Bendamustine vs. fludarabine/cyclophosphamide lymphodepletion prior to BCMA CAR-T cell therapy in multiple myeloma

Sidana, Surbhi; Hosoya, Hitomi; Jensen, Alexandria; Liu, Lawrence; Goyal, Anmol; Hovanky, Vanna; Sahaf, Bita; Bharadwaj, Sushma; Latchford, Theresa; Arai, Sally; Leahy, Sheryl; Mei, Matthew; Budde, Lihua E.; Muffly, Lori S.; Frank, Matthew J.; Dahiya, Saurabh; Htut, Myo; Miklos, David; Janakiram, Murali

doi:10.1038/s41408-023-00929-0

Cited by 12 publications

(3 citation statements)

References 14 publications

(18 reference statements)

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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%

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%

Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel

Ghilardi,

Paruzzo,

Patel

et al. 2024

J Hematol Oncol

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“…Clinical studies evaluating HBI0101/NXC-201 began February 2021 with a phase 1a dose-escalation study, starting with the infusion of 150 × 10 6 CAR-positive T cells and proceeding to 450 × 10 6 and to the target dose of 800 × 10 6 cells. A standard conditioning regimen of fludarabine and cyclophosphamide was given as lymphodepletion prior to CAR-T therapy in patients with adequate renal function, while bendamustine was used as an alternative but equally effective regimen [75] in patients with a creatinine clearance of less than 30 mL/min. Following the encouraging results of the phase 1a trial, from the points of view of both efficacy and toxicity [76], the target dose of 800×10 6 cells was further assessed in phase 1b and 2 studies, including over 80 patients (manuscript under revision).…”

Section: Chimeric Antigen Receptor T-cell Therapymentioning

confidence: 99%

Immune Therapies in AL Amyloidosis—A Glimpse to the Future

Haran,

Vaxman,

Gatt

et al. 2024

Cancers

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Light-chain (AL) amyloidosis is a rare plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chains in target organs, leading to multi-organ dysfunction. Treatment approaches have historically mirrored but lagged behind those of multiple myeloma (MM). Recent advancements in MM immunotherapy are gradually being evaluated and adopted in AL amyloidosis. This review explores the current state of immunotherapeutic strategies in AL amyloidosis, including monoclonal antibodies, antibody–drug conjugates, bispecific antibodies, and chimeric antigen receptor T-cell therapy. We discuss the unique challenges and prospects of these therapies in AL amyloidosis, including the exposure of frail AL amyloidosis patients to immune-mediated toxicities such as cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS), as well as their efficacy in promoting rapid and deep hematologic responses. Furthermore, we highlight the need for international initiatives and compassionate programs to provide access to these promising therapies and address critical unmet needs in AL amyloidosis management. Finally, we discuss future directions, including optimizing treatment sequencing and mitigating toxicities, to improve outcomes for AL amyloidosis patients.

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“…The data suggesting an optimal therapeutic window may lead to individualized dosing, particularly for fludarabine (115). Recent evidence suggests that bendamustin (180mg) is equally effective and possibly less toxic with both, tisa-cel and axi-cel in lymphoma and with cita-cel and ide-cel in multiple myeloma (53,160,161). Moreover, Benda is the preferred LD for patients with renal insufficiency or other comorbidities.…”

Section: Best Current Approachesmentioning

confidence: 99%

Lymphodepletion – an essential but undervalued part of the chimeric antigen receptor T-cell therapy cycle

Lickefett,

Chu,

Ortiz-Maldonado

et al. 2023

Front. Immunol.

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Lymphodepletion (LD) or conditioning is an essential step in the application of currently used autologous and allogeneic chimeric antigen receptor T-cell (CAR-T) therapies as it maximizes engraftment, efficacy and long-term survival of CAR-T. Its main modes of action are the depletion and modulation of endogenous lymphocytes, conditioning of the microenvironment for improved CAR-T expansion and persistence, and reduction of tumor load. However, most LD regimens provide a broad and fairly unspecific suppression of T-cells as well as other hematopoietic cells, which can also lead to severe side effects, particularly infections. We reviewed 1271 published studies (2011-2023) with regard to current LD strategies for approved anti-CD19 CAR-T products for large B cell lymphoma (LBCL). Fludarabine (Flu) and cyclophosphamide (Cy) (alone or in combination) were the most commonly used agents. A large number of different schemes and combinations have been reported. In the respective schemes, doses of Flu and Cy (range 75-120mg/m2 and 750-1.500mg/m2) and wash out times (range 2-5 days) differed substantially. Furthermore, combinations with other agents such as bendamustine (benda), busulfan or alemtuzumab (for allogeneic CAR-T) were described. This diversity creates a challenge but also an opportunity to investigate the impact of LD on cellular kinetics and clinical outcomes of CAR-T. Only 21 studies explicitly investigated in more detail the influence of LD on safety and efficacy. As Flu and Cy can potentially impact both the in vivo activity and toxicity of CAR-T, a more detailed analysis of LD outcomes will be needed before we are able to fully assess its impact on different T-cell subsets within the CAR-T product. The T2EVOLVE consortium propagates a strategic investigation of LD protocols for the development of optimized conditioning regimens.

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Bendamustine vs. fludarabine/cyclophosphamide lymphodepletion prior to BCMA CAR-T cell therapy in multiple myeloma

Cited by 12 publications

References 14 publications

Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel

Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel

Immune Therapies in AL Amyloidosis—A Glimpse to the Future

Lymphodepletion – an essential but undervalued part of the chimeric antigen receptor T-cell therapy cycle

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