Deciphering Second-Line CAR T-Cell Therapy in Large B-Cell Lymphoma

The standard second-line therapy for relapsed/refractory large B-cell lymphoma (LBCL) is salvage chemotherapy followed by high-dose chemotherapy with autologous stem cell transplantation (ASCT) in responding patients. However, this approach is restricted to younger, fit patients and is relatively ineffective for patients with chemotherapy-refractory disease. Chimeric antigen receptor (CAR) T-cell therapies that target CD19 (axicabtagene ciloleucel [axi-cel]; lisocabtagene maraleucel [liso-cel], and tisagenlecleucel [tisa-cel]) have shown durable remissions in up to 40% of patients with LBCL pretreated with more than two treatment lines, including those with refractory disease, and have been approved in the third-line setting. In phase II trials, all three CAR T-cell therapies have shown similar efficacy and toxicity profiles; however, to date, no trials have directly compared them.

With the aim of improving patient outcomes, the three CAR T-cell therapies were evaluated in phase III trials (TRANSFORM, ZUMA7, and BELINDA) in second-line settings, where they were compared with standard chemotherapy followed by ASCT. New results from these trials were presented in December at the 2021 American Society of Hematology annual meeting. Simultaneously, results from ZUMA7 and BELINDA were published in the New England Journal of Medicine.

The ZUMA7 trial compared axi-cel with standard of care. At a median follow up of 24.9 months, the median event-free survival (EFS) was significantly longer with axi-cel than in the ASCT group (8.3 vs. 2.0 months; hazard ratio [HR] 0.40; P<0.001). The overall response rate (ORR) was also higher with axi-cel (83% vs. 50%), with a complete response (CR) rate of 65% vs. 32%, respectively. In the TRANSFORM trial, liso-cel at a follow-up of 6 months showed similar improvement of the EFS and CR rates. In contrast, in the BELINDA trial, at median follow up of 10 months, treatment with tisa-cel compared with standard of care did not improve EFS (3.0 months in both groups; HR 1.07; P=0.69) or CR rate (28.4% vs.27.5%). Of note, side effects were similar across all three trials, and severe side effects were uncommon.

What can we take away from these varied outcomes? The authors of NEJM’s accompanying editorial emphasized that differences in patient selection criteria, real-world chemotherapy variations, and, in particular, use of bridging chemotherapy are important factors that may impact the results of the trials. In ZUMA7, patients could receive only glucocorticoids as bridging therapy, a policy the editorial authors characterized as a “considerable enrollment bias against patients with rapidly progressing or bulky disease.” BELINDA’s trial design did allow for up to two salvage chemotherapy regimens. In addition, the fact that a slightly lower percentage of patients in BELINDA than ZUMA7 proceeded to ASCT may indicate that the BELINDA patients had an overall worse prognosis. Furthermore, shorter processing and turnaround times for axi-cel may have also contributed to the favorable clinical outcomes in the ZUMA-7 trial, attesting that patients with these aggressive lymphomas must receive treatment as soon as possible. The editorial’s takeaway? “The ZUMA-7 trial clearly shows that ASCT-eligible patients with relapsed or refractory large B-cell lymphoma whose disease is controllable with glucocorticoid bridging therapy alone should be prioritized for axicabtagene ciloleucel over ASCT as second-line therapy.” As for BELINDA, the editorial continues, it may be premature to conclude that CAR T-cell therapy should be recommended for all ASCT-eligible patients with large B-cell lymphoma, “particularly those with bulky or rapidly progressing disease that warrants more aggressive bridging chemotherapy.” Taken together, not all patients with relapsed/refractory LBCL are the same, thus evaluating patients’ suitability for CAR T-cell application is important.

Locke FL, et al. N Engl J Med. 2021 Dec 11. [Online ahead of print]
Bishop MR, et al. N Engl J Med. 2021 Dec 11. [Online ahead of print]
Roschewski M, et al. N Engl J Med. 2021 Dec 11. [Online ahead of print]