Bendamustine lymphodepletion before axicabtagene ciloleucel is safe and associates with reduced inflammatory cytokines

Ghilardi, Guido; Paruzzo, Luca; Svoboda, Jakub; Chong, Elise A.; Shestov, Alexander A.; Chen, Linhui; Cohen, Ivan J.; Gabrielli, Giulia; Nasta, Sunita D.; Porazzi, Patrizia; Landsburg, Daniel J.; Gerson, James N.; Carter, Jordan; Barta, Stefan K.; Yelton, Rebecca; Pajarillo, Raymone; Patel, Vrutti; White, Griffin; Ballard, Hatcher J.; Weber, Elizabeth; Napier, Ellen; Chong, Emeline R.; Fraietta, Joseph A.; Garfall, Alfred L.; Porter, David L.; Milone, Michael C.; O’Connor, Roderick; Schuster, Stephen J.; Ruella, Marco

doi:10.1182/bloodadvances.2023011492

Cited by 10 publications

(6 citation statements)

References 71 publications

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“…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 – 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 ].…”

Section: To the Editorsupporting

confidence: 93%

“…The combination of fludarabine and cyclophosphamide (Flu/Cy) is the standard lymphodepletion regimen before commercial CART19 products, including lisocabtagene maraleucel (liso-cel) [ 3 – 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.…”

Section: To the Editormentioning

confidence: 99%

“…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.…”

Section: To the Editormentioning

confidence: 99%

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Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel

Ghilardi,

Paruzzo,

Patel

et al. 2024

J Hematol Oncol

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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.

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Section: To the Editorsupporting

confidence: 93%

Section: To the Editormentioning

confidence: 99%

Section: To the Editormentioning

confidence: 99%

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Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel

Ghilardi,

Paruzzo,

Patel

et al. 2024

J Hematol Oncol

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“…This study highlights the need for dedicated prospective studies to determine an optimal regimen and minimize patient exposure to unnecessary chemotherapy. Experience has also been reported for bendamustine as an alternative fludarabine-sparing regimen that may incur less toxicities ( 22 , 23 ). Within the limitations of a single center retrospective study, it appears that fludarabine 40mg/m 2 and cyclophosphamide 500 mg/m 2 on days -3 and -2 prior to CAR T-cell infusion is safe and efficacious while conserving resources.…”

Section: Discussionmentioning

confidence: 99%

Comparing 2-day vs 3-day flu-CY lymphodepleting regimens for CD19 CAR T-cell therapy in patients with non-hodgkin’s lymphoma

Frame,

Geer,

Kasha

et al. 2024

Front. Immunol.

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IntroductionLymphodepleting chemotherapy (LDC) is critical to CAR T-cell expansion and efficacy. Despite this, there is not a consensus in the literature regarding the optimal LDC regimen, including dose and frequency.MethodsWe retrospectively reviewed consecutive patients at a single institution that received LDC prior to treatment with the CD19 directed CAR T-cell products axicabtagene ciloleucel and tisagenlecleucel. Patients treated at our center received fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 for 3 consecutive days prior to May 2019. After this timepoint patients routinely received fludarabine 40 mg/m2 and cyclophosphamide 500 mg/m2 for 2 consecutive days. Clinical data from each cohort were obtained from the electronic medical record and compared for differences in CAR T-cell efficacy and toxicity.ResultsFrom June 2018 to August 2023, LDC was given to 92 patients prior to CD19 directed CAR T-cell therapy for relapsed non-Hodgkin’s lymphoma. Twenty-eight patients received a 3-day regimen, and 64 patients received a 2-day regimen. In the total cohort, 75% of patients received axicabtagene ciloleucel and 25% received tisagenlecleucel. The overall response rates in both the 2-day regimen group and the 3-day regimen group were similar (69% vs 75%, p= 0.21) as were the complete response rates (50% vs 54%, p=0.82). There were no significant differences between the 2-day and 3-day regimens for grade 2–4 cytokine release syndrome (55% vs 50%, p=0.82), grade 2–4 immune effector cell associated-neurotoxicity syndrome (42% vs 29%, p=0.25), or time to resolution of neutropenia or thrombocytopenia. The rate of prolonged platelet recovery lasting greater than 60 days was higher with the 3-day regimen (9% vs 27%, p=0.026).DiscussionAs the number of patients eligible for CAR T-cell therapy continues to increase, optimizing each component of therapy is necessary. We show that a 2-day regimen of LDC with fludarabine and cyclophosphamide is feasible without significant impact on CAR T-cell efficacy or toxicity. Prospective studies are necessary to further determine the most effective LDC regimen.

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“… 25 , 26 , 27 , 28 However, its use as an alternative lymphodepleting chemotherapy regimen has shown a favorable toxicity profile and similar efficacy to the standard combination of fludarabine and cyclophosphamide (Flu/Cy). 29 , 30 , 31 Nonetheless, the potential benefit of treatment schemas including this agent in the bridging period is not well documented. The additive effect of bendamustine bridging followed by Flu/Cy lymphodepletion could lead to an increased risk of hematological toxicity and infections after CAR T‐cell therapy, as reported when this agent was administered prior to leukapheresis.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of bendamustine‐containing bridging therapy in R/R LBCL patients receiving CD19 CAR T‐cells

Iacoboni,

Sánchez‐Salinas,

Rejeski

et al. 2024

HemaSphere

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Bridging therapy (BT) after leukapheresis is required in most relapsed/refractory (R/R) large B‐cell lymphoma (LBCL) patients receiving chimeric antigen receptor (CAR) T cells. Bendamustine‐containing regimens are a potential BT option. We aimed to assess if this agent had a negative impact on CAR‐T outcomes when it was administered as BT. We included R/R LBCL patients from six centers who received systemic BT after leukapheresis from February 2019 to September 2022; patients who only received steroids or had pre‐apheresis bendamustine exposure were excluded. Patients were divided into two BT groups, with and without bendamustine. Separate safety and efficacy analyses were carried out for axi‐cel and tisa‐cel. Of 243 patients who received BT, bendamustine (benda) was included in 62 (26%). There was a higher rate of BT progressors in the non‐benda group (62% vs. 45%, p = 0.02). Concerning CAR‐T efficacy, complete responses were comparable for benda versus non‐benda BT cohorts with axi‐cel (70% vs. 53%, p = 0.12) and tisa‐cel (44% vs. 36%, p = 0.70). Also, 12‐month progression‐free and overall survival were not significantly different between BT groups with axi‐cel (56% vs. 43% and 71% vs. 63%) and tisa‐cel (25% vs. 26% and 52% vs. 48%); there were no differences when BT response was considered. CAR T‐cell expansion for each construct was similar between BT groups. Regarding safety, CRS G ≥3 (6% vs. 6%, p = 0.79), ICANS G ≥3 (15% vs. 17%, p = 0.68), severe infections, and neutropenia post‐infusion were comparable among BT regimens. BT with bendamustine‐containing regimens is safe for patients requiring disease control during CAR T‐cell manufacturing.

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Bendamustine lymphodepletion before axicabtagene ciloleucel is safe and associates with reduced inflammatory cytokines

Cited by 10 publications

References 71 publications

Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel

Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel

Comparing 2-day vs 3-day flu-CY lymphodepleting regimens for CD19 CAR T-cell therapy in patients with non-hodgkin’s lymphoma

Efficacy and safety of bendamustine‐containing bridging therapy in R/R LBCL patients receiving CD19 CAR T‐cells

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