Impact of CD19 CAR T-cell product type on outcomes in relapsed or refractory aggressive B-NHL

Abstract

CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cells are novel therapies showing great promise for patients with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL). Single-arm studies showed significant variations in outcomes across distinct CD19 CAR T-cell products. To estimate the independent impact of the CAR T-cell product type on outcomes, we retrospectively analyzed data from 129 patients with R/R aggressive B-NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by either a commercially available CD19 CAR T-cell therapy (axicabtagene ciloleucel [axicel] or tisagenlecleucel [tisacel]), or the investigational product JCAR014 on a phase I/II clinical trial (NCT01865617). After adjustment for age, HCT-CI, LDH, largest lesion diameter, and ALC, CAR T-cell product type remained associated with outcomes in multivariable models. JCAR014 was independently associated with lower CRS severity compared to axicel (adjusted OR [aOR], 0.19; 95%CI, 0.08-0.46), with a trend towards lower CRS severity with tisacel compared to axicel (aOR, 0.47; 95%CI, 0.21-1.06; p=0.07). Tisacel (aOR, 0.17; 95%CI, 0.06-0.48) and JCAR014 (aOR, 0.17; 95%CI, 0.06-0.47) were both associated with lower ICANS severity compared to axicel. Lower odds of complete response (CR) were predicted with tisacel and JCAR014 compared to axicel. Although sensitivity analyses using either PET or CT-based response criteria also suggested higher efficacy of axicel over JCAR014, the impact of tisacel versus axicel became undetermined. Higher preleukapheresis LDH, largest lesion diameter, and lower ALC were independently associated with lower odds of CR. We conclude that CD19 CAR T-cell product type independently impacts toxicity and efficacy in R/R aggressive B-NHL patients.

Axicabtagene ciloleucel compared to tisagenlecleucel for the treatment of aggressive B-cell lymphoma

“…We report herein one of the largest European cohort of patients with R/R aggressive B-cell lymphoma treated with commercial CAR T-cells, including a detailed comparison between axi-cel and tisa-cel, which has been very little addressed in previous real-world studies. 23,24,25,26 In our study, patient and disease characteristics at apheresis were similar between both cohorts, suggesting that CAR-T selection was likely driven by other factors including logistical aspects, manufacturing slot availability and expected turnaround time. More patients in the axi-cel group received the CAR-T infusion, probably influenced by the shorter turnaround time.…”

CAR-T cells—Real-time experience applying CAR-T cells—What we have learned so far

“…Recognition, management, and differentiation of CAR-T cell toxicities are crucial for safe and broad employment of this therapy. Real world data confirmed the well-known adverse reactions of CAR-T cells and in some analyses lower severe CRS and ICANS rates were reported most likely due to the fact that clinical experience improved their early detection [6][7][8][9]. Furthermore, use of corticosteroids to mitigate toxicities by inhibiting the proliferation and/or inflammatory cytokine production from CAR-T cells and other immune cells has become more liberal with initiation at lower grades of CRS or ICANS [6,7].…”

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CD19-targeted chimeric antigen receptor-engineered (CAR)-T cells are novel therapies showing great promise for patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B cell lymphoma, mantle cell lymphoma, and follicular lymphoma. EMA-approved and commercially available CAR-T cell products have been used successfully by qualified CAR-T cell centers worldwide and these real world data compare favorably to pivotal study results with overall response rates (ORR) and complete response rates (CR) ranging from 51-93% and 40-64%, respectively [1][2][3][4][5][6][7][8][9].Recently, axicabtagene ciloleucel (axi-cel) received FDA approval based on results of a multicenter, randomized study comparing axi-cel to conventional salvage chemoimmunotherapy and autologous blood stem cell transplantation (ASCT) as second-line treatment in patients with relapsed or refractory DLBCL [10,11]. After a median follow-up of 24.9 months, median event-free survival (EFS) was more than 4-fold greater and ORR was 33% higher with double the CR rate in the axi-cel arm.

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“…CD19-targeted chimeric antigen receptor-engineered (CAR)-T cells are novel therapies showing great promise for patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B cell lymphoma, mantle cell lymphoma, and follicular lymphoma. EMA-approved and commercially available CAR-T cell products have been used successfully by qualified CAR-T cell centers worldwide and these real world data compare favorably to pivotal study results with overall response rates (ORR) and complete response rates (CR) ranging from 51-93% and 40-64%, respectively [1][2][3][4][5][6][7][8][9].…”

CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naïve/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma

“…4G ). The low ALC observed in Patient 003 and high pre-leukapheresis LDH observed in Patient 016 have both been shown to correlate with low odds for CR after CAR-T cell therapy (27). In contrast, Patient 017, who similarly achieved a PR at day 60, exhibited normal patterns of CRP, ferritin, and LDH levels ( Fig.…”