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FAERS Analysis Provides Clarity in Post-CAR T-Cell Therapy SPMs

May 17, 2024

June 2024

Leah Lawrence

Leah Lawrence is a freelance health writer and editor based in Delaware.

Second primary malignancies (SPMs) made up less than 5% of chimeric antigen receptor (CAR) T-cell therapy adverse events (AEs) reported to the U.S. Food and Drug Administration’s (FDA) AE Reporting System (FAERS) database, according to a recent analysis published in Blood.1

SPMs related to CAR T-cell therapy have gained attention recently after the FDA’s decision to add a class-wide black box warning to B-cell maturation antigen-directed and CD19-directed genetically modified autologous CAR T-cell therapies. The warning alerts patients to a risk for developing secondary T-cell malignancies.2

Magdi Elsallab, MD, PhD, and Marcela V. Maus, MD, PhD, both of Harvard University in Cambridge, Massachusetts, and colleagues conducted an analysis of the FAERS database to provide more context to cases of SPMs — specifically T-cell malignancies — and their representation among the total AE reports submitted to the FDA.

Dr. Elsallab and colleagues identified 12,394 unique CAR T-cell therapy AE reports in the database, of which 4.3% were classified as “neoplasms benign, malignant and unspecified.” About half of these reports (51.7%) were related to treatment with axicabtagene ciloleucel (axi-cel) and about one-third (33.0%) to tisagenlecleucel (tisa-cel).

Leukemias were the most frequently reported post-CAR T-cell therapy SPMs, comprising 62.1% of SPMs and 2.7% of all CAR T-cell therapy AE reports. Skin neoplasms comprised 10.1% of SPMs reported and 0.4% of CAR T-cell therapy AE reports. Finally, hematopoietic neoplasms, excluding leukemias and lymphomas, and nervous system tumors each comprised less than 5% of SPMs reported to FAERS.

T-cell malignancies represented 0.1% of the AE reports after CAR T-cell therapy.

“Note that this is not the same as the incidence of T-cell malignancy after CAR-T cell therapy,” Dr. Maus said.

“Establishing and understanding the risk of SPMs, in general, and T-cell malignancy, in particular, after CAR T-cells require more data and surveillance,” Dr. Elsallab added.

Reported T-cell lymphomas included 12 anaplastic large T-cell lymphomas, three peripheral T-cell lymphomas, one angioimmunoblastic T-cell lymphoma, and one enteropathy-associated T-cell lymphoma.

There was a significantly higher reporting odds ratio for myelodysplastic syndromes with axi-cel, tisa-cel, lisocabtagene maraleucel (liso-cel), idecabtagene vicleucel (ide-cel), and ciltacabtagene autoleucel (cilta-cel). Higher reporting odds ratios for acute myeloid leukemia were disproportionately higher with tisa-cel and cilta-cel, and higher odds for anaplastic large T-cell lymphomas were disproportionately more reported with tisa-cel.

Dr. Elsallab noted several limitations to the study that stem mainly from the type and quality of the data that could be obtained from the FAERS.

“The database is for spontaneous reporting, so it does not capture all AE cases,” Dr. Elsallab said. “Also, there is the risk of duplicate submissions and over-reporting of serious AEs.”

Finally, the absence of numbers of total CAR T-cell infusions by each company means the researchers could not estimate the incidence of AEs using the database.

“It is important to note that patients treated with CAR T cells have usually had treatment with many other agents known to increase the risk of SPMs, so at this time the risk of SPMs cannot be solely attributed to the CAR T cells,” said Dr. Maus.

“That being said, based on the available data, the benefits of CAR T-cell therapy still far outweigh the risks,” Dr. Elsallab added. “This position has also been supported by the FDA, which should provide reassurance to patients.”

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


  1. Elsallab M, Ellithi M, Lunning MA, et al. Second primary malignancies after commercial CAR T-cell therapy: analysis of FDA Adverse Events Reporting System (FAERS) [published online ahead of print, 2024 March 14]. Blood. doi: 10.1182/blood.2024024166.
  2. U.S. Food and Drug Administration. 2024 Safety and Availability Communications. Accessed April 12, 2024.


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