) |
≤18y 18(60%) |
Cytogenetics: |
Complex karyotype 7(56%) |
With other gene mutation 10(30%) |
Disease status when receiving HSCT |
CR1 18(60%) |
≥2st CR 6(20%) |
NR 6(20%) |
With extramedullary disease 10(30%) |
HCT-CI |
0 27(90%) |
1 2(6%) |
2 1(3%) |
Median disease course(months) before HSCT 6(3-60) |
Donor type |
HID 23(76%) |
MUD 5(16%) |
MSD 2(6%) |
Conditioning regimen (Intensified MAC) 27(90%) |
Conclusions: The presence of TLS::ERG fusion gene in AML is strongly associated with complex karyotype and EMD. Although allo-HSCT is a promising treatment option, the prognosis remains poor due to a high early relapse rate, even in patients with negative TLS::ERG transcript levels before HSCT.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P030 HIGH TOLERABILITY OF PROLONGED AZACITIDINE MAINTENANCE AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN PATIENTS WITH AML LACKING A TARGETABLE MUTATION
Cuong An Do 1, Anne-Claire Mamez1, Amandine Pradier1,2, Sarah Morin1, Chiara Bernardi1,2, Sarah Prati-Perdikis1, Yan Beauverd1, Thomas Longval1, Maria Mappoura1, Sarah Noetzlin1, Laetitia Dubouchet1, Evgenia Laspa1, Marie Maulini1, Thien-An Tran1, Carmen de Ramon Ortiz1, Stavroula Masouridi-Levrat1, Federico Simonetta1,2, Yves Chalandon1,2, Federica Giannotti1
1Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland, 2Translational Research Center for Oncohematology, University of Geneva, Geneva, Switzerland
Background: Maintenance therapy after allogeneic hematopoietic stem cell transplantation (HSCT) aims to reduce relapse. Targeted maintenance is available for only about 25% of acute myeloid leukemia (AML). Studies employing hypomethylating agents for maintenance in patients without targetable mutations have shown conflicting results.
Methods: We retrospectively analyzed outcomes and tolerability of azacitidine as post-transplant maintenance in a cohort of 23 adult patients with FLT3neg AML, transplanted at our institution between March 2018 and September 2021. Azacitidine was started at hematological reconstitution from day 60 post-transplant, in patients without active GVHD, evidence of relapse or MRD + . It was administrated subcutaneously at 32.5-50 mg/m2 for 5 days every 4 weeks for 2 years, if tolerated. Till May 2020, patients eligible for azacitidine maintenance were FLT3neg AML patients with MRD+ or active disease at transplant. Thereafter, we proposed azacytidine maintenance for all FLT3neg AML. Overall, 48 patients were screened: 25 did not start azacitidine due to MRD positivity (n = 7), relapse (n = 2), prolonged cytopenia (n = 7), GVHD (n = 5), death (n = 1), insurance refusal (n = 2) and physician choice (n = 1). Tolerability was evaluated by total number of cycles administrated, hematological toxicity, infections or other adverse events leading to withdrawal or delay of maintenance schedule.
Results: Median follow-up was 30 months (range 11-62). Among 23 patients, one had active disease and 10 were MRD+ before transplant. Median age at transplant was 57 years (range 39-74). Median time from transplant to azacitidine initiation was 102 days (range 66-244). The median number of cycles was 11 (range 1-25). Overall, 7 patients completed the 2-years schedule and 1 is still ongoing. Among these 8, one extended administration intervals to 6 weeks due to cytopenias occasionally requiring G-SCF, another developed recurrent grade 3 neutropenia at higher doses of azacitidine (50 mg/m2), rapidly resolved with G-CSF. One patient on ruxolitinib had grade 3 neutropenia requiring G-CSF once. None of these 3 patients developed infections related to hematological toxicity. Three patients stopped maintenance for mild adverse events (fatigue, myalgias and pruritis) after 11, 12 and 21 cycles, respectively. Among the remaining 12 patients, 3 permanently stopped maintenance due to GVHD (2 chronic moderate, 1 late acute grade 2) after a median of 2 cycles; 9 switched to pre-emptive or curative treatment due to MRD+ occurrence (n = 8) or relapse (n = 1), after a median of 3 cycles. Overall, 5 patients had GVHD or infections not related to azacitidine leading to temporary interruptions (>28 days) for a median time of 73 days (range 49-168). The probability of 2-years OS and PFS were 82.6% (95%CI 68.5%-99.6%) and 69.6% (95%CI 53.1%-91.2%), respectively. Overall, 7 patients died, 1 of lung cancer and 6 of relapse. The 2-years CI of relapse and NRM were 30%±9.85% and 0%±0% respectively.
Conclusions: In our cohort of AML patients lacking targetable mutations, prolonged post-transplant maintenance with azacitidine was relatively well tolerated and outcomes were encouraging. These data support azacitidine maintenance in AML when targeted therapy is not an option.
Disclosure: Y.C. has received consulting fees for advisory board from MSD, Novartis, Incyte, BMS, Pfizer, Abbvie, Roche, Jazz, Gilead, Amgen, Astra-Zeneca, Servier; Travel support from MSD, Roche, Gilead, Amgen, Incyte, Abbvie, Janssen, Astra-Zeneca, Jazz, Sanofi all via the institution.
F.S. has received institutional consulting fees from BMS/Celgene, Incyte, Kite/Gilead; Speaker fees from Kite/Gilead, Incyte; Travel support from Kite/Gilead, Novartis, AstraZeneca, Neovii, Janssen; Research funding from Kite/Gilead, Novartis, BMS/Celgene.
19: Acute Leukaemia
P031 OUTCOME OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN ACUTE MYELOID LEUKAEMIA FLT3 IN THE ERA OF FLT3 INHIBITORS – STUDY OF THE POLISH ADULT LEUKAEMIA GROUP (PALG)
Elzbieta Patkowska1, Anna Czyz2, Alicja Sadowska-Klasa3, Andrzej Szczepaniak4, Lukasz Bolkun5, Marta Sobas2, Michal Gorka6, Edyta Subocz7, Anna Koclega8, Renata Guzicka-Kazimierczak9, Jan Zaucha3, Lidia Gil4, Marta Libura6, Agnieszka Pluta10, Dorota Bartosinska11, Ewa Lech-Maranda1, Agnieszka Wierzbowska10, Sebastian Giebel12, Barbara Nasilowska-Adamska 1
1Institute of Hematology and Transfusion Medicine, Warsaw, Poland, 2Wroclaw Medical University, Wroclaw, Poland, 3Gdansk Medical University, Gdansk, Poland, 4Poznan University of Medical Sciences, Poznan, Poland, 5Medical University of Bialystok, Bialystok, Poland, 6Warsaw Medical University, Warsaw, Poland, 7Independent Public Health Care Ministry of the Interior of Warmia and Mazury Oncology Center, Olsztyn, Poland, 8Medical University of Silesia, Katowice, Poland, 9Pomeranian Medical University, Szczecin, Poland, 10Medical University of Lodz, Lodz, Poland, 11Centre of Postgraduate Medical Education, Warsaw, Poland, 12National Institute of Oncology, Gliwice, Poland
Background: Allogeneic hematopoietic cell transplantation (allo-HCT) offers a potential survival benefit for patients with FLT3-positive acute myeloid leukemia (AML), particularly those harboring the FLT3-internal tandem duplication mutation (FLT3-ITDmut), which is associated with a poorer prognosis compared to point mutations in the tyrosine kinase domain (FLT3-TKDmut). Little is known about the impact of FLT3-TKDmut in the context of allo-HCT, especially with the use of FLT3 inhibitors. This study aims to analyze the outcomes of allo-HCT in FLT3-positive AML patients, considering the type of FLT3 mutation and post-transplant maintenance treatment.
Methods: This retrospective analysis includes FLT3-positive AML patients, encompassing FLT3-ITDmut and/or FLT3-TKDmut, who received intensive chemotherapy combined with midostaurin and underwent allo-HCT between 2017 and 2023.
Results: The study involved 88 patients, with a median age of 50.3 years (IQR 37.1-62.2), predominantly female (n = 58; 65.91%). FLT3-ITDmut was observed in 67 (76.1%) patients, FLT3-TKDmut in 15 (17%), and both mutations in 6 (6.8%) patients. All patients received intensive chemotherapy with midostaurin, initiated either after the first or second induction in 70 (80%) patients or after consolidation in 18 (20%) patients. The median follow-up period post allo-HCT was 15.7 months (IQR: 8.8-28.7). Allo-HCT was performed in the first complete remission (CR) in 68 (77%) patients, subsequent CR in 12 (13.63%) patients, or active disease in 8 (9%) patients. Most patients received myeloablative conditioning (MAC), including TBI-based MAC (n = 5; 5.6%), with grafts from matched related donors (MRD) (n = 24; 27%), matched unrelated donors (MUD) (n = 45; 51%), mismatched unrelated donors (mMUD) (n = 6; 6.8%), or family haploidentical donors (n = 13; 15%). The median overall survival (OS) post allo-HCT was 11 months, with a 2-year OS probability rate of 62%. Subgroup analysis of 60 patients who initiated midostaurin after the first or second induction and were tested for both FLT3 mutations showed a 2-year OS advantage for AML FLT3-TKDmut and AML FLT3-TKDmut co-occurring with FLT3-ITDmut patients compared to AML FLT3-ITDmut patients (rates: 81% vs 80% vs 67%, respectively), although this difference was not statistically significant (p = 0.289). Sorafenib was administered as maintenance treatment post allo-HCT to 22 (30%) of 73 AML FLT3-ITDmut patients. Univariate analysis of OS for the entire group identified age as the only significant prognostic factor, with better survival in patients under 60 years of age (HR = 0.44; 95% CI 0.2-0.93). In the FLT3-ITDmut subgroup, sorafenib maintenance (HR = 0.08; 95% CI 0.01-0.58), age under 60 years (HR 0.36; 95% CI 0.16-0.82) and male gender (HR 0.33; 95% CI 0.11-0.97) were prognostic factors associated with improved OS in univariate analysis. However, in the multivariate analysis of this subgroup, only sorafenib maintenance remained a favourable prognostic factor for improved OS (HR 0.11; 95% CI 0.01-0.89).
Conclusions: Allo-HCT emerges as an effective curative treatment option, providing satisfactory survival outcomes for both AML FLT3-ITDmut and FLT3-TKDmut patients. In the entire patient group, age stands out as the only significant prognostic factor for OS. However, among FLT3-ITDmut patients, post allo-HCT maintenance treatment with sorafenib remains the sole favorable prognostic factor for OS.
Disclosure: E. Patkowska: KCR- consultancy, Astellas Pharma, Servier, Amgen, Novartis - Honoraria.
19: Acute Leukaemia
P032 CLINICAL CHARACTERISTICS AND PROGNOSIS OF ADULT T CELL ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS WITH ACTIVATING RAS MUTATIONS
Mimi Xu 1,2,3, Yuqing Tu1,2,3, Mengqi Xiang1,2,3, Yi Fan1,2,3, Xiang Zhang1,2,3, Tiemei Song1,2,3, Lian Bai4, Xiaoli Li5, Yang Xu1,2,3, Yuejun Liu1,2,3, Depei Wu1,2,3
1National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China, 2Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China, 3Key Laboratory of Stem Cells and Biomedical, Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Suzhou, China, 4Canglang of Suzhou Hospital, Suzhou, China, 5Soochow Hopes Hematonosis Hospital, Suzhou, China
Background: Several studies indicated that RAS mutations were associated with a poorer outcome in T cell acute lymphoblastic leukemia (T-ALL) patients. However, data regarding the clinical outcomes of adult RAS mutated T-ALL patients undergoing different consolidation treatment are limited. This study was conducted to analyze the clinical characteristics and prognosis of adult T-ALL patients with RAS mutations.
Methods: From January 2016 to December 2022, 137 newly diagnosed adult T-ALL patients were explored for activating RAS mutations in our center. We retrospectively analyzed the clinical characteristics of adult RAS mutated T-ALL patients and compare the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with chemotherapy in these patients. About statistical analysis, overall survival (OS) and event free survival (EFS) were estimated by the Kaplan-Meier method and the log-rank test. The cumulative incidence of relapse (CIR) was estimated using Gray’s test, with non-relapse morality considered a competing risk. The covariates with a P value < 0.2 in univariate analyses were used in the multivariate analyses (Fine-Gray model). A P value < 0.05 was considered statistically significant. Statistical analyses were carried out with SPSS 20.0 and R 4.3.0.
Results: KRAS and NRAS mutations were identified in four (2.9%) of 137 and 15 (11%) of 137 patients, respectively. Overall, 19 (13.9%) of 137 T-ALLs harbored activating RAS mutations, without any accompanying PTEN gene changes. The early precursor T (ETP) was the most common immunophenotype (68.4%), with chromosomal abnormalities accounting for 36.8%, and 3 cases of SET-NUP214 fusion gene positivity. The complete response (CR) rate in one course of treatment for 19 patients was 78.9%, and the total CR rate in two courses was 93.3%, one patient with continuous non-remission died on 5.7 months after diagnosis. The median follow-up of survivals was 26.2 months. The 3-year OS rate was (60±12)%, EFS rate was (41±12)%, and CIR was (61.6±1.9)%. Six patients who only received chemotherapy died within 2 years after diagnosis; The 3-year OS rate and EFS rate of 13 patients who underwent allo-HSCT as consolidation were (90.0±9.5)% and (62.3±15.2)%, respectively. Multivariate analyses revealed that achieved CR after first induction chemotherapy (P = 0.036, HR = 0.075, 95%CI: 0.007-0.849) and allo-HSCT (P = 0.008, HR = 0.031, 95%CI: 0.002-0.398) were independent good factors affecting CIR.
Table 1 Characteristics of 19 adult T-ALL patients with activating RAS mutations.
Total (n = 19) | Allo-HSCT (n = 13) | Chemothreapy (n = 6) | P value | |
---|---|---|---|---|
Gender, male/female, n | 13/6 | 10/3 | 3/3 | 0.241 |
Age at diagnosis [years, M (range)] | 44(21-67) | 38(21-55) | 60(44-67) | 0.001 |
WBC at diagnosis [×109/L, M (range)] | 5.18(0.62-204.7) | 4.82(0.62-204.7) | 8.81(1.55-95.09) | 0.831 |
Blasts in bone marrow [%, M (range)] | 72.5(24-97.5) | 84(47.5-97.5) | 54.5(24-89) | 0.244 |
Immunophenotype, n(%) | 0.018 | |||
Pro-T | 3(15.8) | 0(0.0) | 3(50.0) | |
Pre-T | 3(15.8) | 2(15.4) | 1(16.7) | |
ETP | 13(68.4) | 11(84.6) | 2(33.3) | |
Chromosomal, n(%) | 0.829 | |||
Normal | 12(63.2) | 8(61.5) | 4(66.7) | |
Abnormal | 7(36.8) | 5(38.5) | 2(33.3) | |
Fusion gene, n(%) | 0.200 | |||
SET-NUP214 | 3(15.8) | 3(23.1) | 0(0.0) | |
Negative | 16(84.2) | 10(76.9) | 6(100.0) | |
RAS mutations, n(%) | 0.126 | |||
NRAS mutation | 15(78.9) | 9(69.2) | 6(100.0) | |
KRAS mutation | 4(21.1) | 4(30.8) | 0(0.0) | |
Accompany by NOTCH1/FBXW7 mutations, n(%) | 12(63.2) | 7(53.8) | 5(83.3) | 0.216 |
Conclusions: We concluded that RAS mutations were common in adult T-ALL without accompanying PTEN changes, and had more frequently an immature immunophenotype. Adult RAS mutated T-ALL patients had a high induction response rate, but were prone to relapse. Allo-HSCT might effectively reduce the recurrence rate and improve their survival.
Disclosure: Nothing to declare
19: Acute Leukaemia
P033 PREVENTION AND TREATMENT OF ACUTE MYELOID LEUKEMIA RELAPSE FOLLOWING ALLOGENEIC STEM CELL TRANSPLANT: A NATIONAL SURVEY BY GITMO (GRUPPO ITALIANO TRAPIANTO MIDOLLO OSSEO)
Francesco Saraceni1, Eliana Degrandi2, Simona Piemontese3, Francesco Saglio4, Giorgia Battipaglia 5, Marta Lisa Battista6, Patrizia Chiusolo7, Jacopo Mariotti8, Stefania Bramanti8, Anna Grassi9, Fabio Benedetti10, Manuela Tumino11, Giorgia Saporiti12, Salvatore Leotta13, Sadia Falcioni14, Martina Chiarucci15, Gladis Bortoletto16, Elisabetta Terruzzi17, Annalisa Imovilli18, Carlo Borghero19, Eugenia Piras20, Francesco Zallio21, Vincenzo Federico22, Irene Maria Cavattoni23, Andrea Gilioli24, Alessandra Picardi25, Domenico Pastore26, Anna Paola Iori27, Valentina Giudice28, Carmen Di Grazia29, Luca Castagna30, Michele Malagola31, Attilio Olivieri1, Francesca Bonifazi32, Massimo Martino33
1Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy, 2GITMO Trial Office, Bologna, Italy, 3Ospedale S. Raffaele, Milano, Italy, 4CIttà della Salute e della Scienza, Torino, Italy, 5Università degli studi di Napoli Federico II, Napoli, Italy, 6Azienda sanitaria universitaria Friuli Centrale, Udine, Italy, 7Università Cattolica del Sacro Cuore, Roma, Italy, 8Istituto Humanitas, Rozzano - Milano, Milano, Italy, 9ASST Papa Giovanni XXIII, Bergamo, Italy, 10Ospedale Borgo Roma di Verona, Verona, Italy, 11Azienda Ospedaliera di Padova, Padova, Italy, 12Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Milano, Italy, 13Azienda Ospedaliero - Universitaria Policlinico - Vittorio Emanuele, Catania, Italy, 14AOC Ascoli Piceno, Ascoli Piceno, Italy, 15Azienda Ospedaliera Marche Nord, Pesaro, Italy, 16IRCCS Istituto Oncologico Veneto, Mestre, Italy, 17Azienda Ospedaliera San Gerardo, Monza, Italy, 18AUSL Reggio Emilia, Reggio Emilia, Italy, 19Ospedale S. Bortolo Vicenza, Vicenza, Italy, 20Centro Trapianti Midollo Osseo, Università di Cagliari, Cagliari, Italy, 21Azienda Ospedaliera di Alessandria, Alessandria, Italy, 22ASL Lecce, Lecce, Italy, 23Ospedale Generale Regionale Bolzano, Bolzano, Italy, 24Azienda Ospedaliero Universitaria di Modena, Modena, Italy, 25Ospedale A. Cardarelli - Divisione di Ematologia, Napoli, Italy, 26ASL Brindisi, Brindisi, Italy, 27Università la Sapienza, Roma, Italy, 28Università degli studi di Salerno, Salerno, Italy, 29UO Ematologia e Terapie Cellulari. IRCCS Ospedale Policlinico San Martino, Genova, Italy, 30Azienda Ospedaliera Ospedali Riuniti Villa Sofia - Cervello, Palermo, Italy, 31Università degli Studi di Brescia, Brescia, Italy, 32IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy, 33Azienda Ospedaliera “Bianchi-Melacrino-Morelli” di Reggio Calabria, Reggio Calabria, Italy
Background: Leukemia relapse remains the main cause of treatment failure in patients undergoing allogeneic stem cell transplant (allo-SCT) for acute myeloid leukemia (AML). There is currently no general agreement concerning management of patients at high risk of leukemia recurrence or with overt hematological relapse after allo-SCT.
Methods: We conducted the present survey with the aim to evaluate the current practice in Italy concerning prevention and treatment of AML relapse after allo-SCT. A questionnaire was sent to GITMO centers including specific questions on three main topic: maintenance, preemptive therapy and treatment of hematological relapse. Most of the agents discussed below currently represent off label prescriptions.
Results: In all, 34/60 (57%) of centers performing allo-SCT in Italy completed the questionnaire. 22/34 (65%) routinely employ maintenance strategies (in the absence of measurable residual disease (MRD) or mixed chimerism) after allo-SCT in patients considered at high risk of relapse basing on pre-transplant features (high risk according to ELN 2022 or presence of FLT3-ITD, positive MRD or active disease). Among institutions who deliver maintenance therapy after allo-SCT, in patients harbouring FLT3-ITD 86% administer FLT3 inhibitors (95% Sorafenib, 5% Gilteritinib). In the absence of FLT3-ITD 68% use hypometilating agents (87% azacitidine, 13% decitabine); 2 centers consider addition of venetoclax to hypometilating agents, while one institution prescribes venetoclax as single agent. Interestingly, 26% of institutions administer prophylactic DLI in high risk AML patients, in the absence of MRD relapse or mixed chimerism. With respect to preemptive therapy, the trigger to start treatment is represented by MRD relapse in all centers; 74% of institutions consider mixed chimerism as trigger to start preemptive therapy as well. In patient harbouring FLT3-ITD 82% of centers prescribe FLT3 inhibitors (48% sorafenib +/- azacitidine, 52% gilteritinib). In the absence of FLT3-ITD 62% of institutions use azacitidine (19% with the addition of venetoclax), one institution use venetoclax monotherapy, while 29% use DLI as single approach especially in case of mixed chimerism in the absence of MRD relapse. Nevertheless, 32/34 (94%) use DLI in addition to pharmacologic preemptive therapy.
In patients experiencing haematological relapse after transplant 76% of institutions perform NGS analysis at the time of relapse, while 50% look for HLA loss in case of relapse after haploidentical transplant. In patients harbouring FLT3-ITD 91% of centers treat AML relapse with gilteritinib. In fit patients, in the absence of FLT3-ITD, 44% employ conventional chemotherapy, while 56% consider as first option hypometilating agents (mostly azacitidine) in combination with venetoclax.
All institutions consider second allo-SCT after salvage treatment in patients who relapse after first transplant. 62% of centers perform second allo-SCT only in patients achieving CR2, while 38% regardless achievement of response to salvage. Finally, 97% of institutions prefer a different donor for second allo-SCT, if available.
Conclusions: Most Italian transplant institutions currently implement strategies to prevent AML relapse after allo-SCT, despite the lack of approved agents in this setting. In patients with haematological relapse a second allo-SCT remains a main option after salvage treatment with standard chemotherapy or hypometilating agents in combination with venetoclax.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P034 TRENDS IN THE USE OF HEMATOPOIETIC CELL TRANSPLANTATION FOR ADULTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA: A REPORT FROM THE ACUTE LEUKEMIA WORKING PARTY OF THE EBMT
Sebastian Giebel 1, Myriam Labopin2, Frederic Baron3, Ali Bazarbachi4, Eolia Brissot5, Gesine Bug6, Jordi Esteve7, Norbert-Claude Gorin8, Francesco Lanza9, Arnon Nagler10, Annalisa Ruggeri11, Jaime Sanz12, Bipin Savani13, Christoph Schmid14, Roni Shouval15, Alexandros Spyridonidis16, Jurjen Versluis17, Zinaida Peric18, Mohamad Mohty5, Fabio Ciceri19
1Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland, 2EBMT Unit, Sorbonne Universités, UPMC University of Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA), AP-HP, Saint Antoine Hospital, Paris, France, 3GIGA-I3, University and CHU of Liège, Liège, Belgium, 4American University of Beirut Medical Center, Beirut, Lebanon, 5Sorbonne Universités, UPMC University of Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA), AP-HP, Saint Antoine Hospital, Paris, France, 6University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany, 7Hospital Clínic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain, 8European Society for Blood and Marrow Transplantation, Paris Office, Hopital Saint-Antoine, Paris, France, 9Romagna Transplant Network, Ravenna, Italy, 10Chaim Sheba Medical Center, Tel-Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel, 11IRCCS Bambino Gesù Children’s Hospital, Rome, Italy, 12Hospital Universitari i Politecnic La Fe. Instituto de Investigación Sanitaria La Fe, Valencia, Spain, 13Vanderbilt University Medical Center, Nashville, United States, 14Augsburg University Hospital, Augsburg, Germany, 15Memorial Sloan Kettering Cancer Center, New York, United States, 16University of Patras, Patras, Greece, 17Erasmus University Medical Center Cancer Institute, Rotterdam, Netherlands, 18University Hospital Center Rijeka and School of Medicine, University of Rijeka, Rijeka, Croatia, 19Ospedale San Raffaele s.r.l., Haematology and BMT, Milano, Italy
Background: Indications for hematopoietic cell transplantation (HCT) for adults with acute lymphoblastic leukemia (ALL) evolve over time and vary among countries. In our previous survey we reported continues increase of the number of allogeneic (allo)-HCT procedures between years 2001-2015 [Giebel S, et al., Ann Hematol 2019]. In recent years the role of HCT has been challenged by new protocols incorporating bispecific antibodies or immunotoxins in first-line treatment. The goal of this study was to assess general trends in the number of various types of HCTs performed between years 2010 and 2021 in Europe.
Methods: Data reported to the EBMT registry were used for this analysis. Altogether, 14389 first allogeneic (n = 13795) or autologous (auto-, n = 594) HCTs were performed in the period 2010-2021.
Results: The number of allo-HCTs analyzed in 2-year periods increased from 2074 for years 2010-2011 to 2428 between 2018-2019 (17% increase) and then dropped to 2282 for years 2020-2021 (6% decrease). Similar pattern was observed for the largest European countries (Germany, UK, France, Italy, Spain).
Comparing years 2020-2021 and 2010-2011, median recipient age increased from 37.3 to 41.1 (p<0.0001), the proportion of matched sibling donor transplants decreased from 39% to 24.2%, while the rate of unrelated donor and haploidentical donor transplants increased from 50.8% to 54.3% and 5.1% to 20.2%, respectively; the proportion of cord blood transplants decreased from 5.1% to 1.2% (p<0.0001) (Table). In respective periods the proportion of patients with Ph-negative B-ALL increased from 28.6% to 43.2%, for Ph-positive B-ALL it decreased from 38% to 32.7% while for T-ALL it dropped from 33.4% to 24.1% (p<0.0001). Most patients were treated in the first complete remission: 70.2% between years 2010-2011 and 70.9% between 2020-2021. The proportion of patients administered allo-HCT in active disease decreased from 10.5% to 4.7% in respective periods (p<0.0001). Peripheral blood was used as a source of stem cells for allo-HCT in 74.1% of patients between 2010-2011 and 90.3% of patients between 2020-2021. The use of post-transplant cyclophosphamide increased from 1.7% to 29.6% in respective periods (p<0.0001).
The total number of auto-HCTs was 130 between years 2010-2011 and 48 between 2020-2021 (63% decrease).
Year | ||||||
---|---|---|---|---|---|---|
2010-2011 | 2012-2013 | 2014-2015 | 2016-2017 | 2018-2019 | 2020-2021 | |
Total allo-HCT | 2074 | 2319 | 2309 | 2383 | 2428 | 2282 |
MSD-HCT | 809 | 800 | 721 | 780 | 665 | 553 |
URD-HCT | 1054 | 1242 | 1250 | 1269 | 1285 | 1240 |
Haplo-HCT | 105 | 190 | 278 | 293 | 434 | 462 |
Cord blood | 106 | 87 | 60 | 41 | 44 | 27 |
Auto-HCT | 130 | 98 | 127 | 112 | 79 | 48 |
Conclusions: Results of our analysis indicate moderate increase of allo-HCT procedures for adults with ALL in the period 2010-2019 followed by a slight decrease between 2020-2021 that might be related to SARS-CoV-2 pandemic. The profile of allo-HCTs has changed over time with more frequent use of haploidentical donors, post-transplant cyclophosphamide – based immunosuppression and the use of peripheral blood as predominant source of stem cells. In recent years less patients have been treated with allo-HCT in active disease which may reflect higher efficacy of immunotherapy-based salvage regimens. Auto-HCT is rarely used for the treatment of adults with ALL.
Clinical Trial Registry: Not applicable
Disclosure: GB has received honoraria from Novartis, Jazz, BMS and Gilead and travel grants from Jazz, Gilead and Neovii
19: Acute Leukaemia
P035 ALLOGENEIC STEM CELL TRANSPLANTATION FOR ADULT ACUTE LYMPHOBLASTIC LEUKEMIA - A SINGLE CENTER 25-YEARS EXPERIENCE
Veronika Válková 1,2, Cyril Šálek1,2, Antonín Vítek1, Markéta Marková1,2, Ludmila Nováková1, Mariana Koubová1, Michal Kolář1, Barbora Čemusová1, Hana Bartáková1, Petr Cetkovský1,2, Jan Vydra1,2
1Institute of Hematology and Blood Transfusion, Prague 2, Czech Republic, 2Faculty of Medicine of Charles University, Prague 2, Czech Republic
Background: Allogeneic stem cell transplantation (allo-SCT) may be curative for patients with high risk acute lymphoblastic leukemia (ALL). The aim of our analysis was to compare the results of allo-SCT in ALL over more than two decades and to identify the parameters that influence these results.
Methods: All patients (pts) older than 18 years who underwent allo-SCT at our center from March 1989 to July 2023 were included in the analysis. In total, there were 183 pts, median age 38 years (18-65, only 17% over 55 years), 116 (63%) were male, B-ALL-Ph pos 37%, T-ALL 17%, donors were MSD (26%), MUD (42%), MMUD (23%) and haplo (8%). The majority of grafts were PBPC (82%). Myeloablative conditioning (TBI based) received 158 (86%) pts, 62% of whom received Vep/12Gy TBI. A more detailed analysis in terms of GVHD and MRD was performed on a cohort of patients from 2007 (n = 136). At allo-SCT 105 pts (77%) were in CR1, 23 (17%) in CR2, 6% with active disease. In terms of MRD, 60 patients were negative and 59 positive before allo-SCT.
Results: With a median follow-up of 6.5 years (living pts), 5-year OS was 56% and EFS of 49%. The cumulative incidence of relapse and NRM was 30% and 27% respectively at 5 years. Acute GVHD grade 2-4 occurred in 23%, moderate/severe chronic GVHD in 11%. GRFS at 5 years was 42%. Relapse occurred in 23% of patients, at a median of 8 months. OS after relapse was 22% at 5 years (26% vs 19% in the last decade vs earlier, p= ns). In univariate analysis, significantly better outcomes in terms of OS were observed in the last decade (5y-OS 68%), optimal conditioning seems to be Vep/TBI, worse outcomes were observed in patients over 55 years. Survival was significantly better in pts reaching CR before allo-SCT, and also significantly better in MRD neg versus MRD pos pts (no difference between MRD neg CR1 or CR2), both before allo-SCT and at 3 months after allo-SCT. A multivariate Cox regression analysis confirmed the survival benefit for pts who reached MRD negativity before allo-SCT (p = 0.047) and for transplants from MSD (p = 0.02) or MUD (p = 0.02) over the other donors.
Conclusions: The outcomes of allo-SCT in ALL have improved significantly in the last decade, in our setting mainly due to the reduction of NRM. The role of novel therapies has been observed more in terms of of the possibility of achieving more CR (and even more MRD neg CR) before allo-SCT, rather than in the treatment of relapses after allo-SCT. Our results confirm the essential role of MRD monitoring during ALL treatment and in particular achieving MRD negativity before allo-SCT.
Disclosure: nothing to declare
19: Acute Leukaemia
P036 STRUCTURAL ANALYSIS OF LEUKEMIA-ASSOCIATED PROTEIN PTPN21 REVEALS A DOMINANT-NEGATIVE EFFECT OF THE FERM DOMAIN ON ITS PHOSPHATASE ACTIVITY
Zijun Qian 1,2, Lu Chen1,2, Jie Zhang2, Yuyuan Zheng1, Chun Zhou1,2, Haowen Xiao1,2
1Zhejiang University, Hangzhou, China, 2Sir Run Run Shaw Hospital, Hangzhou, China
Background: High expression level of protein tyrosine phosphatase non-receptor type 21 (PTPN21) has been detected in B-cell non-Hodgkin’s lymphoma and its mutations are associated with disease relapse in B-cell acute lymphoblastic leukemia (B-ALL) patients who received allo-HSCT. Recently, PTPN21 has been shown to be pivotal in maintaining cell mechanical properties and helps retain hematopoietic stem cells (HSCs) in the bone marrow niche through dephosphorylating the cytoskeleton-associated protein Septin1. However, the molecular structure and functions of PTPN21 have been less understood compared to other tyrosine phosphatases like PTP1 B. PTPN21 is a relatively large protein with two structured domains, FERM domain and the catalytic domain (PTP), and a long intrinsically disordered region in the middle. The mechanisms of regulation of PTPN21 phosphatase activity and the effect of mutations on its functions need to be explored.
Methods: We used protein purification and crystallization to determine structures of FERMPTPN21, PTPPTPN21 and a complex structure of the PTP and FERM domains. GST pulldown and MST titration as well as phosphatase assays and site direct mutagenesis were used to determine the interaction of PTP and FERM domains.
Results: Through biochemical assays, we found that PTPN21 FERM domain can interact with PTP domain, resulting in negatively regulating its phosphatase activity in vitro and in vivo. We further explored the structures of FERMPTPN21, PTPPTPN21 as well as a complex structure of the combination of PTP and FERM domains. The FERM-PTP complex structure allowed us to identify critical interface residues and mutations of these residues led to enhanced phosphatase activity of PTPN21 and induced activation of downstream ERK. More importantly, these mutations only activated ERK in the context of wild-typed PTP but not the catalytic inactive C1108S, indicating PTPN21’s phosphatase activity is indispensable.
Conclusions: We’ve demonstrated that PTPN21 catalytic domain PTP is autoinhibited by the FERM domain. Disruption of FERM-PTP interaction results in enhanced PTPN21 activity and activation of downstream MAPK signal pathway. Our work provides novel insights into understanding the role of PTPN21 in various cellular processes by discovering the molecular structure of the FERM and PTP domains of PTPN21. These findings are likely extendable to other FERM-containing tyrosine phosphatases like PTPN14 and PTPN3, which opens up new avenues for further mechanistic studies.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P037 EARLY DETECTION OF RELAPSE AND PROMPT TREATMENT WITH DLI FACILITATED BY PROPHYLACTIC LYMPHOCYTE STORAGE PERI-TRANSPLANT RESULTS IN EFFECTIVE DISEASE CONTROL IN ACUTE LEUKAEMIA AND MDS
Daire Quinn 1, Anne Parker1, Grant McQuaker1, Anne-Louise Latif1, David Irvine1, Ailsa Holroyd1, Dimitris Galopoulos1, Andrew Clark1
1Queen Elizabeth University Hospital, Glasgow, United Kingdom
Background: Relapse following allogeneic stem cell transplant carries a poor prognosis. DLI has been used in this setting but is less effective if delayed or given in the context of haematological relapse.
Methods: Aliquots of DLI from the PBSC collection were stored prophylactically pre-transplant. The transplant dose was always protected and was never < 4x106 CD34 cells/Kg. No DLI were stored if stem cell dose was lower than this threshold. Patients with relapsed acute leukaemia (AL) or MDS were detected early and treated with an effective salvage regimen followed by escalated doses of DLI, starting at 3x105 CD3 cells/Kg (VUD) or 1x106 CD3 cells/Kg (MRD). First dose DLI was given at 6-8 weeks post commencement of salvage treatment. Subsequent DLI doses (3x106, 1x107, 3x107 CD3 cells/Kg) were delivered at 8-12 week intervals intercalated with salvage therapy. Maximum dose was 3x107 CD3 cells/Kg (max cumulative dose 4.63 x107 CD3 cells/Kg). Patients were excluded if they had rapidly progressive disease, BM blasts >50% or ECOG >2.
Results:
Acute Leukaemia | Myelodysplasia | |
---|---|---|
Specific Disease | AML 15, ALL 4 | 12 |
Median Age | 51 (21-66) | 60 (51-66) |
Male sex | 11 | 10 |
Conditioning | ||
RIC | 11 | 12 |
MAC | 8 | |
Mode of Presentation | MRD 10, Haematological 9 | Mixed myeloid chimerism + cytopenia 12 |
2 year DFS | 53% | 42% |
Median FU | 30 months | 22 months |
Between 2015 and 2022 thirty one patients were treated with DLI for relapsed AL (n = 19) or MDS (n = 12). Strikingly, only 4 of these interventions occurred before 2019. Before that time selecting patients with low disease burden and being able to acquire DLI in a rapid time frame was frequently not possible. After 2019 four factors facilitated effective DLI administration- Early disease relapse, detection using MRD combined with assessment of myeloid chimerism, newer agents to achieve remission responses and the ready availability of DLI.
In relapsed MDS all patients had recurrent cytopenias associated with: NGS abnormalities, increasing blast % or cytogenetic abnormalities. Myeloid chimerism ranged from 4-64% at diagnosis returning to 100% donor in all responding patients. In the AL group 10 were diagnosed by MRD methods and 9 had haematological relapse. Median Time to relapse was 10 months in AL and 19 months in MDS
In AL salvage treatment included FLAG, Dasatinib, Gemtuzumab, Ven/Aza, Gilteritininb, Blinatumomab, Inotuzumab, Azacitidine alone or no therapy while MDS patients all received Azacitidine for 4-12 cycles. Median number of DLI infusions was 3. Median total dose was 1.4x107 CD3 cells/Kg in both groups. In responders the median total dose was 4.4x107 CD3 cells/kg. Median FU post DLI was 20 and 30 months overall or for responders in AL and 19 and 22 months in MDS.
CR was achieved in 63% of acute leukaemia and 58% of MDS patients. Two leukaemic patients relapsed at 16 and 34 months. Responses were otherwise durable, 80% remained in CR at 3 years. Three additional MDS patients responded transiently. Acute GvHD occurred in 2 patients. Two patients have moderate chronic GvHD. One died of acute neurotoxicity. Two year DFS was 53% in AL and 42% in MDS.
Conclusions: Combining early detection of disease relapse, followed by treatment with novel therapies and consolidation with DLI provides effective salvage therapy. High levels of durable disease control are achieved and low rates of GvHD are seen resultant on DLI dose escalation. Prophylactic storage of DLI allows this approach and is cost effective.
Clinical Trial Registry: None
Disclosure: None
19: Acute Leukaemia
P038 THIOTEPA, BUSULFAN, AND FLUDARABINE CONDITIONING REGIMEN IN T-CELL REPLETE HLA-HAPLOIDENTICAL BONE MARROW TRANSPLANTATION FOR ADULTS WITH ACUTE MYELOBLASTIC LEUKEMIA IN SECOND COMPLETE REMISSION
Ahmad Ibrahim 1, Ahmad Khalil2, Kamal Al Zahran3, Mohamad Hachem4, Pamela Sfeir5, Amin Abyad6, Jad Ibrahim7, Hussein Abou Abbas8, Ali Youssef8, Charbel Khalil2, Tamima Jisr9
1Makassed University Hospital, Middle East Institute of Health, University of Balamand and Lebanese University, Beirut, Lebanon, 2Middle East Institute of Health, Beirut, Lebanon, 3Middle East Institute of Health and Lebanese University, Beirut, Lebanon, 4Makassed University Hospital and Lebanese University, Beirut, Lebanon, 5University of Balamand, Beirut, Lebanon, 6Burjeel Medical City, Abu Dhabi, United Arab Emirates, 7American University of Beirut, Beirut, Lebanon, 8Makassed University Hospital, Beirut, Lebanon, 9Makassed University Hospital and Beirut Arab University, Beirut, Lebanon
Background: Haploidentical stem cell transplantation (HaploSCT) with thiotepa/busulfan/fludarabine (TBF) conditioning and post-transplant cyclophosphamide (PT-Cy) can achieve comparable outcomes for relapsed acute myeloblastic leukemia (AML) patients (pts) in complete remission (CR) to those of HLA-matched sibling or unrelated donor transplantation. However, a higher incidence of acute and chronic GVHD was reported with peripheral blood stem cell source (PBSC) compared to bone marrow (BM) in adult acute leukemia. In this study, we report the outcomes of adult pts (>18yo) with AML in second CR who underwent HaploSCT with unmanipulated BM source using TBF conditioning and PT-Cy.
Methods: This study is a retrospective analysis conducted between 2/2018 and 2/2023. The TBF-MAC included thiotepa IV 5mg/kg/d on d-7 and -6, IV busulfan 3.2mg/kg/d on d-4, -3, -2, and IV fludarabine 30mg/kg/d from d-5 to d-1. The TBF-RIC, for pts >60yo, involved reduced doses of thiotepa (5mg/kg on d-6) and busulfan (3.2mg/kg/d on d-3 and -2), with identical fludarabine doses. BM was infused on d0. The PT-Cy dose was 50mg/kg/d d + 3 and +4, followed on d + 5 by IV cyclosporine 3mg/kg/d, then tapered over 6 weeks after d + 60 if no GVHD. MMF was given at a dose of 15mg/kg every 12 hours d + 5 to d + 35. GCSF was started d + 5 until neutrophil recovery. Prophylaxis for VOD was ensured by ursodeoxycholic acid. Anti-microbial prophylaxis was given. Pts were monitored by PCR for CMV, EBV, HHV6 until d + 100, and for BK virus if indicated. Azacitidine was given as maintenance therapy after Haplo SCT for all pts, and sorafenib was given in case of FLT3 mutations.
Results: Thirty-two pts were included. Median age was 36yo (19-71). There were 17 females and 15 males. Twenty-four pts (75%) received TBF-MAC, and 8 (25%) TBF-RIC. Median number of nucleated cells infused was 5.2×108 kg (4.1-6.7). All pts achieved neutrophil recovery within a median of 17d (14-31), and platelet recovery (>20 109/L) within a median of 19d (10-42). All pts had full donor chimerism before d + 90. Seven pts (22%) developed grade II-IV aGVHD, including 2 (6%) with grade III–IV. Three pts (9%) developed non-severe cGVHD. Acute GVHD was refractory to steroids in 2 pts and was fatal in one. Fatal VOD occurred in 1 pt (3%). Eight pts (25%) had bacteremia, and 2 (6%) developed invasive fungal infections. Two pts (6%) developed fatal COVID-19. CMV reactivation, successfully treated with ganciclovir, occurred in 14 pts (44%). Seven pts (22%) died of infection, including 2 of COVID-19 and 5 of sepsis. Five pts (16%) relapsed within a median of 9 months (6-25) after Haplo SCT and died from AML between 1 and 6 months after relapse. Within a median follow-up of 22 months (1-68), 18 pts (56%) are still alive in CR with a median of 33 months (11-68). The 3y-OS and-DFS were 57% and 52%, respectively.
Conclusions: HaploSCT with BM source offers a curative therapy for adult AML pts in 2nd CR with low risk of GVHD, and low incidence of relapse. However, infections remained the main cause of death.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P039 REDUCED INTENSITY CHEMOTHERAPY WITH TYROSINE KINASE INHIBITOR FOLLOWED BY ALLOGENEIC STEM CELL TRANSPLANTATION WAS EFFECTIVE IN PATIENTS WITH PHILADELPHIA CHROMOSOME POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA
Dong Won Baek 1, Jung Min Lee1, Hyukjin Choi1, Joon Ho Moon1, Sang Kyun Sohn1
1Kyungpook National University Hospital, Daegu, Korea, Republic of
Background: With the introduction of tyrosine kinase inhibitors (TKI), survival outcomes of adult patients with Philadelphia chromosome positive (Ph-positive) acute lymphoblastic leukemia (ALL) has improved remarkably. Intensive chemotherapy plus TKI is still the standard approach to induce hematologic complete remission (CR) before allogeneic stem cell transplantation (allo-SCT). However, intensive chemotherapy before transplantation may have negative impacts on allo-SCT outcomes, including treatment-related mortality, worsening performance at the time of transplantation. In the current study, we compared the survival outcomes of intensive chemotherapy plus TKI and reduced intensity chemotherapy plus TKI in patients with newly diagnosed Ph-positive ALL. In addition, the clinical role of allo-SCT in the treatment of adult Ph-positive ALL was also evaluated.
Methods: We retrospectively analyzed data from 97 patients with newly diagnosed Ph-positive ALL who received intensive chemotherapy plus TKIs or reduced intensive chemotherapy plus TKIs over the past 10 years. Patients aged ≥ 20 years were included in this study. Patients who were in suitable condition for transplantation and had HLA matched donor underwent allo-SCT. Relapse-free survival (RFS) was determined from the date of diagnosis to the date of disease relapse or death from any cause. Overall survival (OS) was determined from the date of diagnosis to the date of death or last follow-up.
Results: In total, 97 patients were analyzed. Intensive chemotherapy was administered to 69 patients, and median age was 45 (range, 20-73) years old. Reduced intensity chemotherapy was administered to 28 patients, and their median age was 68.5 (range, 27-80) years old. In patients with intensive chemotherapy plus TKI, 55 patients (79.7%) achieved molecular CR after induction chemotherapy, and four patients (5.8%) died during induction therapy. In patients with reduced intensity chemotherapy plus TKI, 20 patients (71.4%) achieved molecular CR, while no one has died during induction therapy. In the intensive chemotherapy group, 46 patients (66.7%) underwent allo-SCT, and 20 patients showed disease relapse and three patients died after transplantation. In the reduced intensity chemotherapy group, 12 patients (42.9%) received allo-SCT, and four patients had relapsed disease and one died. In an analysis targeting only transplanted patients, there was no statistically significant difference in RFS and OS between patients who received intensive chemotherapy and patients with reduced intensity chemotherapy.
Conclusions: Reduced intensity chemotherapy decreased induction mortality compared to intensive chemotherapy. In addition, reduced intensity chemotherapy plus TKI was able to sufficiently induce molecular CR, and subsequent allo-SCT could improve long-term survivals.
Disclosure: The authors declare no conflict of interest.
19: Acute Leukaemia
P040 IMPACT OF CO-MUTATIONS ON THE TRANSPLANT OUTCOMES IN AML PATIENTS WITH DNMT3A MUTATION
Feng-ming Tien1, Xavier Cheng-Hong Tsai 1, Min-Yen Lo1, Hsin-An Hou1, Hwei-Fang Tien1
1National Taiwan University Hospital, Taipei, Taiwan, Province of China
Background: Acute myeloid leukemia (AML) with DNMT3A mutations is classified within intermediate-risk category according to ELN-2022 criteria. However, the impact of co-mutations on the transplant outcomes in this particular group remains to be explored.
Methods: A total of 148 patients (16.7%) with DNMT3A mutations were enrolled from a retrospective cohort of 887 AML patients homogeneously treated with intensive chemotherapy. Gene mutations were examined via targeted NGS, using the TruSight myeloid panel. Notably, none of the patients received oral azacitidine as maintenance therapy. Survival analysis modified according to Simon-Makuch method were used to compare outcomes between allogeneic stem cell transplantation (allo-HSCT) and postremission chemotherapy (PR-CT) in the first complete remission (CR1).
Results: The most frequent co-mutations in DNMT3A mutated patients were NPM1 (52.7%), FLT3-ITD (31.1%), and IDH2 (26.4%). 111 out of 148 (75%) patients achieved CR1. 68 patients received allo-HSCT: 30 with myeloablative conditioning, 38 with reduced intensity conditioning; 15 with a haploidentical donor, 23 with a matched sibling donor, 30 with a matched unrelated donor. Specifically, 30 patients received allo-HSCT at CR1, 11 at CR2, 27 at other disease statuses, resulting in a 5-year overall survival (OS) of 46%, 29%, 15%, respectively. For those with PR-CT without further transplant, the 5-year OS was 13%. Allo-HSCT in CR1 was associated with a better OS than PR-CT (median, not reached (NR) vs 15.3 months, P<0.0001).
Next we delved into the specific genetic subgroup within the DNMT3A mutated patients. In the NPM1-/FLT3-ITD- subgroup, the most frequent co-mutations were IDH2 (47.3%), ASXL1 (18.2%), NRAS (16.4%), IDH1 (16.4%). 37 out of 55 patients attained CR1. The relapse rate was 75% in those receiving PR-CT, and 50% in those receiving allo-HSCT in CR1. The lower relapse rate translate into a significantly better OS (median, 75.1 vs. 19.6 months, P = 0.015) and event-free survival (EFS)(median, 75.1 vs. 8.9 months, P = 0.001) in the allo-HSCT group.
In the NPM1 + /FLT3-ITD- subgroup, currently an ELN-2022 favorable-risk category, 39 out of 47 patients attained CR1. The relapse rate was 36.8% in those receiving PR-CT, and 0% in those receiving allo-HSCT in CR1. Allo-HSCT in CR1 was associated with a significantly better OS (median, NR vs. 98.2 months, P = 0.042) and EFS (median, NR vs. 18.7 months, P = 0.006). Lastly, in the IDH2 mutated subgroup, allo-HSCT in CR1 was associated with a significantly better EFS, while the OS remained similar.
Conclusions: The results indicated that NPM1-/FLT3-ITD- and NPM1 + /FLT3-ITD- subgroups in DNMT3A mutated AML benefit from allo-HSCT in CR1. Larger cohorts are warranted to validate these findings.
Disclosure: No relevant conflict of interest to declare.
19: Acute Leukaemia
P041 SALVAGE TREATMENTS HAVE EXTREMELY POOR OUTCOMES FOR PATIENTS WITH RELAPSED T-ACUTE LYMPHOBLASTIC LEUKAEMIA POST TRANSPLANT
Alexandros Rampotas 1, Fotios Panitsas2, Maximillian Brodermann1, Sridhar Chaganti3, Styliani Bouziana4, Emma Nicholson5, Samantha Drummond6, Sharon Allen7, Andrew King7, Henry Crosland3, Anne-Louise Latif6, Daniele Avenoso4, Claire Roddie1
1University College London Hospital NHS Foundation Trust, London, United Kingdom, 2Laikon University Hospital, Athens, Greece, 3University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom, 4King’s College London Hospital NHS Foundation Trust, London, United Kingdom, 5The Royal Marsden NHS Foundation Trust, London, United Kingdom, 6Queen Elizabeth University Hospital, Glascow, United Kingdom, 7Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
Background: Relapse following allogeneic hematopoietic stem cell transplantation (allo-HCT) in T-Acute Lymphoblastic Leukemia (T-ALL) poses a formidable clinical challenge. Diverse treatment modalities have been employed, showcasing variable efficacy. Notably, recent years have witnessed the emergence of novel therapeutic strategies for T-ALL such as Chimeric Antigen Receptor T-cells targeting CD7, CD5 and CXCR7 among others with a few phase I/II trials being underway. This study examines outcomes in relapsed T-ALL post allo-HCT, spanning the period from 2010 to 2022, across six major UK transplant centers. Our findings underscore the pressing need for innovative therapeutic interventions in this context, emphasizing the urgency for further research and the development of novel approaches to address the poor outcomes of relapsed T-ALL after transplantation.
Methods: Retrospectively, we compiled data from adult cases experiencing post-transplant relapse in T-ALL. Survival analysis, employing Kaplan-Meier methodology and log-rank tests, was conducted. Descriptive analysis was undertaken to assess baseline and disease characteristics. Approval for this project was obtained from the British Society of Blood and Marrow Transplantation. All data management adhered strictly to the principles outlined in the Declaration of Helsinki.
Results: Twenty-one patients with relapsed T-ALL post allo-HCT were identified, and 20 with sufficient data underwent analysis, with a median follow-up of 32.6 months. Baseline and disease characteristics are detailed in Table 1, Median age was 37 years, while high-risk features included a mediastinal mass in 4/20, early T-cell precursor leukemia in 7/19, high white cell count in 8/19, and CNS disease in 4/20. Relapse occurred at a median of 6 months post-transplant. Intensive chemotherapy, including FLAG-IDA (N = 1), Nelarabine (N = 2), Venetoclax and UKALL14 phase 2 (N = 1), Nelarabine and UKALL14 induction (N = 1), was employed in 5/20 patients, while the rest received non-intensive chemotherapy or palliative and supportive options. Donor Lymphocyte Infusions were not utilised for any patient. Out of 5 patients who received intensive chemotherapy, only 1 achieved CR and four patients went on to receive a second transplant. Among them, one succumbed to transplant complications, while three achieved CR. Two patients relapsed after 12 and 18 months, respectively, while one remains in remission at 26 months post-transplant. Median overall survival was 3.18 months (2-5).
Total cohort | N = 20 |
---|---|
Sex | Male 15/20 (75%) |
Female 5/20 (25%) | |
Age (years) (median, IQR) | 37, 23-51 |
Mediastinal mass at diagnosis | Yes 4/20 (20%) |
No 16/20 (80%) | |
Early T-cell precursor leukaemia | Yes 7/19 (37%) |
No 12/19 (63%) | |
Not known 1/19 | |
High White cell count at diagnosis (>100 x10^9/L) | Yes 8/19 (42%) |
No 11/19 (58%) | |
CNS disease | Prior to transplant |
Yes 4/20 (20%) | |
No 16/20 (80%) | |
At Relapse | |
Yes 5/20 (25%) | |
No 15/20 (75%) | |
Prior line of therapy | 1 9/20 (45%) |
2 9/20 (45%) | |
3 2/20 (10%) | |
Type of relapse post allo-HCT | MRD only 2/20 |
Extramedullary Relapse 2/20 | |
Morphological Relapse 15/20 | |
CNS only 1/20 | |
Testicular relapse 0/20 | |
Time to relapse post allo-HCT (months) (median, IQR) | 6, 4-12 |
Type of salvage treatment used | Intensive chemotherapy |
FLAG IDA 1/20 (5%) | |
Nelarabine 2/20 (10%) | |
Nelarabine and UKALL induction protocol 1/20 (5%) | |
Venetoclax and UKALL phase 2 1/20 (5%) | |
Non-intensive chemotherapy | |
Vincristine, steroids and Daratumumab 1/20 (5%) | |
VIncristine and steroids 4/20 (20%) | |
Vincristine 1/20 (5%) | |
Other treatments | |
Radiotherapy 1/20 (5%) | |
Palliative treatment 5/20 (25%) | |
Intrathecal Methotrexate 3/20 (15%) | |
Second transplant | Yes 4/20 (25%) |
No 16/20 (75%) | |
Donor Lymphocyte Infusion | Yes 0/20 (0%) |
No 20/20 (100%) | |
Median Overall survival (months) | 3.18 (2-5) |
Conclusions: The prognosis for post allo-HCT relapsed T-ALL is notably grim, with limited success observed in second transplant cases. Even within this context, outcomes remain disheartening. The anticipation for improved strategies is fervent, emphasizing the crucial need for innovative treatments. Ongoing investigations into CAR-T cell therapies, specifically CD7 and CXCR7, offer promising avenues. It is imperative that these novel approaches are actively incorporated into clinical practice, and patients are encouraged to participate in relevant trials. The urgency to explore and adopt these advanced therapeutic modalities underscores the commitment to enhancing outcomes for individuals grappling with relapsed T-ALL post allo-HCT.
Disclosure: Alex Rampotas received conference fees by Gilead. Claire Roddie declares Honoraria: Gilead Sciences Consulting or Advisory Role: Autolus, Kite/Gilead, Bristol Myers Squibb/Celgene Speakers’ Bureau: Novartis Pharmaceuticals UK Ltd, Gilead Sciences Travel, Accommodations, Expenses: Gilead Sciences, Autolus. Anna Louise Latif declares honoraria from Kite and Novartis. All other authors declare no conflicts of interest.
19: Acute Leukaemia
P042 FEASIBILITY OF ALLOGENEIC STEM CELL TRANSPLANTATION (HSCT) IN PATIENTS WITH ACUTE MYELOID LEUKEMIA PREVIOUSLY TREATED WITH CPX-351: REPORT FROM A SINGLE CENTER
Sabrina Giammarco 1, Elisabetta Metafuni1, Maria Assunta Limongiello1, Federica Sorá2, Eugenio Galli1, Filippo Frioni2, John Marra2, Patrizia Chiusolo2, Simona Sica2
1Fondazione Policlinico Universitario A. Gemelli, Rome, Italy, 2Universitá Cattolica del Sacro Cuore, Roma, Italy
Background: CPX-351 (VYXEOS®), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, was approved for the treatment of t-AML or AML-MRC, based on improved survival and remission and comparable safety versus 7 + 3 chemotherapy in a randomized trial in older adults.
The increased use of CPX 351, in association with reduced intensity conditioning regimen and new strategies of GvHD prophylaxis such as PTCY, allows to proceed with HSCT in older patients or previously heavily treated, improving outcomes.
Methods: To assess the feasibility of HSCT in patients with s-AML and t-AML treated with CPX-351, we collected clinical data on 27 consecutive patients submitted to HSCT at our center from February 2019 to October 2023. Then we compared data with 30 patients with AML submitted to HSCT, previously treated with 7 + 3 induction chemotherapy from January 2019 to April 2020.
Results: Of 49 patients treated with CPX-351 from February 2019, all 27 patients with indication to proceed with HSCT, underwent to transplant to consolidate the obtained response. There were 14 males and 13 female, with a median age of 62 yrs (range 43-69). They were all in complete remission except two. Median HCT-CI was 4 (range 0-7). Unrelated donors were the source in 18 patients, haploidentical donors in 8 pts, sibling donors in 1 patient. Stem cell source was peripheral blood in 23 pts, bone marrow in 3 pts and CBU in 1 patient. The median CD34+ cell dose was 4x106/kg (range 0.1-12.779). The main conditioning regimen was the association of Thiotepa, Busulfan and Fludarabine, modulating the busulfan dose according to patient’s comorbidities and performance status, defined by HCT-CI. GVHD prophylaxis regimen was performed with cyclosporine, mycophenolic acid, and cyclophosphamide at day +3 and +5 after HSCT. Engraftment was reached in all patients except one patient who received CBU. Sepsis were identified in 14 patients out 27.
Seven patients developed acute GvHD, all with skin involvement (Stage 2-3); two patients also with gut involvement (Stage 3)and one patient with pulmonary involvement (severe).
1 years OS was 73%. Comparing the two populations, there was no difference in term of gender, disease status at transplant, donor type, donor sex, stem cell source, conditioning regimen, GVHD prophylaxis, sepsis occurrence and GVHD incidence. Significantly statistical difference was found in terms of median age (p = 0.0016), HCT-CI (p = 0.002) as expected, and in terms of median CD34+ stem cell infused, which were significantly higher in the younger comparison population (p = 0.04). (Table 1).
CPX-351 | 7 + 3 induction | p>0.05 | |
---|---|---|---|
Patients | 27 | 30 | |
Gender male/female | 14/12 | 18/12 | p = 0.3 |
Median age (range) | 62 (43-69) | 50 (24-68) | p = 0.00016 |
Disease status at transplant CR/Refractory | 25/2 | 25/5 | p = 0.2 |
Median HCT-CI (range) | 4 (0-7) | 1 (0-6) | p = 0.002 |
Donor type | |||
MUD 8/8 | 11 | 10 | p = 0.2 |
MUD 7/8 | 6 | 3 | |
Sibling donor | 1 | 6 | |
Haploidentical donors | 8 | 8 | |
CBU | 1 | 3 | |
Donor gender male/female | 19/8 | 23/7 | p = 0.2 |
Stem cell source | |||
PBSC | 23 | 20 | p = 0.2 |
BM | 3 | 7 | |
CBU | 1 | 3 | |
Conditioning regimen | p = 0.5 | ||
Myeloablative | 26 | 27 | |
Reduced intensity regimen | 1 | 3 | |
Median CD34 cell dose x106/kg (range) | 4 0.1-1277() | 9.45 (0.09-8.9) | P = 0.04 |
GVHD prophylaxis | p = 0.6 | ||
PTCY | 31 | 32 | |
OTHER | 3 | 1 | |
GVHD Incidence n°(%) | 7/27 (26%) | 14/30 (46%) | p = 0.2 |
Sepsis n°(%) | 14/27 (51%) | 16/30 (53%) | p = 0.9 |
Relapse n°(%) | 8/27 (29%) | 7/30 (23%) | p = 0.8 |
Overall Survival n°(%) | 19/27 (70%) | 23/30 (76%) | p = 0.8 |
Conclusions: Our monocentric experience showed data in line with those reported in the literature. The growing use of CPX-351 appears to be a safe and effective bridge therapy for HSCT in patients with a poorer prognosis, reproducing outcomes similar to younger population.
Disclosure: No disclosure to declare
19: Acute Leukaemia
P043 COMPARISON OF VENETOCLAX-BASED NON-ANTHRACYCLINE INDUCTION THERAPY VERSUS 3 + 7 FOLLOWED BY HEMATOPOIETIC STEM CELL TRANSPLANTATION IN NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA PATIENTS
Tran-Der Tan 1, Lun-Wei Chiou1
1Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan, Province of China
Background: The current standard treatment for fit newly diagnosed acute myeloid leukemia patients is idarubicin or daunorubicin plus cytarabine (3 + 7 regimen), followed by allogeneic hematopoietic stem cell transplantation. However, less than half of them could enter into allotransplant because of not remission or the occurrence of treatment-related morbidity or mortality. Venetoclax plus azacytidine or low-dose cytarabine could achieve a high CR rate in unfit or elderly patients in phase III trials.
Methods: We conducted a treatment protocol of venetoclax 100 mg and posaconazole 300 mg a day according to the pharmacokinetics plus a standard dose of cytarabine (100 mg/m2/d x 7 days) as the induction and consolidation therapy, followed by allogeneic hematopoietic stem cell transplantation for newly diagnosed transplant-eligible patients. And we compared the efficacy and outcome with our prior 3 + 7 induction followed by allo-transplant patients.
Results:
Between Mar 2019 and Dec 2023, we had 22 consecutive newly diagnosed transplant-eligible AML patients, including 8 therapy-related and 14 de novo AML. Eighteen underwent venetoclax plus standard-dose cytarabine, four underwent venetoclax plus azacitidine induction therapy, and twenty out of twenty-two were followed by allogeneic hematopoietic stem cell transplantation. CRc rate was 94.4% in our cohort and 90.9% in the adverse group of patients. Twenty of twenty-two of our patients were transitioned to allo-transplant, as compared with 46.9% in our previous 3 + 7 induction era between 2009 and 2018. Three-year overall survival was improved from 23% to 53% with the transplant patients’ median age from 43 to 52.8. The duration of neutropenia is similar but there was no significant severe watery diarrhea or oral mucositis in our present cohort as compared to the previous 3 + 7 group of patients.
Conclusions: Venetocla-based non-anthracycline induction therapy is feasible and has more propensity to allogeneic transplant in newly diagnosed AML patients and the pre-transplant CR rate and overall survival were improved as compared with conventional 3 + 7 induction, without more safety concerns.
Disclosure: No disclosure of conflict of interest.
19: Acute Leukaemia
P044 MYELOFIBROSIS GRADE II-III IS AN INDEPENDENT RISK FACTOR FOR RELAPSE OF ACUTE MYELOID LEUKEMIA AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Haixiao Zhang1, Erlie Jiang 2
1Peking Union Medical school, Tianjin, China, 2Peking Union Medical School, Tianjin, China
Background: Acute myeloid leukemia (AML) is a heterogeneous and aggressive disease caused by leukemia blasts. Bone marrow microenvironment (BMM) contributes to AML cell development. Myelofibrosis (MF) is characterized by excessive deposition of bone marrow reticulin fibrosis and other extracellular matrix proteins. MF of unknown etiology in hematological malignancies is acknowledged to be a reactive response to leukemic BMM.
AML with MF (AML-MF) is not recognized as an AML entity by the World Health Organization (WHO) classification system [6]. However, MF was approximately 30-72% at the time of diagnosis of AML and myelodysplastic syndromes (MDS), and 15% was marked reticulin fibrosis. Previous studies have shown that moderate to severe MF is a more advanced risk factor in patients with MDS [8-10]. Data pertaining to the AML-MF treatment and prognosis are very limited [11,12]. As far the only therapy to cure AML has been allogeneic hematopoietic stem cell transplantation (allo-HSCT). MF’s prognostic effect, which can be assessed by regular evaluation at diagnosis, in transplant AML patients is remains unknown.
Methods: To evaluate the prognostic impact of myelofibrosis (MF) on allogeneic hematological stem cell transplantation (allo-HSCT) outcomes in patients with acute myeloid leukemia (AML), we analyzed newly diagnosed patients with AML who received allo-HSCT in the National Longitudinal Cohort of Hematological Disease (NICHE, NCT04645199) from January 2014 to April 2023. Among the 532 patients, 255 (47.93%) patients were classified into the MF-0 group, 209 (39.29%) into the MF-1 group, and 68 (12.78%) into the MF-2-3 group at initial diagnosis according to the European consensus on the grading of MF.
Results: The MF-2-3 group showed poor overall survival, disease-free survival and cumulative incidence of relapse (CIR). Multivariate analyses showed that MF-2-3 (hazard ratio [HR] =2.17, P = 0.023) was an independent risk factor for CIR post-transplantation. Furthermore, MF delayed neutrophil and platelet engraftment and delayed B cell recovery post-transplantation. The MF-2-3 group had a higher cumulative incidence of acute graft-versus-host disease and a lower cumulative incidence of EBV-emia and CMV-emia post-transplantation than the MF-0 and MF-1 groups, however, the difference was not statistically significant.
Conclusions: These findings demonstrate the importance of MF in transplant outcomes and has attracted more attention to AML-MF.
Disclosure: none
19: Acute Leukaemia
P045 INCIDENCE AND MANAGEMENT OF ADULT ACUTE LYMPHOBLASTIC LEUKAEMIA RELAPSE AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN LIMITED RESOURCE COUNTRIES
Rihab Ouerghi1, Nour Ben Abdeljelil 1, Sabrine Mekni1, Insaf Ben Yaiche1, Ines Turki1, Rim Dachraoui1, Dorra Belloumi1, Lamia Torjemane1, Rimmel Kanoun1, Saloua Ladeb1, Tarek Ben Othman1
1Service d’Hématologie et de Greffe, Centre National de Greffe de Moelle Osseuse, Tunis, Tunisia
Background: Relapse remains the major cause of failure in adults with high-risk acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem-cell transplantation (AHSCT). The management of relapsed patients is a clinical challenge, especially in limited resource countries. The aim of our study was to evaluate the cumulative incidence of relapse (CIR) post AHSCT, identify predictive factors of relapse and evaluate the outcome and management of relapsed ALL in adult patients.
Methods: A retrospective study was conducted in adult patients who underwent AHSCT from HLA-identical sibling donors between November 2003 and December 2022. Conditioning regimens consisted of fractionated TBI (F-TBI) (3fractions/9.9Gy) with etoposide or cyclophosphamide or chemotherapy-based regimen (intravenous busulfan). GVHD prophylaxis consisted of cyclosporine and short course of methotrexate. Stem cell sources were bone marrow (BM) or peripheral blood stem cell.
Results: One hundred and five patients (69 males and 36 females) were included. Median age is 30 years (18-50 years): 60 B-ALL (57%) and 45 T-ALL (43%). Cytogenetic analysis was available for 83 patients: 33% of patients had high-risk cytogenetic abnormalities (25% had t(9,22) or positive BCR-ABL transcript). Before AHSCT, 86% of patients were transplanted in first complete remission (CR1). MRD was performed in 66% patients (MFC and/or molecular biology) and was positive in 55% of patients. The median time from diagnosis to AHSCT was 6 months (2-137m). Conditioning regimens were TBI-based in 60% of patients and 51% of patients received peripheral blood stem cell. CMV reactivation was observed in 41% of patients. The CI of acute GVHD (≥grade 2) and chronic GVHD were 32% and 50%, respectively. The CI of NRM was 17.6%. The 2-year CIR was 30% (medullary and combined relapse n = 26, extramedullary relapse n = 6, molecular relapse n = 4). The median time of relapse was 9 months (2-46m). Twenty-two patients were managed with palliative cares and 14 received salvage therapy (chemotherapy +/- radiotherapy n = 9, donor lymphocyte infusion n = 1, ITK only n = 4). A second CR was obtained in 8 patients and 3 patients underwent a second AHSCT. At last follow-up, 7 patients are alive. After a median follow up of 29 months (1-207m), the 2-year OS and EFS for the entire cohort and relapsed patients were 60% vs 31% and 53% vs 14%, respectively. At last follow-up, 49 patients (47 %) died. The main cause of death was relapse (n = 26; 53%). In univariate analysis, chemotherapy-based conditioning regimen was the only significant factor of CIR (p = 0.01).
Conclusions: The prognosis of adult patients relapsing after AHSCT is dismal. To reduce the risk of relapse TBI based conditioning regimen and immunotherapy should be considered when possible.
Disclosure: Nothing to declare
19: Acute Leukaemia
P046 IMPACT OF BODY MASS INDEX ON OUTCOME IN ADULT PATIENTS WITH ACUTE MYELOID AND ACUTE LYMPHOBLASTIC LEUKEMIA UNDERGOING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Iveta Oravcova1,2, Zuzana Rusinakova1, Eva Mikuskova1, Miriam Ladicka1, Ludmila Demitrovicova1, Alica Slobodova1, Vanda Mikudova1, Jana Spanikova1, Radka Vasickova1, Denis Urban1, Kristina Bandurova1, Lubos Drgona1,2, Silvia Cingelova 1
1National Cancer Institute, Bratislava, Slovakia, 2Faculty of Medicine Comenius University, Bratislava, Slovakia
Background: Obesity has been recognized as risk factor for many types of cancer and at the same time it is considered as an adverse prognostic factor associated with cancer survival. This study assessed the effect of body mass index (BMI) on transplantation outcomes in allogeneic hematopoietic cell transplantation (HCT) in AML and ALL recipients.
Methods: We retrospectively analyzed 98 adult AML and ALL patients who were followed up after alloSCT in National Cancer Institute in Slovakia between March 2013 and October 2023.
According to the World Health Organization (WHO) international BMI classification, patients were classified as obese when BMI was ≥ 30kg/m2. We divided patients into 2-groups: BMI < 30kg/m2 (non-obese patients) and BMI ≥ 30kg/m2 (obese patients).
Results: At median follow up 22,3 (4,1-125,8) months, 98 patients entered the analysis (median age at alloSCT 49 years, 53 (54,5%) male). Median BMI value was 24,84 kg/m2. We identified 80 patients with BMI < 30kg/m2 (81,6%) and 18 (18,4%) with BMI ≥ 30kg/m2. There was no difference in the prevalence of obesity between the genders (p = 0,299).
1 and 3- year overall survival (OS) for the BMI < 30kg/m2 group was 68,6% (CI 95%; 58,1% - 79,0%) and 45,9% (CI 95%; 33,3% - 58,5%) with median OS 34,5 months (CI 95% 18,3-57,0); and for the obese group 32,5% (CI 95%; 9,4% - 55,6%) and 13,0% (CI 95%; 0,0% - 27,9%) with median OS 4,6 months (CI 95% 3,0-8,5). The difference between groups was statistically significant, HR 0,34 (95% CI 0,15-0,79); (p = 0,0002).
1 and 3- year relapse free survival (RFS) for the BMI < 30kg/m2 group was 58,8% (CI 95%; 47,8% - 69,8%) and 41,2% (CI 95%; 29,1% - 53,4%) with median RFS 30,1 months (CI 95% 8,5-42,9); and for the obese group 20,7% (CI 95%; 0,4% - 41,1%) and 13,8% (CI 95%; 0% - 31,3%) with median RFS 3,5 months (CI 95% 1,9-4,4). The difference between groups was statistically significant, HR 0,39 (95% CI 0,18-0,87); (p = 0,001).
Obese patients have higher 12-months cumulative incidence of relapse rates than non-obese patients: 53,7% (CI 95%; 29,1%-99,3%) vs 29,5% (CI 95%; 20,5%-42,3%). There was no difference in non-relapse mortality between obese and non-obese patients.
Conclusions: Patients with BMI ≥30kg/m2 had significantly lower one and three-year survival rates and higher cumulative incidence of relapses than those with BMI <30kg/m2.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P047 VENETOCLAX COMBINED WITH HMAS-BASED THERAPY AS PRE-EMPTIVE TREATMENT FOR ACUTE MYELOID LEUKEMIA PATIENTS AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Mimi Xu 1,2,3, Yuqing Tu1,2,3, Mengqi Xiang1,2,3, Yi Fan1,2,3, Xiang Zhang1,2,3, Tiemei Song1,2,3, Lian Bai4, Xiaoli Li5, Yang Xu1,2,3, Yuejun Liu1,2,3, Jia Chen1,2,3, Depei Wu1,2,3
1National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China, 2Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China, 3Key Laboratory of Stem Cells and Biomedical, Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Suzhou, China, 4Canglang of Suzhou Hospital, Suzhou, China, 5Soochow Hopes Hematonosis Hospital, Suzhou, China
Background: Accumulating evidences indicated the effectiveness and importance of measurable residual disease (MRD) guided pre-emptive therapy in acute myeloid leukemia (AML) patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, limited data is available on the pre-emptive utility of venetoclax (VEN) for MRD positive in AML patients post-HSCT. This study was conducted to explore the efficiency and tolerability of VEN combined with hypomethylating agents (HMAs) based treatment for AML patients with MRD positive post-HSCT.
Methods: We collected retrospectively the data from 10 patients who underwent first allo-HSCT with high-risk AML between July 2020 and April 2022 and initiated VEN-based pre-emptive threapy for MRD positivity between March 2021 and July 2022 in our center for analysis. Patients who experienced haematological relapse before VEN-based pre-emptive treatment were excluded. The VEN combined with HMAs-based treatment regimen comprised 100 mg VEN daily on day 1 to day 21 and 15 mg/m2 decitabine on day 1 to day 3 or 75mg/m2 azacytidine on day 1 to day 5 (or day 7). FLT3-ITD positive patients also added FLT3 inhibitor sorafenib (400mg scheduled for days 1 to 21). The primary endpoints of this study were MRD response, overall survival (OS) and event free survival (EFS). The secondary endpoints included adverse events (AEs), cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM).
Results: 10 patients were included. The median age of the patients at the time of transplantation was 49 (range, 16-57)y. The rate of MRD response was 70.0% (7/10) and 71.4% (5/7) of whom achieved MRD response after first circle of VEN-based combination threapy. The median time from initiating VEN-based pre-emptive threapy to MRD response was 64 (10-175) d. For MRD response patients, two of whom appeared hematologic relapse on day 271 and 336 after MRD response respectively. Three patients had not achieved MRD response, 2 of whom experienced hematological relapse and 1 died from severe GVHD and transplantation associated thrombotic microangiopathy. During the study, we found no tumor lysis syndrome and severe AE for all patients. The median follow-up was 440.5 (88-872) d. 5 patients still had EFS and were alive with MRD negative CR at the time of last follow-up. Overall, the 1-y OS and EFS after VEN-based pre-emptive threapy were (80.0±12.6)% and (60.0±15.5)%, respectively. The cumulative incidence of relapse (CIR) at one years was (30.0±2.4)%, and nonrelapse mortality was (10.0±1.0)%.
Table 1 Patient characteristics
Total patients | 10 | % |
---|---|---|
Median age at transplantation, y (range) | 49(16-57) | |
Gender | ||
Male/Female | 5/5 | |
MRD positive detection method before pre-emptive threapy | ||
Flow cytometry | 4 | 40 |
PCR | 8 | 80 |
DNA sequence | 2 | 20 |
Disease status at transplant | ||
CR | 9 | 90 |
MRD− | 1 | 10 |
MRD+ | 8 | 80 |
NR | 1 | 10 |
Donor type | ||
Haploidentical | 7 | 70 |
Identical sibling | 1 | 10 |
Unrelated | 2 | 20 |
Median days of neutrophils ≥0.5 × 109/L after transplant | 11(10-14) | |
Median days of platelets ≥20 × 109/L after transplant | 12.5(10-74) |
Conclusions: We conclude that VEN combined with HMAs-based regimen as pre-emptive treatment is efficient for patients with AML post-HSCT and with acceptable side effects.
Disclosure: Nothing to declare
19: Acute Leukaemia
P048 VENETOCLAX, AZACITIDINE, COMBINED WITH LOW-DOSE CYTARABINE IMPROVE THE REMISSION RATE IN OLDER OR UNFIT PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA
Xiao Han1, Qingxiao Song 1, Kai Wan1, Mengyun Zhang1, Xue Liu1, Hongju Yan1, Cheng Zhang1, Qin Wen1, Xi Zhang1
1Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, China
Background: Older or unfit patients with acute myeloid leukemia (AML) have a dismal prognosis. The combination of venetoclax with azacitidine had promising efficacy, but the minimal residual disease (MRD) negative rate is only 30-40%. In most cases measurable residual disease (MRD) positivity predicts hematologic relapse potentially allowing early therapeutic intervention.
Methods: This is a prospective, one-arm, multicenter, open clinical trial, Adults age ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled. Patients received induction treatment with venetoclax 100mg d1, 200mg d2, 400mg d3-28, azacytidine 75mg/m2 d1-7, cytarabine 10mg/m2 q12h d1-7. The primary observation was the remission rate (CR/CRi) and the negative rate of MRD.
Results: The baseline characteristics of 46 older or unfit patients who can evaluate the efficacy are presented in Table 1. Following the first course of Ven+AZA + LDAC treatment, the outcomes were as follows: 27 patients (58.7%) achieved complete remission (CR) with negative minimal residual disease (MRD), 14 patients (30.4%) achieved CR with positive MRD, 1 patients (2.2%) experienced partial remission (PR), and 4 patient (8.7%) did not achieve remission (NR). The overall response rate (ORR) was 91.3%. Subgroup analysis revealed that out of the 23 older patients, 16 (69.6%) achieved CR with negative MRD, 6 (26.1%) achieved CR with positive MRD. Among the 23 initially diagnosed unfit patients, 11 (47.8%) reached CR, with 8 (34.8%) showing negative MRD, 1 (4.3%) experiencing PR, and 3 (13.0%) not achieving remission. The median follow-up time was 8.3 months (range: 3-24.3 months), and the estimate median overall survival (OS) was 20.34 months. Subgroup analysis revealed that older patients had better survival outcomes compared to unfit patients, although the difference was not statistically significant. Among them, 9 patients had underwent allogeneic hematopoietic stem cell transplantation (HSCT), and 8 of the 9 HSCT patients were alive at the time of manuscript writing, One patient died because of SCT related thrombotic microangiopathy (TMA). This observation might be attributed to the limited sample size, indicating the necessity of gathering more data for comprehensive analysis. Safety: All the 23 older patients had neutropenia, which controlled after therapy, without severe infection and bleeding complications. 23 patients with unfit had severe complications such as severe infection, respiratory failure, or intracranial hemorrhage before treatment, but no treatment-related deaths occurred during the induction period.
Characteristic | N = 46 | Frequency |
---|---|---|
Median (range) | 59.29(32-73) | |
Older (average age) | 23 (49.7) | 50% |
unfit (average age) | 23 (66.4) | 50% |
Male, n (%) | 25 | 54.35% |
Baseline neutropenia, n(%) | ||
Grade 3 | 7 | 15.2% |
Grade 4 | 15 | 32.6% |
FAB classification, n (%) | ||
AML-M1 | 7 | 15.2% |
AML-M2 | 20 | 43.5% |
AML-M4 | 6 | 13.1% |
AML-M5 | 10 | 21.7% |
others | 3 | 6.5% |
Cytogenetic risk category, n (%) | ||
Favorable | 9 | 19.6% |
Intermediate | 20 | 43.5% |
Adverse | 17 | 36.9% |
Somatic mutations | ||
DNMT3A | 12 | 30.77% |
NPM1 | 11 | 28.21% |
FLT3-ITD | 10 | 25.64% |
IDH2 | 7 | 17.95% |
CEBPA | 6 | 15.38% |
IDH1 | 5 | 12.82% |
TP53 | 3 | 7.69% |
Transfusion dependent at baseline, n (%) | ||
Red blood cells | 15 | 32.6% |
Platelets | 13 | 28.3% |
Conclusions: The incidence of remission was higher among newly diagnosed older patients who received Ven+AZA + LDAC, especially CR with negative MRD. However, the remission rate of unfit AML patients has been improved compared to traditional chemotherapy, but the negative rate of MRD has not improved. Infection, chemotherapy-related mortality, and the tolerability were acceptable. At the same time, it would be contribute to provide transplant conditions for patients and prolong survival. However, it is necessary to further expand the sample size and extend the follow-up time to assess the long-term survival rate.
Clinical Trial Registry: ChiCTR2200063804
Disclosure: Nothing to declare.
19: Acute Leukaemia
P049 TARGET THERAPY IN ACUTE LEUKAEMIA RELAPSES AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Riccardo Boncompagni 1, Chiara Camerini1, Ilaria Cutini1, Mirella Giordano1, Antonella Gozzini1, Chiara Nozzoli1, Edoardo Simonetti1, Riccardo Saccardi1
1BMT Unit, Careggi University Hospital, Firenze, Italy
Background: New drugs targeting acute leukaemia antigens or cellular survival/proliferation pathways are granting promising results in patients with relapsed and/or refractory acute leukaemia leading more patients to achieve a control of disease and access to allogenic hematopoietic stem cell transplantation (HSCT), the only potentially curative treatment. Here we investigated if target-therapy can confer a real-life survival advantage also in patients who relapse following HSCT, a population characterized from a very poor prognosis.
Methods: We retrospectively analysed data from patients affected by acute myeloid, mixed-phenotype, lymphoblastic leukaemia (AML, MPAL, ALL respectively) and blast crisis of chronic myeloid leukaemia (CB-CML) who performed allogeneic HSCT at Careggi University Hospital of Florence in the last 10 years. Primary endpoint of the current research was to compare overall survival (OS) and progression free survival (PFS) between patients treated or not with target therapy. Target therapy was administered based on availability at our institution.
Results: We found 288 HSCT performed for 275 patients. Indication for HSCT was AML for 196 (68%), ALL for 74 [24%; 25 (34%) with BCR/ABL mutation, 12 (16%) of T-lineage], CB-CML for 11 (4%) and MPAL for 10 (3%). Median age was 50 (19 – 69) and median comorbidity index (HCT-CI) was high (3; 0 – 9); however reduced intensity conditioning regimen was used only in 93 (32%). A significant number of AML was in active disease status at the time of HSCT (74, 38%), and molecular or cytofluorimetric minimal residual disease was detectable in more than half of the others (86 out of 122, 70%). Median OS was not reached, with 57% of patients alive with a 69 months median follow-up. Relapse incidence after HSCT was 36% (n = 100) and median PFS was reached at 18 months (95% confidence interval [CI]: 7 – 29). In the group who received a target therapy (n = 63) we observed both an OS (45 vs 7 months; p < 0,001) and PFS advantage (26 vs 2 months; p 0<,001). Donor lymphocytes infusions (DLI) was administered in 38% (n = 24) of target therapy group and conferred a further OS advantage (11 vs 42 months; p = 0,022). Finally, 3 out of 13 (23%) patients who performed a second HSCT after savage therapy with target therapy were alive and in complete remission at the time of their last follow-up.
Conclusions: Despite the low potency of monocentre retrospective study, our results support the hypothesis that new therapies for acute leukaemia are effective for patients who relapse following HSCT, and the possibility of combination of DLI and of a subsequent second HSCT may grant a longer survival in this very high-risk population.
Disclosure: We declare no potential conflict of interest.
19: Acute Leukaemia
P050 ALLOGENEIC STEM CELL TRANSPLANTATION IN THE MANAGEMENT OF ADULT ACUTE LYMPHOBLASTIC LEUKAEMIA: A TEN YEAR EXPERIENCE IN IRELAND’S NATIONAL ADULT ALLOGENEIC TRANSPLANT CENTRE
Conor Browne 1, Micheal Brennan1, Mairead Ni Chonghaile1, Sarah Maher1, Greg Lee1, Deirdre Waldron1, Nicola Gardiner1, Michelle Regan1, Lorraine Brennan1, Carmel Waldron1, Catherine M. Flynn1, Eibhlin Conneally1, Patrick J. Hayden1, Robert Henderson1, Elisabeth Vandenberghe1, Christopher L. Bacon1
1St James Hospital, Dublin 8, Ireland
Background: Adult acute lymphoblastic leukaemia (ALL) historically carries a poor prognosis with cure rates of less than 40%. Despite advances in therapeutics, allogeneic stem cell transplantation (AlloSCT) remains pivotal in the management of patients with high risk adult ALL.
Methods: The records of consecutive ALL patients receiving AlloSCT between 01/01/2013 and 31/12/2022 were retrieved from the St. James’ Hospital transplant-database and their electronic medical records. Progression free survival (PFS) and overall survival (OS) were estimated via the Kaplan-Meier method.
Results: 89 patients with ALL received AlloSCT. Clinical details are shown in Table-1. 74 (83%) had B-ALL with a median white cell count (WCC) of 30x109/L (0.5-830) at diagnosis. 15 (17%) had T-ALL with a median WCC of 100x109/L (4.9-470) at diagnosis.
38 patients (43%) had high-risk cytogenetics defined as having either a Philadelphia chromosome t(9;22)(q34;q11), N = 17 (9%), KMT2A rearrangement t(4;11)(q21;q23) N = 12 (13%), complex karyotype N = 2 (2%), low-hypodiploid N = 4 (4%) or near-triploid haplotype N = 3 (3%). 64 patients (72%) achieved complete remission (CR) post induction therapy. 13 (15%) had primary refractory disease and 16 (18%) in remission relapsed prior to transplant requiring re-induction. 73 (82%) were transplanted in CR1, 14 (16%) in CR2, 1 in CR3 and CR4.
The median time from diagnosis to transplant was 6 months (2-85). The median CD34 cell count infused was 3.32x106/kg (0.67-5.7) with a median CD3 cell count of 3.08x107/kg (1.21-52). The median days to neutrophil engraftment was 21 (10-34) and to platelet engraftment was 18 (9-96).
66 patients (74%) developed graft-versus-host-disease (GVHD); 63 (71%) acute-GVHD and 30 (34%) chronic-GVHD. Acute-GVHD occurred at a median of 30 days (13-298) post-transplant. 16 (18%) experienced Grade I, while 47 (53%) developed Grade II-IV acute-GVHD. Of those with acute-GVHD, 15 cases (24%) were steroid refractory requiring additional therapies including ruxolitinib, mycophenolate-mofetil, extracorporeal-photopheresis and ATG.
30 patients (34%) developed viral reactivation involving CMV, EBV or adenovirus. 5 patients had associated EBV post-transplant lymphoproliferative disorder.
9 patients (10%) received donor-lymphocyte infusions (DLI) at a median time of 12 months (4-33) post-transplant. 8 received pre-emptive DLI for mixed chimerism, 1 received therapeutic-DLI for relapsed disease. 3 patients developed acute-GVHD post-DLI. 7 cases (80%) achieved complete donor chimerism post-DLI.
The median duration of follow-up was 36 months (1-129). 18 patients (20%) relapsed at a median time of 8.5 months (1-63) post-transplant. Treatment strategies at relapse included blinatumomab, inotuzumab, Hyper-CVAD, nelarabine, TKIs, palliation and CAR-T therapy.
27 patients (30%) died during follow-up at a median time of 9 months (1-71) post-transplant; relapse-related mortality N = 11 (12%), transplant-related mortality (TRM) N = 14 (16%), lost to follow-up N = 2 (2%). Causes of TRM included GVHD (N = 3), veno-occlusive disease (N = 1), infection (N = 7), EBV-PTLD (N = 1), neurological complication (N = 1) and secondary malignancy (N = 1). The 100-day TRM rate was 6%.
The 5-year OS was estimated at 69% with a 5-year PFS of 62% as shown in Graph-1. OS or PFS didn’t differ significantly between those with acute-GVHD and those without (p = 0.7).
Table 1. Clinical Details
N = 89 | Transplant Details | N = 89 | |
---|---|---|---|
Stem Cell Source: no. (%) | |||
Median Age at Transplant (Range) | 36 (16-61) | Bone Marrow | 58 (65) |
Peripheral blood | 31 (35) | ||
Gender: no. (%) | Conditioning Intensity: no. (%) | ||
Male | 50 (56) | Myeloablative | 68 (76) |
Female | 39 (44) | Reduced Intensity | 21 (24) |
Induction Regimen: no. (%) | |||
UKALL 12/14 | 64 (72) | MAC Conditioning Regimen: no. (%) | |
UKALL 03/11 | 14 (15) | Cyclophosphamide/TBI | 60 (67) |
Hyper-CVAD | 9 (10) | Cy/TBI + ATG | 4 (4) |
FLAG-Ida | 1 (1) | Busulphan/Cyclophosphamide | 2 (2) |
N/A | 1 (1) | Fludarabine/TBI+PTCy | 2 (2) |
Donor Status: no. (%) | RIC Conditioning Regimen: no. (%) | ||
Related | 35 (39) | Flu/Melphalan/Alemtuzumab | 20 (22) |
Unrelated | 54 (61) | Cy/TBI/Alemtuzumab | 1 (1) |
Co-Morbidity Index: no. (%) | GVHD Prophylaxis: no. (%) | ||
HCT-CI 0-1 | 49 (55) | Tacrolimus | 49 (55) |
HCT-CI >/ = 2 | 28 (32) | Ciclosporin | 38 (43) |
HCT-CI N/A | 12 (13) | PTCy/MMF | 2 (2) |
Recipient Viral Status: no. (%) | HLA status: no. (%) | ||
CMV IgG +ve | 39 (44) | Matched 10/10 | 76 (85) |
EBV IgG +ve | 81 (91) | Mismatched (single allelic) | 13 (15) |
Conclusions: AlloSCT in high-risk patients is an effective strategy for the management of adult ALL with a 5 year OS of 69% in this cohort.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P051 FLT3-MUTATED AML: MANAGEMENT AND LONG-TERM OUTCOME OVER 24 YEARS AT A SINGLE CENTER
Saveria Capria 1, Silvia Maria Trisolini1, Lorenzo Torrieri2, Elena Amabile2, Giovanni Marsili3, Alfonso Piciocchi3, Walter Barberi1, Daniela Diverio1, Daniela Carmini1, Massimo Breccia2, Maurizio Martelli2, Clara Minotti1
1AOU Policlinico Umberto I, Rome, Italy, 2Sapienza University, Rome, Italy, 3GIMEMA Foundation, Rome, Italy
Background: The introduction of tyrosine kinase inhibitors (TKIs) in the treatment of FLT3-mutated AML has been a therapeutic breakthrough. However, prognosis remains challenging.
Methods: We retrospectively analyzed all patients with FLT3-mutated AML who were eligible for intensive therapy and treated at our institution since 1999, focusing on changes in management over time and the impact of TKI treatment.
Results: The cohort comprised 140 patients (68M/72F) with a median age of 51 years (14-73), 28 (21%) had WBC ≥100,000/µl at diagnosis and 38 were older than 60 years. The ITD/TKD ratio was 120/20 and 73 patients (52%) had NPM1 co-mutation.
Until 2018, 101/140 patients received the DCE regimen without TKI, while 39/140 patients diagnosed since 2018 received 3 + 7+midostaurin.
The overall CR rate was 64% (90/140), and 73% (53/73) in NPM1-mutant patients, regardless of TKI treatment during induction.
The CR rate was similar in both younger and older patients and was positively influenced by co-existing NPM1 mutation (p: 0.032) and WBC count <100,000/µl (p = 0.013) in univariate analysis. TKI administration during induction did not have a significant effect.
In a multivariate model adjusting for sex and age, only WBC count was confirmed to have an independent prognostic impact on response (OR 3.04 – CI 1.23-7.71 – p = 0.017).
Allogeneic transplantation was performed in 41/90 patients who achieved CR1 (22/60 no-TKI and 19/30 TKI), the transplantation rate between no-TKI and TKI patients is not statistically significant. Autologous transplantation was performed in 18 patients. No transplantation was performed in 31 patients.
The median probability of EFS at 3 and 6 years is comparable between autografted and allografted patients (1.1 vs. 1.6 years respectively – p = 0.9).
The cumulative incidence of 1-year non-relapse mortality was 0.00% for autologous and 28% (CI: 15-42) for allogeneic transplantation (p = 0.007), while the cumulative incidence of 1-year and 3-year relapse was 39% (CI: 17-61) vs. 15% (CI: 6.1-28) and 57% (CI: 30-77) vs. 21% (CI: 9.5-35), respectively (p = 0.004).
There was no statistical difference in outcome based on TKI administration at induction, although these data may be affected by the smaller number of patients in the TKI group.
Forty-three patients (34 no-TKI and 9 TKI) were refractory to induction. Twenty-five received salvage treatment (10 CHT + TKI, 4 single-agent TKI, 11 standard CHT). Of the 14 patients who received a TKI-containing regimen, 11 underwent allogeneic transplantation while none of the patients in the standard CHT group underwent transplantation. The 5-year OS of transplanted patients after salvage treatment is 51%.
Overall, 70/140 patients received stem cell transplantation, 18 autologous and 52 allogeneic (41 CR1 and 11 refractory). In 8/52 cases, preemptive TKI treatment was administered post-transplant due to FLT3 mutation recurrence in morphologic CR; all patients are alive at a median of 65 months (range 16-98) post-transplant and TKI treatment was discontinued after 2 years of continuous CR.
Conclusions: Allogeneic transplantation remains crucial in FLT3-mutated AML. However, several unanswered questions remain, such as how to optimize the use of different inhibitors to achieve the best pre-BMT response, and the potential impact of preemptive post-transplant therapy.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P052 THE ROLE OF TOLEROGENIC DENDRITIC CELLS IN SUPPRESSING AND DCLEU IN INCREASING ANTILEUKEMIC CYTOTOXICITY
A.S. Hartz1, L. Li1, H. Aslan1, E. Pepeldjiyska1, E. Rackl1, T. Baudrexler1, P. Bojko2, J. Schmohl3, A. Rank4, C. Schmid4, H.M. Schmetzer 1
1Working-Group: Immune-Modulation, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany, 2Rotkreuzklinikum Munich, Munich, Germany, 3Department of Hematology and Oncology, Stuttgart, Germany, 4University Hospital of Augsburg, Augsburg, Germany
Background: Novel immunotherapies that overcome immunescape of acute myeloid leukemia (AML) cells are urgently needed. AML establishes a tolerant, immune-inert microenvironment e.g. by accumulating tolerogenic dendritic cells (tDCs). TDCs are dendritic cells and can be generally characterized by a modified cytokine production, ultimately leading to T-cell anergy. In this study we focused on tDCs expressing ILT-3, CTLA4, PD-1, IL3RA.
Leukemia-derived dendritic cells (DCleu) can be generated ex vivo directly from leukemic whole blood (WB) by using (clinically approved) GM-CSF and PGE-1 (Kit-M), leading to antileukemic immune responses after mixed lymphocyte culture enriched with patients’ T-cells (MLC).
Aims: To evaluate Kit-M on frequencies of DCleu or tDCs and on DC mediated (antileukemic) effects and to correlate results with patients’ clinical characteristics.
Methods: WB samples from 18 AML patients and 5 healthy WB samples were treated with vs without Kit-M to generate DC/DCleu and to quantify tDCs. After MLC, leukemia specific/antileukemic effects were assessed through the degranulation-, the intracellular IFNγ production- and the cytotoxicity fluorolysis assay. Quantification of cell subtypes was performed via flow cytometry.
Results: Treating leukemic WB with Kit-M vs control increased significantly frequencies of (mature) DCleu without induction of blast proliferation and significantly decreased frequencies of tDCs (DCs co-expressing ILT-3, CTLA4, PD-1 or IL3RA). After T-cell enriched MLC of Kit-M treated vs. not pretreated WB, frequencies of immunoreactive cells (e.g. non-naïve T-cells, CIK cells) were (significantly) increased, of regulatory T-cells (e.g. CD152 + T-cells) were (significantly) decreased, of activated T-cells (e.g. CD154 + T-cells) were increased and degranulating (CD107a + ) and intracellular IFNγ positive (e.g. CD107a+ non-naïve, - central memory, - non-naïve) T-cells were (significantly) increased. A cytotoxicity fluorolysis assay showed an improved blast lysis in Kit-M treated WB compared to control. We found negative correlations between frequencies of tDCs and improved blastolytic functionality and confirmed positive correlations between frequencies of DC/DCleu and improved blastolytic functionality. In patients with favourable (vs adverse) ELN risk stratification and response to chemotherapy (vs no response) lower frequencies of tDCs were found.
Conclusions: Kit-M treatment of leukemic WB was shown to induce DC/DCleu, to reduce tDCs and to induce leukemia-specific antileukemic immune cells after mixed lymphocyte culture. Reduction of tDCs correlated negatively with improved blastolytic functionality. Kit-M in vivo treatment could lead to an improved immune response and overcoming the immunosuppressive tumor environment in vivo.
Disclosure: Modiblast Pharma GmbH (Oberhaching, Germany) holds the European Patent 15 801 987.7-1118 and US Patent 15-517627 ‘Use of immunomodulatory effective compositions for the immunotherapeutic treatment of patients suffering from myeloid leukemias’, with whom H.M.S. is involved with.
19: Acute Leukaemia
P053 TREATMENT EFFICACY OF BLINATUMOMAB FOR MAINTENANCE THERAPY OF PATIENTS WITH B-LINEAGE ACUTE LYMPHOBLASTIC LEUKEMIA RECEIVING ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION
Jiayu Huang1, Luxiang Wang1, Chuanhe Jiang1, Zilu Zhang1, Zengkai Pan1, Ling Wang2, Jieling Jiang2, Jiong Hu2, Jun Zhu3, Lijing Shen4, Suning Chen5, Yang Cao6, Xiaoxia Hu 1
1State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 2Shanghai Institute of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 3GoBroad Medical Institute of Hematology (Shanghai Center), Liquan Hospital, Shanghai, China, 4Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 5National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China, 6Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Background: Allogeneic hematopoietic cell transplantation (allo-HSCT) is still a potentially curative therapy for high-risk B-lineage acute lymphoblastic leukemia (B-ALL). However, relapse is the major cause for transplant failure, especially within the first two years after allo-HSCT.
Methods: This multicenter, retrospective study was designed by the First Affiliated Hospital of Soochow University, Wuhan Tongji Hospital, Shanghai Renji Hospital, Shanghai Zhaxin Hospital and Shanghai Ruijin Hospital, to evaluate the efficacy and safety of blinatumomab as maintenance therapy after allo-HSCT in B-ALL patients. Consecutive patients diagnosed with B-ALL from November 2021 to April 2023 were screened, and the eligibility criteria were as followed: (1) aged ≥ 14 years; (2) patients were MRD-negative measured by flow cytometry with a sensitivity of 0.02%; (3) B-ALL with CD19 expression; (4) patients with complete medical information. The last follow-up was November 30, 2023. As pre-determined schedule, blinatumomab was administrated as a continuous infusion for 14-21 days.
Results: A total of 17 patients were retrospectively enrolled. The median age was 30-year old (range, 14-60). Before allo-HSCT, one patient was in relapse, four in second complete remission (CR) and the other patients (n = 12) in first CR. 76.5% patients (n = 13) were categorized as high-risk B-ALL according to NCCN 2023. 88.2% (n = 15) patients received graft from haploidentical donors. The median interval from transplant to the start of blinatumomab maintenance was 102 days (range, 42 to 227), with a median course of 1 (range, 1-6). Only four treatment courses were temporarily discontinued due to infection in the first cycle of blinatumomab maintenance, but the remaining thirty treatment courses were completed without interruptions. With a median follow-up of 269 days (range, 120-674), the 1-year overall survival (OS), event-free survival, relapse, and graft versus host disease (GVHD)-free and relapse-free survival for all patients were 69.1% (95% CI 44.2%-100%), 72.6% (95% CI 49.9%-100%),10.4% (95% CI 8.3-12.5%) and 72.9% (95% CI 50.3%-100%) respectively. One patient (P15) received one cycle of blinatumomab at 3-month after allo-HSCT, and relapsed at 8.5 months. Outcomes of patients based on different classification were shown in Table 1. Patients with negative MRD pre-HSCT had a superior OS as compared to those with positive MRD (not reached vs. 286 days P = 0.024). Two patients died of non-relapse causes related to blinatumomab, including transplant-associated thrombotic microangiopathy (n = 1) and blood stream infection (n = 1). The incidence of grade III-IV acute GVHD associated with blinatumomab was 2.9% (n = 1).
Table 1: Follow-up outcome of allo-HSCT patients based on MRD pre-allo-HSCT or R-DRI or NCCN 2023 risk
Classification | Total (n) | Outcome | ||
---|---|---|---|---|
Sustained remission (n,%) | Relapse (n,%) | NRM (n,%) | ||
Pre-allo-HSCT | ||||
MFC-MRD- | 14 | 13(92.9) | 0(0) | 1(7.1) |
MFC-MRD+ | 3 | 1(33.3) | 1(33.3) | 1(33.3) |
R-DRI | ||||
Intermediate risk | 12 | 11(91.7) | 0(0) | 1(8.3) |
High risk | 5 | 3(60) | 1(20) | 1(20) |
NCCN 2023 | ||||
Standard risk | 4 | 3(75) | 0(0) | 1(25) |
High risk | 13 | 11(84.6) | 1(7.7) | 1(7.7) |
Conclusions: Blinatumomab maintenance after allo-HSCT is safe and feasible, however, its long-term effect on immune reconstitution should be concerned.
Clinical Trial Registry: Not applicable.
Disclosure: This work was supported by the National Natural Science Foundation (82170206 to X.H.) and all authors have no conflict of interest to declare.
19: Acute Leukaemia
P054 EFFICACY, SAFETY AND TOLERABILITY OF MITOXANTRONE HYDROCHLORIDE LIPOSOME CONTAINING REGIMEN IN TREATING RELAPSED ACUTE MYELOID LEUKEMIA AFTER ALLOGENIC STEM CELL TRANSPLANTATION
Li Liu 1, Yigeng Cao1, Ni Lu1, Erlie Jiang1
1Center of Hematopoietic Stem Cell Transplantation, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Background: Disease relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a prevalent cause of poor prognosis and decreased survival rate for patients (pts) diagnosed with acute myeloid leukemia (AML). Currently, chemothrapy is one of the common strategies, however its efficacy is still limited. Mitoxantrone hydrochloride liposome (Lipo-MIT) is an innovative drug which could potentially provide a new approach for relapsed AML after allo-HSCT.
Methods: From April 29, 2022 to April 19, 2023, 13 adults with relapsed AML after allo-HSCT were enrolled (patient’s characteristics in Table 1). All ofpatients received the Lipo-MIT containing regimen with the dose levels of Lipo-MIT between 20 mg/m2 to 24 mg/m2, followed with donor lymphocyte infusion (DLI). The median dose of Lipo-MIT administered in clinical practice was 19.90 (range 17.00-31.51) mg/m2 per cycle.
Results: The study included a total of 13 pts with a median age of 35 (range 20-53) years old. The risk classification at initial diagnosis, based on the 2022 European LeukemiaNet (ELN) criteria, was favorable (1/13), intermediate (8/13) and adverse (4/13). Prior to the last allo-HSCT, all patients achieved remission, with 9 pts in complete remission 1 (CR1), 1 pts in CR2, and 3 pts in CR3 or higher. The pre-HSCT minimal residual disease (MRD) status, assessed by flow cytometry, was negative in 9 pts and positive in 4 pts. Three patients had extramedullary infiltration but not central nervous system (CNS) leukemia. Before the enrollment, 9 pts experienced their first relapse, with 5 relapsing within 12 months and 4 after 12 months, as well as 4 ptshad relapsed more than one time.
After one cycle of treatment, 4 pts achieved CR with negative MRD, 1 patient achieved CR but MRD remained positive, and 4 pts achieved CR with incomplete hematologic recovery (CRi). Both overall response rate (ORR) and composite (CRc) was 69.23% (95% CI 38.57-90.91%). The most common treatment regimen among patients who achieved CR/CRi was a MAC-based regimen (Lipo-MIT, cytarabine and cyclophosphamide, with or without targeted drugs), used in 6 out of 9 pts.
The median follow-up period was 6.41 months (range 2.10-16.43). Disease progression occurred in 4 out of 13 pts. Seven patients died after treatment, however, no correlation with treatment was obeserved. The median progression-free survival (PFS) was 3.06 months (range 0.62-7.62), while the median overall survival (OS) was 9.49 months (range 2.10-16.43). The hematological grade 3/4 TRAEs were anemia (53.85%), thrombocytopenia (46.15%), leukopenia (38.46%), and neutropenia (23.08%). The most common non-hematological grade 3/4 TRAEs was infections (76.92%), but no fetal infections were occoured.
Conclusions: Lipo-MIT containing therapy, particularly the MAC-based regimen, appears to be an effective and tolerable treatment for relapsed AML after allo-HSCT. It is worthwhile to further explore safety and more effective combination therapy of Lipo-MIT.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P055 STUDY ON THE EFFICACY AND SAFETY OF BLINATUMOMAB MAINTENANCE THERAPY OF HIGH RISK PH NEGATIVE ALL AFTER ALLO-HSCT
Zhang Jianping1, Li Nannan1
1Hebei Yanda Ludaopei Hospital, Langfang, China
Background: Immunotherapy provides more opportunities for Allo-HSCT after complete remission for refractory/recurrent B-ALL. However, it is still difficult to achieve long-term survival after Allo-HSCT recurrence, especially recurrence in the early stage. Therefore, how to reduce the recurrence of high-risk PH-negative B-ALL through prevention is still an urgent problem to be solved.
Methods: Group entry criteria:
- 1.
With high-risk cytogenetic and molecular biological changes in accordance with the definition of ELN.
- 2.
Receiving an immunotherapy before transplantation, there is still MRD positive or MRD returning to positive in a short time after turning negative.
- 3.
Extramedullary leukemia occurred before transplantation.
- 4.
MRD 10-6 to 10-4 after transplantation. Treatment: two months after Allo-HSCT, if there’s no active GVHD or uncontrolled infection, we’ll give two weeks Blinatumomab continuous injection. If there’s no contraindication after 45 days we’ll give another cycle of Blinatumoma. During the course we observe the infusion reaction, hepatorenal toxicity, hematotoxicity, GVHD and other complications.
Results: There are ten patients accepted Blinatumomab after Allo-HSCT. 3 patients got fever, 1patient got hypertension. 1patient got TA-TMA. 1patient developed chromosome clone from the donor, which returned to normal after three months. 2patients developed limited cGVHD. All other patient survive disease-free.
Conclusions: It is safe and feasible to Blinatumomab maintenance therapy of high risk PH negative ALL after Allo-HSCT
Disclosure: no
19: Acute Leukaemia
P056 THE IMPACT OF PRE-TRANSPLANT MDS-ASSOCIATED SOMATIC MUTATIONS AND CO-MUTATIONS IN PATIENTS WITH AML ON POST-TRANSPLANT OUTCOMES
Khalid Halahleh 1, Ayat Taqash1, Isra Muradi2, Farah Alul1, Osama Alsmadi1, Mohamad Ma’koseh1
1King Hussein Cancer Center, Amman, Jordan, 2Ahliyya Amman University, Al-Salt, Jordan
Background: Acute myeloid leukemia (AML) with myelodysplasia-associated gene mutations (MDS + ) is a new disease entity introduced in the International Consensus Classification of Myeloid Neoplasms 2022(ICC 2022). MDS-associated somatic mutations (MDS +) include SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2. The aim of this study is to assess the frequency of this disease entity of AML, and evaluate the impact of pre-transplant MDS-associated somatic mutations on post-transplant outcomes.
Methods: Using King Hussein Cancer Center Registry, out of 176 newly diagnosed AML patients, 162 had available genomic abnormalities using targeted next-generation sequencing gene panel at diagnosis between “2016 – 2023”. 117 patients achieved complete remission (CR) and included in this analysis. Leukemia free survival (LFS) and overall survival (OS) were calculated using Kaplan Meier methods using a log-rank test and a Cox proportional hazard model was used for unadjusted analyses of time-to-event endpoints. Cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) were calculated using the Gray method. Factors with P < 0.05 in univariate analyses were included in multivariate analyses. P < 0.05 was considered statistically significant.
Results: 100 patients (85.5%) had de novo AML. Median age was 46y (18-78y). 82 patients (70%) were males. Pathogenetic mutations were detected in 104 (89%), -VUS in eight (6.7%) and 5 patients (4.3%) had negative on targeted gene panel. We identified 23 patients (20%) with at least one of MDS-associated mutations (MDS + ) and 94(80%) were negative (MDS-). 72 patients (69%) were in CR1, 54 (46%) received allo-HSCT (17 in CR1). Patients-disease-transplant-related covariate were comparable between the two groups, except patients age was younger (P-0.001) and more secondary AML in MDS+ group (P-0.016).
The median follow-up for survivors (n-45) was 16 months (0.5-52 months). 3-year CIR, LFS and OS were 39% (95% CI: 23%-55%), 61% (95% CI: 49%-76%), and 26% (95% CI: 16%-37%) respectively. The MDS+ group had less relapses (3-year CIR, 5% vs 40%) (Hazard ratio [HR]:1.327, 95% confidence interval [CI]: 0.758-2.323; P-0.79), comparable LFS (75.5% vs 60%) (HR: 0.853, 95% CI: 0.249-2.928; P-0.8), and OS of 24% vs 26%) (HR: 1.327, 95%CI: 0.758-2.323; P-0.322). In univariable cox regression analysis for LFS and OS, and NRM, none of the factors analyzed including gender, age (< 45y vs ≥ 45y), ELN 2022 AML classification, and MDS+ vs MDS- groups, was statistically significant for OS or NRM (all P>0.05). Younger age was statistically significant for LFS (P-0.018). Among the 23 MDS+ patients who achieved CR, and received allogeneic HSCT (n -7) showed better OS (3-year OS, 86% (53% vs Zero) (HR: 0.061, 95% CI: 0.008-0.476, P-0.0076), a trend toward improvement in LFS (3-year,100% vs zero%) (HR: NA, 95% CI: NA vs NA, P-0.9972) than those who received consolidation chemotherapy considering allo HSCT as non-time dependent covariate. No patients relapsed in the allogeneic HSCT patients (3-year, zero vs 49%) (95% CI: 8%- 82%; P-0.063), and NRM was comparable between the two groups (P-0.998).
Conclusions: MDS-associated somatic gene mutations are an independent prognostic factor for adverse outcomes in AML that might be overcome by allotransplant.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P057 TRIALS IN PROGRESS: A PHASE 1B SINGLE-ARM, OPEN-LABEL STUDY OF EMAVUSERTIB IN COMBINATION WITH AZACITIDINE AND VENETOCLAX IN AML PATIENTS IN COMPLETE RESPONSE WITH MRd
Adolfo de la Fuente 1, Claudio Cerchione2, Sebastian Scholl3, Jan Moritz Middeke4, Gaurav S. Choudhary5, Dora Ferrari5, Reinhard von Roemeling5, Uwe Platzbecker6
1MD Anderson Cancer Center, Madrid, Spain, 2Istituto Romagnolo per lo Studio dei Tumori, Meldola, Italy, 3Universitätsklinikum Jena, Jena, Germany, 4Technische Universität Dresden, Dresden, Germany, 5Curis Inc, Lexington, United States, 6University Hospital Leipzig, Leipzig, Germany
Background: Emavusertib is a novel potent oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) with additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4). Inhibition of these onco-proteins may induce remission thereby addressing a critical unmet need for novel therapies in acute myeloid leukemia (AML). Clinical studies with emavusertib monotherapy have demonstrated a significant reduction in AML blasts with clinical and molecular responses, including patients with relapsed or refractory AML, previously treated with an HMA and/or FLT3 inhibitors (Metzeler 2022).
Azacitidine + venetoclax (aza+ven) has been approved in newly diagnosed, unfit patients with AML. In the VIALE-A study, composite complete response (CRc) (CR, CRh, or CRi) in the absence of measurable residual disease (MRD) of <1 residual blast/1000 leukocytes (MRD negative [MRD−]) resulted in longer duration of response (DOR), event-free survival, and overall survival (OS), and better HSCT outcome compared with patients who achieved CRc but were MRD+ (Pratz, 2022). In pre-clinical studies, emavusertib in combination with aza+ven demonstrated synergistic antileukemic effects in AML cell lines, including azacitidine- or venetoclax-resistant cell lines. Adding emavusertib to aza+ven in MRD+ patients at the time of CR may convert MRD status without adding significant toxicity and confirm that emavusertib can be safely added to aza+ven as a potential new regimen in front-line therapy.
Methods: This is a single-arm, open-label Phase 1b trial evaluating safety and tolerability, PK, and conversion of MRD status with emavusertib as an add-on agent to aza+ven in AML patients who achieved CR or CRh with MRD+ based on local testing (EU CT Number 2023-505828-58-00). The primary objective of the study is to determine a safe and tolerable dosing schedule for the triple combination. Secondary objectives include MRD conversion rate, DOR, OS, and pharmacokinetics. The study will enroll approximately 24 patients at 5 to 10 sites globally. Patients will have received azacitidine and venetoclax as first line therapy and achieved CR or CRh after 1-6 cycles of aza/ven. If MRD status remains positive, emavusertib will be added to the existing well tolerated aza+ven regimen. The starting emavusertib dose is 200 mg BID for 7 days per cycle of 28 days. If well tolerated, duration of emavusertib treatment will be extended to 14 and 21, respectively; no intra-patient change of emavusertib dosing duration is planned. The patients will continue triple treatment (emavusertib+aza+ven) until consent withdrawal, disease progression, intolerable toxicity, or not achieving MRD- within 6 cycles of triple treatment. In this Phase 1b trial, MRD can be evaluated by local testing of bone marrow. Key exclusion criteria include residual toxicities and significant comorbidities.
Results: Not applicable.
Conclusions: Not applicable.
Clinical Trial Registry: EU CT Number 2023-505828-58-00
Disclosure: Nothing to Declare.
19: Acute Leukaemia
P058 PREVALENCE OF ELIGIBILITY FOR GERMLINE MUTATION TESTING IN PATIENTS WITH MDS/AML UNDERGOING ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT IN A US ACADEMIC MEDICAL CENTER
Tyler Fugere 1, Samuil Ivanovsky1, Gomathy Nageswaran1, Brad Fugere1, Urooj Hudda1, Sravani Gundarlapalli1, Lakshmi Yarlagadda1, Zhongning “Jim” Chen1, Cesar Gentille1
1University of Arkansas for Medical Sciences, Little Rock, United States
Background: Predisposition to acute myeloid leukemia (AML) is increasingly recognized and referral for genetic counseling, germline testing, and extension of these services to family members should be considered in select patients. The National Comprehensive Cancer Network (NCCN) and European LeukemiaNet (ELN) have outlined suggestive disease features to prompt germline testing. Recognition of these familial syndromes is important to support clinical decision-making and assess the risk for hematological malignancies for family members. Given their rarity, it is unclear how many patients are actually screened. Our goal was to assess the prevalence of patients that met criteria for testing and that were referred for further evaluation in an academic medical center in the US.
Methods: We identified 132 patients who received a hematopoietic cell transplant for myelodysplastic syndrome (MDS) or AML at University of Arkansas Medical Sciences from July 1, 2018 to October 5, 2023. We determined the prevalence of eligibility for testing by considering patients who were either <40 years old at diagnosis or had a mutation with VAF >30% and had either a personal or family history of cancer as being eligible based on NCCN guidelines. We collected diagnosis date, transplant date, relapse date, and date of last contact or death to determine progression free survival (PFS) and overall survival (OS) per Kaplan-Meier. Age, disease type, conditioning regimen and eligibility for testing were analyzed using Cox proportional hazard regression.
Results: Overall, 102 patients had AML and 30 had MDS; 36 received a myeloablative and 96 a reduced intensity transplant. Thirty-six patients (27.3%) met criteria for germline testing but only 4 were tested. Of patients who met criteria for testing, median age was 55 years. NPM1 was the most prevalent mutation (10.3%) followed by DNMT3A (8.9%), FLT3 (7.6%), RUNX1 (6.3%) and TP53 (6.3%); 24 of these patients had at least 1 mutation that has been reported to be potentially germline. Outcomes for PFS and OS were not different between patients eligible for testing and ones who were not per Kaplan-Meier or multivariate analysis; median PFS and OS were not reached for either group.
Conclusions: Prior studies have identified a prevalence of germline mutations in AML of 7-14%, however, the prevalence of patients meeting eligibility for testing or getting tested in routine clinical practice has not been described. In our cohort, more than 20% of transplanted patients with MDS/AML met criteria and less than 5% were tested despite most of them having at least 1 potential germline mutation. Even though there was no apparent effect on outcomes, our sample size and lack of germline confirmatory testing makes interpretation of these results challenging. We believe awareness of the features suggestive of a germline disease is paramount and needs to increase to capture as many patients as appropriate as it could affect conditioning and donor options for transplant as well as help prevention or early detection of other hematologic or solid cancers.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P059 REFINED DISEASE RISK INDEX APPLIED IN AN UPPER-MIDDLE INCOME COUNTRY AS A TOOL TO ESTIMATE OVERALL SURVIVAL AFTER ALLOGENEIC STEM CELL TRANSPLANTATION IN HAEMATOLOGICAL MALIGNANCIES
Shirley Quintana-Truyenque1, Naty López-Córdova 1, Jessica Meza-Liviapoma1, Lourdes López-Chavez1, Cindy Alcarraz-Molina1, Victor Mallma-Soto1, Claudio Flores-Flores2, Jule Vasquez-Chavez1
1Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Peru, 2Universidad Peruana San Juan Bautista, Lima, Peru
Background: Allogeneic haematopoietic stem cell transplantation (Allo-HSCT) is a potentially curative option in a greater number of haematological malignancies. There are some prognostic models developed to estimate risks and survival in patients who will have this treatment. The Refined Disease Risk Index (R-DRI) stratifies neoplasms based on the status of the disease and remission before transplantation, there are 4 risk groups: low (LR), intermediate (IR), high (HR) and very high (V-HR), which correlate with overall survival (OS) at 2 years and have demonstrated to not been affected by age, conditioning intensity, graft source or donor type. The aim of the study was to estimate the overall survival post Allo-HSCT in our institution in relation to the R-DRI with the objective of implement its use in the Peruvian patients.
Methods: We reviewed retrospectively the data of 172 adults who underwent an Allo-HSCT between 2012 and 2023 in the Bone Marrow Transplantation (BMT) unit of the National Institute of Neoplastic Diseases (INEN). The information was extracted from the unit registry and was completed using the electronic medical record. Patients over 15 years of age were included. All donors were related, and the source used was peripheral blood. Risk classification was performed according to the R-DRI. Survival was estimated using the Kaplan-Meier method and comparisons were made using the Log-Rank test.
Results: The median age at HSCT was 26 years (range: 15 - 63), 51% of patients were male. Most frequent diagnoses were acute lymphoblastic leukaemia (ALL), Acute Myeloid Leukaemia (AML), Mixed-Phenotype Acute Leukaemia (MPAL), and Chronic myeloid leukaemia (CML), with 85, 41, 13 and 11 cases, respectively. Other diagnoses were (Myelodysplastic syndrome (MDS), Acute lymphoblastic lymphoma [LBL], Hodgkin lymphoma, and aggressive T/NK cell leukaemia with 8, 6, 1 and 1 cases, respectively. According to the R-DRI classification (does not include MPAL and LBL), patients were stratified as LR, IR, HR, and V-HR in 5%, 38%, 35% and 22% of cases, respectively. The risk that predominated in each diagnostic group was as follows: for ALL, AML, CML, and MDS were IR (46%), HR (51.2%), LR (45.5%) and HR (75%), respectively. The median follow-up was 3.9 years. The median OS for the entire cohort was not reached, and the survival rate at 2 and 4 years according to R-DRI for LR, IR, HR, V-HR were 100%, 68.3% and 57.4%, 64.7 and 53.5%, 47.4 and 38.3%, respectively. The 4y-OS rate of the combined IR and HR group vs V-HR was 54.6% and 38.3%, respectively (p = 0.071).
Conclusions: OS in our patients according to the R-DRI was higher than the reported in the literature, with a greater difference between the intermediate and high versus very high-risk groups. The R-DRI is an important tool that allows to estimate the prognosis after allogeneic transplant in our population; however, it must be taken into consideration that this study is retrospective and there are patients who did not reach the median follow-up, so it is recommended to continue with prospective studies.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P060 PREEMPTIVE DONOR LYMPHOCYTE INFUSION AFTER ALLOGENEIC STEM CELL TRANSPLANTATION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA – SINGLE CENTRE ANALYSIS OF EFFECTIVENESS AND SAFETY
Anna Łojko Dankowska 1, Ewa Bembnista1, Paula Matuszak1, Magdalena Matuszak1, Bartosz Małecki1, Andrzej Szczepaniak1, Anna Wache1, Dominik Dytfeld1, Lidia Gil1
1Poznan University of Medical Sciences, Poznań, Poland
Background: Acute myeloid leukemia (AML) is a disease with intermediate sensitivity to donor lymphocyte, therefore effectiveness in patients (pts) with relapse of disease after allogeneic stem cell transplantation (alloHCT) is limited. However, donor lymphocyte infusion (DLI) can be used earlier to prevent relapse as a prophylaxis in pts with complete remission or as a preemptive treatment in patients with mixed chimerism or with positive minimal residual disease (MRD + ) in flow cytometry.
Methods: We retrospectively analyzed records of twenty adult patients with AML treated in our center with alloHCT from HLA-identical sibling (n = 5) or matched unrelated (n = 6) or haploidentical (n = 9) donor, conditioned with myeloablative (n = 12) or reduce intensity conditioning, who received DLI between 2018 and 2023 as a preemptive treatment due to decrease chimerism (n = 8) or MRD+ (n = 12). Median age at the transplantation was 44 years (range 23-65), median time between transplantation and first DLI was 9 months (range 4-50). Three pts were after second alloHSCT. At the time of first infusion all pts were without immunosuppression and without any symptoms of graft versus host disease (GvHD).
Results: The median follow up among survivors since first DLI was 22 months (range 1-58). Median number of DLI received per patient was 4 (range 1-8), the median CD3+ lymphocyte count per one infusion was 2,3x10e6 per kilogram of body weight (/kg) (range 0,1-20). The cumulative lymphocytes count per one patient was 7,64x10e6 CD3+ cells/kg, range 0,1-54,88. The minimum time between two infusions was 4, the maximum 30 and the median 7 weeks. DLI was effective (increase chimerism above 95% or negative MRD) in 11 pts (55%), 9 (45%) of them remained alive in remission of disease to date. One patient died due to secondary malignancy and one due to infection. Relapse of disease occurred in 8 pts and 7 of them died due to relapse. Acute GvHD were observed in only 3 pts (G2 = 2, G4 = 1), all these pts responded to DLI, but one died due to infection complications. Median overall survival (OS) was 24 months for whole group, 2 years OS for responders was 80%. 12 pts (60%) currently alive.
Among pts who responded to DLI the median cumulative lymphocyte count per one patient was 16,21x10e6 CD3+ cells/kg, (range 1,27-53,54). Among pts who did not respond to DLI the median cumulative lymphocyte count per one patient was 4,09x10e6 CD3+ cells/kg (range 0,1-54,88). Pts with GvHD received the median cumulative lymphocyte count 51,19x10e6 CD3+ cells/ kg (range 16,21-53,54). The difference was not statistically significant p = 0,57.
Conclusions: The relapse of AML after alloHCT remains the major reason for failure and is connected with poor prognosis. DLI can be effective tool to prevent relapse, but the optimal application, timing and dosage, has not yet been established. Our results confirm that this method is safe and associated with low risk of death. The effectiveness of DLI in preventing relapse could be increased in AML pts by combining with other drugs, but perhaps also by increasing the lymphocyte dose.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P061 IN CHILDREN WITH RELAPSED/REFRACTORY ACUTE LYMPHOBLASTIC LEUKEMIA GIVEN ALLOGENEIC-HSCT EMPLOYING REDUCED-INTENSITY CONDITIONING, GVHD IS LESS FREQUENT IF THE PROCEDURE IS CONDUCTED ON AN OUTPATIENT BASIS
Edgar Jared Hernández-Flores1, Moisés Manuel Gallardo-Pérez2, Max Robles-Nasta2, Daniela Sánchez-Bonilla2, Merittzel Abigail Montes-Robles3, Guillermo Ocaña-Ramm1, Olivia Lira-Lara4, Juan Carlos Olivares-Gazca2, David Gómez-Almaguer5, Óscar González Llano5, Yajaira Valentine Jiménez-Antolinez5, Guillermo José Ruiz-Delgado 2,1, Guillermo José Ruiz-Arguelles2,1
1Universidad Popular Autónoma del Estado de Puebla, Puebla, Mexico, 2Centro de Hematología y Medicina Interna, Clínica Ruiz, Puebla, Mexico, 3Universidad Anáhuac Puebla, Puebla, Mexico, 4Universidad Veracruzana, Veracruz, Mexico, 5Servicio de Hematología del Hospital Universitario “Dr. José Eleuterio González”, Monterrey, Mexico
Background: Advance in transplant technology (donor matching, alternative donor source, conditioning regimens), and supportive care have significantly improved the post-hematopoietic stem cell transplantation (HSCT) survival. Allogeneic HSCT is employed in the treatment of relapsed/refractory acute lymphoblastic leukemia (RR-ALL) in children. Outpatient conduction of reduced intensity allografting is being employed more frequently.
Methods: Compare the long term results of allografting children with B cell RR-ALL employing reduced intensity conditioning, the procedure being conducted either as inpatients or outpatients.
Results: 37 patients were analyzed. 18 were allografted as inpatients (IP) and 19 as outpatients (OP). In the statistical analysis, the two comparative groups have no significant differences in terms of age, sex, platelets recovery and acute GVHD. The table shows the salient features of these two groups. The median follow up for outpatient group is 35 months (IQR: 9-59) meanwhile the median follow up for inpatient is 20 months (IQR: 11-33). The median OS for the OP was 33 months, whereas for IP was 50 months (p = 0.342). Time to recover >500 neutrophils in was shorter in OP (12 versus 14 days), whereas the prevalence of chronic GVHD was significantly lower in OP (10% versus 61%).
Table 1. Salient features of 37 patients given allo-HSCT employing reduced intensity conditioning as inpatient or outpatient. a= p value obtained by chi square. b= p value obtained by Mann-Whitney´s U. c = p value obtained by student’s T-test. d= p value obtained by log-rank chi square.
Outpatient (n = 19) | Inpatient (n = 18) | p | |
---|---|---|---|
Female | 10 | 6 | 0.130 a |
Male | 7 | 12 | |
Mean Age | 8.1 + 4.1 | 7.8 + 4.2 | 0.840 c |
Relapsed/ refractory | 10/9 | 16/2 | |
Days to >500neutrophils | 12 (IQR = 3) | 14 (IQR = 4.25) | 0.022 b |
Days to >20,000 platelets | 13 (IQR = 1) | 14(IQR = 2.25) | 0.090 b |
Acute GVHD, II-IV | 8 | 7 | 0.842 a |
Chronic GVHD | 2 | 11 | 0.001 a |
Median OS | 33 | 50 | 0.342 d |
Median follow up (months) | 35 (IQR = 50) | 20 (IQR = 22) | 0.620 b |
Conclusions: These results suggest that allo-HSCT employing a reduced-intensity conditioning can be conducted safely as outpatients in children with RR-ALL could indicate. Moreover, the prevalence of chronic GVHD is lower in patients allografted as outpatients outside that there is no difference in children survival given outcome or income Allo-HSCT.
Clinical Trial Registry: NCT05780554
Disclosure: Nothing to declare.
19: Acute Leukaemia
P062 IMPLEMENTATION OF NON-TBI CONDITIONING AND POST-TRANSPLANT CYCLOPHOSPHAMIDE FOR PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA IN RESOURCE-LIMITED SETTINGS
Lusine Krmoyan 1,2, Inga Khalatiani1,2, Mane Gizhlaryan1, Karen Meliksetyan1
1YEOLYAN Hematology and Oncology Center, Yerevan, Armenia, 2Yerevan State Medical University, Yerevan, Armenia
Background: Resource limitations in countries such as Armenia often impede access to advanced medical interventions, including haploidentical hematopoietic stem cell transplantation (HSCT). Consequently, patients with acute leukemia requiring allogeneic HSCT encounter significant challenges in seeking treatment abroad. This study documents innovative strategies employed in a resource-limited setting to facilitate HSCT for three pediatric patients without the option of international treatment.
Methods: A comprehensive preparatory protocol was established for two patients necessitating haploidentical HSCT due to the unavailability of high-resolution typing, chimerism assessment, donor-specific antibodies (DSA) testing, total body irradiation (TBI), and T cell depletion. The protocol included pre-treatment with rituximab to reduce DSA, followed by a conditioning regimen of fludarabine, treosulfan, and thiotepa. Cyclosporine A (CsA) from day -2 and mycophenolate mofetil (MMF) from day -1 were supplemented for acute graft-versus-host disease (aGVHD) prophylaxis, and post-transplant cyclophosphamide (PTCy) was administered on days +3 and +4 for in vivo T cell depletion. Peripheral blood and bone marrow were used as stem cell sources for one patient each. In a separate case involving allogeneic HSCT from a fully matched sibling donor, a similar preparatory protocol was implemented, with bone marrow as the stem cell source. Fludarabine, treosulfan, and thiotepa constituted the conditioning regimen, supplemented by CsA from day -2 and methotrexate on days +1, +3, and +6 to prevent graft-versus-host disease (GVHD).
Results: Despite resource constraints and the absence of advanced testing and treatment options, the patients exhibited promising outcomes. Post-transplantation assessments on days +30, +60, and +90 revealed chimerism levels more than 99% and negative minimal residual disease (MRD). Noteworthy complications, including severe gastrointestinal tract acute GVHD (grade II-III), HHV6 reactivation, and severe CMV reactivation, were encountered and managed in one patient.
Conclusions: This study demonstrates the successful implementation of non-TBI-based conditioning regimens and emphasizes the role of PTCy in achieving favorable outcomes in a resource-limited setting. PTCy emerges as a crucial strategy in reducing GVHD risks and facilitating HSCT despite limited technological resources, offering hope for patients facing similar constraints worldwide.
Disclosure: Nothing to disclouse.
19: Acute Leukaemia
P063 RELAPSE AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN PATIENT WITH ACUTE MYELOBLASTIC LEUKEMIA
Insaf Ben Yaiche1, Nour Ben Abdejelil 1, Rihab Ouerghi1, Ines Turki1, Sabrine Mekni1, Lamia Torjemane1, Dorra Belloumi1, Rimmel Kanoun1, Saloua Ladab1, Tarek Ben Othman1
1Centre National de Greffe de Moelle Osseuse, Tunis, Tunisia
Background: Allogeneic hematopoietic stem-cell transplantation (AHSCT) is the only curative treatment for high-risk acute myeloid leukemia (AML). However, the relapse remains a substantial risk of after AHSCT
Methods: A retrospective descriptive study, included all consecutive patients with AML, who underwent AHSCT from HLA-matched sibling donor, between January 2018 and December 2022. Conditioning consisted on busulfan-iv and cyclophosphamide (BU/CY) or fludarabine-based. GVHD prophylaxis included cyclosporine and short course of methotrexate +/- antithymocyte-Globulin. Stem cell source was bone marrow or peripheral blood stem cells (PBSC). The study aimed to estimate cumulative incidence of relapse (CIR) after AHSCT and describe management therapy of relapsed patients.
Results: Sixty-three patients (9 children, 54 adults) were included with a median age of 33 years (6-49y). The sex-ratio was 1.86. At diagnosis, 21% patients were classified as low-risk (n = 13), 49% intermediate risk (n = 31), 24% high-risk (n = 15), unclassified risk in 6% (n = 4: missing data).
The median time from diagnosis to AHSCT was 7 months (4-54 months). At transplant, 84% of patients were in first complete remission (CR1). Conditioning regimen was BU/CY in 83% of patients. Stem cell source was PBSC in 59% of patients.
After a median follow-up of 32 months (2-67 months), the CIR was 27% (early n = 6, late n = 9). Median time of relapse was 15 months (3-20 months). Relapses were medullary and combined (n = 11), extramedullary (n = 2), molecular (PML-RARA, n = 1) and Cytogenetic (11q23 n = 1).
Among the 15 relapsed patients, 11 (73%) received salvage therapy (chemotherapy n = 8, DLI +/- azacitidine n = 2, ATRA n = 1). Second CR was observed in 6 patients, among them, 5 underwent a second AHSCT. At last follow-up, 45 patients are alive, 18 patients (28%) died (relapse n = 10, NRM n = 8). CI of NRM was 13%.
The 3-year overall survival and event-free survival were 31% vs 83% (p = 0.001) and 7% vs 82% (p<10-3), in relapsed and non-relapsed patients, respectively.
Conclusions: The prognosis of patients with AML relapsing after AHSCT is poor. Adapted risk stratification treatment at diagnosis, before and after AHSCT may improve outcomes.
Disclosure: Nothing to declare.
19: Acute Leukaemia
P064 IAMP21 ACUTE LYMPHOBLASTIC LEUKEMIA WITH DELETION AROUND SUBTELOMERIC REGION OF CHROMOSOME 21: REPORT OF ONE CASE AND REVIEW OF LITERATURE
Jiantuo Liu 1, Hongrui Li1, Xiangjun Chen2, Yanli He2
1Cytogenetics Laboratory, Wuhan Kindstar Medical Laboratory Co., Ltd, Wuhan, China, 2Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Background: Herein, our report describes the case of a 4-year-old man who presented initially with fever and bilateral instep pain in july 2023.
Methods: we performed a retrospective study to analyze the clinical characteristics, laboratory examination, and treatment.
Results: Physical examination were as follows, T 37.8°C, B 23/min, HR 101/min, BP 88/60mmHg, he was mentally ill and pale. One lymph node with a diameter of 1.5cm is palpable in the right neck. One or two lymph nodes with a diameter of 0.5cm is palpable in the bilateral groin, with soft texture, easy movement and no tenderness. Superficial lymph nodes in the left neck and armpit were not touched. Bilateral tonsil degree I, no exudate attachment. Normal cardiopulmonary function, no liver and spleen enlargement, limbs without muscle tension, extremity warm. Blood routine examination showed that, white blood cell count (WBC) 2.62×109/L, red blood cell count (RBC) 3.25×1012/L, hemoglobin (Hb) 82g/L, neutrophil absolute value 0.48×109/L, lymphocyte absolute value 1.82×109/L, monocyte absolute value 0.14×109 /L. platelet count 165×109/L, C-reactive protein 9.16mg/L, primitive naive cells 8%. The bone marrow examination showed 68.4% of naive lymphocytes, and the immunotype was consistent with B-ALL diagnosis. The RNA-seq showed normal result in tumor cells. RT-PCR test were negative by screened 43 fusion genes of leukemia. The patient showed a normal karyotype. Interphase FISH were as follows, MLL(-), BCR/ABL(-), PBX1/TCF3(-), MEF2D(-), the ETV6/RUNX1 probe observed the cluster of green signals indicates the amplification of RUNX1. The Tel21q probe captured one green signal indicates the deletion around subtelomeric region of chromosome 21. Above these characteristics defined iAMP21. According to the Chinese Children’s Cancer Group study ALL 2020(CCCG-ALL-2020), the patient was divided into intermediate risk group. Induction regimens were typically based on a backbone that included a combination of vincristine, prednisone and pegaspargase with daunorubicin, the patient remained MRD + (0.06%,>0.01%)after induction therapy(day46). High-dose methotrexate (HD-MTX), 6-mercaptopurine (6-MP) were incorporated into consolidation regimens, the patient achieved MRD negative(<0.01%) over a duration of 3 months. Maintenance regimens were based on a backbone of daily 6-MP and weekly methotrexate with the addition of periodic vincristine and prednisone. To date, the patient remained MRD negative after a total of five months of treatment.
Conclusions: Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of B-cell acute lymphoblastic leukaemia (B-ALL). It has since been estimated that B-ALL with iAMP21 accounts for 2% of all pediatric B-ALLs. In this study, we have validated the existence of iAMP21 with deletion around subtelomeric region of chromosome 21. iAMP21 is associated with inferior outcome, who require more intensive therapy.
Disclosure: Nothing to declare.
20: Aplastic Anaemia
P065 RESULTS OF HSCT WITH TCRΑΒ AND CD19-DEPLETION FROM MATCHED RELATED DONORS AND INFUSIONS OF CD45RA DEPLETED DONOR LYMPHOCYTES IN PEDIATRIC SEVERE APLASTIC ANEMIA
Daria Shasheleva1, Larisa Shelikhova1, Anna Bogoyavlenskaya1, Rimma Khismatullina1, Svetlana Radygina1, Dmitriy Balashov1, Yakov Muzalevsky1, Tatiana Salimova1, Dina Baidildina1, Elena Kurnikova1, Dmitriy Pershin 1, Pavel Trakhtman1, Galina Novichkova1, Alexei Maschan1, Michael Maschan1
1Dmitry Rogachev Federal Research Centre of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Background: HSCT from matched family donors results in most favorable outcomes among children with severe aplastic anemia (SAA). Despite overall success, morbidity, associated with acute and chronic graft-versus-host disease (GVHD) is not completely prevented with current standard of pharmacologic prophylaxis. Depletion of ab T cells from the graft prevents GVHD, and improves outcome of hematopoietic stem cell transplantation from haploidentical donors, while infusions of donor memory lymphocytes (mDLI) (CD45RA-depleted) are able to transfer pathogen-specific immunity without the risk of GVHD. We evaluated the outcomes of ab T cell depletion and add-back of intermediate-dose mDLI among the pediatric SAA recipients of matched related grafts.
Methods: A total of 24 children with SAA (11 female, 13 male, median age 9,8 y) underwent allogenic HSCT from matched family donors (MFD) between February 2015 and May 2023, for all pts it was the first allo HSCT. TCR αβ + /CD19+ depletion of HSCT with CliniMACS technology was implemented in all cases. The median dose of CD34+ cells was 7,1 x106/kg (range 2,76-13,2), αβ T cells - 23x103/kg (range 1-184). All pts received an additional injection of memory T-cell (CD45RA-depleted) on day 0 at 1 million T cells per kg.
All patients received cyclophosphamide at 100 mg/kg, fludarabine at 100 mg/m2, rituximab 100mg/m2 and serotherapy with either rabbit ATG at 5 mg/kg (n-1) or horse ATG at 100 mg/kg (n-23).
Post-transplant GVHD prophylaxis included calcineurin (CNI)-based regimen and abatacept 10mg/kg on days -1, +7, +14 and +28. 22 pts received a graft from a 10/10 HLA-matched sibling, 2 from 9/10. Median time of follow-up for survivors was 2,9 years (range: 0.8 – 9.8).
Results: Primary engraftment was achieved in all evaluable patients (100%) with donor chimerism, the median time to neutrophil and platelet recovery was 11 (6-18) and 13 (9-19) days, respectively. One patient had aGvHD grade II and there were no incidence of grade III-IV aGvHD and TRM. The CI of CMV viremia was 17% with no incidence of CMV disease. No cases of ADV and EBV viremia and EBV disease were recorded. Two pts had thrombotic microangiopathies (TMA) with good response to rituximab, one pt. had partial red cell aplasia. The median recovery of T cells was on day+60 was 0,26 (0,04-0,9). Event-free and overall survival were 100%.
Conclusions: ab T cell-depleted transplantation with intermediate dose memory T cell add-back definitively prevents GvHD and provides a platform for safe HSCT from matched family donors in patients with SAA.
Disclosure: M. Maschan - Miltenyi Biotec: Honoraria
D. Balashov - Octafarm: Other: Lecture fee
20: Aplastic Anaemia
P066 MITOCHONDRIAL METABOLISM IN FANCONI ANEMIA PATIENTS POST HEMATOPOIETIC STEM CELL TRANSPLANTATION
Filomena Pierri1, Enrico Cappelli1, Stefano Regis1, Silvia Ravera2, Federica Grilli1, Gianluca Dell’Orso1, Stefano Giardino1, Maura Faraci 1
1IRCCS Istituto Giannina Gaslini, Genova, Italy, 2University of Genoa, Genova, Italy
Background: Fanconi anaemia (FA) is a rare genetic condition characterized by congenital abnormalities, progressive bone marrow failure (BMF), chromosome fragility, and cancer susceptibility. In addition to a DNA repair defect, FA patients present a pro-inflammatory condition with increased cytokine production and sensitivity and defective mitochondrial metabolism associated with a poor cellular response to oxidative stress. These defects are involved in the pathogenesis of BMF, concerning not only hematopoietic stem cells (HSCs) but also bone marrow (BM) derived mesenchymal stromal cells (MSCs), which are responsible for organizing a functional HSC niche in vivo and secrete cytokines and matrix proteins that function in HSC self-maintenance and marrow retention.
Hematopoietic Stem Cell Transplantation (HSCT) is the only curative treatment option for FA haematological manifestations. However, this procedure does not result in gene correction of MSCs and other somatic cells, which lead to a persistence of some FA features in the BM microenvironment of transplanted patients that are not fully explored so far.
In this study, we analysed the peripheral blood (PB) mononuclear cells (MNCs) energy metabolism of transplanted FA patients, comparing to their healthy donors and to patients affected by idiopathic severe aplastic anaemia (SAA) to investigate the persistence of some FA features in BM microenvironment post-HSCT.
Methods: We studied, before HSCT and at different time points after HSCT, MNCs metabolism from 4 FA patients undergoing haploidentical α/β/CD19 depleted HSCT (one for BMF and 2 for cytogenetic abnormalities without myelodysplasia), and 4 patients with SAA, 2 transplanted from a Matched Unrelated Donor (MUD), 1 from a Matched Related Donor (MRD), 1 from a haploidentical donor (Post Transplant Cyclophosphamide platform). We also collected samples of the 4 healthy donors of FA patients at the same time points of the recipients.
Oximetric, spectrophotometric, and enzymatic analyses have been used to analyse mitochondria metabolism and antioxidant response in pre and post HSCT peripheral blood (PB) in FA patients compared to PB from their healthy donor and SAA patients.
Results: MNCs from transplanted FA patients showed impaired mitochondrial function and reduced ATP synthesis compared to healthy donors and transplanted SAA. However, the associated oxidative stress was counteracted by antioxidant defences, although a slight increase in lipid peroxidation (MDA) was observed. Interestingly, treatment of MNCs with cytokine inhibitors corrects the mitochondria impairment, suggesting the persistence of a pro-inflammatory state in the bone marrow niche that can alter the mitochondrial metabolism.
Conclusions: In transplanted FA patients, the molecular signals secreted in the microenvironment remain, at least in part, those before transplantation, as the niche in the bone marrow consists of the patient’s somatic cells. This condition justifies the persistence of a pro-inflammatory state even after transplantation, which could lead to mitochondrial dysfunction not observed in healthy donors and SAA.
Therefore, understanding the composition of the bone marrow microenvironment in FA patients after HSCT could lead to the development of new therapeutic approaches to improve the long-term outcomes of transplanted FA patients.
Disclosure: None conflict of interest
20: Aplastic Anaemia
P067 ATLG HAS BETTER SAFETY THAN RATG IN THE TREATMENT OF ADULT AA WITH ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Zhang Jianping 1, Lu Yue1, Zhao Yanli1, Xiong Min1, Liu Deyan1, Cao Xingyu1, Wei Zhijie1, Sun Ruijuan1, Zhou Jiarui1
1Hebei Yanda Ludaopei Hospital, Langfang, China
Background: rATG has stronger immunosuppressive effect than ATLG, therefore rATG is the main choice for AA to receive Allo-HSCT. ATLG is only used as an alternative choice for patients who have received ATG treatment. Some studies have shown that the application of ATLG in Allo-HSCT in patients with leukemia can achieve the same efficacy as rATG, and has better safety. Our study is to observe whether ATLG can achieve the same curative effect as rATG and has better safety when AA patients receive Allo-HSCT.
Methods: In this study, a retrospective analysis was made of adult AA patients who received Allo-HSCT in our hospital from March 1, 2012 to June 1,2023. through the analysis of OS, GFFS, GVHD, CMV/EBV activation we explore whether ATLG can achieve the same curative effect as rATG and has better safety.
Results: A total of 218 eligible patients, male 110cases, female 108cases, median age 29y(18-58). VSAA 41cases, SAA 79cases, AA-PNH 34cases, TD-NSAA 64cases. Conditioning with rATG149 cases, ATLG 58 cases. Donor: MSD 39cases, URD 76cases, HID 103cases; Stem cell source: PBSC 86cases, BMSC + PBSC 132 cases. Graft count: MNC8.3 (2.99-18.52)×108/kg, CD34 + 5.0 (1.14- 18.31)×106/kg, CD3 + 1.75 (0- 20.44)×108/kg. Of the 218 patients, there were 212 assessable by neutrophil engraftment, median time 13d(9-41). There were 200 assessable by platelet engraftment, median time 13d(4-78). Median follow-up 34m(1-136), 5y OS 82.72%(0.76-0.88). 5y GFFS 68.41%(0.61-0.75). 5y OS: rATG 85.8%, ATLG76%, P = 0.390; 5y GFFS: rATG69.3%, ATLG64.1%, P = 0.178. Primary engraftment failure 2cases(0.0091%), secondary engraftment failure 1case(0.0045%). aGVHD (II-IV) in 100day rATG 22.15% (16.39%-29.93%), ATLG 27.59%(18.18%-41.86%), P = 0.39240. cGVHD in 5 years rATG31.54%(24.35%-40.86%), ATLG 33.87%(22.89%-50.10%), p = 0.66537. CMV recurrence rate in 180d:rATG65.44% (58.20%-73.57%), ATLG 46.95%(35.65%-61.82%); P = 0.00957. Incidence of EBV in 360days rATG33.56%(26.77%-42.06%); ATLG: 8.77%(3.80%-20.26%); P<0.001.
Conclusions: In AA patients who received Allo-HSCT, compared with rATG, ATLG had equivalent OS and GFFS, and equivalent aGVHD and cGVHD, and the incidence of CMV and EBV decreased significantly. ATLG is safe and reliable for GVHD prophylactic in patients with AA undergoing Allo-HSCT.
Disclosure: none
20: Aplastic Anaemia
P068 TREATMENT WITH DARATUMUMAB IN 4 PATIENTS WITH IMMUNE ANEMIA AFTER HSCT WITH ABO INCOMPATIBILITY OR OTHER IMMUNE-ERYTHROCYTE DISCREPANCIES
Marina Aranguren Ostolaza1, Candela Ceballos Bolaños 1, Itziar Oiartzabal Ormategui1, Nerea Arratibel Zalacain1, Pamela Millacoy Austenrritt1, Mónica Fernández Pérez1, Maria Cruz Viguria Alegria1, Carlos Manuel Panizo Santos1, Irene Sánchez Prieto1, Monserrat Lozano Lobato1
1Donostia University Hospital, Donostia-San Sebastian, Spain
Background: ABO group incompatibility is observed in up to 50% of HSCT cases. This increases the recipient’s risk of experiencing acute or delayed hemolytic reactions, delayed engraftment of red blood cells, and pure red cell aplasia (PRCA), which can lead to anemia with clinical repercussions, increased transfusion requirements, and related consequences such as iron overload or increased alloimmunizations. Although there is no standardized therapy for this group of complications, recently described severe post-transplant immune anemia cases have responded favorably to Daratumumab treatment. Its effectiveness is believed to stem from the direct immunosuppressive effect on antibody-producing plasma cells. However, we propose the additional hypothesis that the presence of CD38 receptors on the recipient’s red blood cell membrane and the antigen-antibody binding at this level may confer protection against hemolysis.
Methods: We present a descriptive study of 4 patients undergoing HSCT at the Donostia University Hospital between 2019 and 2022. All 4 patients received peripheral blood stem cell infusion from HLA identical unrelated donors and a conditioning regimen. All showed mixed chimerism by day +30, with two achieving complete chimerism by day +100. All 4 patients, due to major AB0 group incompatibility or other immune-erythrocyte discrepancies, presented PRCA or peripheral hemolytic anemia with severe clinical and analytical impact. After failed transfusion support and Rituximab therapy, all 4 received Daratumumab treatment.
Results: Patients with PRCA received between 3 and 8 weekly Daratumumab cycles. The mean pre-transplant packed red cell transfusion was 15.3 (range 1-27), during transplantation was 38 (range 12-61), and after completing Daratumumab treatment until now was 0.33 (range 0-1). Therefore, we observed a 99.13% reduction in transfusion support. Hemoglobin levels before Daratumumab initiation were 3.4 g/dL, 6.8 g/dL, and 8 g/dL. After the last cycle, they increased to 4.8 g/dL, 7 g/dL, and 13.9 g/dL, respectively. Patients reached maximum levels of 17.3 g/dL, 14.2 g/dL, and 14.5 g/dL without transfusion support. The mean days to achieve the target Hb>9g/dL after the last cycle were 44.66 days, and to maintain Hb>12 g/dL were 66.33 days.
The patient diagnosed with hemolytic anemia is analyzed separately due to the uniqueness of their evolution and response to treatment. In this case, we observed an optimal response to Daratumumab but also dependency on treatment due to episodes of severe anemia after its withdrawal. The outcome was the administration of 18 cycles and ultimately a second HSCT.
Lastly, laboratory findings showed significantly reduced agglutination and hemolysis when exposing AB red blood cells from a patient on Daratumumab treatment to anti-A and anti-B antibodies compared to the control using AB red blood cells without Daratumumab against these antibodies.
Conclusions:
-
Daratumumab is effective in post-transplant immune anemia confirmed by the increase in hemoglobin levels from early treatment phases, with a mean of 44.66 days to reach Hb>9g/dL after the last cycle.
-
Patients treated with Daratumumab reduced packed red cell transfusion requirements.
-
The binding of anti-CD38 on red blood cell membranes might exert a protective function against hemolysis by preventing the binding between anti-A or anti-B antibodies in ABO incompatibility.
Disclosure: Nothing to declare
20: Aplastic Anaemia
P069 UPFRONT T-REPLETE HAPLO-IDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR CHILDREN WITH SEVERE APLASTIC ANEMIA: A SINGLE CENTER EXPERIENCE FROM JORDAN
Ayad Ahmed Hussein 1, Nour Awni Ghanem1, Bayan Majed Alaaraj1, Tariq Ahmed Abdelghani1, Dina Mohammad Abu Assab1, Hadeel Hassan Al-Zoubi1
1Bone Marrow and Stem Cell Transplantation Center, Istishari Hospital, Amman, Jordan
Background: Severe aplastic anemia (SAA) is a potentially fatal disease that can be cured with hematopoietic stem cell transplantation (HSCT). Matched sibling donors are not always readily available, leading to delayed referral for HSCT after immunosuppressive therapy, which has a poor prognosis.
Methods: This is a retrospective analysis of all pediatric patients with SAA who received upfront haplo-identical HSCT at Dr. Ayad Bone Marrow and Stem Cell Transplantation center, Istishari Hospital, Amman-Jordan from October 2016 till November 2021.
Results: Seven patients with a median age of 7 years (2-10) were included. Five were males. All patients received rabbit anti-thymocyte globulin (rATG) 0.5 mg/kg on day −9 and 2 mg/kg on days −8 and −7, fludarabine 30 mg/m2/day IV on days −6 to −2, cyclophosphamide 14.5 mg/kg/day IV on days −6 to −5, and 200 cGy TBI in a single fraction on day-1. The graft versus host disease (GVHD) prophylaxis was with post-transplant cyclophosphamide (PT/Cy) at 50 mg/kg/day IV on days +3 and +4 post-HSCT. Mycophenolate Mofetil and tacrolimus were started on day +5 and stopped on days +28 and +365 post-HSCT, respectively. The donor was one of the parents in all cases. Four donors were 5/10, two 7/10 and one 8/10 HLA-matched. Five donor-recipient pairs had major blood group incompatibilities. Five patients received peripheral blood stem cells (PBSC), and two received GCSF-primed bone marrow (BM) grafts. The median time for neutrophil and platelet engraftment was 14 (12–17) and 18 (16–22) days, respectively. One patient developed primary graft failure and was successfully engrafted after a second transplant. None of the patients required ICU admission. Grade I- II acute GVHD occurred in four patients. Three patients had CMV reactivation, one EBV reactivation, and one BK virus cystitis. Two patients had chronic GVHD, of which one was extensive. At a median follow-up time of 55 months (26–90), all patients are alive and transfusion-independent.
Conclusions: Matched related donor (MRD) HSCT is recommended for patients with SAA and proven to improve the long term survival. Upfront T-replete haplo-identical HSCT is an effective and safe option in patients who lack MRD. Our data indicates that this approach might be feasible in countries with limited resources. This approach might change treatment algorithm for patients with SAA in the future. More prospective studies with a larger sample size are required.
Disclosure: Nothing to declare.
20: Aplastic Anaemia
P070 PERIPHERAL BLOOD AS GRAFT SOURCE FOR APLASTIC ANEMIA TRANSPLANT: OUTCOMES OF YOUNG ADULTS AND ADULTS IN A MEXICAN PUBLIC HOSPITAL
Guillermo Sotomayor Duque 1, Severiano Baltazar Arellano1, Roxana Saldaña Vazquez1, Humberto Guerra Ramos1, Raul Ramos1, Alma Fabiola Alvarado Charles1, Karen Machuca Adame1, Luis Omar Gudiño Cobos1, Victor Valerio Bugarin1, Rosa Elva De leon Cantú1, Roberto Hernandez Valdez1, Jose Marcelino Chavez Garcia1
1IMSS UMAE 25 Monterrey, Monterrey, Mexico
Background: Aplastic anemia (AA) is a benign hematologic pathology characterized by an autoimmune T-cell mediated attack on marrow niche and its consequent failure. Allogeneic transplant is the curative treatment of choice for patients under 40 years of age with a matched related donor (MRD); for patients who do not have an identical donor, or who have failed immunosuppressive therapy; related haploidentical transplantation has become a feasible option in several centers around the world.
Methods: Retrospective study in IMSS UMAE 25 Monterrey, Mexico. Descriptive analysis was performed with measures of central tendency, medians, and frequencies. Survival analysis was performed with the Kaplan Mier method and comparative with log rank with a significant p value <0.05.
Results: A total of 16 patients were included in a period from January 2017 to January 2023; 9 male (56%) and 7 female (44%) with a median age of 32 years (15-58). Only 4 patients had a MRD, 12 underwent an haploidentical transplant. Median follow-up was 8 months (1-20). Conditioning was based on a non-myeloablative scheme (ATG-Flu-Cy) in 83% and RIC scheme (Bu-Flu-Cy) in 17%. GVHD prophylaxis, was based on methotrexate and cyclosporine for the MRD group and tacrolimus, mycophenylate mofetil and post transplantation cyclophosphamide for the haploidentical one. Median CD34+ was 12.74 x 106 (6.9-21.6); graft source was peripheral blood in all patients and the donor was male in 100% of cases. Blood group compatibility was 94%. Previous to transplantation 3 patients underwent desensitization for donor-specific anti-HLA antibodies using a protocol that included plasma exchange, IVIg, Rituximab and MMF. Median chimerism of 99% (2-100%) was reach by day 30. Primary graft failure occurred in 1 patient and secondary failure in two. CMV reactivation befall in 31%. The incidence of GVHD at 18 and 24 months was 28% and 52% respectively (G I/II), with no patient developing acute or extensive severe GVHD.
Median time the follow-up was 9 months (1-27). Overall survival (OS) was 80% at 24 months in all patients; 75% in the MRD group and 83% for the haploidentical (log rank 0.049, p = 0.82). Patients younger than 40 years had OS at 24 months of 100% and for those older than 40 years it was 54% (log rank 4.71, p = 0.029)Fig 1. The sustained hematological response was 75% for MRD and 52% for HAPLO at 2 years (log rank 0.25, p 0.63) Fig 2. Transplant related mortality (TRM) was 19% (one patient due to primary graft failure, one due to CMV infection and one patient due to cerebral hemorrhage).
Conclusions: In our small cohort peripheral blood as graft source proved no difference in OS and GVHD frequency in either group, with a TRM below 20%. Patients under 40 years of age benefits the most from transplantation in a timely and early manner.
Disclosure: No disclosure
20: Aplastic Anaemia
P071 UPFRONT HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) IN CLASSICAL PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)
Lorie Gandhi 1, Col (Dr) Rajiv Kumar1, Brig(Dr) Rajan Kapoor1
1Army Hospital Research and Referral, New Delhi, India
Background: Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare acquired hematological disorder characterized by episodic intravascular hemolysis. While Eculizumab is the standard of care in the West, the drug is seldom used in India due to its prohibitive cost. Hematopoietic Stem Cell Transplantation (HSCT) remains the only curative therapy.
Methods: A retrospective, observational study was conducted comprising classical/hemolytic PNH patients who underwent HSCT at our center from the year 2009 to 2023.
Results: Nine patients (five male, four female) with classical PNH who underwent HSCT were identified. Indication for transplant was hemolysis and recurrent need for blood transfusion for all patients. The median age was 28 years (Range 17-48 years). Median time from diagnosis to transplant was 15 months (8 months- 7 years). 3 patients initially presented as non- severe aplastic anemia with a small PNH clone size and later progressed to classical PNH. Out of 9, 7 patients were previously treated with androgens and steroids, 1 patient with Cyclosporine and 1 with Cyclosporine and Eltrombopag. One patient had a pulmonary thromboembolic episode. All patients had hyper-cellular marrow before transplant and median PNH clone size was 76% (28%- 92%). All patients underwent matched sibling donor (MSD) transplant. All received Myeloablative conditioning regimen (MAC): 5 received FLU-BU-ATG(BU-Busulphan, FLU- Fludarabine, ATG- Antithymocyte Globulin) 3 BU-CY-ATG, (CY-Cyclophosphamide) 1 FLU-BU-CY-ATG and 1 BU-CY. Median CD34+ stem cell dose was 6.0 × 106/kg (range 4.38–12.93 × 106/kg). All received cyclosporine and methotrexate as GVHD prophylaxis. Stem cells were derived from peripheral blood for all patients. All patients showed successful engraftment. Clone size at 90 days was <1% for all patients. Acute Graft Versus Host Disease (GVHD) Grade I–II occurred in 3 patients. Grade I-II Chronic GVHD occurred in three patients. Out of 9, 5 patients had CMV reactivation. 3 patients (33.33%) died. One patient (28-year-old male, received BU-CY conditioning) succumbed to Grade IV gut GVHD, 161 days post- transplant. One patient (48-year-old female received FLU-BU-CY-ATG) succumbed to veno-occlusive disease (VOD) post 23 days of transplant and one patient (31-year-old-male, received FLU-BU-ATG conditioning, with a history of thrombosis and a time from diagnosis to transplant of 7 years) died at day 256 post-transplant due to fungal pneumonia. The 6 surviving individuals are transfusion independent. Their median follow up was 8.5 months (3 months- 10 years).
Conclusions: Findings in this study suggest that in the setting of non availability of complement inhibitors, allogenic transplant with matched sibling donor has a curative potential in classical hemolytic PNH. Myeloablative conditioning is preferred. We found 100% engraftment with PBSC in patients with a history of multiple blood transfusions. Addition of ATG may prevent grade IV GVHD. Use of two alkylating agents as a part of conditioning regimen may increase chance of VOD. Early tapering of immunosuppression may prevent life threatening fungal pneumonia in PNH patients who have prior long term steroid exposure.
Disclosure: Nothing to declare
20: Aplastic Anaemia
P072 A REAL-WORLD ANALYSIS OF TREATMENT ADHERENCE AND CLINICAL OUTCOMES FOR PATIENTS WITH PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA (PNH) RECEIVING PEGCETACOPLAN
Koo Wilson 1, Carly Rich1, Zalmai Hakimi1, Regina Horneff1, Jesse Fishman2, Jennifer Mellor3, Lucy Earl3, Yasmin Taylor3, Alice Simons3
1Sobi Pharmaceuticals, Stockholm, Sweden, 2Apellis Pharmaceuticals, Massachusetts, United States, 3Adelphi Real World, Manchester, United Kingdom
Background: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, multi-systemic disease, which can be fatal if left unmanaged. It is characterised by thrombosis, impaired bone marrow function and complement mediated haemolysis. Currently available treatments include complement protein 5 inhibitor (C5i), which inhibit intravascular haemolysis (IVH), however patients can still experience anaemia and fatigue due to residual IVH and emerging extravascular haemolysis (EVH). Pegcetacoplan is the first approved complement protein 3 inhibitor (C3i), for adults with PNH. It proximally blocks complement activation resulting in broader control of both IVH and EVH. Currently, there is limited real-world data to understand how adherence and administration of pegcetacoplan may impact clinical outcomes for patients with PNH. The aim of this study was to describe the effectiveness and treatment adherence of patients with PNH receiving pegcetacoplan.
Methods: Data were drawn from the Adelphi PNH Disease Specific Programme™, a real-world cross-sectional survey of physicians, and their patients with PNH from January-November 2022 in the United States (US), France, Italy, Germany, and Spain. Patients were eligible for inclusion if prescribed PEG for ≥1 month. Physicians completed surveys utilising data from patients’ medical charts alongside their own clinical judgement regarding patient demographics, pegcetacoplan dosing and frequency of administration, treatment adherence, and clinical outcomes. Descriptive statistics were reported.
Results: Fourteen physicians completed record forms for 61 patients receiving pegcetacoplan. Mean ± SD age was 37.1 ± 11.3 years and 59.0% were male. Patients had been diagnosed with PNH for a mean of 3.7 ± 3.3 years and were receiving pegcetacoplan for 5.9 ± 4.0 months. All patients received 1080 mg of pegcetacoplan per dose, with 98.3% receiving it every 3-4 days and 68.9% self-administered their treatment. Physicians reported 95.1% of patients receiving pegcetacoplan were completely adherent to their treatment regimen. At data collection, physicians reported a mean haemoglobin score of 11.5 ± 1.6 g/dL which was improved from 9.0 ± 1.5 g/dL at pegcetacoplan initiation. Improvement in lactate dehydrogenase (LDH) was seen from PEG initiation to date of data collection (30.0% vs 57.4% reporting LDH <1.5 x ULN), and a higher proportion reported no fatigue (1.6% vs 31.1%, respectively). Physicians considered all patients to have ‘well or very well controlled’ disease.
Conclusions: This study demonstrates high adherence in a real world setting to pegcetacoplan, with almost all patients receiving this treatment in line with the label indication. Physicians reported improvement in patient haemoglobin, LDH levels and reported a high level of disease control for these patients. Further research is needed to understand the long-term adherence and utilisation of pegcetacoplan in a real-world setting.
Disclosure: Wilson, Koo; Rich, Carly; Hakimi Zalmai, and Horneff, Regina are employees of Sobi and may own stocks/shares of the company. Fishman, Jesse is an employee of Apellis Pharmaceuticals and owns stocks/shares of the company. Mellor, Jennifer; Earl, Lucy; Taylor, Yasmin; Simons, Alice are full-time employees of Adelphi Real World, which received funding for participating in this research.
20: Aplastic Anaemia
P073 EXPERIENCE OF SALVAGE HAPLO-HSCT WITH PTCY FOR ACQUIRED SEVERE APLASTIC ANEMIA
Yuliya Mareika1, Nina Minakovskaya1, Natalia Kirsanava 1, Dmitriy Prudnikov1, Mariya Naumovich1, Lubov Zherko1, Aliaksei Kakunin1, Aliaksei Lipnitski1, Volha Mishkova1, Katsiaryna Vashkevich1, Anzhalika Solntsava1
1Republican Scientific and Practical Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
Background: Hematopoietic stem-cell transplantation (HSCT) from the human leucocyte antigen (HLA)-matched sibling donor (MSD) is the first choice for the treatment of severe aplastic anemia (SAA). An improvement over last decade’s results of HSCT from HLA-match unrelated donor (MUD) has made HSCT from MUD the front-line option treatment with no prior failed immunosuppressive therapy (IST) for young. Unfortunately, half of the patients do not have an available HLA-identical donor. They are considered for IST or alternative donor HSCT in case of treatment failure.
Methods: Two patients, diagnosed with idiopathic SAA, underwent a haploidentical HSCT from HLA 6/10 mismatch-related donor (fathers) after the failure of IST with severe infection complications and repeated granulocyte transfusions for the life-saving treatments (table 1). Conditioning regimen consisting total lymphoid irradiation (TLI) 4 Gy, antithymocyte globulin (ATG) (Genzyme) 7,5 mg/kg, fludarabin 150 mg/m2, thiotepa 10 mg/kg, cyclophosphamide (Cy) 30mg/kg, rituximab 200 mg/m2, was followed by transfusion of unmanipulated hematopoietic stem cells. Post-transplant Cy (PtCy) (40 mg/kg on days +3 and +4) was given to reduce the incidence of acute graft-versus-host disease (aGVHD). Granulocyte colony-stimulating factor (G-CSF) 5 μg/kg (from day +5) has been used post-HSCT for earlier neutrophil engraftment. MSC infusion was performed (day +11) to neutrophil and platelet engraftment, a lower risk of aGVHD.
Results: Both patients are alive and well at six and three months. Recovery of neutrophils and platelets was prompt with 100% donor chimerism. None severe toxic or infectious complications were diagnosed after HSCT. Nobody developed acute GVHD or any other immune complications. Immune reconstitution (CD4 + >100 microL) was achieved early. (Table 1).
Conclusions:
Granulocyte transfusion is a reasonable option to control infections and prepare the patients for HSCT. Conditioning regimen TLI/ATG/fludarabin/thiotepa/Cy/rituximab with PtCy reduces the incidence of graft rejection and severe aGVHD. Haplo-HSCT with PtCy in patients with SAA who failed IST with life-threatening comorbidity is a feasible salvage treatment with stable engraftment and an acceptable complication profile.
Table 1
Patient | 1 | 2 |
---|---|---|
Age (year)/sex | 2 y.o., female | 18 y.o., male |
Prior IST | CSA + ATG+steroids+G-CSF | CSA + ATG+steroids+G-CSF |
Heavily transfused preHSCT | Yes | Yes |
Complications preHSCT | Cardiomyopathy with heart failure, enterocolitis, bronchiolitis | acute kidney failure, granulomatosis with polyangiitis, pneumonia, sepsis, EBV, HHV-6 |
Granulocyte transfusions preHSCT (n) | 7 | 9 |
Time to HSCT from 1st day IST (days) | 205 | 85 |
Source of HSC | Bone marrow | Peripheral blood |
CD 34+ (x106/kg) | 5,52 | 5,32 |
CD 3+ (x106/kg) | 56,9 | 357 |
aGvHD prophylaxis | CSA, MMF→medrol | Medrol, ruxolitinib (w/o CSA – high risk TMA) |
Granulocyte recovery (day) | +25 | +14 |
Thrombocyte ≥20 (day) | +24 | +39 |
Chimerism +30 day (%) | 100 | 100 |
Chimerism +60 day (%) | 100 | 100 |
Acute GVHD | no | no |
Complications | Local cellulitis, CMV | ВKV hemorrhagic cystitis and nephropathy, mucositis HSV, CMV |
CD4 + > 100microL (day) | +30 | +71 |
Follow up | Alive and well (6 mo post) | Alive and well (3 mo post) |
- F – female, M – male, CSA - cyclosporine A, EBV - Epstein-Barr Virus, HHV-6 - human herpes virus 6, MMF - Mycophenolate mofetil, TMA - thrombotic microangiopathy, CMV – Cytomegalovirus, ВКV – BK-virus, HSV - herpes simplex virus
Disclosure: Nothing to declare
21: Autoimmune Diseases
P074 THYMIC SIZE LONGITUDINAL CHANGES ON CHEST HIGH-RESOLUTION COMPUTED TOMOGRAPHY AFTER AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS
Gregory Pugnet 1, Samia Collot1, Antoine Petermann1, Pauline Lansiaux2, Gwenaëlle Lorillon3, Nassim Ait Abdallah2, Mathieu Resche-Rigon4, Cécile Borel1, Zora Marjanovic5, Dominique Farge2
1CHU Toulouse, Toulouse, France, 2Unité de Médecine Interne (UF 04), CRMR MATHEC, Maladies Auto-Immunes et Thérapie Cellulaire, Centre de Référence des Maladies Auto-Immunes Systémiques Rares d’Ile-de-France MATHEC, AP-HP, Hôpital St-Louis, Paris, France, 3Service de Pneumologie et Allergologie, AP-HP, Hôpital St-Louis, Paris, France, 4SBIM Hôpital St-Louis, AP- HP, Université de Paris, Paris, France, 5Hématologie Clinique et Thérapie Cellulaire- Hôpital Saint-Antoine, AP-HP, Paris, France
Background: The thymus is a central lymphatic organ responsible for T-cell differentiation and maturation throughout life. The thymus reaches its maximum absolute weight at puberty, and thymic involution then begins, with fatty infiltration of the gland. Incomplete thymus involution is observed in 12 to 15% of systemic scleroderma (SSc) patients and Meunier et al. reported an association between SSc-related interstitial lung disease and incomplete thymus involution. However, few data exist on thymic evolution after resetting the “immunologic clock” by autologous stem cell transplantation (aHSCT) in early diffuse cutaneous systemic scleroderma. The aim of this study was, therefore, to evaluate thymic involution frequency in SSc patients who underwent aHSCT and thymic size longitudinal changes on chest high-resolution computed tomography (HRCT) after transplant.
Methods: Chest HRCT evaluation was performed before aHSCT and afterwards during yearly routine clinical and paraclinical follow-up in 33 consecutive dcSSc-patients between January 2000 and January 2016. Two independent chest radiologist experts blindly assessed the thymus. Patients were retrospectively classified as clinical responders or clinical non-responders according to: at least 25% improvement in mRSS and/or 10% improvement in FVC or carbon monoxide diffusing lung capacity as compared with baseline, and without need for additional immunosuppression within the 24 months after transplant.
Results: Altogether we evaluated 33 SSc patients (20 female, 13 male) with a mean age at transplantation of 45.5 ±13.5 years and a disease duration of 28.0 ±17.7 months. 27.3% (n = 9) of the evaluated patients showed incomplete involution of the thymus at baseline. At 24 months after aHSCT, significant enlargement of thymus tissue were observed as compared with before aHSCT (p = 0.001). Among the 24 patients with complete involution of the thymus at baseline two of them grows after transplant.
Nineteen patients were clinical responders at 2 years (probability of response 0.68, 95% CI (0.49;0.82). All the patients with an increase in thymic size were in the clinical responders group. The mean absolute change from baseline in thymic size at month 24 was +23.6 mm2 in the clinical responders group and −38.1 mm2 in the clinical non-responders group (p = 0.002).
Table 1: Patients (n = 33) clinical and functional characteristics and Systemic Sclerosis organ involvement before treatment by autologous hematopoietic stem cell transplantation
Characteristics | n (%) or mean ± SD | n |
---|---|---|
Age at aHSCT, years | 45.5 ±13.5 | 33 |
Sex, female | 20 (60.6) | 33 |
Disease duration since SSc diagnosis, months | 28.0 ±17.7 | 33 |
Body mass index (kg/m2) | 24.0 ±3.7 | 33 |
Smoking status (ever vs never) | 9 (27.3) | 33 |
Skin involvement | ||
Modified Rodnan Skin Score (0-51) | 24.0 ±10.9 | 32 |
Lung involvement | 33 | |
Interstitial lung disease | 29 (87.9) | 33 |
Pulmonary Hypertension | 3 (9.1) | 33 |
Cardiac involvement | 17 (51.5) | 33 |
Gastrointestinal involvement | 16 (48.5) | 33 |
Immunological status and biological values | ||
Antitopoisomerase-1 antibody positive | 23 (69.7) | 33 |
Thymic size (mm2) | 88.8 ±173.7 | 33 |
Incomplete involution | 9 (27.3) | 33 |
- SD: standard deviation; BMI: body mass index; AHSCT: autologous hematopoietic stem cell transplantation
Conclusions: Real-world data show a significant thymic size increase within two years after aHSCT for early diffuse cutaneous systemic scleroderma which is associated with clinical response.
Disclosure: The authors declare non conflict of interest for this work.
21: Autoimmune Diseases
P075 LONG TERM PERSISTENCE OF T MEMORY STEM CELLS FOLLOWING AUTOLOGOUS HAEMATOPOIETIC STEM CELL TRANSPLANTATION FOR MULTIPLE SCLEROSIS
Melissa Khoo1,2, Carole Ford1, Jennifer Massey1,2,3, Kevin Hendrawan4, Malini Visweswaran1,2, John Zaunders1,2, Ian Sutton3, Barbara Withers3, David Ma1,2,3, John Moore 1,2,3
1St Vincent’s Centre for Applied Medical Research, Sydney, Australia, 2The University of New South Wales, Sydney, Australia, 3St Vincent’s Hospital Sydney, Sydney, Australia, 4The University of Queensland, Brisbane, Australia
Background: Autologous haematopoietic stem cell transplantation (AHSCT) is a high-efficacy therapy for severe autoimmune diseases, including Multiple Sclerosis (MS). While the mechanisms underlying the clinical benefits are still under investigation, the regeneration of a diverse T-cell repertoire is thought to play a critical role in the re-establishment of self-tolerance. T memory stem cells (Tscm) have been reported to be important novel players in post-transplant immune reconstitution in the haploidentical allogeneic setting. The role of Tscm in autoimmune AHSCT is however unknown. Here, we present the first study to examine Tscm in patients with MS undergoing AHSCT, and also in a non-autoimmune non-Hodgkin’s lymphoma (NHL) comparator group.
Methods: Multicolour flow immunophenotyping of T-cell subpopulations (Tscm (CD3+CCR7+CD45RO-CD45RA+CD27+CD95+), naïve (Tn), central memory (Tcm), transitional memory (Ttm), effector memory (Tem), and terminal effector (Tte) T-cells, recent thymic emigrants (RTE)) was performed on PBMCs (pre-AHSCT; d8, d14, 3m, 6m, 12m, 24m, 36m post-AHSCT) and leukapheresis product cryopreserved from MS and NHL patients undergoing AHSCT with BEAM conditioning (following written informed consent (HREC SVH 10/206), according to the Declaration of Helsinki; MS: n = 22, NHL: n = 5, Healthy Controls (HC): n = 4). Alterations in plasma levels of IL-7 and IL-15 were detected using Milliplex High-Sensitivity Bead-Based Assays. Statistical analysis was performed using: repeated measures ANOVA with Holm-Sidak Post-Hoc test (timepoint analysis), and 2-way ANOVA (mixed-effects) with Sidak Post-Hoc test (MS vs NHL), with logarithmic transformations if required after residual analysis (p<0.05); non-parametric Mann-Whitney U test (pre-AHSCT vs HC; p<0.05); using GraphPad Prism 8.
Immunophenotyping of longitudinal PBMC samples revealed significantly elevated levels of both CD4+ and CD8+ Tscm in MS patients post-AHSCT (p<0.03 and p<0.04 respectively), with this difference persisting long-term to at least 36m. In contrast, no changes in Tscm levels were detected in NHL patients post-AHSCT. While pre-AHSCT, significantly higher proportions of CD8+ Tscm were observed in both MS and NHL patients compared to HC (MS: 8-fold, p<0.0005; NHL: 13-fold, p<0.02). The kinetics of the remaining T-cell subpopulations (Tn, Tcm, Ttm, Tem, Tte, and RTE) were as expected post-AHSCT for both MS and NHL, with patterns of transient differences that returned to baseline by 12-36m. Early post-AHSCT we detected significantly increased levels (>4-fold) of plasma IL-15 in both MS (d8: p<0.001; d14: p<0.05) and NHL (d8: p<0.01), which subsequently returned to baseline in NHL, but decreased below baseline in MS. Conversely, significantly reduced plasma IL-7 was found at d8, 3m and 6m post-AHSCT for MS (p<0.01), whilst NHL displayed no differences.
Conclusions: To our knowledge, this is the first study to demonstrate Tscm expansion in an autoimmune HSCT setting. Elevated CD4+ and CD8+ Tscm post-AHSCT was specific to MS patients, with the absence of Tscm changes in NHL suggesting this is unique to MS patients and not only a consequence of post-conditioning lymphopenia. Interestingly, this persisted long-term in MS patients with Tscm remaining elevated out to 36m. Furthermore, the surge in IL-15 early post-AHSCT, in conjunction with persistently decreased IL-7 levels, suggests a shift in the IL-15/IL-7 balance, which may contribute to Tscm expansion in MS patients.
Disclosure: Authors: Nothing to declare
21: Autoimmune Diseases
P076 EFFECTS OF HIGH DOSE IMMUNOSUPPRESSIVE THERAPY WITH AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE SCLEROSIS FROM PATIENT’S PERSPCTIVE: LONG-TERM QUALITY OF LIFE OUTCOMES
Denis Fedorenko 1, Vladimir Melnichenko1, Anatoly Rukavitsin1, Nikolai Vasilev1, Tatiana Nikitina2, Natalia Porfirieva3, Tatiana Ionova2
1Pirogov National Medical Surgical Center, Moscow, Russian Federation, 2Saint-Petersburg State University Hospital, Saint-Petersburg, Russian Federation, 3Multinational Center for Quality of Life Research, Saint-Petersburg, Russian Federation
Background: Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease of the central nervous system which can lead to severe disability and result in profound quality of life (QoL) impairment. Patient’s QoL is an important outcome of MS treatment. It is shown that high-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (AHSCT) is a valuable option in MS which results in clinical and QoL improvement. The data about long-term QoL outcomes after HDIT + AHSCT are limited. We aimed to evaluate QoL changes in patients with MS at different time-points terms after HDIT + AHSCT.
Methods: Patients with different types of MS who underwent HDIT + AHSCT were enrolled in a longitudinal, prospective and single-center study. Two low-intensity regimens BEAM-like and Cyclophosphamide were applied. RAND SF-36 was used for QoL assessment before AHSCT, at 6 and 12 months after AHSCT, then every 6 months during 2 years after AHSCT and then every 12 months after 2 years of follow-up. Patients who could not answer the questionnaire themselves were excluded and incomplete questionnaires were eliminated. For comparisons t-test or Wilcoxon test as well as Generalized Estimating Equations were used.
Results: In total, 240 patients with MS were included in the analysis: 132 relapsing-remitting MS (RRMS) (55%), 75 secondary progressive MS (SPMS) (31.3%) and 33 primary progressive MS (PPMS) (13.7%). Median age – 40 years old [Q1; Q3 – 32; 49], 35.8% - males. Median baseline EDSS – 4 [Q1; Q3 – 2; 6]. BEAM-like was used in 85 patients (35.4%), Cyclophosphamide – in 155 patients (64.6%). Mean follow-up was 21 months (range: 6-97). We found a significant increase of all 8 SF-36 scales in 12 months post-transplant as compared with base-line in the entire group (p<0.05). In RRMS patients the values of all SF-36 scales significantly improved (p<0.01) In patients with progressive MS statistically significant improvement was registered for 4 out of 8 SF-36 scales (p<0.01); changes for role functioning scales, bodily pain and mental health scales were not statistically significant. During the entire period of follow-up in patients without progression or relapse QoL further improved. Significant positive changes by all SF-36 scales as compared to baseline were observed for the whole group (p≤0.001). For patients with both remitting and progressive MS positive changes for physical and mental health components of SF-36 were revealed during the follow-up post-transplant (p<0.001 for physical and mental health components in remitting MS and physical component of progressive MS; p = 0.012 for mental health component in progressive MS).
Conclusions: HDIT + AHSCT resulted in significant and sustained improvement of QoL in MS patients post-transplant. Meaningful QoL improvement was observed both in patients with remitting and progressive MS at long-term follow-up.
Clinical Trial Registry: No
Disclosure: Nothing to declare
21: Autoimmune Diseases
P077 THE MATHEC-SFGM-TC REGISTRY FOR CELL THERAPY IN AUTOIMMUNE DISEASES: A DEDICATED TOOL FOR REAL-WORLD DATA COLLECTION
Pauline Lansiaux1, Manuela Badoglio2, Grégory Pugnet3, Mathieu Puyade4, Emmanuel Chatelus5, Thierry Martin5, Louis Terriou6, Alexandre Maria7, Marc Ruivard8, Jacques-Olivier Bay8, Bertrand Dunogué9, Matthieu Allez1, Hélène Zéphir10, Arsène Mékinian11, Eric Deconinck12, Sabine Berthier13, Françoise Sarrot-Reynaud14, Frédéric Garban14, Nicolas Maubeuge4, Guillaume Mathey15, Cristina Castilla-Llorente16, Céline Labeyrie17, Régis Peffault de la Tour18, Marie Robin19, Zora Marjanovic11, Dominique Farge 1
1AP-HP, Hôpital Saint-Louis, Paris, France, 2EBMT Paris Study Office, Paris, France, 3CHU Toulouse, Toulouse, France, 4CHU Poitiers, Poitiers, France, 5CHU Strasbourg, Strasbourg, France, 6CHU Lille, Lille, France, 7CHU Montpellier, Montpellier, France, 8CHU Clermont-Ferrand, Clermont-Ferrand, France, 9AP-HP, Hôpital Cochin, Paris, France, 10CHRU Lille, Lille, France, 11AP-HP, Hôpital Saint-Antoine, Paris, France, 12CHRU Besançon, Besançon, France, 13CHU Dijon, Dijon, France, 14CHU Grenoble, Grenoble, France, 15CHU Nancy, Nancy, France, 16Institut Gustave Roussy, Villejuif, France, 17AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France, 18AP-HP Hôpital Saint-Louis, Paris, France, 19SFGM-TC, Hôpital Saint-Louis, Paris, France
Background: The European Society for Blood and Marrow Transplantation (EBMT) and International Society for Cellular Therapy (ISCT) Joint Accreditation Committee (JACIE) guidelines underline the necessity to yearly report all consecutive hematopoietic stem cell transplantation (HSCT) and patient’s real world data (RWD) monitoring in the EBMT registry, which allows healthcare professionals to assess activity, practices and treatment outcomes and ultimately to improve patient care. A 2015 European Medicines Agency (EMA) initiative encouraged better use of existing registries or development of new, high-quality registries where no existing RWD is available. In orphan rare autoimmune diseases (AD), registries represent an important source of safety and RWD, specifically for patients receiving HSCT or other Cellular Therapies (CT), as Mesenchymal Stroma Cell (MSC) or CAR-T. The EBMT Registry minimum data-set for AD contains transplant data and short-term (Day 100) post-transplant complications with a need to develop AD specific and longer-term monitoring RWD acquisition both at national and European levels.
Methods: Based on a tight collaboration with EBMT under the auspices of the French-speaking Society for Marrow Transplantation and Cellular Therapy (SFGM-TC), the MATHEC-SFGM-TC registry www.mathec.com)) was developed to register and follow-up all AD patients treated by CT in France. It is hosted by Epiconcept certified Health Data Host and compliant with the French independent administrative authority (CNIL) controlling the use of personal data. The selection of variables was based on those collected for the EBMT Registry core dataset and those used for studies promoted by the AD working part. RWD to be collected, include: a) CT treatments (HSCT/ other CT type, donor, source and associated procedures, complications and survival status) plus b) AD specific diagnosis, clinical biological RWD at baseline and during routine follow-up evaluation after CT at 3, 6 and 12 months, then biannually until 5 years and annually at least until 10 years for long-term follow-up. The MATHEC-SFGMTC centers were asked to include all consecutive AD patients receiving HSCT or other CT, with repeated alerts to update the follow-up as recommended by EBMT and by SFGM-TC. Informed consent was obtained for all patients before inclusion. Data managers were adequately trained and supervised by relevant CT and AD specialists to optimize data quality. All registry data are reported here.
Results: On December 6th 2023, 248 AD patients were included in the MATHEC-SFGM-TC registry: 225 patients with 229 HSCT (228 autologous, 1 allogeneic) since 1997 were followed in 31 centers for a median duration of 48 (19-115) months. CT and AD-specific and long-term RWD were collected for HSCT in 152 rheumatologic (138 scleroderma, 5 polychondritis), 55 neurological (43 multiple sclerosis, 7 CIPD) and 11 Crohn disease patients after either standard cyclophosphamide (n = 122), BEAM (n = 12), low dose cyclophosphamide (n = 62), or other (n = 16) conditioning with ATG (n = 179) and/or Rituximab (n = 45). RDW for MSC (20 Scleroderma, 8 Lupus) and CAR-T (1 lupus) patient were collected.
Conclusions: Combining RWD from multiple centres at registry national level are essential to conduct robust studies in rare AD with a sufficient number of patients and disease specific data.
Disclosure: Nothing to declare
21: Autoimmune Diseases
P078 ATG AND OTHER SEROTHERAPY IN CONDITIONING REGIMENS FOR ASCT IN AUTOIMMUNE DISEASES: A SURVEY OF THE EBMT AUTOIMMUNE DISEASES WORKING PARTY (ADWP)
Azza Ismail1, Rosamaria Nitti 2, Basil Sharrack1, Manuela Badoglio3, Pascale Ambron3, Myriam Labopin3, Tobias Alexander4, John Snowden5, Greco Raffaella2
1Sheffield NIHR Translational Neuroscience BRC, Sheffield Teaching Hospitals NHS Foundation Trust & University of Sheffield, Sheffield, United Kingdom, 2Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy, 3EBMT Paris study office / CEREST-TC - Saint Antoine Hospital - INSERM UMR 938 - Université Pierre et Marie Curie, Paris, France, 4Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany, 5Sheffield Teaching Hospitals NHS Foundation Trust; Division of Clinical Medicine, School of Medicine and Population Health, The University of Sheffield, Sheffield, United Kingdom
Background: Serotherapy is a key component of conditioning regimens for autologous hematopoietic stem cell transplant (ASCT) in autoimmune diseases (AD), however, it may be delivered in various dosing combinations across different centers.
Methods: Between December 2022 and November 2023, a survey on the current use of serotherapy for ASCT in ADs, with a focus on anti-thymocyte globulin (ATG), was undertaken by the Autoimmune Diseases Working Party (ADWP) among European Society for Blood and Marrow Transplantation (EBMT) centers, having performed more than 5 ASCTs for AD in adult patients since 2015.
Results: Forty-six EBMT centers (66%) responded to the survey. Among responding centers, 23.9% perform ASCT for neurological AD indications, 15.2% for rheumatological ADs, 58.7% for multiple indications. All centers use ATG, 12 centers (26.1%) also use Rituximab (91.7% of them use it in addition to ATG administration), no center uses Alemtuzumab.
Many centers (58.7%) use the same conditioning regimen for all AD indications. Cyclophosphamide-ATG is the most frequently used regimen (88.8% of centers), followed by BEAM-ATG (22.3%), whereas RIC regimens like cyclophosphamide-fludarabine-ATG were used less frequently. Most centers (93.5%) use ATG for all AD indications. Only one center uses serotherapy-free regimen (cyclophosphamide only), for neurologic indications.
Thymoglobuline is the most commonly used ATG type (89.1% of centers). Four centers report using Grafalon and one center uses Atgam. Among centers using Thymoglobuline, 41.5% administer a total dose (TD) of ≥7.5 mg/kg, while 53.6% administer <7.5 mg/kg. Each center using Grafalon administers a different TD (range 7.5-90 mg/kg). ATG administration is always fractionated over multiple days, most frequently 3 (32.6%) or 5 days (37%); half of centers divide the TD equally for each day of administration.
Rituximab TD is 500 mg (25% of centers) or 1000 mg (75%), the 1000 mg TD is equally fractionated in two days by 6/9 centers. Most centers administer ATG during chemotherapy (63%), while Rituximab is administered before chemotherapy (25%) or before chemotherapy and after HSC infusion (50%).
Test dose is used by 34.8% of centers before ATG administration (ranges 0.28-25 mg or 0.5-1 mg/kg), no center uses rituximab test dose. ATG administration is slower (48.9% of centers administer it over 12 hours) than Rituximab administration (41.7% of centers administer it over 4 hours and 41.7% over 6 hours).
Premedication is used to prevent serotherapy-related adverse events, including antihistamines (100% of centers), paracetamol (91.1%) and steroids (98%), in particular 37.8% of centers administer methylprednisone 1 mg/kg or equivalent and 35.6% administer methylprednisone 2 mg/kg or equivalent. One third of centers repeats premedication at fixed times during a single infusion.
For ATG, 80.4% of centers successfully administer the planned TD to all patients, for Rituximab, 75% of centers administer the TD to all patients. Among HSCT performed for neurologic indications, about half of patients develop clinical relapse during serotherapy administration.
Conclusions: This survey reveals a high degree of consistency across EBMT centres regarding the use of serotherapy in ASCT for AD. However, a wide variability in doses suggests the need for consensus guidelines to best standardize practice.
Disclosure: None related to the manuscript. AI and RN contributed equally to the work.
21: Autoimmune Diseases
P079 ADOPTING A STANDARD OF CARE: AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR SCLERODERMA
Ernesto Ayala 1, Madiha Iqbal1, Hemant Murthy1, James Foran1, Vivek Roy1, Mohamed Kharfan-Dabaja1
1Mayo Clinic Florida, Jacksonville, United States
Background: Three prospective comparative trials have proven the superiority of autologous hematopoietic stem cell transplantation (aHSCT) over other treatments in patients with Scleroderma. A position statement from the American Society for Blood and Marrow Transplantation endorses its use as “standard of care”. However, it remains underutilized in the US.
Methods: This is an IRB approved, retrospective review of all patients with Scleroderma that have undergone aHSCT at Mayo Clinic Florida since April 2020, and completed at least 3 months of follow up. Scleroderma diagnosis was made/confirmed by our Rheumatology Department based on published criteria.
Results: Twenty four patients were included. Median age at transplant was 49 years (range 21-68). 70% of patients were female, 54% were Caucasian. Median time from diagnosis to transplant was 33 months (5-188). Skin was involved in 100% patients, lung (interstitial disease) in 79%, esophagus in 75%, heart in 12%. Right heart catheterization was done in 13 patients (when recommended by Cardiology) with mild pulmonary hypertension found in 5. Gastric antral vascular ectasia was found/treated in one patient. Median time from consultation to transplant was 2 months (1-24). Hematopoietic stem cell mobilization was induced with G-CSF (24 patients) with the addition of plerixafor (13 patients). Median number of peripheral blood stem cell harvests was 2 (1-3). Myeloablative conditioning was used in 3 patients: Cyclophosphamide + rabbit ATG + 800 cGy total body irradiation (2 patients) or melphalan + rabbit ATG (1 patient with synchronic multiple myeloma). Non-myeloablative conditioning was used in 21 patients: Cyclophosphamide + rabbit ATG (19 patients) or cyclophosphamide + fludarabine + rabbit ATG. Two patients had modifications of conditioning due to volume overload. Twenty three grafts were CD34+ selected. Median number of infused CD34+ cells was 5.98 x 10^6/kg. Granulocyte engraftment occurred at a median of 12 days (0-14) and platelet engraftment at a median of 12 days (0-15), as well. Median hospital stay was 20 days (2-46). Two patients died during the conditioning regimen, one of them of a spontaneous pneumothorax followed by cardiac arrest, the second one from acute bowel ischemia and ARDS. Both had advanced cardiopulmonary disease from scleroderma. One patient died of severe pneumonitis, attributed to myeloablative radiation therapy. One late mortality (day +60 was due to multilobar pneumonia in the setting of cirrhosis with massive ascites. Median follow up after transplant is 12.5 months. Median modified Rodnan skin score pre-transplant was 24 (4-44), post-transplant was 12 (0-28). Median forced vital capacity (FVC) pre-transplant was 80% (41-103), post-transplant 74% (46-108). Median corrected DLCO pre-transplant was 66%, post-transplant was 60% (47-70). Non-relapse mortality was 16%. Relapse was 14%. For transplanted patients, 1 year overall survival is 91% (CI 80-100) and relapse free survival is 78.5% (CI 61-100).
Conclusions: High dose immune ablation with a non-myeloablative conditioning regimen induces durable remissions in most patients with Scleroderma. Mobilization and harvest of hematopoietic stem cells can be accomplished successfully without chemotherapy, even if CD34 selection is planned. Patients with advanced cardiopulmonary disease have a high risk of morbidity and mortality and should be excluded of this approach.
Disclosure: Nothing to disclose.
21: Autoimmune Diseases
P080 FLUDARABINE AND CYCLOPHOSPHAMIDE AS A SAFE AND EFFECTIVE LYMPHOABLATIVE CONDITIONING REGIMEN FOR MULTIPLE SCLEROSIS (MS)
Denis Fedorenko 1, Anatoly Rukavitsin1, Nikolai Vasilev1, Vladimir Melnichenko1, Tatiana Ionova2
1Pirogov National Medical Surgical Center, Moscow, Russian Federation, 2Saint-Petersburg State University Hospital, Saint-Petersburg, Russian Federation
Background: At present, high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (AHSCT) has been used with increasing frequency as a therapeutic option for MS patients. BEAM and cyclophosphamide 200 mg/kg are mostly common used as conditioning regimens for MS patients, but toxicity of both is still high. Thus, a new approach to reduce toxicity for MS patients is needed. The study is aimed to analyze toxicity of new conditioning regimen based on Fludarabine, Cyclophosphamide and Rituximab (R-Flu/Cph) to compare with traditional Cyclophosphamide and Rituximab (R-Cph) in MS patients.
Methods: 232 MS patients were included in this study, median age - 40 years; men/women – 132/100; relapsing-remitting MS – 125 patients, primary progressive MS – 61 patients, secondary progressive MS - 46 patients. EDSS score was from 1.0 to 7.5 (median - 4.0). All patients received AHSCT. Conditioning regimens were: R-Cph (Cyclophosphamide 200 mg/kg + Rituximab 500 mg/m2) – 49 patients, R-Flu/Cph (Fludarabine 150 mg/m2 + Cyclophosphamide 100 mg/kg + Rituximab 500 mg/m2) – 183 patients.
Results: Hematologic toxicity of regimens: duration of neutropenia was from 7 to 12 days (median - 10 days) in R-Cph group and from 3 to 10 days (median - 6 days) - in R-Flu/Cph group. The median duration of thrombocytopenia in R-Cph regimen was 7 days, in R-Flu/Cph - 4 days. Platelet transfusion received 63% of patients in R-Cph group and only 8.2% of patients in R-Flu/Cph group. Anemia grade I-II was observed in 90% of patients in booth groups. Oral mucositis was observed in 26% patients in R- Cph+R group (Grade I - 61,5 %; Grade II - 38,5 %) and in 4% of patients in R-Flu/Cph group (Grade I - 100 %). Enteropathy was observed more in R-Cph group - 16 % (grade II) to compare with R-Flu/Cph group (11%, mainly grade I) Infections: the incidence of infectious complications was higher in R-Cph group – 26% of patients to compare with R-Flu/Cph group - 11.4% of patients. One patient died from sepsis in R-Cph group (TRM – 2.0%), TRM in R-Flu/Cph group was 0%. Hepatic toxicity: in R-Flu/Cph group 10% of patients had hepatic toxicity (grade I and II). In R-Cph group hepatic toxicity was observed in 18% of patients (grade II). Range of immunosuppression: the minimal count of lymphocytes was significant lower in R-Flu/Cph group 0,0001 – 0,01 х 109/l (median 0.0008 х 109/l), than in R-Cph group (minimal count of lymphocyte - 0,001 – 0,06 х109/l, median 0.009 х 109/l, p<0.05).
Conclusions: R-Flu/Cph is a very promising program with less toxicity profile, less incidence of infections and significantly deeper rate of lymphoablation. Also TRM was 0% in R-Flu/Cph group to compare with 2% in R-Cph group. Further studies are needed to assess long-term effectiveness and toxicity of new conditioning regimen.
Clinical Trial Registry: No
Disclosure: Nothing to declare
21: Autoimmune Diseases
P081 IMMUNE RESET AND GRAFT COMPOSITION IN AUTOLOGOUS TRANSPLANTATION FOR MULTIPLE SCLEROSIS: EARLY RECOVERY OF NATURAL KILLER CELLS MAY BE IMPORTANT IN EFFECTING DURABLE RESPONSES
Latoya Reid 1, Oliver Gittner2, Malia Begley3, Rowayda Peters3, Andy Drake3, Matthias Klammer3
1University Hospital of the West Indies, Kingston, Jamaica, 2Steve Mills Stem Cell and Immunotherapies Laboratory, NHS Blood and Transplant, Southampton, United Kingdom, 3St. George`s University Hospital, NHS Foundation Trust, London, United Kingdom
Background: Autologous Haematopoietic Stem Cell transplantation (ASCT) is an effective therapeutic modality in patients with relapsing/remitting multiple sclerosis (MS) through immune regeneration with a less auto-inflammatory response pattern, but the mechanism of achieving durable responses remains poorly understood.
In malignant disease, we have previously studied graft composition and revealed high variability of NK cell content in the graft, early NK cell recovery post HSCT and an association of absolute lymphocyte count >0.5 x 10e9/L at D + 15 with more durable remission.
Similarly, early NK reconstitution post ASCT in MS may be responsible for later shaping a less auto-inflammatory immune reconstitution.
Methods: We monitored lymphocyte subsets (CD4, CD8, NK and B cells) monthly for three months and at 6 and 12 months after ASCT in 16 patients transplanted for Multiple Sclerosis. Autologous stem cells were mobilized with Cyclophosphamide 1.5 mg/m2 and GCSF and patients underwent HSCT after conditioning with Cyclophosphamide and ATG. The non-stem cell component of the graft was analyzed by flow cytometric analysis for B, T, NK cells and neutrophils using defrosted cryovials.
Results: Patient and disease characteristics are summarized in Table 1. The median age at ASCT was 35.5 years with a median EDSS score of 4. Most patients received Alemtuzumab (38%) followed by Natalizumab (31%) as their last disease modifying therapy prior to transplant. The median lines of therapy were two with a median of 14 months duration between last highly effective immunosuppressive therapy and transplant.
In the post-transplant period, total T cell numbers did not return to the low normal range until day 240. The CD4/CD8 ratio was clearly inverted until beyond Day 180. In contrast, in the early post-transplant period (Day 30), we saw the highest absolute number of NK cells with a sharp fall to low normal number in subsequent time points. This is also reflected in a high, inverted CD 56: CD 4 ratio in the first month post ASCT, only reverting to a physiological range at Day 240.
Table 1: Demographics and Disease Characteristics
Number of Patients | 16 |
Sex No. (%) | |
Female | 11 (69%) |
Male | 5 (31%) |
Age in years | |
Median | 35.5 |
Range | 24-49 |
Expanded Disability Status Scale (EDSS) score | |
Median | 4 |
Range | 1.5-6.5 |
Last immunosuppressant prior to transplant No. (%) | |
Alemtuzumab | 6 (38%) |
Natalizumab | 5 (31%) |
Ocrelizumab | 4 (25%) |
Pulsed Steroids | 1(6%) |
Lines of immunosuppressive therapy | |
Median | 2 |
Duration between last highly effective immunosuppressive therapy and transplant (months) | |
Median | 14 |
Conclusions: Early immune recovery post ASCT in patients with MS is characterized by a high, inverted NK cell/ CD4 ratio, a finding we previously reported in malignant disease (Multiple Myeloma). Recent studies suggest that NK cells have an immunoregulatory function on Th17 responses, a pro inflammatory mediator implicated in Multiple Sclerosis. Further studies into the early kinetics of immune reconstitution in patients with MS post ASCT, the impact of previous therapies and the non-stem cell component of the graft are required to understand if these shape the durable immune reset and it`s mechanism.
Disclosure: Nothing to declare
21: Autoimmune Diseases
P082 REDUCED PRO-INFLAMMATORY INTERLEUKINS IL-6 AND IL-8 SECRETED BY SKIN FIBROBLASTS IN SYSTEMIC SCLEROSIS PATIENTS AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION
Gunter Assmann 1,2, Jan Weghorn1, Michael Schmidt1, Joerg Henes3, Claudia Pfoehler4, Frank Neumann2
1RUB University Hospital JWK Minden, Minden, Germany, 2Jose Carreras Center of Immungenetics and Gene Therapy, University of Saarland, Homburg, Germany, 3University Hospital Tuebingen, Tuebingen, Germany, 4University Hospital of Saarland Medical School, Homburg, Germany
Background: Systemic sclerosis (SSc) is an autoimmune connective tissue disease defined by fibrosis of skin and internal organs as well as vascular impairment accompanied by a significantly higher mortality rate than in the general population. Early severe courses of SSc should be provided for intensified treatment such as hematopoietic stem cell transplantation (autoTx).
In addition to the fibrosis several features of SSc often show a phenotype of auto-inflammation which is thought to be mediated by the TH17 pathway in addition to other inflammatory factors.
Methods: Here we investigated cultures of skin fibroblasts derived from SSc (3 to 6 months) after successful autoTx as well as without autoTx to evaluate the different expression of pro-inflammatory cytokines (interleukin-1-beta, interleukin-6 (IL-6), interleukin-8 (IL-8)) after stimulation of interleukin-17 (IL-17) and combined with tumor growth factor-beta (TGF-beta), measured by concentrations (ng/ml, +/-standard error) in the cellular supernatant using ELISA tests.
SSc patients (n = 8, aged 43 to 65 years) and three of them after autoTx (n = 3, aged from 54 to 59 years) underwent a skin biopsy of the lateral abdominal wall or forearm.
The cells were stimulated by 25 ng/ml of IL-17 and/or 2.5 ng/ml of TGF-beta for 48h. The differences between SSc and SSc after autoTx were statistically analysed by t-test (with fisher`s correction).
The ethics committee of the Saarland Medical Association has approved the experimental study (EK120/23).
Results: IL-6 secreted by skin fibroblasts showed a significantly higher concentration in SSc patients without autoTx compared to SSc after autoTx. After in-vitro stimulation of the skin fibroblasts by IL-17 the IL-6 as well as IL-8 concentrations were significantly higher in SSc patients without autoTx to SSc without autoTx (figure 1). Furthermore, after IL-17 stimulation together with TGF-beta the concentration of IL-8 (but not IL-6) supernatant concentrations also resulted in significantly higher values for SSc fibroblasts in patients without autoTx compared to patients after autoTx (1.99 + /-0.23 vs. 0.63 + /-0.06 [p = 0.0008]). IL- 1beta concentrations did not show any differences between the subgroups (data not shown).
Conclusions: Skin fibroblasts derived from SSc patients showed significantly stronger IL-6 and IL-8 driven pro-inflammatory properties than skin fibroblasts derived 3 to 6 months after the hematopoietic stem cell transplantation. In what way (1) IL-6 and IL-8 may be a potential biomarker for disease activity of SSc and (2) IL-17 could be a predominant pathway for activity in SSc patients remains the subject of further research.
Disclosure: G. Assmann: advisory boards, research grants from: UCB, Astrazeneca, Boehringer-Inglheim, Novartis, BMS, Vifor Pharm; C. Pfoehler: advisory boards, research grants from UCB, Novartis, BMS, Astrazeneca, AbbVie; J. Henes: advisory boards, research grants from: AbbVie, BMS, Boehringer-Ingelheim, Chugai, GSK, Janssen, NEOVII, Novartis, Pfizer, UCB; remaining authors: no discloser
21: Autoimmune Diseases
P083 THE QUALITY OF LIFE OF PERSONS WITH MULTIPLE SCLEROSIS IMPROVES AFTER AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION
Olivia Lira-Lara1, Moisés Manuel Gallardo-Pérez2, Miranda Melgar-de-la-Paz3, Paola Negrete-Rodríguez4, Luis Enrique Hamilton-Avilés5, Guillermo Ocaña-Ramm5, Max Robles-Nasta2, Daniela Sánchez-Bonilla2, Juan Carlos Olivares-Gazca2, Guillermo José Ruiz-Delgado 2,5, Guillermo José Ruiz-Arguelles2,5
1Universidad Veracruzana, Veracruz, Mexico, 2Centro de Hematología y Medicina Interna, Clínica Ruiz, Puebla, Mexico, 3Universidad Anáhuac Puebla, Puebla, Mexico, 4Universidad de las Américas Puebla, Puebla, Mexico, 5Universidad Popular Autónoma del Estado de Puebla, Puebla, Mexico
Background: Multiple sclerosis (MS) is a complex inflammatory, demyelinating and neurodegenerative disease of the central nervous system that causes a whole spectrum of neurological disorders as well as patient’s perception of an abnormal physical, emotional or cognitive state, associated with a profound decrease in the quality of life of affected patients. Currently, autologous hematopoietic cell transplantation (ASCT) is a validated therapeutic approach and has been shown to be superior to the use of new immunomodulatory agents. However, the impact of ASCT on the quality of life of patients with MS remains largely unknown. The objective is to identify the impact of autologous HSCT in the quality of life in patients with MS in a single institution.
Methods: A quasi-experimental, longitudinal, prospective and single-center study was conducted in our institution. The quality of life was determined in patients with MS before and one year after ASCT; it was determined by applying the MS-QoL 54 instrument which is a validated instrument for this pathology. The variables related to the physical and mental components of the instrument as well as demographic characteristics were studied. Patients who could not answer the questionnaire themselves were excluded as well as incomplete questionnaires. ASCT was conducted as outpatients following the “Mexican method”, which employs high-dose both cyclophosphamide and rituximab.
Results: 38 patients answered the questionnaire before and one year after the ASCT. 21 (56%) were female. Median age was 47 years (SD ± 8.85). Of the selected patients, 22 (58%) had relapsing-remitting MS, 12 (32%) primary progressive MS, whereas 4 (11%) had secondary progressive MS. The physical and mental components were analyzed between the quality of life in the patients prior to the ASCT and the follow-up after one year. In the energy component the differences observed before and one year after the ASCT were statistically significant (40.73 vs 49.57, p = 0.04), as well as the differences in the health perceptions (47.1 vs 56.31, p = 0.011), health distress component (40.65 vs 55.26, p = 0.002) and chance in health (31.57 vs 63.81, p <0.0001). On the other hand, in the physical component the differences between before and after one year of ASCT were not statistically significant (p = 0.069) as well as the differences in the mental component either (p = 0.218).
Conclusions: The study suggests that ASCT improves some aspects of the quality of life of persons with MS.
Disclosure: Nothing to declare
21: Autoimmune Diseases
P084 AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN THE TREATMENT OF MULTI-REFRACTORY STIFF PERSON SYNDROME: A CASE STUDY
Tamim Alsuliman 1, Dimitri Psimaras2, Nicolas Stocker1, Simona Sestili1, Anne Banet1, Zoé Van de Wyngaert1, Agnès Bonnin1, Manuela Badoglio3, Mathieu Puyade4,5, Dominique Farge6,5, Mohamad Mohty1, Zora Marjanovic1,5
1Saint-Antoine Hospital, APHP Sorbonne University, Paris, France, 2Hôpital Universitaire Pitié-Salpêtrière, Paris, France, 3EBMT Paris Study Office, Paris, France, 4CHU de Poitiers, Poitiers, France, 5MATHEC, Paris, France, 6Saint-Louis Hospital, Paris, France
Background: Autologous hematopoietic stem cell transplantation (AHSCT) has been successfully used to treat several types of autoimmune diseases (AD) such as multiple sclerosis. (1,2)
The “stiff person syndrome” (SPS) is a rare neurological AD with a prevalence of 1 to 2 patients per million (3), predominantly observed in women (2-3 female/1 man). (3) It is characterized by progressive stiffness of skeletal muscles, episodic painful muscle spasms, and prevention of volitional movements and ambulation in severe cases. Lumbar para-spinal rigidity limits the range body mobility. Spasms due to increased muscle stiffness occur spontaneously or secondary to different external and internal stimuli.(3–5)
Methods: Informed consent was obtained from the patient for the publication of this report. AHSCT is indicated with a grade 1 level of evidence for the treatment of multi-refractory / recurrent SPS. The national committee of transplantation in AD (MATHEC) approved the AHSCT, as a “Clinical Option”, for this patient. The mobilization was performed using cyclophosphamide 1g/m2 D1 and D2 plus G-CSF 30 MUI/day from D6. The conditioning regimen was cyclophosphamide 200 mg/kg total dose, Anti-thymoglobulin 6 mg/kg and Rituximab 500 mg before the conditioning and 500 mg in post-AHSCT.
Results: A 53-years-old female was diagnosed, at the age of 48 years (2016), with Stiff Person Syndrome muscular stiffness. One year later, onset of dysarthria and cerebellar instability were noticed. Neurological cerebellar symptoms progressively increased, with pyramidal involvement over 8 years. Contractions associated with instability increased and later she could no longer run. No cognitive disorder was described.
The spinal cord and brain MRI, alongside EMG did not show damage to the peripheral motor neuron. The ocular movement test was in favor of a cerebellar syndrome with defected floculli. The lumbar puncture revealed the presence of high anti-GAD antibodies titer in the CSF and plasma. The PET CT/CT did not show any underlying neoplasia. Diagnostic criteria included lower back and limbs stiffness, stimulated by emotions, oculomotor disorders, very good response to Valium.
She received six courses of IVIG from September 2016 to May 2017, with the onset of dysarthria. Rituximab was administered three times within two years. Cyclophosphamide was also administered concomitantly for six months. Azathioprine showed no efficacy while fampridine was not tolerated.
At the end of 2019, the Scale for the Assessment and Rating of Ataxia (SARA) score was at 11. Ocular movements test showed worsening nystagmus. Gabapentin was consequently initiated, then stopped rapidly for inefficacy. The patient was referred to hematology department and treated by AHSCT without major complications in 2021.
Six months Post-AHSCT the patient had better flexibility and mobility, could walk for 2 hours with mild assistance. Dysarthria improved with a SARA at 7.5.
2-years Post-AHSCT speech comprehension improved. She walks alone> hour without assistance. Maintain good balance on uneven ground. SARA was at 6.
Table1: Neurological manifestations: before, 6 months, and 2-years post-AHSCT
Before AHSCT | Post-AHSCT period | 2 years post-AHSCT | ||
---|---|---|---|---|
SARA | 11 | 7.5 | 6 | |
Speech comprehension | impacted | Good | Very good | |
Walking | Very hard, robot-like | Better | Very good | |
Aide for walking | Permanent | Only if uneven ground | None | |
Stiffness | Severe | Very mild | Almost no stiffness | |
Flexibility | No flexibility | Better | Very good | |
Dysarthria | Severe | Better | Very good |
Conclusions: AHSCT, as an intensive immunablation followed by was well tolerated and a very effective treatment for this patient with of immunotherapy -refractory SPS. This experience supports its use for refractory stiff-person syndrome.
Disclosure: Nothing to declare
4: CAR-based Cellular Therapy – Clinical
P085 BRIDGING THERAPY PRIOR TO TREATMENT WITH ANTI-CD19 CAR T CELLS FOR RELAPSED/REFRACTORY ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN AND YOUNG ADULTS - A MULTINATIONAL RETROSPECTIVE ANALYSIS
Maike Breidenbach1, Peter Bader2, Andishe Attarbaschi3, Claudia Rossig4, Roland Meisel5, Markus Metzler6, Marion Subklewe1, Fabian Mueller7, Paul-Gerhard Schlegel8, Irene Teichert von Lüttichau9, Jean-Pierre Bourquin10, Gabriele Escherich11, Gunnar Cario12, Peter Lang13, Ramona Krauss1, Arend von Stackelberg14, Semjon Willier15, Christina Peters3, Tobias Feuchtinger 16,1
1Ludwig Maximilians University Munich, Munich, Germany, 2Goethe University Frankfurt, University Hospital, Frankfurt, Germany, 3St. Anna Children’s Hospital, Vienna, Austria, 4University Children’s Hospital Muenster, Muenster, Germany, 5Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany, 6University Hospital Erlangen, Erlangen, Germany, 7Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany, 8Pediatric Hematology and Oncology and Stem Cell Transplantation, University Children’s Hospital Wuerzburg, Wuerzburg, Germany, 9TUM School of Medicine, Children’s Hospital Munich Schwabing, Technical University of Munich, Munich, Germany, 10University Children’s Hospital Zurich, Zurich, Switzerland, 11Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 12University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany, 13University Children’s Hospital Tübingen, Tübingen, Germany, 14Charité Universitaetsmedizin, Berlin, Germany, 15University Medical Center Freiburg, Freiburg, Germany, 16Pediatric Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany
Background: Chimeric antigen receptor (CAR) T cells targeting CD19 are a well-established treatment option for children and young adults suffering from relapsed and/or refractory B-lineage acute lymphoblastic leukemia (ALL). Bridging therapy is the treatment between eligibility and administration of CAR T cells. Bridging has been designed to achieve a low leukemia burden prior to CAR T cell infusion. However, systematic data of bridging therapy are still limited and the effect on outcome, side effects and response to CAR T cell therapy is still poorly understood. With this retrospective, multinational, large-scale study, we strive to understand the impact of low- and high-intensity bridging regimens on a variety of outcome parameters in order to improve the basis for clinical decision making in bridging therapy prior to CAR T cell administration.
Methods: Real-world data were collected from 82 patients receiving 87 CAR T cell therapies from twelve sites in Germany, Austria and Switzerland. Treatments were classified into categories 1) no systemic therapy, 2) low-intensity therapy and 3) high-intensity therapy. Bridging therapies were defined as high-intensity if at least one chemotherapeutic agent of the following was given: cyclophosphamide/ifosfamide, etoposide, anthracyclines or other agents with high toxicity potential (intravenous methotrexate, platinum-based antineoplastic drugs, thiotepa, high-dose cytarabine, fludarabine). Low-intensity bridging therapies comprised the administration of steroids, vincristine, low-dose cytarabine, PEG-asparaginase/Erwinia asparaginase and oral maintenance therapy (mercaptopurine, thioguanine, oral methotrexate, hydroxyurea). The administration of specific chemotherapeutic agents as well as immunotherapies and targeted therapies was assessed. CAR therapies comprised CD19 2nd generation CAR T cell products from commercial and academic providers.
Results: 38 of 87 treatments were classified as high-intensity and 34 as low-intensity bridging regimens. Prior to 14 CAR T cell administrations no systemic bridging therapy was given, 1 of 87 bridging regimens could not be stratified. Between eligibility and apheresis, mostly low-intensity therapy or no systemic therapy was given. Within the period between apheresis and CAR T cell infusion, treatment diversified due to the heterogeneity of the cohort. Patient characteristics are listed in Table 1. Patients receiving a high-intensity bridging therapy had a significantly higher tumor burden at time point of eligibility defined by blasts in bone marrow and by measurement of minimal residual disease (MRD) compared to patients treated with a low-intensity or no systemic bridging therapy. Tumor burden within the two groups converged over the time of bridging therapy. However, until time of lymphodepletion, patients in the high-intensity group had significantly more often bacterial adverse events and mucositis and showed a lower performance status (Karnofsky/Lansky) than patients in the low-intensity/no systemic therapy group. High-intensity bridging therapy did not improve overall or disease-free survival.
Conclusions: In this retrospective cohort data, a low-intensity bridging therapy was associated with equivalent outcome of CAR T cell therapy in terms of overall and disease-free survival, when compared to high-intensity regimens. High-intensity bridging therapy was associated with more mucositis, bacterial adverse events and worsened performance status. Our study suggests that a low-intensity bridging regimen may be preferred whenever tumor burden and disease kinetics allow this treatment strategy.
Disclosure: Bader: Medac: Consultancy, Patents & Royalties: medac, Research Funding; Novartis: Consultancy, Research Funding; Neovii: Research Funding; BMS: Research Funding. Attarbaschi: JazzPharma: Honoraria. Rossig: Amgen, BMS, Novartis, Pfizer, Roche, MSD: Honoraria. Meisel: medac: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; CELGENE BMS: Consultancy, Research Funding, Speakers Bureau; Bluebird Bio: Consultancy, Speakers Bureau; CRISPR Therapeutics: Consultancy, Research Funding, Speakers Bureau; Vertex: Consultancy, Research Funding, Speakers Bureau; Miltenyi Biotech: Research Funding; Gilead/KITE: Research Funding. Subklewe: Incyte Biosciences: Consultancy, Honoraria; AvenCell: Consultancy, Honoraria; Ichnos Sciences: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel Support, Speakers Bureau; AstraZeneca: Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding; Seagen: Research Funding; Roche: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead/Kite: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding; Molecular Partners: Consultancy, Honoraria, Research Funding; GSK: Speakers Bureau; LAWG: Speakers Bureau; Springer Healthcare: Speakers Bureau; AbbVie: Consultancy, Honoraria; Autolus: Consultancy, Honoraria; advesya (CanCell Therapeutics): Consultancy, Honoraria; Genmab US: Consultancy, Honoraria; Interius BioTherapeutics: Consultancy, Honoraria; Nektar Therapeutics: Consultancy, Honoraria; Orbital Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Scare: Consultancy, Honoraria. Mueller: Miltenyi, BMS, Novartis, Gilead, Janssen, Incyte, AstraZeneca, Abbvie, Sobi, Beigene: Honoraria; BMS, AstraZeneca, Gilead: Research Funding; AstraZeneca, BMS, Gilead, Janssen, Miltenyi biomedicine, Novartis: Consultancy. Cario: JazzPharma: Speakers Bureau; Servier, Amgen: Research Funding. Peters: AMGEN, Neovii, Jazz: Research Funding; Novartis: Consultancy; Riemser, Medac: Honoraria; AOP Orphan Drugs, Jazz, Neovii: Other: Meeting/Travel grant; Novartis, AMGEN: Membership on an entity’s Board of Directors or advisory committees. Feuchtinger: Servier: Research Funding; Miltenyi Biotec: Research Funding.
4: CAR-based Cellular Therapy – Clinical
P086 SAFETY AND EFFICACY COMPARISON OF HUMANIZED CD19 CAR-T VERSUS BLINATUMOMAB THERAPY FOR RELAPSED/REFRACTORY B-ALL PATIENTS
Kexin Wang 1,2,3,4, Songfu Jiang5, Yongxian Hu1,2,3,4, He Huang1,2,3,4
1Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, 2Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China, 3Institute of Hematology, Zhejiang University, Hangzhou, China, 4Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, China, 5The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
Background: Chimeric antigen receptor T-cells targeting CD19 (CART19) and blinatumomab are 2 major types of novel immunotherapy strategies for patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL). Choosing which types of immunotherapies to use for individual patients can be a challenge.
Methods: We performed a study to compare the efficacy and safety of blinatumomab versus CART19 for R/R B-ALL. Patient data in CART19 cohort were from the clinical trial (NCT04532268). Data in blinatumomab cohort were from the real-world data. The complete remission (CR) rate, overall survival (OS), leukemia-free survival (LFS), and toxicities were compared in the 2 cohorts.
Results: A total of 106 patients were enrolled including 61 patients in hCART19 cohort and 45 patients in blinatumomab cohort. 36.06% (22/61) patients in hCART19 cohort and 46.67% (21/45) patients in blinatumomab cohort bridged to allogenic hematopoietic stem cell transplantation (allo-HSCT) respectively (P>0.05). The age, gender, prior treatment lines, and extramedullary disease were no statistically different between two cohorts (P>0.05). The tumor burden in hCART19 cohort was higher than blinatumomab (44.60% vs. 2.29%, P<0.001). CR or CR with incomplete count recovery (CRi) rate by day 28 was 96.6% (56/61) in hCART19 cohort with 53 patients having minimal residual disease (MRD) negativity, and 77.8% (35/41) in blinatumomab cohort with 34 patients having MRD negativity, respectively (P = 0.008). With a median follow-up of 10 months, patients receiving allo-HSCT after infusion have similar OS and LFS in two cohorts. For patients not receiving allo-HSCT after infusion, the median LFS was 54 days in blinatumomab cohort and 180 days in hCART19 cohort, the median OS was 300 days in hCART19 cohort and not reached in blinatumomab cohort. In addition, subgroup analysis revealed that patients with higher tumor burden (MRD>20%) before infusion have better CR rate (70.6% vs. 33.3%, P = 0.007) in hCART19 cohort than in blinatumomab cohort, as well as better OS after 30 days from infusion (P = 0.023). For patients with lower tumor burden (MRD≤20%), CR rate and OS are similar in hCART19 and blinatumomab cohort (CR: 83.3% vs. 77.8%, P = 0.514). Patients with higher tumor burden in hCART19 cohort had a higher incidence of severe cytokine release syndrome than blinatumomab (53.7% vs. 31.2%, P = 0.011). The incidence of severe immune effector cell-associated neurotoxicity syndrome in two cohorts were similar (4.9% vs. 0%, P = 0.656). All toxicities were reversible.
Conclusions: Our study suggests that hCART19 has better complete remission efficacy and long-term survival than blinatumomab in R/R B-ALL patients with high tumor burden (MRD>20%). For patients with low tumor burden, blinatumomab has similar therapeutic efficacy with hCART19. Thus, for patients with low tumor burden, blinatumomab is a good choice while for high tumor burden, hCART19 is a good choice.
Disclosure: Nothing to declare.
4: CAR-based Cellular Therapy – Clinical
P087 PREDICTIVE VALUE OF PRE-TREATMENT CIRCULATING TUMOR DNA GENOMIC LANDSCAPE IN PATIENTS WITH R/RMM UNDERGOING ANTI-BCMA CAR-T THERAPY: INSIGHTS FROM TUMOR CELLS AND T CELLS
Rongrong Chen 1, Chunxiang Jin1, Tingting Yang1, Kai Liu1, Mengyu Zhao1, Mingming Zhang1, Pingnan Xiao1, Jingjing Feng1, Ruimin Hong1, Shan Fu1, Jiazhen Cui1, Simao Huang1, Guoqing Wei1, He Huang1, Yongxian Hu1
1The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Background: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T (CAR-T) therapy has demonstrated remarkable efficacy and safety in patients with refractory or relapsed multiple myeloma (R/RMM). Circulating tumor DNA (ctDNA) reportedly exhibits distinct advantages in addressing the challenges posed by tumor heterogeneity in distribution and genetic variations in R/RMM.
Methods: Herein, we performed a comprehensive ctDNA analysis of 108 patients with R/RMM to determine its predictive value for prognosis after CAR-T therapy.
Results: We observed that high ctDNA level (å 1430ng/ml) strongly associated with shorter progression-free survival (PFS)(P = 0.007). Moreover, it was also significantly related to higher percentages of multiple myeloma cells in the bone marrow that was measured using flow cytometry (P = 0.013), lower percentages of CAR-T cells in the peripheral blood at peak (P = 0.037), and higher percentages of CD8+ T cells in the peripheral blood (P = 0.034), which enabled the integration of tumor and T cell effector-mediated factors for assessing treatment failure. Alterations in several individual genes indicated poor outcomes, including IGLL5 (P = 0.004), which plays a significant role in the immune response; IRF4 (P = 0.024), which is involved in NF-κB signaling pathway; and CREBBP (P = 0.041), which participates in the epigenetic regulation of gene expression. Multivariate logistic regression analysis revealed that ERBB4 expression was significantly associated with resistance to CAR-T cell therapy (P = 0.04). Among the five patients with ERBB4 mutation, four failed to achieve a complete response, and all (5/5) of them exhibited progression within 6 months. In addition, patients with two multiple-site ctDNA mutations had poor outcomes, with PFS of less than 6 months (P <0.001).
Conclusions: Finally, we built a ctDNA-based risk model that serves as an adjunct non-invasive measure of substantial tumor burden and a prognostic genetic feature that can assist in predicting the response to anti-BCMA CAR-T therapy.
Clinical Trial Registry: The study was conducted in accordance with the tenets of the Declaration of Helsinki and registered in the Chinese Clinical Trial Registry (ChiCTR2100046474) and National Clinical Trial (NCT04670055, NCT05430945).
Disclosure: Nothing to declare
4: CAR-based Cellular Therapy – Clinical
P088 FINAL RESULTS OF PROSPECTIVE CLINICAL TRIAL EVALUATING OUTPATIENT ADMINISTRATION OF AXICABTAGENE CILOLEUCEL IN HIGH-GRADE B CELL LYMPHOMA
Bhagirathbhai Dholaria1, Shakthi Bhaskar1, Vivek Patel1, Eden Biltibo1, Salyka Sengsayadeth1, Andrew Jallouk1, James Jerkins1, Brittney Baer1, Nur Ali1, David Morgan1, Muhamed Baljevic1, Bipin Savani1, Adetola Kassim1, Olalekan Oluwole 1
1Vanderbilt University Medical Center, Nashville, United States
Background: Pivotal trials of Axicabtagene Ciloleucel (axi-cel) were conducted in the inpatient setting because of the high rate of severe Cytokine Release Syndrome (CRS) and Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS).
Methods: We devised a single-center non-randomized prospective trial (NCT05108805) to evaluate the feasibility and safety of outpatient administration of axi-cel. The primary endpoint of the study was to explore the safety and feasibility of outpatient Axi-cel. Eligible pts with R/R DLBCL per axi-cel FDA package label and met ZUMA 1 criteria were included in the study. They were fitted with wearable devices to measure temp, BP, Pulse-ox and heart rate for continuous remote monitoring. Pts were seen in-person once daily and had remote video telehealth evaluation at 16:00 and 22:00 daily through day 14. Fever up to 102F without other symptoms was managed in outpatient clinic. Here we report the final outcomes of complete study cohort.
Results: Twenty consecutive patients (pts) were treated from January 2022 to October 2023. Data cut off was December 16, 2023. The median pt age was 68 (range: 35-81) yrs and stage III-IV disease in 18 (90%) pts. Before lymphodepletion, baseline LDH was 251 U/L. The median number of therapies was 2.5 (range: 1-4), 10 (50%) pts ≥ 3 lines of therapies. The estimated median follow-up was 178 (95% CI: 81-258) days. Prophylactic dexamethasone 10mg/day, days 0-2 was given to 18 (90%) pts. 18 (90%) pts remained outpatient at least 72 hours after axi-cel administration, and one (5%) pt remained outpatient through day 30. The median time from day 0 to hospitalization was 3 (range 1-6) days and the median hospital stay was 5.5 (range 0-21) days. The reason for hospitalization was CRS in all admitted pts. Overall CRS was reported in 19 (95%) pts (grade 1 = 11, grade 2 = 8), ICANS in 8 (40%) pts (grade 1 = 4; grade 3 = 4). Time onset from day 0 to CRS was 3 (range 1-6) days and ICANS was 5 (range: 4-10) days. No pt had grade ≥3 CRS or grade ≥4 ICANS or treatment-related death by last follow-up. The median duration of CRS and ICANS were 3 days, each (Table 1).
Two (10%) pts required ICU admission (COPD exacerbation, SVT due to CRS) through day 30. By day 30, 14 (70%) pts achieved CR. There were 3 (15%) pts with PD/refractory disease at the last follow-up with one death from relapsed disease. Median EFS or OS was not reached by last follow up. Six-month estimated OS was 91% (95% CI: 0.74-1.0) and EFS was 81% (95% CI: 0.62-1.0). Our results were favorable compared to ZUMA 1 which reported median hospitalization of 15 days, grade ≥ 3 CRS and ICANS in 13% and 28% of pts, respectively and 6-months PFS of 49%.
Table 1: Outcomes of patients
Outcomes | N = 20 (%) |
---|---|
Day 30 responses | |
CR | 14 (70%) |
SD | 4 (20%) |
PD | 2 (10%) |
Day 90 responses (N = 17) | |
CR | 11 (65%) |
PR | 1 (6%) |
SD | 2 (12%) |
PD | 3 (18%) |
Best response | |
CR | 17 (85%) |
SD | 1 (5%) |
PD | 2 (10%) |
Median Time to hospitalization from day 0 (N = 19), days | 3 (1- 6) |
Median inpatient days by D + 30, days | 5.5 (0-21) |
Pts with ICU admission by D + 30, N | 2 (10%) |
CRS | |
Grade 0 | 1 (5%) |
Grade 1 | 11 (55%) |
Grade 2 | 8 (40%) |
Median time to CRS from day 0, days | 3 (1-6) |
Median duration of CRS, days | 3 (1-5) |
ICANS | |
Grade 0 | 12(60%) |
Grade 1 | 4 (20%) |
Grade 3 | 4 (20%) |
Median time to ICANS from day 0, days | 5 (4-10) |
Median duration of ICANS, days | 3 (1-9) |
Tocilizumab given | 17 (85%) |
Median doses of tocilizumab | 2 (0-3) |
Prophylactic dexamethasone | 18 (90%) |
Systemic steroids in addition to prophylactic dexamethasone | 8 (40%) |
Conclusions: This prospective feasibility trial confirmed that axi-cel can be safely administered in the outpatient settings with prophylactic steroids and remote monitoring with wearable devices without compromising safety or efficacy of CAR T therapy. Longer follow-up data will be presented at the meeting.
Disclosure: Bhagirathbhai Dholaria: Institutional research funding: Janssen, Angiocrine, Pfizer, Poseida, MEI, Orcabio, Wugen, Allovir, NCI, Atara, Gilead, Molecular templates, BMS, AstraZeneca, Adicet. Consulting/Advisor: MJH, Janssen, Pluri Biotech, BOXER CAPITAL, Ellipsis pharma, Lumanity, Autolus, Acrotech, ADC therapeutics, Gilead
Olalekan Oluwole: Consultancy and advisory board for: Pfizer, Kite, Gilead, AbbVie, Janssen, TGR, ADC, Novartis, Caribou, Cargo, Epizyme, Nektar, Autolus, Allogene. Institution funding: Kite, Pfizer, Daichi Sankyo, Allogene. Honoraria: Pfizer, Gilead
Eden Biltibo: BeiGene (consulting)
Andrew Jallouk: Kite-Gilead (consulting)
Rest of the authors declare no relevant COI.
4: CAR-based Cellular Therapy – Clinical
P089 EUPLAGIA-1: SEVEN-DAY VEIN-TO-VEIN POINT-OF-CARE MANUFACTURED GLPG5201 ANTI-CD19 CAR-T CELLS DISPLAY EARLY PHENOTYPES IN RELAPSED/REFRACTORY CLL INCLUDING RT
Esmée P. Hoefsmit 1, Sandra Blum2, Claire Vennin1, Kirsten Van Hoorde3, Sergi Betriu4, Leticia Alserawan4, Julio Delgado4, Nadia Verbruggen5, Anna D.D. van Muyden1, Henriëtte Rozema1, Ruiz Astigarraga1, Margot J. Pont1
1Galapagos BV, Oegstgeest, Netherlands, 2Galapagos GmbH, Basel, Switzerland, 3Open Analytics NV, Antwerp, Belgium, 4Hospital Clínic de Barcelona, Barcelona, Spain, 5Galapagos NV, Mechelen, Belgium
Background: The efficacy of chimeric antigen receptor T-cell (CAR-T) therapies relies in part on the preservation of early T-cell phenotypes and robust expansion in patients. Our decentralized and automated point-of-care (PoC) manufacturing platform allows administration of fresh autologous GLPG5201 CAR-T cells with a vein-to-vein time of 7 days.
Methods: Euplagia-1 (CTIS: 2022-501686-47-00) is an ongoing Phase 1/2 dose escalation study of PoC manufactured GLPG5201, an anti-CD19 4-1BB/CD3z CAR-T cell product, in patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), including Richter Transformation (RT). Feasibility of PoC manufacturing, T-cell phenotyping in apheresis starting material and in final product as well as correlation between T-cell phenotypes and in-patient pharmacokinetics were evaluated. Data cut-off was 06 September 2023. T-cell phenotyping was assessed using exploratory flow cytometry (n = 12 evaluable patients at data cut-off) and pharmacokinetics were determined by qPCR (n = 13 evaluable patients at data cut-off).
Results: All phase 1 GLPG5201 clinical batches (n = 15) were successfully manufactured at the PoC facility and infused as a fresh product at one clinical site. Encouraging clinical efficacy was observed, with a 93% best objective response rate and a 57% complete response rate in the intention-to-treat analysis set (clinical data submitted in a separate abstract). The median vein-to-vein time was 7 days (range 7–14), with 80% of patients (12/15) receiving GLPG5201 in 7 days. Characterization of GLPG5201 showed an increase in CD4+ and CD8+ CAR-T cells with early phenotypes (naïve, stem cell memory [TN/SCM] and central memory [TCM]) compared to apheresis starting material. The median increase in percentage of early phenotypes (i.e. TN/SCM + TCM) in CD4+ and CD8+ CAR-T cells was 24.0 (increased in 8/10 patients) for CD4+ T-cells and 52.1 (increased in 10/10 patients) for CD8+ T-cells. Robust in vivo expansion of GLPG5201 was detected in all patients treated with both dose levels (DL1: 35×106 CAR+ T-cells, n = 6; DL2: 100×106 CAR+ T-cells, n = 7). Median peak expansion (Cmax) was 4.4×105 copies/μg DNA (range 0.52×105 – 9.2×105), median time to peak expansion (Tmax) was 14 days (range 9 – 20) and median area under the curve from day 0–28 (AUCd0-28) was 6.1×106 copies/μg DNA x days (range 0.63×106 – 9.6×106). Higher exposure (AUCd0-28) was observed for patients infused with DL2 (median AUCd0-28 8.8×106 copies/μg DNA x days) compared to DL1 (median AUCd0-28 3.5×106 copies/μg DNA x days). Expansion and exposure were similar for patients with CLL and patients with CLL + RT. 8/10 patients had measurable GLPG5201 in peripheral blood at week 14 post-infusion. Persisting CAR-T cells were detected up to 15 months post-infusion. Moreover, abundance of both TN/SCM CD4+ and CD8+ CAR-T cells in the final product positively correlated with CAR-T cell exposure in patients (Spearman rank correlation (95% CI) for CD4+: 0.791 (0.27-0.99) and for CD8+: 0.791 (0.28-0.98); n = 11).
Conclusions: The Galapagos PoC manufacturing platform enables a 7-day vein-to-vein infusion. Early phenotype CAR-T cells were enriched in the final product compared to apheresis starting material. GLPG5201 demonstrated robust expansion and durable persistence in CLL and CLL + RT patients post-infusion.
Clinical Trial Registry: CTIS: 2022-501686-47-00
Disclosure: Esmée P. Hoefsmit: Employee of Galapagos BV, Netherlands
Sandra Blum: Employee of Galapagos GmbH, Switzerland
Claire Vennin: Employee of Galapagos BV, Netherlands
Kirsten Van Hoorde: Employee of Open Analytics NV, Belgium
Sergi Betriu: Nothing to declare
Leticia Alserawan: Nothing to declare
Julio Delgado: Nothing to declare
Nadia Verbruggen: Employee of, and shareholder in, Galapagos NV, Belgium
Anna D. D. van Muyden: Employee of Galapagos BV, Netherlands
Henriëtte Rozema: Employee of Galapagos BV, Netherlands
Ruiz Astigarraga: Employee of Galapagos BV, Netherlands
Margot J. Pont: Employee of Galapagos BV, Netherlands
The study was funded by Galapagos NV (Mechelen, Belgium).
4: CAR-based Cellular Therapy – Clinical
P090 INCIDENCES AND FACTORS ASSOCIATED WITH EARLY HEMATOTOXICITY AFTER CAR T-CELL THERAPY ASSESSED BY EHA/EBMT ICAHT CRITERIA
Emily Liang 1,2, Aya Albittar1, Andrew Portuguese1,2, Jennifer Huang1,2, Natalie Wuliji1,2, Qian Wu1, Joseph De Los Reyes1,2, Nikki Pin1, Aiko Torkelson1, Delaney Kirchmeier1, Abigail Chutnik1, Barbara Pender1, Joshua Hill1,2, Noam Kopmar1,2, Rahul Banerjee1,2, Andrew Cowan1,2, Damian Green1,2, Ajay Gopal1,2, Christina Poh1,2, Mazyar Shadman1,2, Alexandre Hirayama1,2, Brian Till1,2, Erik Kimble1,2, Lorenzo Iovino1,2, Aude Chapuis1,2, Folashade Otegbeye1,2, Ryan Cassaday1,2, Filippo Milano1,2, Cameron Turtle3, David Maloney1,2, Jordan Gauthier1,2
1Fred Hutchinson Cancer Center, Seattle, United States, 2University of Washington, Seattle, United States, 3University of Sydney, Sydney, Australia
Background: The observation that distinct patterns of hematologic toxicity are not adequately captured by CTCAE grading led to the recently developed EHA/EBMT immune effector cell-associated hematotoxicity (ICAHT) grading system (Rejeski et al, Blood, 2023). We applied the ICAHT grading system to patients undergoing CAR T-cell therapy at a large institution in the US and assess factors associated with grade ≥3 ICAHT.
Methods: Adults who underwent CAR T-cell therapy for hematologic malignancies with commercial or investigational products at our center between 2013 and 2023 were included (n = 454). Grading of early hematotoxicity (day-0-30 after CAR T-cell cell infusion) was automated using the heatwaveR package in R per ICAHT criteria detailed in Rejeski et al, Blood, 2023. Associations with 50 patient, disease-related, and laboratory factors, and ICAHT grade ≥3 were modeled using univariate and multivariable logistic regression.
Results: The most common disease types were aggressive non-Hodgkin lymphoma (n = 216; 48%), acute lymphoblastic leukemia (n = 82; 18%), and multiple myeloma / plasma cell leukemia (n = 61; 13%) (Table). The most common CAR T-cell products were investigational CD19 CAR T-cell products (n = 180; 40%), axicabtagene ciloleucel (n = 114; 25%), and lisocabtagene maraleucel (n = 58; 13%).
Incidences of early ICAHT grades 1, 2, 3, and 4 were 141 (31%), 177 (39%), 47 (10%), and 30 (7%), respectively. Patients with grades 3-4 ICAHT had worse overall survival compared to those with grade 0-2 ICAHT (median of 6 s. 18 months, p < 0.001).
Baseline patient factors associated with grade 3-4 ICAHT included ALL (reference: aggressive NHL, OR = 3.0, 95% CI, 1.7-5.6, p < 0.001) and age (OR = 0.97, 95% CI, 0.96-0.99, p = 0.003). Pre-lymphodepletion (LD) laboratory factors associated with grade 3-4 ICAHT included ANC (OR = 0.18 per log10, 95% CI, 0.10-0.30, p < 0.001), lactate dehydrogenase (OR = 7.4 per log10U/L, 95% CI, 3.3-17.4, p < 0.001), C-reactive protein (CRP; OR = 5.9 per log10mg/L, 95% CI, 2.8-14.0, p < 0.001), and ferritin (OR = 6.5 per log10mg/L, 95% CI, 3.0-16.0, p < 0.001). Peak CRP (OR = 12.8, 95% CI, 5.3-33.9, p < 0.001) and ferritin (OR = 5.6, 95% CI, 3.7-8.7, p < 0.001) after CAR T-cell infusion were strongly associated with grade 3-4 ICAHT. In a multivariable model including disease type, pre-LD ANC, pre-LD LDH, and peak CRP, pre-LD ANC (OR = 0.22, 95% CI, 0.11-0.42, p < 0.001), pre-LD LDH (OR = 5.0, 95% CI, 1.7-14.6, p = 0.003), and peak CRP (OR = 6.7, 95% CI, 2.7-18.4) remained independently associated with grade 3-4 ICAHT.
Table. Demographic, disease, and treatment characteristics (N = 454)
Age at infusion, median (range) | 60 (50, 68) |
Male sex | 286 (63%) |
Prior HCT | 186 (41%) |
Disease | |
Aggressive NHL | 216 (48%) |
ALL | 82 (18%) |
MM/PCL | 61 (13%) |
Indolent NHL | 53 (12%) |
CLL | 42 (9%) |
CAR T-cell product | |
Investigational CD19 CAR T-cell product | 180 (40%) |
Commercial CD19 CAR T-cell product with CD28 costimulatory domain (axi-cel, brexu-cel) | 143 (31%) |
Commercial CD19 CAR T-cell product with 4-1BB costimulatory domain (liso-cel, tisa-cel) | 70 (15%) |
Commercial BCMA CAR T-cell product (cilta-cel, ide-cel) | 61 (13%) |
Conclusions: We found that 17% of patients undergoing CAR T-cell therapy at our center developed grade 3-4 hematotoxicity by EHA/EBMT ICAHT criteria. Grade 3-4 ICAHT was associated with worse OS. Multivariable logistic regression of factors associated with grade 3-4 ICAHT identified pre-LD ANC, pre-LD LDH, and peak CRP as independent predictors of grade 3-4 ICAHT.
Disclosure: Joshua Hill: allovir: Consultancy, Research Funding; moderna: Consultancy; deverra: Research Funding.
Rahul Banerjee: BMS: Consultancy; Janssen: Consultancy; Genentech: Consultancy; SparkCures: Consultancy; Sanofi: Consultancy; Caribou: Consultancy; Pfizer: Consultancy; Pack Health: Research Funding.
Andrew Cowan: BMS, Adaptive: Consultancy; Adaptive Biotechnologies, Harpoon, Nektar, BMS, Janssen, Sanofi, Abbvie: Research Funding.
Damian Green: Cellectar Biosciences: Research Funding; SpringWorks Therapeutics: Research Funding; Celgene: Consultancy; GlaxoSmithKline: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding; Janssen Biotech: Consultancy, Research Funding; Ensoma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Juno Therapeutics A BMS Company: Patents & Royalties, Research Funding.
Ajay Gopal: Compliment Corporation: Current holder of stock options in a privately-held company; Incyte, Kite, Morphosys/Incyte, ADCT, Acrotech, Merck, Karyopharm, Servier, Beigene, Cellectar, Janssen, SeaGen, Epizyme, I-Mab bio, Gilead, Genentech, Lilly, Caribou, Fresenius-Kabi: Consultancy; Merck, I-Mab bio, IgM Bio, Takeda, Gilead, Astra-Zeneca, Agios, Janssen, BMS, SeaGen, Teva, Genmab: Research Funding.
Christina Poh: BeiGene: Consultancy; Seattle Genetics: Consultancy; Incyte: Research Funding; Acrotech: Consultancy.
Mazyar Shadman: Fate Therapeutics: Consultancy; Genmab: Consultancy, Research Funding; Vincerx: Research Funding; MorphoSys/Incyte: Consultancy, Research Funding; Eli Lilly: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy; AbbVie: Consultancy, Research Funding; Mustang Bio: Consultancy, Research Funding; ADC therapeutics: Consultancy; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; MEI Pharma: Consultancy; Regeneron: Consultancy; TG Therapeutics: Research Funding.
Alexandre Hirayama: Novartis: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Nektar Therapeutics: Honoraria, Research Funding; Juno Therapeutics, a Bristol Myers Squibb Company: Research Funding.
Till: Mustang Bio: Consultancy, Patents & Royalties, Research Funding; BMS/Juno Therapeutics: Research Funding; Proteios Technology: Consultancy, Current holder of stock options in a privately-held company.
Kimble: Juno/BMS: Research Funding.
Lorenzo Iovino: Mustang Bio: Current equity holder in publicly-traded company.
Aude Chapuis: Juno Therapeutics: Research Funding.
Ryan Cassaday: Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Incyte: Research Funding; Autolus: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Vanda Pharmaceuticals: Research Funding; Jazz: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; PeproMene Bio: Membership on an entity’s Board of Directors or advisory committees; Seagen: Other: Spouse was employed by and owned stock in Seagen within the last 24 months.
Filippo Milano: ExCellThera Inc.: Research Funding.
David Maloney: A2 Biotherapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Other: Member of the Scientific Advisory Board; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Rights to royalties from Fred Hutch for patents licensed to Juno Therapeutics/BMS, Research Funding; Janssen: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria, Research Funding; Mustang Bio: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Lyell Immunopharma: Other: Member, CAR T Steering Committee; Incyte: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Other: Member, Scientific Review Committee, Research Scholars Program in Hematologic Malignancies; Kite, a Gilead Sciences: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Umoja: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Participation on a Data Safety Monitory Board, Research Funding; Genentech: Consultancy, Honoraria, Other: Chair and Member of the Lymphoma Steering Committee; MorphoSys: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Other: Member of the JCAR017 EAP-001 Safety Review Committee and Member, CLL Strategic Council, Member of the JCAR017-BCM-03 Scientific Steering Committee under BMS, Research Funding; Amgen: Consultancy, Honoraria; Navan Technologies: Consultancy, Honoraria, Other: Member of the Scientific Advisory Board; Bioline Rx: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Other: Participation on a Data Safety Monitory Board; Fred Hutch: Other: rights to royalties for patents licensed to Juno; Navan Technologies: Current holder of stock options in a privately-held company; Chimeric Therapeutics: Other: Member of the Scientific Advisory Board; ImmPACT Bio: Other: Member, Clinical Advisory Board, CD19/CD20 bi-specific CAR-T Cell Therapy Program; Interius: Other: Member, Clinical Advisory Board.
Jordan Gauthier: Kite Pharma: Consultancy, Honoraria; MorphoSys: Consultancy, Research Funding; Angiocrine Bioscience: Research Funding; Century Therapeutics: Other: Independent data review committee; Celgene (a Bristol Myers Squibb company): Research Funding; Legend Biotech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Juno Therapeutics (a Bristol Myers Squibb company): Research Funding; Sobi: Consultancy, Honoraria, Research Funding.
4: CAR-based Cellular Therapy – Clinical
P091 COMPARISON OF IMMUNOPHENOTYPIC AND FUNCTIONAL PROPERTIES OF ANTI-CD19 CAR-T CELL PRODUCTS MANUFACTURED USING CLINIMACS PRODIGY AND G-REX PLATFORMS
Ekaterina Malakhova1, Dmitriy Pershin 1, Viktoria Vedmedskaia1, Mariia Fadeeva1, Elena Kulakovskaya1, Oyuna Lodoeva1, Tatiana Sozonova1, Elvira Musaeva1, Yakov Muzalevskii1, Alexei Kazachenok1, Vladislav Belchikov1, Anastasia Melkova1, Larisa Shelikhova1, Olga Molostova1, Michael Maschan1
1Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, Moscow, Russian Federation
Background: The use of anti-CD19 CAR-T cell therapy for treating B cell malignancies has shown impressive results in recent years. Today, there are several cell culture platforms that allow the manufacturing of cell products for subsequent clinical use; the issue of choosing a platform for the manufacturing of CAR-T remains relevant. This study compares the immunophenotypic and functional properties of final anti-CD19 cell products manufactured using the CliniMACS Prodigy and G-Rex platforms.
Methods: A total of 73 cell products were obtained, 49 of which were produced according to сGMP using the automated CliniMACS Prodigy® system (Miltenyi Biotec) and 24 using the G-Rex®10M-CS bioreactor (Wilson Wolf). Autologous and haploidentical cell sources were used for the manufacturing (no statistical differences in the cell composition in the start product of the processes). At the start of manufacturing with CliniMACS Prodigy® system, 100 million CD4+ and CD8 + T cells were selected at CliniMACS Prodigy, after which T lymphocytes were activated, transduced, and expanded in an automated closed system. For production in the G-Rex bioreactor, 5 million CD4+ and CD8 + T cells were selected by sorting using MACSQuant Tyto (Miltenyi Biotec). Lentiviral Vector aCD19 CAR was used for T cell transduction in both platforms (without using transduction enhancers and spinoculation). During the stages of manufacturing, the efficiency of transduction, composition, immunophenotypic and functional properties of cell products were determined using flow cytometry. Functional testing included TNFα secretion assay and degranulation assay (CD107a + ) upon incubation with the CD19+ cell line JeKo-1.
Results:
CliniMACS Prodigy (final product) | G-Rex (final product) | P value | CliniMACS Prodigy (start product) | G-Rex (start product) | P value | |
---|---|---|---|---|---|---|
CD8+ Naïve | n/a | 45.7% (0.7-91.9%), N = 46 | 38.1% (14.4-80.9%), N = 24 | ns | ||
CD4+ Naïve | n/a | 37.7% (3.9-75.1%), N = 46 | 49.3% (16.7-78.7%), N = 24 | ns | ||
CD8+ Central memory | 86.1% (6.4-99.1%), N = 49 | 69.0% (22.0-89.0%), N = 19 | 0.0006 | 5.5% (0.9-23.8%), N = 46 | 6.4% (0.6-27.5%), N = 24 | ns |
CD4+ Central memory | 83.4% (3.9-98.8%), N=49 | 72.0% (39.0-88.0%), N=19 | 0.0093 | 32.6% (13.7-64.4%), N=46 | 31.7% (16.7-53.1%), N=24 | ns |
CD8+ Effector memory | 12.0% (0.7-85.5%), N=49 | 31.0% (10.0-76.0%), N=19 | 0.0001 | 22.6% (0.7-85.3%), N=46 | 22.7% (4.8-56.1%), N=24 | ns |
CD4+ Effector memory | 16.0% (1.2-89.9%), N=49 | 28.0% (12.0-58.0%), N=19 | 0.0032 | 22.5% (5.0-73.7%), N=46 | 10.7% (4.0-45.3%), N=24 | ns |
CD8 + TEMRA | n/a | 18.9% (2.4-62.9%), N=46 | 18.1% (3.7-55.2%), N=24 | ns | ||
CD4 + TEMRA | n/a | 0.7% (0.2-10.7%), N=46 | 1.0% (0.1-5.4%), N=24 | ns | ||
CD8 + CD279+ | 7.7% (0.5-20.9%), N=47 | 7.6% (0.9-30.9%), N=16 | ns | 24.9% (0.6-67.9%), N=45 | 23.9% (6.8-46.0%), N=21 | ns |
CD4 + CD279+ | 13.6% (1.5-43.6%), N=48 | 18.3% (0.5-40.7%), N=16 | ns | 29.2% (4.1-62.2%), N=45 | 20.0% (7.0-44.8%), N=21 | 0.0341 |
CD8 + TIGIT+ | 7.6% (1.0-33.4%), N=35 | 7.7% (2.0-20.9%), N=22 | ns | 22.9 (2.9-63.7%), N=34 | 32.3% (4.8-59.1%), N=23 | ns |
CD4 + TIGIT+ | 4.5% (0.7-16.5%), N=34 | 2.9% (1.0-9.4%), N=22 | 0.0348 | 17.7% (7.1-48.9%), N=35 | 14.6% (5.4-24.0%), N=23 | 0.0220 |
Degranulation assay for CD8 + CAR-T cells | 39.4% (22.5-57.0%), N=17 | 9.6% (2.0-22.9%), N=24 | <0.0001 | n/a | n/a | n/a |
Degranulation assay for CD4 + CAR-T cells | 33.4% (16.8-51.5%), N=17 | 13.5% (2.0-30.8%), N=24 | <0.0001 | n/a | n/a | n/a |
TNFα secretion assay for CD8 + CAR-T cells | 33.6% (14.2-100%), N=35 | 3.1% (0.8-10.9%), N=24 | <0.0001 | n/a | n/a | n/a |
TNFα secretion assay for CD4 + CAR-T cells | 68.8% (25.1-87.4%), N=34 | 10.6% (4.6-24.3%), N=24 | <0.0001 | n/a | n/a | n/a |
A comparison of the immunophenotypic and functional properties of final cell products produced using the CliniMACS Prodigy or G-Rex platforms is presented in Table. Using both platforms, we obtain a stable product with sufficient expansion and transduction of T cells for subsequent CAR-T therapy. There was a tendency for the Tcm population to predominate in the final cell product, as well as low expression of cellular exhaustion markers in products manufactured by both methods. However, transduction efficiency was statistically significantly higher in products manufactured using the CliniMACS Prodigy system (p < 0.0001), and there was a greater predominance of Tcm over Tem in these products compared to products manufactured in bioreactor G -Rex. All products showed functional activity against the target cell line, but in products obtained using CliniMACS Prodigy it was more pronounced.
Conclusions: Both CliniMACS Prodigy and G-Rex platforms can be used to produce a high quality CAR-T cell product. Despite lower transduction efficiency and T cell counts in the final cell products in the G-Rex bioreactor, this was sufficient for subsequent CAR-T therapy. Regarding the differences in effector function found as well as the composition of Tcm/Tem, further analysis of the correlation with clinical response and CRS is required.
Clinical Trial Registry: Clinical Trial (NCT03467256)
Disclosure: Nothing to declare.
4: CAR-based Cellular Therapy – Clinical
P092 ALLOGENEIC HSCT AFTER CAR T-CELL THERAPY HAD DELAYED PLATELET ENGRAFTMENT, HIGHER RISK OF CYTOMEGALOVIRUS VIRUS VIREMIA AND THROMBOTIC MICROANGIOPATHY COMPARED TO CHEMOTHERAPY
Luxin Yang 1, Xiaoyu Lai1, Lizhen Liu1, Jimin Shi1, Yanmin Zhao1, Jian Yu1, Huarui Fu1, Yongxian Hu1, Mingming Zhang1, He Huang1, Yi Luo1
1The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) after Chimeric antigen receptor-modified T-cell (CAR T-cell) may achieve durable remission and long-term survival for relapsed/refractory acute lymphoblastic leukemia. However, reliable comparison of treatment-related toxicity of allo-HSCT after CAR-T therapy and traditional chemotherapy lacked.
Methods: Consecutive patients who received CAR T-cells therapy then underwent allo-HSCT during June 1st, 2016 and January 1st, 2023 were included. Propensity score matching was conducted between the CAR T-cells and chemotherapy cohort. The matching process incorporated disease, patient age, minimal residual disease (MRD) before HSCT, time interval from diagnosis to HSCT, donor resource, donor age and sex with a 1:1 ratio.
Results: Fifity-five patients with B cell acute lymphoblastic leukemia (ALL) and four patients with T cell ALL were included in the CAR T cohort. Most patients (86.4%) received anti-CD19 CAR T, four patients received anti-CD19/CD22 CAR T and four patients received anti-CD7 CAR T. All the patients achieved complete remission before transplantation. The median time from CAR T infusion to allo-HSCT was 84 (43-512) days. Thirty-four (57.6%) patients experienced grade 1-2 cytokine release syndrome (CRS) and twenty-five (42.4%) patients experienced grade 3-4 CRS. The median age was 28 (12-67) and 17.1(16-60) years in the CAR T and chemotherapy cohort, respectively. The patient age, gender, disease, minimal residual disease at HSCT, donor resource, donor gender and age were quite comparable between the two cohorts. The median time of neutrophil engraftment were 13 (7-20) and 12 (8-19) days in the CAR T and chemotherapy cohort. The CAR-T cohort had longer platelet engraftment time than chemotherapy cohort (15 days versus 13 days, p=0.042). Patients in the CAR T cohort had higher cumulative incidence of hemorrhagic cystitis (37.3% versus 15.3%, p=0.005). The 100-days cumulative incidence of septicemia of two cohorts were low (3.4% versus 5.1%, p=0.47). The 100-days cumulative incidence of EB virus viremia was 50.8% for the CAR T cohort and 40.7% for chemotherapy cohort (p= 0.48). The cumulative incidence of CMV virus viremia was higher for patients who underwent allo-HSCT after previous CAR T than chemotherapy (76.3% versus 62.7%, p=0.01). In the CAR T cohort, transplant-associated thrombotic microangiopathy (TA-TMA) occurred in four patients. No one in the chemotherapy cohort underwent TA-TMA. The incidence of TA-TMA was higher in the CAR T cohort (76.3% versus 62.7%, p=0.01). There is no difference in the cumulative incidence of grades III-IV acute graft-versus-host disease (GVHD) between cohorts (10.2% versus 16.9%, p=0.29). The cumulative incidence of any grades chronic GVHD in the CAR T cohort was 38.2%, which was significantly higher than 15.3% in the chemotherapy cohort (p=0.034). The incidence of moderate to severe chronic GVHD was comparable between cohorts. There was no difference between two cohorts in 2-year overall survival, progression-free survival, incidence of relapse and non-relapse mortality (NRM).
Conclusions: Allo-HSCT after CAR-T therapy had higher risk of transplant related toxicity compared to traditional chemotherapy. The incidence of survival, NRM, acute GVHD and moderate to severe chronic GVHD was comparable.
Disclosure: The authors declare that they have no competing interests.
4: CAR-based Cellular Therapy – Clinical
P093 AUTOMATED GRADING OF IMMUNE EFFECTOR CELL-ASSOCIATED HEMATOTOXICITY
Emily Liang 1,2, Kai Rejeski3, Sandeep Raj3, Aya Albittar1, Jennifer Huang1,2, Andrew Portuguese1,2, Natalie Wuliji1,2, Qian Wu1, Aiko Torkelson1,2, Delaney Kirchmeier1,2, Abigail Chutnik1, Barbara Pender1, Joshua Hill1,2,2, Noam Kopmar1,2, Rahul Banerjee1,2, Andrew Cowan1,2, Christina Poh1,2, Mazyar Shadman1,2, Alexandre Hirayama1,2, Erik Kimble1,2, Lorenzo Iovino1,2, Roni Shouval3, Jordan Gauthier1,2
1Fred Hutchinson Cancer Center, Seattle, United States, 2University of Washington, Seattle, United States, 3Memorial Sloan Kettering Cancer Center, New York, United States
Background: Following CAR T-cell therapy, hematologic toxicity has emerged as a substantial limitation due to associated infections and increased morbidity. Recognizing unique patterns of hematologic toxicity beyond the scope of CTCAE criteria prompted the development of the EHA/EBMT immune effector cell-associated hematotoxicity (ICAHT) grading system (Rejeski et al, Blood, 2023). Manually assessing longitudinal data is prone to subjectivity and demands extensive labor. Here we use a computational approach to automate the process of ICAHT grading to improve efficacy and accuracy of grading CAR T-cell-associated hematotoxicity.
Methods: The heatwaveR package (Schlegel and Smit, Journal of Open Source Software, 2023; https://robwschlegel.github.io/heatwaveR/), implemented through the R programming language, was originally created to identify marine heatwaves and coldspells. Utilizing this package requires a data table with the following columns: subject IDs, dates (multiple rows per patient), the laboratory value of interest (in this case, ANC) for each date, and the threshold above or below which events should be detected (e.g., 500 or 100 cells/μL).
Using the detect_event() function in heatwaveR, we can expediently identify instances where ANC decreases below the threshold and the duration of each instance, defined as the number of consecutive days during which the ANC is below the threshold (neutropenia “streak”). We also can set the minimum duration of streaks and whether to join streaks across a pre-specified number of days. We set the minimum streak duration to 1 day and required streaks to be joined if ANC did not recover above 500 or 100 for ≥3 consecutive days between streaks, based on the CIBMTR criteria for neutrophil engraftment.
Results: We applied heatwaveR to our longitudinal ANC dataset of patients undergoing CAR T-cell therapy at our center (Table). In this dataset, the most common disease types were aggressive non-Hodgkin lymphoma (n= 216; 48%), acute lymphoblastic leukemia (n= 82; 18%), and multiple myeloma / plasma cell leukemia (n= 61; 13%). The most common CAR T-cell products were investigational CD19 CAR T-cell products (n= 180; 40%), axicabtagene ciloleucel (n= 114; 25%), and lisocabtagene maraleucel (n= 58; 13%). We set thresholds of 500 and 100 to represent the cutoffs for ICAHT grading. For each patient, we extracted the maximum “streak” where ANC ≤ 500 and ≤ 100 cells/μL, then applied the ICAHT guidelines for duration and depth of neutropenia.
Thirteen percent of patients did not meet ICAHT criteria. In the remaining patients, the majority displayed grade 1 (31%) or grade 2 (39%) ICAHT. We noted grade 3 and grade 4 ICAHT in 10% and 7% of cases, respectively.
Table. Demographic, disease, and treatment characteristics (N= 454)
Age at infusion, median (range) | 60 (50, 68) |
Male sex | 286 (63%) |
Prior HCT | 186 (41%) |
Disease | |
Aggressive NHL | 216 (48%) |
ALL | 82 (18%) |
MM/PCL | 61 (13%) |
Indolent NHL | 53 (12%) |
CLL | 42 (9%) |
CAR T-cell product | |
Investigational CD19 CAR T-cell product | 180 (40%) |
Commercial CD19 CAR T-cell product with CD28 costimulatory domain (axi-cel, brexu-cel) | 143 (31%) |
Commercial CD19 CAR T-cell product with 4-1BB costimulatory domain (liso-cel, tisa-cel) | 70 (15%) |
Commercial BCMA CAR T-cell product (cilta-cel, ide-cel) | 61 (13%) |
Conclusions: This is a novel application of the heatwaveR package to automate ICAHT grading, eliminating subjectivity and labor. This approach allows rapid and automated ICAHT grading in large datasets. External validation of heatwaveR in a separate dataset from Memorial Sloan Kettering Cancer Center is ongoing. We plan to develop an online tool to help clinicians easily apply this approach to grade the severity of hematotoxicity per ICAHT criteria.
Disclosure: Kai Rejeski: BMS/Celgene: Consultancy, Honoraria; Novartis: Honoraria; Kite/Gilead: Other: Travel Support, Research Funding; Pierre-Fabre: Other: Travel Support.
Joshua Hill: allovir: Consultancy, Research Funding; moderna: Consultancy; deverra: Research Funding.
Rahul Banerjee: BMS: Consultancy; Janssen: Consultancy; Genentech: Consultancy; SparkCures: Consultancy; Sanofi: Consultancy; Caribou: Consultancy; Pfizer: Consultancy; Pack Health: Research Funding.
Andrew Cowan: BMS, Adaptive: Consultancy; Adaptive Biotechnologies, Harpoon, Nektar, BMS, Janssen, Sanofi, Abbvie: Research Funding.
Damian Green: Cellectar Biosciences: Research Funding; SpringWorks Therapeutics: Research Funding; Celgene: Consultancy; GlaxoSmithKline: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding; Janssen Biotech: Consultancy, Research Funding; Ensoma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Juno Therapeutics A BMS Company: Patents & Royalties, Research Funding.
Ajay Gopal: Compliment Corporation: Current holder of stock options in a privately-held company; Incyte, Kite, Morphosys/Incyte, ADCT, Acrotech, Merck, Karyopharm, Servier, Beigene, Cellectar, Janssen, SeaGen, Epizyme, I-Mab bio, Gilead, Genentech, Lilly, Caribou, Fresenius-Kabi: Consultancy; Merck, I-Mab bio, IgM Bio, Takeda, Gilead, Astra-Zeneca, Agios, Janssen, BMS, SeaGen, Teva, Genmab: Research Funding.
Christina Poh: BeiGene: Consultancy; Seattle Genetics: Consultancy; Incyte: Research Funding; Acrotech: Consultancy.
Mazyar Shadman: Fate Therapeutics: Consultancy; Genmab: Consultancy, Research Funding; Vincerx: Research Funding; MorphoSys/Incyte: Consultancy, Research Funding; Eli Lilly: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy; AbbVie: Consultancy, Research Funding; Mustang Bio: Consultancy, Research Funding; ADC therapeutics: Consultancy; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; MEI Pharma: Consultancy; Regeneron: Consultancy; TG Therapeutics: Research Funding.
Alexandre Hirayama: Novartis: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Nektar Therapeutics: Honoraria, Research Funding; Juno Therapeutics, a Bristol Myers Squibb Company: Research Funding.
Till: Mustang Bio: Consultancy, Patents & Royalties, Research Funding; BMS/Juno Therapeutics: Research Funding; Proteios Technology: Consultancy, Current holder of stock options in a privately-held company.
Kimble: Juno/BMS: Research Funding.
Lorenzo Iovino: Mustang Bio: Current equity holder in publicly-traded company.
Aude Chapuis: Juno Therapeutics: Research Funding.
Ryan Cassaday: Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Incyte: Research Funding; Autolus: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Vanda Pharmaceuticals: Research Funding; Jazz: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; PeproMene Bio: Membership on an entity’s Board of Directors or advisory committees; Seagen: Other: Spouse was employed by and owned stock in Seagen within the last 24 months.
Filippo Milano: ExCellThera Inc.: Research Funding.
David Maloney: A2 Biotherapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Other: Member of the Scientific Advisory Board; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Rights to royalties from Fred Hutch for patents licensed to Juno Therapeutics/BMS, Research Funding; Janssen: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria, Research Funding; Mustang Bio: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Lyell Immunopharma: Other: Member, CAR T Steering Committee; Incyte: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Other: Member, Scientific Review Committee, Research Scholars Program in Hematologic Malignancies; Kite, a Gilead Sciences: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Umoja: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Participation on a Data Safety Monitory Board, Research Funding; Genentech: Consultancy, Honoraria, Other: Chair and Member of the Lymphoma Steering Committee; MorphoSys: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Other: Member of the JCAR017 EAP-001 Safety Review Committee and Member, CLL Strategic Council, Member of the JCAR017-BCM-03 Scientific Steering Committee under BMS, Research Funding; Amgen: Consultancy, Honoraria; Navan Technologies: Consultancy, Honoraria, Other: Member of the Scientific Advisory Board; Bioline Rx: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Other: Participation on a Data Safety Monitory Board; Fred Hutch: Other: rights to royalties for patents licensed to Juno; Navan Technologies: Current holder of stock options in a privately-held company; Chimeric Therapeutics: Other: Member of the Scientific Advisory Board; ImmPACT Bio: Other: Member, Clinical Advisory Board, CD19/CD20 bi-specific CAR-T Cell Therapy Program; Interius: Other: Member, Clinical Advisory Board.
Jordan Gauthier: Kite Pharma: Consultancy, Honoraria; MorphoSys: Consultancy, Research Funding; Angiocrine Bioscience: Research Funding; Century Therapeutics: Other: Independent data review committee; Celgene (a Bristol Myers Squibb company): Research Funding; Legend Biotech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Juno Therapeutics (a Bristol Myers Squibb company): Research Funding; Sobi: Consultancy, Honoraria, Research Funding.
4: CAR-based Cellular Therapy – Clinical
P094 RELEVANT STUDIES ON CYTOKINES LEVEL AND CAR-T EXPANSION ASSOCIATED TO CD7 CAR-T THERAPY
Dongchu Wang1, Hui Wang1, Man Chen 1
1Hebei Yanda Lu Daopei Hospital, Langfang, China
Background: In the past few years, CD7 became a highly reliable marker of CAR-T therapy treating T cell acute lymphocytic leukemia(T-ALL). In this case, better understanding of CD7 CAR-T therapy on cellular level became meaningful.
Methods: PB samples were collected from 70 patients treated with CD7 CAR-T from Dec. 2020 to Nov. 2022 in Hebei Yanda Ludaopei Hospital. There were 56 males and 14 females, 2-60 with median age 19. Based on criteria of CRS and assessment results, 70 patients were split in different groups. According to CRS level, two groups were set as low (CRS0-1, 56 of 70) group and high group (CRS2-4, 14 of 70). 55 of 70 were classified as CR/CRi group, 15 of 70 were Non-CR group.
IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-17F, IL-22, TNFα, TNFβ, IFN-γ, IL-2RA/sCD25, MIP-1α, MCP-1, GM-CSF, IL-15, REG3a, Elafin, ST-2, Granzyme B, TNFRI were measure with microbeads with Calibur flow cytometer, CAR-T cells, target cells(CD7+ cells), T cells subsets(CD3 + , CD4 + , CD8 + , CD8 + TCM, CD8 + TEM, Treg) were tested with Canto flow cytometer. All the cellular variations were calculated by comparing value of peak-time to value of D0 which was used as baseline. Time points day0, 4, 7, 11, 14, 21, 30 were monitored after CAR-T infusion.
Results: Patients in all 4 groups had similar median age and transfection efficiency. Based on criteria of CRS level, patients were split into low group and high group. CAR-T peak time was appeared significantly later in high group. In high group, CD8 + TEM cells was amplified significantly more than that in low group at peak time point. Clearance rates of target cells in low group were significantly higher. The level of IL-4, IL-6, IL-8, IL-10, IL-22, IFN-γ, sCD25, MCP-1, IL-15, GranzymeB were significant higher in high group. All median peak time of those 10 cytokines in high group were calculated, from day 10 up to day 15 after CAR-T infusion. MCP-1 had the largest time gap, which means MCP-1 reached peak time 9 days earlier than that of CAR-T cells. The median peak-time gap between cytokines level with CAR-T cells expansion was 6 days.70 patients were classified as CR/CRi group and Non-CR group. CAR-T expansion, T cell subsets variation showed no statistical difference between two groups, and only target cells clearance rate was significantly higher in CR group. For all 24 cytokines measured in this study showed no significant differences between both groups.
Conclusions: 10 cytokines were correlated to severity of CRS after CD7 CAR-T therapy. 10 cytokines showed positive correlation to the level of CRS, and reached peak time earlier than that of CAR-T expansion, which means all these 10 cytokines could be used as indicators to predict occurrence and severity of CRS. Concurrence time of peak expansion of CD7 CAR-T cells, and amplification of CD8 + TEM cells were significantly related to CRS. For all the patients who reached complete remission or CRi, CD7+ clearance rates were higher with statistical significance. Our results proved potential indicators for CRS prediction and prognosis.
Disclosure: Nothing to declare
4: CAR-based Cellular Therapy – Clinical
P095 AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION COMBINED WITH CAR-T CELL THERAPY SIGNIFICANTLY IMPROVES PROGRESSION-FREE SURVIVAL IN RELAPSED REFRACTORY CENTRAL NERVOUS SYSTEM LYMPHOMA
Rui Liu 1, Fan Yang1, Fei Xue1, Zhonghua Fu1, Yuelu Guo1, Shaomei Feng1, Peihao Zheng1, Lixia Ma1, Hui Shi1, Biping Deng1, Xiaoyan Ke1, Kai Hu1
1Bejing Gobroad boren hospital, Beijing, China
Background: Relapsed or refractory Central nervous system lymphoma(R/R CNSL) is challenging to manage clinically. CAR-T therapy has demonstrated efficacy in relapsed and refractory large B-cell lymphoma, with some studies indicating a favourable response rate for R/R CNSL. Nevertheless, disease-free survival and long-term outcomes are suboptimal. Our study aims to explore the efficacy of CAR-T and the factors affecting its long-term survival in R/R CNSL. Additionally, we analysed the safety and effectiveness of ASCT combined with CAR-T therapy.
Methods: This single-centre, retrospective study analysed patients with R/R CNSL who received CAR-T therapy at the Beijing GoBroad Boren Hospital between 2019/03 and 2023/08. 69 patients were included. 46% were male, the median age is 51 (range19-79); 33% (23/69) is PCNSL, 67% (46/69) is SCNSL. The common histology in SCNSL was DLBCL(n=32), followed by HGBL(n=4), PMBL(n=3), BL (n=2), MCL (n=2) and others. Median number of previous treatment lines is 4 (range2-8). 70% (48/69) were IPI≥3.74% (51/69) were resistant to HD-MTX. 52% (36/69) were resistant to BTK inhibitors. 17% (12/69) patients had failed previous autologous hematopoietic stem cell transplantation. 68%(47/69) were parenchymal involved, 17%(12/69) were CNS involved, 14%(10/69) were both. The patients underwent a median of 1 (range 0-5) cycle of bridging therapy. 65.2%(45/69) achieve objective response (CR=33;PR=12) after bridging therapy. According to the response to bridging treatment, patients were divided into two groups: Bridging Effective (BE) group, comprising patients with CR/PR, and Bridging Ineffective (BI) group, comprising patients with SD/PD. In the BE group, 53.3% (24/45) received ASCT combined with CAR-T therapy.
Results: The 3-month ORR was 70% (48/69), and CRR is 61% (42/69). Incidences of any-grade CRS and ICANS were 70% (48/69) and 12% (8/69), with severe (≥3) CRS and ICANS at 12.5% (6/48) and 62.5% (5/8), respectively. BE group exhibited significantly higher 3-month ORR (84.4% vs. 41.6%) and CRR (82.2% vs. 20.8%) compared to BI group. Median follow-up time was 22.65 months. Median Progression-Free Survival (PFS) for BE group was 43.07 months, significantly longer than BI group’s 6.08 months (P<0.0001). Median Overall Survival (OS) was not reached for BE group, while it was 12.79 months for BI group (P<0.0001). 1-year OS rates were 100% vs. 51.4% (P<0.0001), and 1-year PFS rates were 74.7% vs. 9.9% (P<0.0001) for BE and BI groups, respectively. Among the 45 BE group patients, ASCT combined with CAR-T therapy showed more patients with ECOG performance status ≥ 2, more prior therapy lines, and all were HD-MTX-resistant (Table 1). Median PFS in ASCT combined with CAR-T cohort was significantly prolonged (not reached vs. 14.76 months, p=0.0008). Median OS was not reached in this cohort, whereas in CAR-T cohort, it was 27.48 months. However, there was no statistically significant difference. No statistical difference was observed in CRS and ICANS between the two cohorts.
Variable | CAR-T (n=21) | ASCT + CAR-T(n=24) | p-value |
---|---|---|---|
age (>60) | 8/21(38%) | 2/24(8%) | 0.018 |
sex(male) | 6/21(29%) | 12/24(50%) | 0.148 |
IPI≥3 | 11/21(52%) | 17/24(71%) | 0.208 |
ECOG≥2 | 7/21(33%) | 17/24(71%) | 0.013 |
Histology | |||
-PCNSL | 9/21(43%) | 11/24(46%) | 0.843 |
-SCNSL | 12/21(57%) | 13/24(54%) | |
Previous HD-MTX_resistance | 15/21(71%) | 24/24(100%) | 0.005 |
Previous BTK inhibitors_resistance | 14/21(67%) | 13/24(54%) | 0.398 |
Previous auto-HCT | 5/21(24%) | 3/24(12.5%) | 0.328 |
Previous_regimen_lines≥3 | 11/21(52%) | 20/24(83%) | 0.027 |
Conclusions: Effective bridging therapy can significantly improve the efficacy of CART in the treatment of R/R CNSL. After bridging therapy is effective, the treatment model of ASCT combined with CAR-T can significantly improve disease-free survival.
Clinical Trial Registry: ChiCTR2200058972/https://www.chictr.org.cn/index.html
Disclosure: Nothing to declare
4: CAR-based Cellular Therapy – Clinical
P096 SAFETY AND EFFICACY OF BENDAMUSTINE VERSUS FLUDARABINE-CYCLOPHOSPHAMIDE LYMPHODEPLETION PRIOR TO CAR-T CELL THERAPY WITH AXICABTAGENE CILOLEUCEL FOR NON-HODGKIN LYMPHOMA: A SINGLE-INSTITUTION STUDY
Anthony Stack 1, Yuliya Shestovska1, Rachel Thomas2, Matthew Hamby1, Asya Varshavsky-Yanovsky1, Peter Abdelmessieh1, Michael Styler1, Henry Fung1, Rashmi Khanal1
1Fox Chase Cancer Center/Temple University Health System, Philadelphia, United States, 2Temple University Hospital, Philadelphia, United States
Background: Previously, bendamustine (Benda) lymphodepletion (LD) was shown prospectively to yield similar efficacy, with lower rates of Cytokine Release Syndrome (CRS), neurotoxicity (ICANS) and hematologic toxicity compared to fludarabine-cyclophosphamide (FluCy) prior to tisagenlecleucel, a 4-1BB-costimulated CAR-T cell product; however, the safety and efficacy of bendamustine lymphodepletion prior to axicabtagene ciloleucel (axi-cel), a CD28-costimulated CAR-T cell product, is largely unknown.
Methods: We performed a retrospective analysis to compare safety and efficacy outcomes of patients treated for non-Hodgkin lymphoma with axi-cel at Fox Chase Cancer Center from 10/1/2018 to 7/14/2023. All patients received lymphodepletion with Benda (90 mg/m2/day x 2 days) or FluCy (Flu 30 mg/m2/day and Cy 500 mg/m2/day x 3 days) based on availability, physician preference and institutional practice. P values were calculated using Mann-Whitney test for continuous variables and Fisher’s exact test for categorical variables. Grading of hematologic toxicities is based on the Common Terminology Criteria for Adverse Events Version 5.0.
Results: In total, 20 patients received Benda and 17 patients received FluCy LD prior to axi-cel and were included in our analysis. The ratio of high-grade/low grade lymphoma in the Benda vs FluCy groups was 2.3 and 3.3, respectively. In both groups, ≥90% had Eastern Cooperative Oncology Group performance scores ≤1, an identical median age of 63 and similar rates of bridging therapy utilization (75% vs 76%, respectively). Of note, 95% of patients in the Benda group received CRS/ICANS prophylaxis (all dexamethasone), compared to only 12% in the FluCy group (1 dexamethasone and 1 tocilizumab).
Overall (ORR) and complete response rates (CR) were [ORR 90%, CR 75%] and [ORR 65%, CR 53%] in the Benda and FluCy groups, respectively, and were not statistically different (p>.05). Likewise, 3-month progression-free and overall survival did not differ between groups. CRS rate was identical in both arms, occurring in 70%, while ICANS occurred in 15% after Benda vs 47% after FluCy (p=.069).
In the first 30 days post-CAR-T infusion, patients receiving Benda vs FluCy experienced significantly lower rates of grade 3-4 anemia (10% vs 58%, p=.004), neutropenia (30% vs 100%, p<.001), and thrombocytopenia (25% vs 65%, p=.022), respectively. Additionally, Benda vs FluCy patients experienced significantly higher median nadirs in hemoglobin (10.5 vs 7.4 g/dL, p=.008), absolute neutrophils (ANC) (1.35 vs 0 K/mm3, p<.001) and platelets (117 vs 34 K/mm3, p=.003), required fewer transfusions of red blood cells (10% vs 41%, p=.052) and platelets (5% vs 35%, p=.034), and had numerically lower requirement for G-CSF (15% vs 47%, p=.069), respectively.
In the first 30 days, patients receiving Benda vs FluCy LD experienced fewer days with platelets <50 k/mm3 (mean 2.6 vs 9.4 days, p=.010), and with ANC <1000 K/mm3 (mean 1.8 vs 12 days, p<.001), respectively. Persistent grade ≥3 anemia, thrombocytopenia and neutropenia beyond 30 days were uncommon and did not significantly differ between groups.
Conclusions: In this retrospective study comparing Benda to FluCy lymphodepletion prior to axi-cel, Benda yielded similar efficacy with significantly less early hematologic toxicity. Although CRS and ICANS rates were similar, this is confounded by increased utilization of prophylaxis in the Benda group.
Disclosure: Henry Fung has received honoraria from Incyte, AstraZeneca, Janssen Oncology, and Kite. Asya Varshavsky-Yanovsky has participated on advisory boards and/or has provided consultancy for Pfizer, Janssen and BMS. Peter Abdelmessieh has participated on advisory boards for AbbVie and Sobi. Anthony Stack, Yuliya Shestovska, Rachel Thomas, Matthew Hamby, Michael Styler and Rashmi Khanal have no conflicts of interest to declare.
4: CAR-based Cellular Therapy – Clinical
P097 PSEUDOPROGRESSION: A FREQUENT AND CLINICALLY RELEVANT ADVERSE EVENT OF CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY
Torsten Schroeder 1, Tjark Martens1, Guranda Chitadze1, Fatih Yalcin1, Heiko Trautmann1, Britta Kehden1, Monika Brüggemann1, Christine Heinen1, Philipp Nakov,1, Nicolas Spath1, Lukas Sprenger1, Anca-Maria Albici1, Laura-Jane Kramp1, Matthias Ritgen1, Dominique Wellnitz1, Sebastian Lippross1, Maciej Simon1, Ingram Iaccarino Idelson1, Nico Gagelmann2, Wolfram Klapper1, Lars Fransecky1, Thomas Valerius1, Natalie Schub1, Christiane Pott1, Katja Weisel2, Winfried Alsdorf2, Fabian Müller3, Claudia Baldus1, Friedrich Stölzel1
1University Hospital Schleswig-Holstein, Kiel, Germany, 2University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 3University Hospital of Erlangen, Erlangen, Germany
Background: CAR-T-cell therapy (CARTCT) expands the range of therapeutic options for patients with hematologic malignancies. While complications such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are well known and consensus grading classifications for documentation and treatment of these adverse events are used, pseudoprogression (PP) is mainly described after checkpoint inhibition. Some reports on CARTCT induced PP (CARTiPP) exist distinguishing it from progressive disease, while only few reports focus on acute local complications. Considering the paucity of data about CARTiPP, we aimed to assess patients treated in our clinical routine. We defined CARTiPP as initial volume increase of malignant manifestations within ten days of CARTCT followed by tumor regression without another cause being more probable. Distinction from true progression of malignancy can be achieved either retrospectively or by histopathological findings. Another special CARTiPP presentation may be severe bone pain in patients suffering from malignant bone lesions which was repeatedly observed after anti-BCMA CAR-T cells.
Methods: Here, we characterize a retrospective multicentric patient cohort with the occurrence of CARTiPP. Evaluation of clinical, laboratory, radiological, and/or histopathological data was carried out. We rated all events in a proposed grading scale for CARTiPP severity.
Results: A total of n=22 patients were identified with CARTiPP throughout a treatment period of 57 months with n=176 patients receiving 180 CAR-T-cell therapies. Thus, we observed a total CARTiPP frequency of 12 %.
Patients with CARTiPP had different B-cell non-Hodgkin lymphoma subtypes (n=10/114) or multiple myeloma (n=12/56) and were treated with commercial anti-CD19 or anti-BCMA CAR-T-cells. The median age of patients was 59 years (range 39-76 years). Staging before CARTCT assessed n=5 patients in very good partial remission (VGPR), n=3 in partial remission, n=6 with stable disease (SD) and n=8 with progressive disease (PD). The rate of CARTiPP was notably higher in multiple myeloma than in B-cell lymphoma patients (21 vs. 9 %) - findings that need to be confirmed by additional studies.
We observed variable complications, e.g. superior vena cava syndrome, severe bone pain, soft tissue swelling with airway compression and postrenal kidney injury. Concomitant CRS occurred in n=21, ICANS in n=5 patients. Complication management ranged accordingly from intensified monitoring to treatment with glucocorticoids/tocilizumab to invasive ventilation and once limb amputation due to compartment syndrome. There was no CARTiPP-associated mortality. In four affected cases intensive care treatment was required.
Conclusions: CARTiPP may be still underreported and lacks classification and prospective reporting in clinical trials and registries investigating CARTCT. Frequency and sometimes severity underline the need for raising awareness of treating physicians. Laboratory analyses and imaging may supplement clinical assessment and should be further examined. Establishment of risk assessment, preventive measures and early treatment to reduce therapy-induced morbidity/mortality as well as a systematic documentation analogous to CRS and ICANS is required for CARTiPP. The increasing availability of CAR-T-cell therapies for a steadily expanding number of disease entities with variable manifestations and different disease stages makes an increasing frequency of CARTiPP plausible.
Disclosure: - Friedrich Stölzel:
Travel Support: Janssen, medac
Honoraria: medac, GWT, Abbvie, Servier, Pierre Fabre
Research funding: medac, Servier
- Claudia Baldus:
advisory and speakers honoraria for Astrazeneca, BMS, Janssen, Kite, Novartis, Jazz, Astellas, Amgen
- Winfried Alsdorf:
Honoraria: GSK, Janssen
Travel/accomodations/expenses: Biontech, Janssen, Immatics
Research funding (institution): Affimed, Biontech
- Fabian Müller:
Advisory and speakers honoraria for Astrazeneca, BMS, Jansen, Kite, kyverna, Miltenyi, Novartis,
Research support from Astrazeneca, Kite.
4: CAR-based Cellular Therapy – Clinical
P098 CAR-T CELL TREATMENT OF LARGE B-CELL LYMPHOMA (LBCL): DO PROGRAM DURATION AND TREATMENT LINE MATTER?
Maria-Luisa Schubert 1, Michael Schmitt1, Andrea Bondong1, Mandy Wegner1, Simon Renders1, Isabelle Krämer1, Carsten Müller-Tidow1, Peter Dreger1
1University Hospital Heidelberg, Heidelberg, Germany
Background: At our institution, CD19-directed CARTs for treatment of multiply relapsed/refractory LBCL were introduced in November 2018 and extended to 2nd line (2L) application in September 2022. The aim of this study was to analyze development of patient characteristics and outcomes over time.
Methods: Eligible for this retrospective analysis were all adult patients who received commercial or experimental CD19 CARTs at the University of Heidelberg. Patients were grouped into 3 cohorts: cohort A >2L 2018-2020; cohort B >2L 2021-2023; cohort C intent-to 2L treatment. Primary endpoint was relapse/progression-free survival (PFS). Descriptive statistics were applied.
Results: Altogether 93 patients (cohort A: n=43, cohort B: n=35, cohort C: n=15) met the eligibility criteria. Of note, introduction of 2L CARTs was associated with a 67% decrease of >2L indications in 2023. Axicabtagene ciloleucel (axicel), tisagenelecleucel (tisacel), lisocabtagen maraleucel (lisocel), and experimental CARTs were used in 73%, 18%, 6%, and 3% of patients, respectively. Cohorts A and B were comparable in terms of underlying diagnosis with DLBCL as the predominant indication, and in terms of the proportion of patients who had received a prior autoHCT. Compared to cohort A, patients from cohort B were significantly older (median age 57 (20-76) vs 67 (25-82) years; p 0.049), but contained fewer patients who received CARTs beyond the 3rd (49% vs 70%; p 0.067) and 4th line (6% vs 30%; p 0.0083), respectively. More patients in cohort B had received holding/bridging therapies (89% vs 70%; p 0.057), with a smaller proportion of patients with refractory disease at lymphodepletion (46% vs 81%; p 0.0058). In cohort C, median age was 63 (26-82) years, holding/bridging was administered to 87%, and 67% of the patients had active disease at lymphodepletion. Because of progression through bridging therapy, 27% of the patients intended to receive 2L CARTs actually underwent CART infusion as 3rd-line therapy.
With an overall response rate of 74%, 74%, and 78%, response was comparable across all cohorts. However, CR was more frequently reached in cohort C (57% vs 36% (A) and 40% (B)). Crude non-relapse mortality (NRM) was 12%, 6%, and 7% across the cohorts A, B, and C, respectively, with infections being the predominant cause of death. All NRM events except one occurred with axicel. 12-month PFS was 30%, 43%, and 56% across cohorts A, B, and C, respectively (Logrank for trend p=0.052; HR 1.72 (0.96-2.72) for comparison of cohort A with cohort B) (Figure).
Conclusions: Despite constant response rates, PFS and NRM of >2L CARTs seem to improve with longer CART program duration. This might be partly explained with better patient selection, earlier use of CARTs, and more effective bridging strategies. The advent of 2L CARTs associates with a strong reduction, but not a complete abrogation of >2L indications. Whether 2L CART applications are indeed associated with superior outcomes compared to delaying CART administration beyond 2L needs to be confirmed by further studies.
Disclosure: MLS: honoraria Kite/Gilead. MS: honoraria BMS, Kite/Gilead, Novartis. RS: honoraria Kite/Gilead. PD: honoraria Novartis, Kite/Gilead, BMS, Miltenyi.
4: CAR-based Cellular Therapy – Clinical
P099 REAL-WORLD EXPERIENCE OF CAR T-CELL THERAPY: A SINGLE CENTRE EXPERIENCE
Francys Lopez Llanos1, Inês Rocha2, Gilda Teixeira1, Isabelina Ferreira1, Pedro Sousa1, Maria João Gutierrez1, Susana Pereira 1, Ana Carolina Freitas1, Carla Espadinha1, Nuno Miranda1
1IPOFG, Lisboa, Portugal, 2Centro Hospitalar Universitário Lisboa Central, Lisboa, Portugal
Background: Chimeric antigen receptor (CAR) T-cell therapy has changed the landscape of treatment for relapsed/refractory B cell lymphomas. We present real world patient characteristics and outcomes from a Portuguese center.
Methods: This is a single-center, retrospective study of consecutive patients receiving CAR-T cell therapy between October 2019 and December 2023. Data were retrieved by reviewing individual electronic health records at the Instituto Português de Oncologia Francisco Gentil, Lisbon, Portugal.
Results: 50 patients were accepted for CAR-T therapy. Median age was 60 [26- 74] years, 94% (N=47) had ECOG PS1 and male-to-female ratio was 2:1. Regarding diagnosis, 78% (N=39) had histologically diffuse large B-cell lymphoma (DLBCL), 4% (N=2) follicular lymphoma and 18% (N=9) mantle cell lymphoma (MCL). 36% (N=18) had ≥ 3 lines of therapy prior CAR-T49 patients (98%) underwent leukapheresis and 42 (84%) received CAR-T therapy (3 DLBCL and 3 LCM did not undergo lymphodepletion to medical complications or rapidely progressive disease, 1 is awaiting infusion). 81% (N=34) received Axicabtagene, 14.3% (N=6) with Bretuxabtagene and 4.8% (N=2) with Tisagenlecleucel. Median delay (Md) between leukapheresis and infusion was 64 days [30 - 141]. CRS occurred in 35 patients (83.3%), with grade 3 in 11,9% (N=5). ICANS occurred in 10 patients (23.8%), with grade 3 in12% (N=5). Infections were documented in 10 and pancytopenia in 9. Two second neoplasms were diagnosed 1 AML and 1 MDS.
PET-CT was used to evaluate post-CAR-T response. At D + 100, 33 patients (78.6%) had completed evaluation, 63.6% (N=21) in complete response (CR), 15.2% (N=5) partial response (PR) and 21.2% (N=7) disease progression (DP). At D + 180, of 22 patients (66.7%) with complete evaluation, 63.6% (N=14) in CR, 31.8% (N=7) in DP and 4.6% (N= 1) in PR. There are patients who have not yet reached assessment time intervals.
Post-CAR-T DP occurred in 16 patients (38.0%), in whom Md time between infusion and DP was 3 months [1-16]. Death occurred in 14 patients (33.3%), mostly due to DP (11 patients, 78.6%); the Md time between infusion and death was 6 months [1-29]. Two fatalities were infection related: 1 HHV6 encephalitis and 1 COVID19.
With a median OS of infused patients was estimated at 29.7 months [95% CI: 23.3-36.1] and PFS was 9.0 months [95% CI: 1.9-16.0].
There was a trend to higher mortality in older than 65 vs younger (p=0.19).
There was no difference between PFS with a vein-to-vein time below or over median.
We observed a significant difference in PFS when making cohorts for year of infusion: before 2021 PFS=24,6 months vs 2022 11.4 vs 2023 5.4 p=0.041.
Conclusions: Relapsed and refractory NHL, in anti-CD20 era, constitute a large patient population in need of new solutions. CAR-T therapy provides an answer for some, with acceptable toxicity. Our real-world data shows that over the years, with broader selection criteria, inclusion of older patients, and those with higher disease burden, worse outcomes are observed. Accessment of disease burden prior to CAR-T may help selecting more adequate candidates,. Better patient selection is necessary also due to economic burden of this therapy.
Disclosure: The authors declare no conflit of interests
4: CAR-based Cellular Therapy – Clinical
P100 IMPACT OF ACUTE KIDNEY INJURY IN LYMPHOMA PATIENTS TREATED WITH AXICABTAGENE CILOLEUCEL
Cristina Soler1, Rafael Hernani 1, Ariadna Pérez1, Jose Luis Piñana1, Juan Carlos Hernández-Boluda1, Ana Benzaquen1, Rosa Goterris1, Montse Gómez1, Paula Amat1, Blanca Ferrer1, Francesc Moncho1, Isidro Torregrosa1, Jose Luis Górriz1, María José Terol1, Carlos Solano1
1Hospital Clínico Universitario, INCLIVA Research Institute, Valencia, Spain
Background: Chimeric antigen receptor T-cell (CAR-T) therapy has improved outcomes in patients with relapsed/refractory (R/R) hematological malignancies. However, there is limiting data regarding the impact of acute kidney injury (AKI) on outcomes following CAR-T infusion.
Methods: Adult patients with R/R large B-cell lymphoma (LBCL) receiving commercial axicabtagene ciloleucel were consecutively enrolled at Hospital Clínico Universitario de Valencia from December 2019 to August 2023. Data regarding patient and disease characteristics, treatment course, and clinical outcomes were prospectively collected. Cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded following CARTOX scale. Chronic kidney disease (CKD) was defined by Kidney Disease Improving Global Outcomes (KDIGO) staging using estimated glomerular filtration rate (eGRF). Acute kidney injury (AKI) was defined by Common Terminology Criteria for Adverse Events version 5. The renal function was monitored from the onset of lymphodepleting chemotherapy (LDC) until one month after infusion. Subsequently, monitoring continued until day 90, unless death or R/R, whichever occurred first. All patients received allopurinol or rasburicase as tumor lysis syndrome prophylaxis.
Results: A total of 48 adult patients with R/R LBCL were included in this study (diffuse large B-cell lymphoma, n=44; primary mediastinal large B-cell lymphoma, n=4). Briefly, the median age was 56 years (range, 22–75). Three (6%), 7 (15%) and 9 (19%) patients had prior history of CKD, diabetes, or high blood pressure, respectively. Baseline eGRF was graded as follows: 1 (n=28), 2 (n=17) and 3a (n=3). Most patients were primary refractory (53%) and had progressive disease (63%) at LDC. Myc was rearranged in 11 (23%) patients. Baseline EASIX score was 2.47 (range, 0.49–552).
Sixteen (33%) patients developed AKI (grade 1, n=10; grade 2, n=6) at a median time of 14 days (-4 – 57) after CAR-T infusion. Of them, five (31%), 6 (38%) and 5 (31%) patients developed AKI between LDC and CAR-T infusion, within the first month following CAR-T infusion or beyond, respectively. AKI showed no association with any baseline characteristics. Only age (>65 years) correlated with abnormal baseline eGFR in univariate analysis (71% vs 29%, P 0.018). Neither CKD, abnormal baseline eGFR (>= G2 KDIGO) or AKI had an impact on toxicity (CRS/ICANS), overall response rate (ORR), or survival (Table 1). Six (13%) patients required nephrologist support due to the following causes: AKI (n=4), electrolyte imbalances (n=1), adjustment of nephrotoxic medications owing to a prior kidney transplant (n=1). None of the patients required renal replacement therapy. Twenty-six (54%) patients remained alive with a median follow-up of 384 days (range, 63–1323).
Conclusions: In this study, we found no correlation between CKD, baseline eGFR, or AKI and outcomes post-CAR-T therapy for R/R LBCL. Notably, one-third of patients experienced mild AKI throughout three distinct time periods: i) from LDC and CAR-T infusion; ii) from CAR-T infusion to day 30; iii) from day 30 to day 90.
Disclosure: Nothing to declare
4: CAR-based Cellular Therapy – Clinical
P101 CHARACTERISTICS OF CENTRAL NERVOUS SYSTEM RELAPSE AFTER CD19 CAR-T CELL THERAPY IN R/R NHL
Mengyu Zhao 1, Tingting Yang1, YeTian Dong1, Jiazhen Cui1, Delin Kong1, Wenfa Huang2, Lei Wang2, Lixin Wang2, He Huang1, Yongxian Hu1
1Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, 2lnternational Cancer Center, Shenzhen University General Hospital, Shenzhen, China
Background: CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable antitumor activity against relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). However, NHL with central nervous system (CNS) relapse carries a poor prognosis and high mortality. We reported an analysis of 80 patients with NHL who underwent CAR-T cell therapy, and described the characteristics including the international prognostic index (IPI) and other clinical variables to evaluate the outcomes of CNS relapse in NHL patients treated with CAR-T cell therapy.
Methods: A total of 80 patients with NHL treated with CD19 CAR-T cell therapy in our center between April 2017 and November 2022 was retrospectively analyzed. Patient characteristics, laboratory parameters, and clinical outcomes were collected. CNS relapse was diagnosed by cerebrospinal fluid cytology, MRI or PET-CT.
Results: Baseline characteristics of all 80 patients are summarized. The median age was 58.5 (range, 10 to 79) years, and 57.5% of patients were male. Overall, 67 (83.8%) patients achieved complete remission (CR) or partial remission (PR) after CD19 CAR-T therapy. Seven (8.43%) patients developed isolated CNS relapse after CAR-T cell therapy, all of which were heavily pre-treated with multiple lines of chemotherapy prior to CAR-T cell therapy, and one of them had received autologous stem cell transplant before infusion of CAR-T cells. Only 4 of 7 patients with isolated CNS relapse achieved CR (n=4), and the median time to isolated CNS relapse from CAR-T cell infusion was 6.3(range, 1.53 to 25.8) months. Thirty-seven patients (46.2%) developed systemic recurrence without CNS involvement, with the median time from CAR-T to relapse of 3.2 (range, 0.467-30.8) months. The other 36 patients remained in remission at the last follow-up. During the median follow-up of 13.5 months of the whole cohort, the number of recorded deaths in isolated CNS relapse, systemic only recurrence, and no relapse patients was 5 (71.4%), 22 (59.4%), 1(2.78%), respectively. The 1-year OS and 1-year PFS of patients with isolated CNS recurrence was significantly lower compared to the no relapse group (OS, 35.7% [95%CI 12.1–100] vs 97.22% [95%CI 92–100], P<0.001; PFS, 28.6% [95%CI 8.86–92.2] vs 100% [95%CI 100–100], P<0.001), but showed no difference compared to the systemic only recurrence group (OS: 53.3% [95%CI 39.3–72.4], P=0.79; PFS: 13.0% [95%CI 5.53-30.5], P=0.17).
Conclusions: In conclusion, patients with CNS relapse showed significant difference in 1-year outcomes with no relapse group but not systemic relapse group in our study, which suggested the importance of effective prophylaxis against CNS relapse. Further investigation is necessary to better define the characteristics of patients who will benefit from prophylaxis.
Clinical Trial Registry: ChiCTR1800015575; NCT03118180; NCT04532281; NCT04532268; NCT04213469
Disclosure: Nothing to declare
4: CAR-based Cellular Therapy – Clinical
P102 DAY7-CART COUNT ENHANCES PREDICTIVE POWER OF PET30 AND POSSIBLY ANTICIPATES CD19 LOSS IN RELAPSE AFTER CART
Fabian Müller 1,2, Viktoria Blumenberg3,2, Veit L. Bücklein3,2, Ralph A. Bundschuh4,2, Dennis Harrer5,2, Klaus Hirschbühl4,2, Johannes Jung6,2, Wolfgang Kunz3,2, Igor Yakushev7,2, Anna Lena Illert6,2, Simon Völkl1,2, Rainer Claus4,2, Leo Hansmann5,2, Judith Hecker6,2, Dirk Hellwig8,2, Andreas Mackensen1,2, Marion Subklewe3,2, Michael Beck1,2
1University Hospital of Erlangen, Erlangen, Germany, 2Bavarian Cancer Research Center, Resp. Site, Germany, 3LMU University Hospital, LMU Munich, Munich, Germany, 4University Hospital of Augsburg, Augsburg, Germany, 5Clinic III Internal Medicine, University Hospital Regensburg, Regensburg, Germany, 6Klinikum Rechts der Isar, Technische Universität München, München, Germany, 7Klinikum Rechts der Isar, Technische Universität München, Munich, Germany, 8University Hospital of Regensburg, Regensburg, Germany
Background: CD19. CAR T cell therapy (CAR-T) has revolutionized current treatment practice in relapsed/refractory diffuse-large B cell Lymphoma (DLBCL) and transformed follicular lymphoma (tFL) by achieving cure in previously palliative situation. Despite this progress, predicting patients benefitting from CAR-T remains challenging. Independently, higher cell numbers at day 7 of CAR-T cell expansion (CAR-peak, at least 20/µl), as well as a negative PET scan as early as day 30 (PET30) have shown to be individually of high predictive power for lasting responses.
Here, we aimed to combine PET30 and d7-CAR-T-count to test whether they support each other’s predictive power.
Methods: DLBCL patients were treated with Tisa-cel, Axi-cel, or Liso-cel at 5 university hospitals of the Bavarian center of cancer research (BZKF) where clinical data was collected. CAR T cell numbers were assessed by flow cytometry. PET-CT scans were analyzed in a standardized manner among the five individual sites. The more recently implemented PET30 and the PET90 were analyzed.
Results: Overall 67 patients with DLBCL-NOS and four with tFL, together with a median age of 64.4 years were treated with CAR-T. 64 patients received bridging therapy to which 33 patients responded (PR/CR) and 30 did not (SD/PD, 8 missing data). 5 patients had an ECOG of 2 + , and 36 an IPI of 3+ at lymphodepletion when mean of LDH was 352 U/L, of CRP was 8.8 mg/L, and of ferritin was 808.6 ng/mL. By ROC analyses, response to bridging and the metabolic-IPI before CAR-T as well as PET30 and CAR-peak after infusion strongly predicted durable response. For 30 of the 71 patients, both, PET30 and day7-CAR-T-count were available. Among those, best long-term outcome was observed in patients with >20 CAR-T cells/µl and negative PET30 (8 patients). Only one/eight patients relapsed at month 5 and was CD19-negative. In contrast, none of the patients with positive PET30 and low Day7-CAR-T-count showed long-term remission. Of the 12 patients with positive PET30 and high CARs, one converted to CR, two died of unknown cause (NRM), one died of CAR-toxicity, and 8 relapsed. 6 of those 8 relapses were biopsied of which 3 presented with CD19 loss. Lastly, of 4 patients with negative PET30 and low Day7-CAR-count, one is in lasting remission, the others relapsed CD19 positive, where assessed.
Conclusions: In this small, retrospective cohort, PET30 and Day7-CAR-T-count greatly support each other in predicting lasting remission vs. relapse. In addition, relapse after high-CAR peak was associated with CD19 loss in 4 of 7 cases, whereas relapse after low CAR-peak was not possibly suggesting distinct resistance mechanisms.
Clinical Trial Registry: N/A
Disclosure: This research was funded by the Bavarian Cancer Research Center.
FM received honoraria and served on advisory boards for BMS, Janssen, Kite, Kyverny, Miltenyi, and Novartis and receied research support from AstraZeneca and Kite.
VBlu received research funding from Bristol Myers Squibb (BMS)/Celgene, Kite/Gilead, Janssen, Novartis, Roche, and Takeda and research funding and honoraria/consultancy fee from Kite/Gilead, Janssen, and Novartis.
VBue received research funding and/or honoraria from Amgen, Celgene/BMS, Kite/Gilead, Novartis, and Pfizer.
AM received honorarai and served on advisory boards for BMS, Janssen, Kite, Kyverny, Miltenyi, and Novartis and receied research support from Kyverna and Miltenyi.
MS received research funding, speaker’s bureau fee, and/or consultancy fee from Amgen, AstraZeneca, Aven Cell, BMS/Celgene, CDR-Life, Kite/Gilead, GlaxoSmithKline, Ichnos Sciences, Incyte Biosciences, Janssen, Miltenyi Biotec, Molecular Partners, Novartis, Pfizer, Roche, Seattle Genetics, and Takeda.
RB, DH, KH, JJ, WK, IY, ALI, SV, RC, LH, DH, and MB have no relevant conflict of interest.
4: CAR-based Cellular Therapy – Clinical
P103 EXCELLENT OUTCOME OF CAR-T CELL THERAPY IN CHILDREN WITH PB-ALL RELAPSING POST HSCT, WHO HAD VERY LOW MRD AT LYMPHODEPLETING CHEMOTHERAPY – POLISH CENTRES’ EXPERIENCE
Karolina Liszka 1, Paweł Marschollek1, Iwona Dachowska - Kałwak1, Monika Mielcarek-Siedziuk1, Jowita Frączkiewicz1, Anna Panasiuk1, Igor Olejnik1, Natalia Haze1, Monika Richert-Przygońska2, Krzysztof Czyżewski2, Robert Dębski2, Jan Styczyński2, Krzysztof Kalwak1
1Wroclaw Medical University, Wrocław, Poland, 2Nicolaus Copernicus University in Torun, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
Background: CAR-T cell therapy brought about a revolution in pB-ALL treatment, improving the survival chances of children in whom the conventional options of therapy failed. Although the outcome is impressive (the newest ELIANA trial update results show 3-year EFS of 44% and OS of 63%, respectively), there’s still a question how to use the whole potential of CAR-T cells. CAR-T cell therapy is effective in treatment of pB-ALL relapse post HSCT, however acc. to Bader et al., outcome in patients with very early relapse (<6 months post HSCT) is significantly worse. In our series it was aimed to achieve the lowest possible MRD before lymphodepleting chemotherapy (LDC) independently from interval between HSCT and relapse.
Methods: We included 18 patients (10 boys, 8 girls, aged 2-17 yrs) with pB-ALL who relapsed post HSCT and were treated with tisagenlecleucel in Polish centres in Wroclaw and Bydgoszcz in years 2020-2023. All patients were severely pretreated, 3 children underwent two HSCT procedures. In 8 patients it was the first relapse, in 7 patients the second, in 2 children the third relapse and 1 patient relapsed four times before CAR-T cells infusion. Median time range between HSCT and relapse prior to CAR-T cell therapy was 9.3 months (range 2-132 months). Negative MRD before LDC was achieved in 5 patients, in others it ranged from below 10-4 to 1x10-2. Different strategies were used as bridging therapy – conventional chemotherapeutics and/or immunotherapeutic drugs.
Results: In the analysed cohort, 16 out of 18 (88%) children remain alive and well with negative MRD. In this group, median time between HSCT and relapse was 10.3 months. Three patients relapsed earlier than 6 months post HSCT. Two CD19-negative relapses were observed – both children died. Median observation time in presented patients is 12 months, 2-year OS is 82.5% and 2-year EFS is 83.6%. No CRS/ICANS ≥ grade III were observed.
Conclusions: Very low disease burden before LDC, stated as CR with negative or low MRD, ensured excellent 2-year OS and EFS. CAR-T cell therapy increases the chance for cure in high-risk patients, in whom HSCT had not guaranteed long-lasting remission. To enhance the probability of optimal outcome, the goal should be to obtain as low disease burden before LDC as possible, ideally with negative MRD. Every patient requires an individualized approach to bridging therapy but our results highlight the need for maximal possible reduction in MRD before LDC in patients relapsing post HSCT, especially when they relapse early. CR before CAR-T cells infusion not only lowers the risk of relapse but also minimizes the occurrence of post infusion complications such as CRS, ICANS or HLH.
Disclosure: Karolina Liszka – no conflict of interest
Paweł Marschollek – no conflict of interest
Iwona Dachowska – Kałwak – no conflict of interest
Monika Mielcarek-Siedziuk – speaker’s bureau: Novartis, medac, Amgen
Jowita Frączkiewicz – speaker’s bureau: Gilead
Anna Panasiuk – no conflict of interest
Igor Olejnik – no conflict of interest
Natalia Haze – no conflict of interest
Monika Richert-Przygońska - Lecture fees: Novartis, Gilead. Conference participation: Gilead
Krysztof Czyżewski – Lecture fees: Novartis, Gilead. Conference participation: MSD.
Robert Dębski - Lecture fees: Novartis
Jan Styczyński – lecture fees: Novartis, Gilead, MSD, AstraZeneca. Advisory Board: MSD, AstraZeneca, Pfizer, Moderna. Conference participation: medac, Roche
Krzysztof Kałwak – speaker’s bureau: medac, Novartis, Pierre Fabre, Neovii. Advisory Board: Pfizer, MSD
4: CAR-based Cellular Therapy – Clinical
P104 THE DARK SIDE OF CORTICOSTEROIDS IN CD19. CAR-T CELL THERAPY
Marcello Roberto 1,2, Francesco Iannotta1, Francesco De Felice1,2, Beatrice Casadei1, Gianluca Storci1, Serena De Matteis1, Noemi Laprovitera1, Francesca Vaglio1, Barbara Sinigaglia1, Enrica Tomassini1, Enrico Maffini1, Mario Arpinati1, Francesco Barbato1,2, Margherita Ursi1,2, Salvatore Nicola Bertuccio1, Daria Messelodi1, Irene Salamon1, Maria Naddeo1, Elisa Dan1, Luca Zazzeroni1, Cinzia Pellegrini1, Matteo Carella1,2, Marianna Gentilini2,1, Pier Luigi Zinzani1,2, Massimiliano Bonafè1,2, Francesca Bonifazi1
1IRCCS-Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy, 2University of Bologna, Bologna, Italy
Background: Chimeric antigen receptors (CAR)-T cells represent an advanced therapy targeting the CD19 antigen on B cells, with consistent efficacy and relative safety in patients diagnosed with relapsed or refractory (r/r) B‐cell lymphomas. Corticosteroids are often used for the management of CAR-T cell toxicities. However, conflicting data are described about their harmful impact on CAR-T cell therapy and patient’s outcome. This study aimed to explore the role of corticosteroids after infusion in overall survival (OS) and progression-free survival (PFS).
Methods: The study cohort included seventy-five patients with r/r B-cell lymphomas admitted to the “advanced cell therapy unit of IRCCS_AOU of Bologna” for CD19. CAR-T cell therapy. The median age was 60 years (19-71). The cell product was axi-cel (n=45, 60%) or tisa-cel (n=30, 40%). After infusion, 63 (84%) developed cytokine release syndrome (CRS) of any grade: 40 (53%) developed grade 1; 18 (24%) grade 2; 5 (7%) grade ≥3. Twenty-two (29%) patients developed immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade: 6 (8%) developed grade 1, 7 (9%) grade 2, 9 (12%) grade ≥3. Thirty-eight (51%) patients received corticosteroids within 30 days after infusion for CRS and/or ICANS management (not for any other indications). Cumulative corticosteroid doses were reported as methylprednisolone-equivalent (median 1120 mg, range 380-13035). Available blood samples after CAR-T cell infusion were analyzed by FACS for CAR+T cell tracking.
Results: As expected, we found a strong association between corticosteroid administration after infusion and severe toxicities (grade ≥2 CRS and/or any grade ICANS occurrence). Thus, in order to determine the contribution of these variables on the time-dependent outcomes (OS and PFS), their distributions were marginalized. At first, we selected a subgroup of patients without severe toxicities (n=45) experiencing at most persistent grade 1 CRS. When comparing patients who received steroid (n=12; median methylprednisolone-equivalent dose was 1002.5 mg) with those who did not receive it (n=33), no significant differences in OS (p=0.80) and PFS (p=0.08) were found. Next, to address the impact of severe toxicities we focused on patients receiving corticosteroid (n=38) verifying that only grade ≥2 CRS impacted on OS (p=0.04) but not on PFS (p=0.08). Noteworthy, in a multiple Cox regression model (also including age, disease histotype, stage and bulky, CAR-T cell product, bridging therapy response, pre-lymphodepletion LDH levels) grade ≥2 CRS did not retain its significativity, while cumulative corticosteroid dose was associated with OS (p=0.002) and PFS (p=0.018). Finally we found no correlation between cumulative corticosteroid dose and CAR+T cell peak and area under curve (AUC0-30) levels as measured by MFC.
Conclusions: This evidence suggests that a higher cumulative corticosteroid dose after CAR-T cell infusion may have a harmful effect in OS and PFS, without compromising CAR+T cell expansion. Further analyses in larger cohorts are needed to confirm this result and to investigate the detrimental effect of steroids on CAR-T cell activity rather than quantity.
Disclosure: FB: scientific advisory boards and speaker fees: NEOVII, NOVARTIS, KITE, GILEAD, PFIZER, CELGENE, MSD.
PLZ: scientific advisory boards: Secura Bio BIO, Celltrion, Gilead, Janssen-Cilag, BS, Servier, Sandoz, MSD, TG Therap., Takeda, Roche, EUSA Pharma, Kiowa Kirin, Novartis, ADC Therap., Incyte, Beigene; consultancy: EUSA Pharma, MSD, Novartis; speaker’s bureau: Celltrion, Gilead, Janssen-Cilag, BMS, Servier, MSD, TG Therap., Takeda, Roche, EUSA Pharma, Kiowa Kirin, Novartis, Incyte, Beigene.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
4: CAR-based Cellular Therapy – Clinical
P105 MATCHING-ADJUSTED INDIRECT COMPARISON OF EFFECTIVE CHARACTERISTICS AMONG DIFFERENT BCMA TARGETING CAR-T IN TREATMENT OF RELAPSED OR REFRACTORY MULTIPLE MYELOMAS
Chunrui Li 1, Lu-Gui Qiu2, Di Wang1, Yongping Song3, He Huang4, Jianyong Li5, Bing Chen6, Jing Liu7, Xi Zhang8, Yu-Jun Dong9, Kai Hu10, Peng Liu11, Jian-Qing Mi12, Kaiyang Ding13, Zhenyu Li14, Qi’e Dong15, Fuyuan Zhang15, Guang Hu15, Wen Wang15
1Institute of Hematology; Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, 2Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin, China, 3The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China, 4The First Affiliated Hospital, Zhejiang University, Hangzhou, China, 5The First Affiliated Hospital of Nanjing Medical University, Nanjing, China, 6Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, China, 7Third Xiangya Hospital of Central South University, Changsha, China, 8Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, China, 9Peking University First Hospital, Beijing, China, 10Beijing Boren Hospital, Beijing, China, 11Zhongshan Hospital, Fudan University, Shanghai, China, 12State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China, 13The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China, 14Affiliated Hospital of Xuzhou Medical University, Xuzhou, China, 15Nanjing IASO Biotechnology Co., Ltd., Nanjing, China
Background: Several studies on BCMA targeting CAR-T cell therapies have disclosed their results, each with different characteristics in efficacy. These BCMA CAR-T cell therapies have been used in different marketing and clinical settings. However, there are no controlled studies directly comparing different CAR-T cell therapies. This analysis used matching-adjusted indirect comparisons (MAIC) to evaluate the comparative efficacy of Equecabtagene Autoleucel (Eque-cel) versus Ciltacabtagene Autoleucel (Cilta-cel), Idecabtagene vicleucel (ide-cel), zevorcabtagene autoleucel (zevor-cel, CT053) in patients with relapsed or refractory multiple myeloma.
Methods: Primary data sources included individual patient data from the FUMANBA-1 study (NCT05066646; N=103 for efficacy set) for Eque-cel and summary-level data from the CARTITUDE-1 study (NCT03548207; N=97 for efficacy set) for cilta-cel; data from CARTIFAN-1 study (NCT03758417; N=48 for efficacy set) for cilta-cel; data from KARMMA study (NCT03361748; N=128 for efficacy set) for ide-cel; data from LUMMICAR STUDY (NCT03975907 N=102 for efficacy set) for zevor-cel. Inter-study differences in design, eligibility criteria, baseline characteristics, and outcomes were assessed and aligned to the extent feasible. Clinically relevant prognostic factors were adjusted in a stepwise fashion by ranked order.
Results: This analysis revealed many different characteristics of these BCMA CAR-T therapies in RRMM, with eque-cel showing a better trend in MAIC-weighted efficacy outcomes.
The MAIC of the response rates, including overall and complete response rates and MRD negativity rate, were compared by odds ratio (OR) and 95% confidence intervals (CI). In FUMANBA-1 study versus CARTIFAN study, eque-cel showed a better trend than cilta-cel for overall response rate. When FUMANBA-1 study was compared to LUMMICAR study, eque-cel showed a better trend than zevor-cel for overall response rate and significantly better for complete response rate. In FUMANBA-1 study versus CARTITUDE-1 study, due to very limited effective sample size resulting from different patient characteristics, no clear trend was detected. When FUMANBA-1 study was compared to KARMMA study, eque-cel showed a better trend than ide-cel in overall response rate, complete response rate, and particularly MRD negativity rate, even with a limited effective sample size. The specific data is shown in the following table.
Because the median PFS was not reached in FUMANBA-1 study, 12-month PFS rate and 12-month MRD negativity maintaining rate were calculated by MAIC-weighted methods. Eque-cel showed higher 12-month PFS rate and MRD negativity maintaining rate after such adjustments. The specific data is also shown in the following table.
Table Summary of ORR,≥CR rate, MRD negativity rate,12 month PFS rate, and 12 month MRD negativity maintaining rate
FUMANBA-1(eque-cel) versus CARTIFAN(cilta-cel) | FUMANBA-1(eque-cel) versus LUMMICAR (zevor-cel) | FUMANBA-1(eque-cel) versus KARMMA(ide-cel) | FUMANBA-1(eque-cel) versus CARTITUDE1(cilta-cel) | |
---|---|---|---|---|
MAIC(ESS*=75) | MAIC(ESS=49.4) | MAIC(ESS=10.7) | MAIC(ESS=7.2) | |
OR (95%CI) | OR (95%CI) | OR (95%CI) | OR (95%CI) | |
ORR | 5.65 (0.94,33.9) | 5.17(0.69,38.82) | 11.57 (0, inf) | 0.19 (0, inf) |
≥CR rate | 1.15(0.49,2.71) | 6.08 (2.88, 12.83) | 3.20 (0, inf) | 0.29 (0, inf) |
MRD negativity rate | 0.8(0.08,8.36) | / | 28.59 (0, inf) | / |
12-month PFS rate | 82.3% | 93.2% | 75.8% | 94.2% |
12-month sustained MRD negativity | 77.8% | 76.4% | 84% | 100% |
- *ESS: effective sample size
Conclusions: After matching and adjusting for clinically relevant prognostic factors, eque-cel demonstrated a better trend of short-term efficacy when compared to cilta-cel of CARTIFAN study, ide-cel of KARMMA study and zevor-cel of LUMMICAR study. Eque-cel also showed a favorable long-term efficacy in patients with heavily pretreated relapsed or refractory MM.
Disclosure: Nothing to declare. Professor Lu-Gui Qiu is the corresponding author of this study.
4: CAR-based Cellular Therapy – Clinical
P106 IMPACT OF EARLY CAR– CD4+ T-LYMPHOCYTES RECOVERY FOLLOWING CAR-T CELL INFUSION FOR RELAPSED OR REFRACTORY B CELL LYMPHOMAS
Massimiliano Gambella 1,2, Simona Carlomagno2, Rosa Mangerini1, Nicoletta Colombo1, Alessia Parodi1, Chiara Ghiggi1, Livia Giannoni1, Elisa Coviello1, Chiara Setti2, Silvia Luchetti1, Alberto Serio1, Antonella Laudisi1, Monica Passannante1, Alessandra Bo1, Elisabetta Tedone1, Simona Sivori2, Emanuele Angelucci1, Anna Maria Raiola1
1IRCCS Ospedale Policlinico San Martino, Genova, Italy, 2University of Genoa, Genova, Italy
Background: CAR– CD4+ T cell lymphopenia is an emerging issue following CAR-T infusion. We focused on potential determinants of CD4+ T cell recovery and investigated a possible association with survival. We also described the kinetics of CAR– CD8+ T, NK, and NKT cell recovery following CAR-T therapy for aggressive B-cell lymphomas.
Methods: We investigated a cohort of patients affected by Diffuse Large B-cell Lymphoma or Mantle Cell Lymphoma, treated at IRCCS Ospedale Policlinico San Martino, Genova, with commercially available CAR-T products. Peripheral blood immune cell subpopulations were characterized before lymphodepletion and following CAR-T infusion through multiparametric-flow cytometry, primarily focusing on CAR– lymphoid subpopulations. Infectious complications were analyzed according to CD4– T cell recovery.
Results: Thirty-one consecutive patients were selected for the analysis. Six-month cumulative incidence of CAR– CD4+ T cell recovery (i.e., ≥ 200cells/μl) was 0.43 (95% CI: 0.28-0.65). Among possible determinants of CD4+ T cell recovery, we recognized infusion of a 4-1BB product (tisagenlecleucel, TSA) in comparison with CD28-based ones (axicabtagene/brexucabtagene, AXI/BRX) (hazard ratio [95% CI]: 5.79 [1.16-24.12] p= 0.016). Higher CD4+ T cell counts resulted with TSA at month-1, -2, and- 3 following infusion. Moderate to severe infectious complications were registered in patients with pro