CONFERENCE UPDATE: NCCN 2021

Improving response in B-cell lymphomas with chimeric antigen receptor T-cell therapy

11 May 2021

The prognosis of patients with large B-cell lymphoma refractory to first- or second-line therapy is poor with a low objective response rate (ORR) to standard-of-care therapy of 26% and median overall survival (OS) of only 6.3 months.1 When managing patients with refractory large B-cell lymphoma, chimeric antigen receptor T-cell (CAR-T) therapies targeting CD19 have been demonstrated to improve ORR and were subsequently approved by the Food and Drug Administration (FDA) for treating relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL).

Axicabtagene ciloleucel is one such FDA-approved CAR-T product that was evaluated in the pivotal, multicenter phase 2 ZUMA-1 study.1 In this study, 77 and 24 patients with DLBCL or follicular lymphoma (FL), respectively, were recruited.1 Each patient received lymphodepleting chemotherapy followed by a target dose of 2x106 CAR-T cells per kg of bodyweight.1 After a median follow-up period of 27.1 months, the ORR was 83% with 58% of patients achieving complete remission (CR).1 The median progression-free survival (PFS) was 5.9 months with the median OS not reached.1 Overall, axicabtagene ciloleucel induced a durable response with a median OS greater than 2 years and a manageable long-term safety profile in patients with rrDLBCL.1

Another approved anti-CD19 CAR-T, tisagenlecleucel, was studied in the pivotal international, multicenter phase 2 JULIET study.2 In this study, 111 patients with either DLBCL or FL were included.2 After 1 cycle of lymphodepleting chemotherapy, the patients received a median dose of 3.0×108 CAT-T cells.2 After a median follow-up period of 19.3 months, the ORR was 54% with 40% of patients achieving CR.2 Notably, 34 patients achieved CR at 3 months, with 6 and 1 patients relapsed within and after 12 months of CAR-T therapy, respectively.2 Despite a shorter follow-up than the ZUMA-1 study, tisagenlecleucel has a high and durable response rate and is a promising agent for patients with rrDLBCL.2

Lisocabtagene maraleucel is also an approved CAR-T which was studied in the multicenter TRANSCEND study among patients with DLBCL, FL or indolent non-Hodgkin lymphomas (NHL).3 In the study, 269 patients received lymphodepleting chemotherapy followed by a target dose of 100x106 CAR-T cells.3 Of 256 efficacy-evaluable patients, the ORR was 73% and 53% of patients achieved CR.3 With a median PFS of 12.3 months, 42% and 30% of patients have developed cytokine release syndrome (CRS) and neurological toxicity, respectively.3 6% of patients also developed dose-limiting toxicity.3 With a high ORR and a low incidence of grade 3 or worse CRS and neurological events, lisocabtagene maraleucel is an effective treatment among patients with rrDLBCL.3

rrDLBCL aside, Dr. Stephen Schuster, Director of the Lymphoma Program and Lymphoma Translational Research at the Abramson Cancer Center, University of Pennsylvania, United States, noted that the clinical outcome of mantle cell lymphoma (MCL) patients following CAR-T remains sparse. That said, a recently published study had recruited 68 rrMCL patients who had a median of 3 prior therapies including Bruton's tyrosine kinase (BTK) inhibitor therapy.4 These patients were given a single infusion of the CAR-T brexucabtagene autoleucel at a dose of 2×106 CAR-T cells per kg of bodyweight.4 After a median follow-up of 12.3 months, the ORR was 93% with a 12-month PFS and OS of 61% and 83%, respectively.4 Notably, 67% of patients achieved CR, indicating that CAR-T therapy for rrMCL patients can also induce durable remission.4

For patients with relapsed/refractory indolent NHL, the unpublished multicenter, single-arm phase 2 ZUMA-5 study showed that axicabtagene ciloleucel had an ORR of 94% and 85% as well as a CR of 80% and 60% for those with FL and marginal zone lymphoma (MZL), respectively. Similarly, the ongoing ELARA trial showed encouraging results with CAR-T where 65% of FL patients had achieved CR. Dr. Schuster concluded, “We can combine CAR-T with other therapies and move [the treatment regimen] earlier. This will change the landscape of treating [many diseases including rrDLBCL].”

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