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Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel
Journal of Hematology & Oncology volume 17, Article number: 19 (2024)
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.
To the editor
Anti-CD19 chimeric antigen receptor T cell therapies (CART19) are now a standard treatment for relapsed and/or refractory large B-cell lymphoma (LBCL) patients [1]. Lymphodepletion ensures the appropriate environment for CART cell engraftment and effector functions [2]. The combination of fludarabine and cyclophosphamide (Flu/Cy) is the standard lymphodepletion regimen before commercial CART19 products, including lisocabtagene maraleucel (liso-cel) [3,4,5]. Bendamustine has been demonstrated to be a safe and effective lymphodepletion regimen before tisagenlecleucel [6, 7] (for which is an FDA-approved lymphodepletion ) and, more recently, axicabtagene ciloleucel [8, 9]. However, data regarding the efficacy of bendamustine before liso-cel, a 4-1BB co-stimulated, fixed CD4:CD8 T-cell ratio product, are lacking.
To this goal, we retrospectively evaluated 31 LBCL patients treated with bendamustine lymphodepletion (90 mg/m2 daily over two days) followed by liso-cel at the University of Pennsylvania between 5/2021 and 12/2023 (Table 1). The data cut-off date was 3/15/2024. The choice of bendamustine lymphodepletion was not driven by specific patient characteristics but rather it has been our predominant lymphodepletion strategy due to our extensive experience [6, 9] coupled with fludarabine shortage [10]. Outcome and laboratory data were obtained from electronic medical records. Response was assessed according to Lugano criteria and toxicities using ASTCT criteria and CTCAE v5.0. This retrospective study was approved by the Institutional Review Board.
Seven out of 31 patients (22.6%) would not have met the inclusion criteria for the liso-cel clinical trials [3, 5], due to previous CART19 treatment (n = 2), older age (n = 4), and elevated bilirubin (n = 1). Conversely, histologies slightly differed from registration studies. The median time from apheresis to infusion was 43 days (range: 32–150). The best response rate was complete response for 77.4% of patients, partial response for 3.2%, and no response for 19.4% (Fig. 1A). With a median follow-up of 6.3 months, the 6-month progression-free survival (PFS) and overall survival were 59.9% (Fig. 1B) and 91.1% (Fig. 1C), respectively. The incidence of cytokine-release syndrome (CRS) was 9.7% (all grade 1) and immune effector cell associated neurotoxicity syndrome (ICANS) was 9.7% (two cases of grade 1 and one of grade 2). There were no cases of grade ≥ 3 CRS or ICANS (Fig. 1D). No infections were observed during the first 30 days after liso-cel. Fourteen patients (45.2%) received liso-cel infusion in the outpatient setting (Fig. 1E). The median hospitalization time was 8 days. The median absolute lymphocyte count (ALC) at the time of liso-cel infusion was 0.10 × 109/L (IQR 0.09–0.20). The median absolute neutrophil count (ANC) nadir was 2.30 × 109/L (IQR 0.70–2.80), with 29.0% of patients with grade ≥ 3 neutropenia. The median hemoglobin nadir was 10.8 g/dL (IQR 9.9–12.3). The median platelet nadir was 124 × 109/L (IQR 68–175), with 9.7% of patients with grade ≥ 3 thrombocytopenia (Fig. 1F). Neutrophils, hemoglobin, and platelet counts were generally stable during the four weeks after liso-cel infusion while lymphocytes progressively recovered over time (Fig. 1G). At 3 months, among the 16 patients with ongoing responses, we observed median ALC of 0.60 × 109/L (IQR 0.40–0.80), median ANC 3.30 × 109/L (IQR 2.54–4.56), median hemoglobin 12.9 g/dL (IQR 11.3–13.8), and median platelet count 198 × 109/L (IQR 139–238) (Fig. 1H).
In conclusion, we observed that bendamustine lymphodepletion was overall effective and associated with manageable toxicities. The median PFS in our analysis was not reached, as compared to that of the phase 2 TRANSCEND-NHL-001 that was 6.8 months [3, 4] and of the phase 3 TRANSFORM trials, i.e., 10.1 months [5]; however, the median follow-up for the present study is significantly shorter and patients received liso-cel both in 2nd and >3rd line. In our cohort, incidence of CRS and ICANS of any grade were 9.7% and 9.7%, respectively, while in the TRANSCEND-NHL-001 they were 42% and 30%, and in the TRANSFORM 49% and 11%, respectively [3, 5]. Although different CRS criteria were used, the overall incidence and severe cases can be compared as shown by Pennisi et al. [11]. No patients received tocilizumab. ICANS was effectively treated with steroids. Neutropenia of grade ≥ 3 was 60% in TRANSCEND-NHL-001 [3] and 82% in TRANSFORM [5] versus 29% in the present study. Indeed, no infection-related events were observed in our cohort, while 12% and 15% of patients in the TRANSCEND-NHL-001 and TRANSFORM, respectively, developed severe infections [3,4,5]. These data are in line with previous publications demonstrating that bendamustine lymphodepletion is associated with reduced incidences of CRS, ICANS, hematological toxicities, and infections compared with Flu/Cy [6, 8, 9, 12].
Data availability
All requests for raw and analyzed data and materials will be promptly reviewed by the University of Pennsylvania to determine if they are subject to intellectual property or confidentiality obligations. Patient-related data may be subject to patient confidentiality. Any data and materials that can be shared will be released via a material transfer agreement. Other data generated from this study are available from the corresponding author upon reasonable request.
Abbreviations
- ALC:
-
Absolute lymphocyte count
- ANC:
-
Absolute neutrophil count
- CART19:
-
Anti-CD19 chimeric antigen receptor T cell therapy
- CRS:
-
Cytokine-release syndrome
- Flu/Cy:
-
Fludarabine and cyclophosphamide lymphodepletion
- ICANS:
-
Immune effector cell associated neurotoxicity syndrome
- IQR:
-
Interquartile range
- LBCL:
-
Large B cell lymphoma
- Liso-cel:
-
Lisocabtagene maraleucel
- PFS:
-
Progression-free survival
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Acknowledgements
We would like to acknowledge the work of nurses and clinical research staff at the Hospital of the University of Pennsylvania. We would like to thank all our patients and their families.
Funding
This work was supported by the Laffey McHugh Foundation (to MR, JS, no grant number), the Berman and Maguire Funds for Lymphoma Research at Penn (to SJS, no grant number), NIH NCI P01 PCA214278C (MR) the R01/37-CA262362-01A1 (MR), the SITC-Mallinckrodt Pharmaceuticals Adverse Events in Cancer Immunotherapy Clinical Fellowship (to GG, no grant number), the Mario Luvini fellowship grant—Fondazione Ticinese per la Ricerca sul Cancro (to GG, no grant number), and the Leukemia and Lymphoma Society Scholar in Clinical Research award (to AG, grant #2329-20).
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Authors and Affiliations
Contributions
GG: conceptualized, designed and conducted the study, acquired data, analyzed data, and wrote the manuscript. LP: acquired data. PV: acquired data. JS: treated patients; ERC: acquired data. EF: acquired data. EAC: treated patients. GGa: acquired data. SDN: treated patients. JDL: treated patients. JC: treated patients. RP: acquired data. SKB: treated patients. GW: acquired data. EW: acquired data, treated patients. EN: treated patients. DLP: treated patients. ALG: designed research study; SJS: conceived the use of bendamustine as lymphodepletion, treated patients, and designed the CART protocols; and MR: conceptualized, designed the research studies, analyzed data, and wrote the manuscript. All authors reviewed and approved the manuscript.
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This retrospective study was approved by the Internal Review Board (IRB). The study was conducted according to the Declaration of Helsinki. The need for informed consent was waived as per IRB guidelines.
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Competing interests
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.
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Ghilardi, G., Paruzzo, L., Patel, V. et al. Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel. J Hematol Oncol 17, 19 (2024). https://doi.org/10.1186/s13045-024-01542-9
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DOI: https://doi.org/10.1186/s13045-024-01542-9