Axi-cel CAR-T cell therapy in second line for aggressive B-cell lymphoma confers an overall survival benefit over standard of care salvage chemotherapy.

The standard of care first line therapy for many types of aggressive B-cell lymphoma is R-CHOP combination chemo-immunotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). 85% of patients with advanced stage disease are in remission after R-CHOP, and approximately 75% in remission never relapse. For those who have relapsed or primary refractory aggressive lymphoma, unfortunately things look bleaker, and prior to the era of CAR-T cell therapy, the vast majority (70-80% or more) would die of lymphoma.

CAR-T cell therapy is a radically different cancer therapy from combination chemotherapy. White cells are removed from patients with lymphoma using leukapheresis. The T cells are isolated by the manufacturing lab, and a bastardized T-cell receptor with an antibody for a business end that targets some cancer-associated antigen. In the case of B-cell lymphoma, the antigen is CD19. When the engineered T-cells are ready, they are infused back into the patient, proliferate, and start attacking CD19-positive lymphoma cells. 50-60% of patients with refractory or relapsed disease can get to a complete response by 30 days after infusion, and most of those will stay in remission. At 5 years after CAR-T infusion, 35-40% of all patients treated are still in remission. This was first studied and approved as a third line treatment, following salvage chemotherapy +/- high dose chemotherapy and stem cell rescue. The obvious next question is whether or not this treatment was better than salvage chemotherapy in the second line.

Prior to 2021, the standard of care was to administer salvage platinum-based combination chemotherapy to patients who were not remission after first line R-CHOP, or who relapsed after R-CHOP. If the tumor bulk shrank by more than half, a single high dose cycle of combination chemotherapy was given followed by stem cell rescue (autologous stem cell transplantation). For patients who get through the high dose chemotherapy, the long-term survival is in the 40% range. However, many didn't respond to second line chemotherapy. Those patients went on to CAR-T cell chemotherapy.

The ZUMA-7 trial enrolled patients with aggressive B-cell lymphoma who were refractory to first line treatment or who relapsed in under a year, predicting a poor response to second line chemotherapy. Patients were randomized to go straight to CAR T with axi-cel anti-CD19 CAR T cell therapy or to standard of care salvage chemotherapy followed by high dose chemo/ASCT for responders. Most of those who did not respond or who relapsed after second-line chemotherapy did go on to get CAR-T cell therapy, so the comparison ended up being 2nd line versus 3rd line CAR T for many patients. The initial report in December 2021 at ASH from Zuma-7 showed that 98% of patients randomized to second-line CAR T got CAR T cells infused, while a distinct minority randomized to salvage chemotherapy made it to HDCT/ASCT. There was a large progression-free survival benefit to CAR T cell therapy in the second line, but the overall survival data were immature.

Based on these data and strong biologic plausibility (patients predicted to do poorly with chemotherapy do poorly with chemotherapy, generally), second-line CAR T for refractory or early-relapsed aggressive B-cell lymphoma became standard of care. However, there were some holdouts (including insurers of course) who were waiting to see if there was an overall survival benefit. One would expect an OS benefit, because in a deadly but curable disease, PFS tends to become OS.

Last week, the 5 year update from the Zuma-7 trial was recently published, which showed that the substantial advantage in progression free survival has now become an overall survival benefit at 5 year follow-up. The 9% absolute increase in overall survival at 4 years (55% vs 46%) is even more notable in that patients given how many of the standard of care arm ended up getting CAR T cell therapy in a later line. So this trial really is comparing second-line CAR T cell therapy to third line therapy, and the survival in the "control" arm was therefore quite a bit higher than the historical expected survival in the era before CAR T. It is now inarguable that the correct treatment for patients who relapse early after R-CHOP or who are refractory is going straight to CAR T with all due haste.

As of 2023, the treatment for aggressive B cell lymphoma has changed dramatically compared to 5 years ago, with substantially increased survival in relapsed/refractory disease. The next major step forward, with bispecific T cell engaging antibody immunotherapy is already here, but that's a topic for another post.