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. 2024 Apr 22;17(1):19.
doi: 10.1186/s13045-024-01542-9.

Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel

Guido Ghilardi  1   2   3 , Luca Paruzzo  1   2   3 , Vrutti Patel  1   2   3 , Jakub Svoboda  1   2   3 , Emeline R Chong  1   2   3 , Eugenio Fardella  1   2   3 , Elise A Chong  1   2   3 , Giulia Gabrielli  1   2   3 , Sunita D Nasta  1   2   3 , Daniel J Landsburg  1   3 , Jordan Carter  1   2   3 , Raymone Pajarillo  1   2   3 , Stefan K Barta  1   2   3 , Griffin White  1   3 , Elizabeth Weber  1   3 , Ellen Napier  1   3 , David L Porter  1   3 , Alfred L Garfall  2   3 , Stephen J Schuster #  1   2   3 , Marco Ruella #  4   5   6
Affiliations

Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel

Guido Ghilardi et al. J Hematol Oncol. .

Abstract

Bendamustine has been retrospectively shown to be an effective and safe lymphodepletion regimen prior to the anti-CD19 chimeric antigen receptor T cell (CART) products tisagenlecleucel and axicabtagene ciloleucel, as well as the anti-BCMA CART products idecabtagene vicleucel and ciltacabtagene autoleucel. However, bendamustine as lymphodepletion prior to lisocabtagene maraleucel (liso-cel), a 4-1BB co-stimulated, fixed CD4:CD8 ratio anti-CD19 CART product, has not been described yet. Thus, we studied a cohort of sequentially-treated patients with large B-cell lymphomas who received bendamustine lymphodepletion before liso-cel at the University of Pennsylvania between 5/2021 and 12/2023 (n = 31). Patients were evaluated for toxicities and responses. Of note, 7 patients (22.6%) would have dnot met the inclusion criteria for the registrational liso-cel clinical trials, mostly due to older age. Overall and complete response rates were 76.9% and 73.1%, respectively. At a median follow-up of 6.3 months, the 6-month progression-free and overall survival were 59.9% and 91.1%, respectively. Rates of cytokine-release syndrome (CRS) and neurotoxicity (ICANS) of any grade were 9.7% and 9.7%, respectively, with no grade ≥ 3 events. No infections were reported during the first 30 days following liso-cel infusion. Neutropenia ≥ grade 3 was observed in 29.0% of patients; thrombocytopenia ≥ grade 3 occurred in 9.7%. In conclusion, bendamustine lymphodepletion before liso-cel appears to be a strategy that can drive tumor responses while ensuring a mild toxicity profile.

Keywords: Bbendamustine; Ccytokine-release syndrome (CRS); Chimeric antigen receptor T cells (CART); Immune effector cell associated neurotoxicity syndrome (ICANS); Lisocabtagene maraleucel; Lymphodepletion; Non-Hodgkin lymphoma (NHL); Toxicities.

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Conflict of interest statement

GG served as a scientific consultant for viTToria Biotherapeutics. MR holds patents related to CD19 CAR T cells, served as a consultant for NanoString, Bristol Myers Squibb, GlaxoSmithKline, Bayer, and AbClon, receives research funding from AbClon, NanoString, Oxford NanoImaging, viTToria biotherapeutics, CURIOX, and Beckman Coulter. MR 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. EAC served as a consultant for Novartis, Beigene, KITE, Tessa, and Juno/BMS. SKB served as a consultant to Acrotech, Kyowa Kirin, Daiichi Sankyo, and Seagen. SDN received research funding from Pharmacyclics, Roche, Rafael, FortySeven/Gilead. JDL received research funding from Curis, Takeda, and Triphase, and served on the 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 costimulated T cells. 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. AG: Research support (via my institution) from Janssen, Novartis, Tmunity, and CRISPR therapeutics; Consultancies/honoraria from Janssen, Novartis, BMS, GSK, Legend Bio; DSMB membership for Janssen. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Efficacy and safety of bendamustine lymphodepletion before lisocabtagene maraleucel. A. Best response after liso-cel. Light blue represents complete response, blue represents partial response, and dark blue represents no response. B. Progression-free survival after liso-cel. C. Overall survival after liso-cel. D. CRS and ICANS of any grade incidence. E. Infusion setting of liso-cel infusion. Light gray represents the inpatient setting and dark gray represents outpatient setting. F. Hematologic toxicities within 30 days after liso-cel infusion. Dot plots highlight individual nadir values of neutrophils, hemoglobin and platelets levels. Shadows of yellow background highlight the range of specific abnormal levels. G. Blood counts over time during the 4 weeks after liso-cel infusion. Values are expressed as median and 95% confidence interval error bars. Shadows of yellow background highlight the range of specific abnormal levels. H. Blood counts at 3 months after liso-cel infusion. Dot plots highlight individual nadir values of lymphocytes, neutrophils, hemoglobin, and platelets levels. Shadows of yellow background highlight the range of specific abnormal levels Abbreviations: CR: complete response; CRS: cytokine release syndrome; ICANS: immune effector cell-associated neurotoxicity syndrome; N: number; NR: not response; PR: partial response
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References

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