Although chimeric antigen receptor (CAR) T-cell therapy has transformed treatment for patients with relapsed and refractory blood cancers, it can also cause an array of immune-related adverse events, including cytokine-release syndrome, immune effector cell–associated neurotoxicity syndrome, and immune effector cell–associated hematotoxicity. The therapy has also been linked to causing second primary malignancies, which prompted the U.S. Food and Drug Administration (FDA), in January 2024, to require all six CAR T-cell therapies to carry a black box warning of a risk of second primary malignancies following treatment.

To delineate the frequency and subtypes of second primary malignancies following CAR T-cell therapy, Tix et al conducted a meta-analysis of clinical studies in which patients with lymphoma or multiple myeloma received CAR T-cell therapy. They found that the rate of second primary malignancies compared to patients receiving previous standard-of-care therapy was not statistically significant, 5% vs 4.9%, respectively. “Ultimately, these findings question the FDA’s class-wide warning, suggesting that [second primary malignancy] development rather reflects exposure to previous therapies and extended follow-up than being intrinsically linked to CAR T-cell therapy itself,” concluded the study authors. The study by Tix et al was published in Clinical Cancer Research.

Study Methodology

The researchers conducted a literature search in the MEDLINE, Embase, and Cochrane Library CENTRAL databases. Following extraction of second primary malignancy cases and assignment of malignant origin, they analyzed second primary malignancy point estimates using random effect models. The researchers screened all studies for the six FDA-approved CAR T-cell products in multiple myeloma and lymphoma, including idecabtagene vicleucel, lisocabtagene maraleucel, ciltacabtagene autoleucel, tisagenlecleucel, brexucabtagene autoleucel, and axicabtagene ciloleucel.

Key Results

The researchers identified 326 second primary malignancies across 5,517 patients from 18 clinical trials and 7 real-world studies. With a median follow-up of 21.7 months, the overall second primary malignancy point estimate was 5.8% (95% confidence interval [CI] = 4.7–7.2). Second primary malignancy estimates were associated with treatment setting (clinical trial > real-world setting), duration of follow-up, and number of prior treatment lines, which were each confirmed as independent study-level risk factors of second primary malignancies in a meta-regression model.

A subgroup meta-analysis of the four trials that randomized CAR T-cell therapy vs standard of care revealed a similar risk of second primary malignancies with either treatment strategy (P = .92). In a distribution analysis of second primary malignancy subtypes, hematologic malignancies were the most common (37%), followed by solid tumors (27%) and nonmelanoma skin cancers (16%). T-cell malignancies represented a small minority of events (1.5%).

“These data raise awareness of [second primary malignancies] as a clinically relevant long-term adverse event in patients receiving CAR T-cell therapy. However, our findings do not indicate that [second primary malignancy] frequency is higher with CAR T vs previous standard-of-care strategies,” concluded the study authors.

Clinical Relevance

“These data do not suggest there is an increased risk of [second primary malignancies] relative to other standard-of-care therapies,” said corresponding study author Kai Rejeski, MD, a visiting investigator and research fellow in the Adult Bone Marrow Transplantation Service at Memorial Sloan Kettering Cancer Center and principal investigator of this study, in a statement. “I worry that the warning labels may intimidate patients who receive this therapy, which may not be founded.”

Dr. Rejeski continued: “CAR T-therapy is the first treatment in more than 20 years to show an overall survival benefit compared to the standard of care in refractory large B-cell lymphoma. I would strongly caution against withholding this therapy because of the miniscule risk of developing T-cell malignancies.”

Disclosure: Funding for this study was provided by the School of Oncology of the German Cancer Consortium, the Walter Benjamin Fellowship by the German Research Foundation, Arnold Ventures, the Else Kröner Forschungskolleg within the Munich Clinician Scientist Program, the Bruno and Helen Jöster Foundation, the Bavarian Center for Cancer Research, and the National Cancer Institute. For full disclosure of all study authors, visit aacrjournals.org/clincancerres.