Bendamustine is safe and effective for lymphodepletion before tisagenlecleucel in patients with refractory or relapsed large B-cell lymphomas.

BACKGROUND

Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T.

PATIENTS AND METHODS

We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading.

RESULTS

Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide.

CONCLUSIONS

Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization.

Informations de copyright

Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Disclosure MR holds patents related to CD19 CAR T cells, served as a consultant for NanoString, Bristol Myers Squibb (BMS), GlaxoSmithKline, Bayer, and AbClon, receives research funding from AbClon, NanoString, and Beckman Coulter, and is the scientific founder of viTToria Biotherapeutics. JS served as a consultant for Genmab, Adaptive, AstraZeneca, BMS, Imbrium, ADCT, Atara, Pharmacyclics, Seattle Genetics and received research funding from AstraZeneca, BMS, Incyte, Merck, Seattle Genetics, Pharmacyclics, and TG therapeutics. RTM served as an advisor or consultant for AlloVir, Artiva, CRISPR Therapeutics, Incyte, and Novartis, reports honoraria from BMS/Celgene, Incyte, Intellia, and Kite, has received research support from BMS, AlloVir, and Novartis, has participated in data and safety monitoring boards for Athersys, Vor Pharma, and Novartis, and has a patent with Athersys. EAC served as consultant for Novartis, Beigene, KITE, Tessa, Juno/BMS. SKB served as consultant to Acrotech, Kyowa Kirin, Daiichi Sankyo, and Seagen. SDN received research funding from Pharmacyclics, Roche, Rafael, FortySeven/Gilead. UJ served as a consultant to Novartis, received research funding from Novartis and honoraria from Novartis, BMS/Celgene, Gilead, Janssen, and Miltenyi. JDL received research funding from Curis, Takeda, and Triphase, served on Board of Directors or advisory committees or data and safety monitoring board for Incyte, ADCT, Karyopharm, and Morphosis. SJS served as a consultant to AstraZeneca, BeiGene, Celgene, Genentech, Genmab, Fate Therapeutics, Roche, Incyte, Juno Therapeutics, Legend Biotech, Loxo Oncology, MorphoSys, Mustang Biotech, Nordic Nanovector, Novartis, and Regeneron, received research funding from AbbVie, Adaptive Biotechnologies, Celgene, DTRM, Genentech, Roche, Juno Therapeutics, Merck, Novartis, Incyte, Pharmacyclics, and TG Therapeutics, received honoraria from Celgene and Novartis, and holds patents related to CD19 CAR T cells and autologous co-stimulated T cells. JNG: Kite: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy; Pharmacyclics: Consultancy. AG: Amgen: Honoraria; Tmunity Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; GSK: Honoraria; Novartis: Research Funding. DLP: National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly-traded company, ended employment in the past 24 months; American Society for Transplantation and Cellular Therapy: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; American Society of Hematology: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity: Patents & Royalties; Wiley and Sons Publishing: Honoraria: UJ has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 945393. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA and from the Medical-Scientific Funds of the City of Vienna, Cancer Research Funds Project—Nr. 21098. All other authors have declared no conflicts of interest.