Risks and causes of non-relapse mortality after CAR T-cell therapy

A retrospective registry study by the European Society for Blood and Marrow Transplant (EBMT) evaluated the risk and causes of non-relapse mortality (NRM) associated with CAR T-cell therapy, as well as differences by disease indication and therapeutic product [1]. NRM remains a clinically relevant concern, with infectious complications representing a leading cause. Other causes of NRM included CAR T-cell therapy-related toxicities (32.8%) and secondary malignancies (9.5%).

“Approval studies of CAR T-cell products demonstrated low mortality due to small patient numbers and relatively short follow-up. Early real-world data showed higher NRM, which may reflect treatment of more advanced patients later in the disease course,” noted Dr Charlotte Graham (King’s College London, UK). A recent meta-analysis reported an NRM of 5–10% following CAR T-cell therapy for haematological malignancies [2]. The study presented by Dr Graham was conducted by the EBMT Transplant Complications Working Party, using real-world registry data to assess NRM risk across disease types and CAR T-cell products.

A total of 6,928 adult patients who received a licensed CAR T-cell therapy between 2019 and 2023 for a haematological malignancy were included. Of these, 5,573 patients were treated for B-cell lymphoma (BCL), 583 for multiple myeloma (MM), 514 for mantle cell lymphoma (MCL), and 258 for B-cell acute lymphoblastic leukaemia (B-ALL). There were 2,887 deaths overall; 2,214 (76.7%) were attributed to disease progression or relapse. NRM accounted for 673 deaths (23.3%).

The 1-year post-infusion incidence of NRM by disease indication was:

MCL: 13.3% (95% CI 10.5–16.5);
B-ALL: 9.8% (95% CI 6.5–14.0);
BCL: 6.9% (95% CI 6.2–7.6);
MM: 5.3% (95% CI 3.6–7.5).

The highest 1-year NRM was observed in patients with MCL treated with brexucabtagene-autoleucel (brexu-cel) (13.3%), followed by patients with B-ALL treated with brexu-cel (11.4%). The lowest 1-year NRM was seen in patients with BCL treated with lisocabtagene maraleucel (liso-cel) (4.0%).

The leading causes of NRM were infection (n=191, 35.4%), CAR T-cell therapy-related toxicities (n=177, 32.8%), and secondary malignancies (n=51, 9.5%). “Our results allow us to create strategies focused on infection prophylaxis, surveillance and management, which could enhance CAR T-cell outcomes,” concluded Dr Graham.

Graham C, et al. Non-relapse mortality following CAR-T cell therapy: a study by the EBMT Transplant Complications Working Party. GS2-6, EBMT congress 2026, 22–25 March, Madrid, Spain.
Cordas Dos Santos DM, et al. Nat Med. 2024;30(9):2667-2678.