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Infections were the main cause of nonrelapse mortality among patients who received chimeric antigen receptor (CAR) T-cell therapy for lymphomas and multiple myeloma, according to a systematic review and meta-analysis.

Of 574 reported nonrelapse deaths after CAR T-cell therapy, 50.9% were attributed to infections, reported Kai Rejeski, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues.

Notably, CAR T-cell-specific toxicities -- such as immune effector cell-associated neurotoxicity syndrome/neurotoxicity, cytokine release syndrome, and hemophagocytic lymphohistiocytosis -- were responsible for just 11.5% of nonrelapse deaths. Secondary malignancies accounted for 7.8%, and 7.3% were due to cardiovascular/respiratory events.

"Owing to the critical role of infections as the main driver of NRM [nonrelapse mortality] across CAR T-cell products and disease entities, there is a pressing need for comprehensive evidence-based guidelines that inform infection prevention and management after CAR T-cell therapy," Rejeski and colleagues wrote in .

"Knowledge of the expected infection risk for each CAR T-cell product may help to guide antimicrobial prophylaxis, immunoglobulin replacement therapy and granulocyte-colony-stimulating factor support, particularly in high-risk patients," they noted.

In a accompanying the study, Viktoria Blumenberg, MD, and Marcela V. Maus, MD, PhD, both of Massachusetts General Hospital and Harvard Medical School in Boston, said the study's findings set the stage for further clinical and scientific investigation, particularly as CAR T-cell therapies receive more approvals for various hematologic malignancies, and show promise for solid tumors.

"Future investigations should focus on enhancing efficacy while minimizing toxicity and NRM," they wrote. "The results from [Rejeski and colleagues] highlight the impact of infections on NRM and call for further mechanistic investigations into CAR T-cell-induced hematopoietic suppression, along with clinical monitoring and management strategies to mitigate infection risk and improve patient outcomes in the evolving landscape of CAR T-cell therapy."

This systematic review and meta-analysis included 7,604 patients across 18 clinical trials and 28 real-world studies with various types of lymphoma and multiple myeloma who were treated with the CD19-targeted CAR T-cell products axicabtagene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (tisa-cel; Kymriah), lisocabtagene maraleucel (liso-cel; Breyanzi) and brexucabtagene autoleucel (brexu-cel; Tecartus), or the BCMA-targeted CAR T-cell products ciltacabtagene autoleucel (cilta-cel; Carvykti) or idecabtagene vicleucel (ide-cel; Abecma).

Among the patients, the most common disease types were large B-cell lymphoma (5,806 patients), followed by multiple myeloma (n=1,193), mantle-cell lymphoma (n=340), and indolent lymphoma (n=265).

The authors found that the cumulative incidence rates of nonrelapse mortality were not reported in any of the 18 clinical trials, and in just half of the real-world studies. To compensate for the lack of this type of data in these trials, they determined nonrelapse mortality point estimates using random-effect models based on proportions, and compared them with 1-year nonrelapse mortality rates in the real-world studies that did report them, and found no significant differences.

Across all patients, the median follow-up was 13.4 months, and the overall nonrelapse mortality point estimate across all studies was 6.8%. These point estimates were highest in patients with mantle-cell lymphoma (10.6%), followed by multiple myeloma (8.0%), large B-cell lymphoma (6.1%), and indolent lymphoma (5.7%).

Among all CAR T products, cilta-cel had the highest overall nonrelapse mortality (15.2%), followed by brexu-cel (10.6%), axi-cel (7.3%), and ide-cel (6.3%). The lowest rates were seen with tisa-cel (4.2%) and liso-cel (3.8%).

For the nonrelapse deaths attributed to infections, the specific pathogen was not identified in most cases. Among the 103 nonrelapse deaths with a reported pathogen, 53.4% were related to COVID-19. Others involved fungal infections (19.4%), bacterial infections (21.4%), and non-COVID viral infections (4.8%).

Infections were more likely the cause of death in real-world settings (64.6%) than in clinical trials (59.1%), and this remained true even when excluding COVID-related deaths.

Among deaths attributable to secondary malignancies, one-third resulted from myelodysplastic syndrome or acute myeloid leukemia, 22.2% from carcinoma, and 2.2% from sarcoma. The remaining malignancy-related deaths were not specified.

As for deaths related to cardiovascular or respiratory events, the leading causes were respiratory failure (23.3%) and thromboembolic events (20.9%).

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