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Study Sheds Light on LBCL Outcomes With Third-Line Therapies

April 18, 2024

May 2024

Katie Robinson

Katie Robinson is a medical writer based in New York.

Adults with relapsed or refractory large B-cell lymphoma (R/R LBCL) appeared to have better outcomes when cellular therapy was given in second line (2L) rather than third line (3L). This is according to a post-hoc analysis, published in Blood Advances, which suggested further study to establish 3L cellular therapy as a feasible option for patients with an initial response to 2L anti-CD19 chimeric antigen receptor (CAR) T-cell therapy.

“CAR-T is considered standard of care (SOC) for patients with LBCL with primary refractory disease or relapse within 12 months. There is no standard practice in how to manage patients who don’t respond to 2L CAR-T or relapse afterward,” said corresponding author Armin Ghobadi, MD, associate professor of medicine at Washington University School of Medicine in St. Louis. “The goal was to shed light on subsequent therapy and outcomes of patients who enrolled in the ZUMA-7 trial, didn’t respond to 2L axicabtagene ciloleucel (axi-cel), SOC chemotherapy, or autologous transplant, and received subsequent therapy.”

In the phase III ZUMA-7 trial, 2L axi-cel (2 × 106 CAR T cells/kg) improved outcomes versus 2L SOC for adults with R/R LBCL. In the post-hoc analysis, the researchers assessed progression-free survival (PFS) and overall survival (OS) among patients with R/R LBCL who did and did not receive 3L anti-lymphoma therapy per investigator discretion in ZUMA-7. In the SOC group, 3L therapy included cellular immunotherapy or no cellular immunotherapy. In the axi-cel group, 3L therapy included chemotherapy and cellular immunotherapy — limited to axi-cel retreatment for patients who initially responded to axi-cel — and other treatments. Patient and disease characteristics at the start of 3L therapy were unavailable.

Of the 179 patients in the SOC group, 71% received 3L therapy. The median time to 3L therapy was 2.8 months. For the 68 patients who received 3L cellular immunotherapy and the 59 patients who did not, the median PFS was 6.3 versus 1.9 months, and the median OS was 16.3 versus 9.5 months, respectively.

The authors completed no formal comparative statistical analyses, but they noted that outcomes from patients who received 3L cellular immunotherapy “appeared numerically inferior to those who received 2L cellular immunotherapy in ZUMA-7.” With 2L axi-cel, the median PFS was 14.7 months versus 6.3 months with 3L cellular immunotherapy in the SOC group, and the median OS was not reached versus 16.3 months, respectively.

Of the 180 patients in the axi-cel group, 47% received 3L therapy. The median time to 3L therapy was 4.4 months. For the 60 patients who received 3L chemotherapy and the eight who received 3L cellular immunotherapy, the median PFS was 1.7 versus 3.5 months, and the median OS was 8.1 months versus not reached, respectively. Of the 60 patients treated with 3L chemotherapy, 10 had hematopoietic cell transplantation after salvage chemotherapy. For the patients who did and did not reach hematopoietic cell transplantation, the median PFS was 11.5 versus 1.6 months, and the median OS was 17.5 versus 7.2 months, respectively. Of the eight patients who received 3L cellular immunotherapy, the six who received subsequent hematopoietic cell transplantation were alive at the March 18, 2021, data cutoff.

“In patients with R/R disease after 2L CD19 CAR-T, outcomes are poor. If trials are available, those patients must be enrolled,” Dr. Ghobadi said. “Another option includes using novel chemotherapy and, in cases of chemosensitive disease, consolidation of the response with autologous transplant. 3L cell therapy can be an option for those patients. We didn’t have patients using bispecific post-2L CAR-T because of the timing of the study, but novel CD20 T-cell redirectors can be considered as well.”

“R/R to 2L CAR-T is becoming a major problem, and we need clinical trials using innovative therapies, including cellular therapies, to improve the outcome in these patients. Some of those trials, like the CD22 CAR-T trial for relapse post-CD19 CAR-T, are ongoing,” Dr. Ghobadi said.

One of the limitations to the post-hoc analysis was that the disease assessments were per investigator and not performed at defined time points, with no blinded central review. Further, the impact of patient and disease characteristics on outcomes was undetermined because these characteristics were unavailable at the start of 3L therapy. Finally, the responses from patients in the axi-cel group who received subsequent 3L anti-CD19 CAR T-cell therapy “should be interpreted cautiously given the limited sample size,” noted the authors, who suggested further study with a larger number of patients.

Any conflicts of interest declared by the authors can be found in the original article.


Ghobadi A, Munoz J, Westin JR, et al. Outcomes of subsequent anti-lymphoma therapies after second-line axicabtagene ciloleucel or standard of care in ZUMA-7 [published online ahead of print, 2024 February 5]. Blood Adv. doi: 10.1182/bloodadvances.2023011532.



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