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

Ghilardi, Guido; Chong, Elise A.; Svoboda, Jakub; Wohlfarth, Philipp; Nasta, Sunita; Williamson, Staci; Landsburg, J.D.; Gerson, James N.; Barta, Stefan K.; Pajarillo, Raymone; Myers, Jessie; Chen, A.I.; Schachter, Levanto; Yelton, Rebecca; Ballard, Hatcher J.; Dwinal, Alexandria Hodges; Gier, Shannon; Victoriano, Danielle; Weber, Elizabeth; Napier, Ellen; Garfall, Alfred L.; Porter, David L.; Jäger, Ulrich; Maziarz, Richard T.; Ruella, Marco; Schuster, Stephen J.

doi:10.1016/j.annonc.2022.05.521

Cited by 55 publications

(41 citation statements)

References 30 publications

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“…Potential modifications to lymphodepleting protocols. For example, cyclophosphamide can be replaced by bendamustine ( 32 ), And 3. Reasonable application of corticosteroids and tocilizumab for CRS.…”

Section: Discussionmentioning

confidence: 99%

Cytopenia after chimeric antigen receptor T cell immunotherapy in relapsed or refractory lymphoma

et al. 2022

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BackgroundPatients with relapsed or refractory (R/R) lymphomas have benefited from chimeric antigen receptor (CAR)-T-cell therapy. However, this treatment is linked to a high frequency of adverse events (AEs), such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematologic toxicity. There has been increasing interest in hematological toxicity in recent years, as it can result in additional complications, such as infection or hemorrhage, which remain intractable.MethodsWe conducted a retrospective, single-institution study to evaluate the patterns and outcomes of cytopenia following CAR-T-cell infusion and potential associated factors.ResultsOverall, 133 patients with R/R lymphoma who received CAR-T-cell therapy from June, 2017 to April, 2022 were included in this analysis. Severe neutropenia, anemia and thrombocytopenia occurred frequently (71, 30 and 41%, respectively) after CAR-T-cell infusion. A total of 98% of severe neutropenia and all severe thrombocytopenia cases occurred in the early phase. Early severe cytopenia was associated with CRS incidence and severity, as well as peak inflammatory factor (IL-6, C-reactive protein (CRP), and ferritin) levels. In multivariate analysis, prior hematopoietic stem cell transplantation (HSCT), baseline hemoglobin (HB), and lymphodepleting chemotherapy were independent adverse factors associated with early severe cytopenia. In addition, 18% and 35% of patients had late neutrophil- and platelet (PLT)-related toxicity, respectively. In multivariate analysis, lower baseline PLT count was an independent factor associated with late thrombocytopenia. More severe cytopenia was associated with higher infection rates and poorer survival.ConclusionsThis research indicates that improved selection of patients and management of CRS may help to decrease the severity of cytopenias and associated AEs and improve survival following CAR-T-cell therapy.Clinical Trial Registrationhttps://www.clinicaltrials.gov/ct2/show/NCT03196830, identifier NCT03196830.

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Section: Discussionmentioning

confidence: 99%

Cytopenia after chimeric antigen receptor T cell immunotherapy in relapsed or refractory lymphoma

et al. 2022

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“…In addition, pentosan, clofarabine (30 mg/m 2 daily for 5 days), Cy 440 mg/m 2 /day and etoposide 100 mg/m 2 /day for 2 days, cytarabine 300 mg/m 2 (single dose) and etoposide 150 mg/m 2 (single dose), methotrexate 1 g/m 2 on day 1 and cytarabine 1 g/m 2 every 12 hours on days 2 and 3, Cy 300 mg/m 2 every 12 hours on days 1–3, vincristine 1.5 mg/m 2 (maximum 2 mg) on day 3, and adriamycin 50 mg/m 2 on day 3 were employed as lymphodepleting regimens before CAR T-cell therapy and showed effective outcomes. 117 , 121 …”

Section: Procedures Of Car T-cell Productionmentioning

confidence: 99%

“… Regimen Dosage Advantage Disadvantage Refer. Cy 300 mg/m 2 every 12 hours for 3 days It effectively prolongs the persistence of infused cells and increases the effectiveness of treatment It could cause adverse effects, ranging from mild to severe symptoms 117 Bendamustine 90 mg/m 2 /day for 2 days It is an effective lymphodepletion regimen before tisa-cel in R/R lymphoma. It also reduces hematological toxicities and infectious complications compared with Flu/Cy.…”

Section: Procedures Of Car T-cell Productionmentioning

confidence: 99%

“…CAR T-cells may remain in the body months after the infusion has been completed, preventing cancer recurrence and resulting in long-term remission for some kinds of blood cancer. 117 …”

Section: Mechanism Of Action Of Car T-cell Therapymentioning

confidence: 99%

“…CAR T-cell therapy is a more versatile ACT that can generally generate long-term remission in blood cancer patients and spark excitement among patients and oncologists. 117 However, this therapy has inherent limitations as modified T-cells can only detect antigens that are only naturally expressed on the cell surface, narrowing the ranges of potential target antigens. Generally, CAR T-cell therapeutic approach is not as effective as expected due to several challenges.…”

Section: Challenges Of Car T-cell Therapy and The Possible Solutionsmentioning

confidence: 99%

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Current updates on generations, approvals, and clinical trials of CAR T-cell therapy

Dejenie

G/Medhin

Terefe

et al. 2022

Human Vaccines & Immunotherapeutics

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Chimeric antigen receptor (CAR) T-cell therapy is a novel, customized immunotherapy that is considered a ‘living’ and self-replicating drug to treat cancer, sometimes resulting in a complete cure. CAR T-cells are manufactured through genetic engineering of T-cells by equipping them with CARs to detect and target antigen-expressing cancer cells. CAR is designed to have an ectodomain extracellularly, a transmembrane domain spanning the cell membrane, and an endodomain intracellularly. Since its first discovery, the CAR structure has evolved greatly, from the first generation to the fifth generation, to offer new therapeutic alternatives for cancer patients. This treatment has achieved long-term and curative therapeutic efficacy in multiple blood malignancies that nowadays profoundly change the treatment landscape of lymphoma, leukemia, and multiple myeloma. But CART-cell therapy is associated with several hurdles, such as limited therapeutic efficacy, little effect on solid tumors, adverse effects, expensive cost, and feasibility issues, hindering its broader implications.

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Bendamustine lymphodepletion is a well‐tolerated alternative to fludarabine and cyclophosphamide lymphodepletion for axicabtagene ciloleucel therapy for aggressive B‐cell lymphoma

Ong,

Pak,

Mei

et al. 2023

American J Hematol

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Fludarabine/cyclophosphamide (Flu/Cy) is established for lymphodepletion (LD) prior to standard‐of‐care CAR T‐cell therapy for lymphoma. There is ongoing need to test alternative LD regimens to preserve efficacy, improve safety, and address challenges including the recent national fludarabine shortage. We retrospectively evaluated outcomes among patients with relapsed/refractory aggressive B‐cell lymphoma who received bendamustine (n = 27) or Flu/Cy (n = 42) LD before axicabtagene ciloleucel (axi‐cel) at our institution. The median change in absolute lymphocyte count from pre‐LD to time of axi‐cel infusion was −0.6×109/L in bendamustine cohort and −0.7×109/L in Flu/Cy cohort. The best overall response/complete response rates were 77.8% (95% CI: 57.7%–91.4%)/48.1% (95% CI: 28.7%–68.1%) among bendamustine cohort and 81.0% (95% CI: 65.9%–91.4%)/50.0% (95% CI: 34.2%–65.8%) among Flu/Cy cohort. Six‐month progression‐free survival were 43.8% (95% CI: 24.7%–61.3%) and 55.6% (95% CI: 39.0%–69.3%) in bendamustine and Flu/Cy cohorts, while 6‐month overall survival were 81.5% (95% CI: 61.1%–91.8%) and 90.4% (95% CI: 76.4%–96.3%), respectively. Relative to Flu/Cy‐treated patients, bendamustine‐treated patients did not show an increase in hazards associated with experiencing progression/relapse/death (aHR:1.4 [95% CI: 0.7–2.8]; p = .32) or death (aHR:1.6 [95% CI: 0.5–5.6]; p = .46), after adjusting for baseline number of prior therapies and refractory disease. Any grade/grade ≥3 CRS were observed in 89%/3.7% and 86%/4.8% among bendamustine and Flu/Cy cohorts, while any grade ICANS/grade ≥3 ICANS were observed in 30%/19% and 55%/31% respectively. While more Flu/Cy‐treated patients experienced grade ≥3 neutropenia compared with bendamustine‐treated patients (100% vs. 68%), grade ≥3 infectious complications were comparable (24% vs. 19% respectively). More patients received bendamustine LD and axi‐cel as outpatient than Flu/Cy cohort, without increased toxicities and with shorter median inpatient stays. In conclusion, we observed comparable efficacy and lower any grade ICANS among patients receiving bendamustine relative to Flu/Cy LD, followed by axi‐cel.

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

Cited by 55 publications

References 30 publications

Cytopenia after chimeric antigen receptor T cell immunotherapy in relapsed or refractory lymphoma

Cytopenia after chimeric antigen receptor T cell immunotherapy in relapsed or refractory lymphoma

Current updates on generations, approvals, and clinical trials of CAR T-cell therapy

Bendamustine lymphodepletion is a well‐tolerated alternative to fludarabine and cyclophosphamide lymphodepletion for axicabtagene ciloleucel therapy for aggressive B‐cell lymphoma

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