Incidence of Secondary T-Cell Malignancies Following CAR T-Cell Therapy

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Investigators have found that second primary malignancies following chimeric antigen receptor (CAR) T-cell therapy were reported in 4.3% of CAR T-cell therapy adverse event reports submitted to the U.S. Food and Drug Administration’s (FDA) Adverse Event Reporting System, with T-cell malignancies representing only 0.1% of the reports, according to a recent analysis published by Elsallab et al in Blood


CAR T-cell therapies, which areapproved to treat certain hematologic malignancies, involve extracting a patient’s T cells from their blood and modifying them to target a specific protein on cancer cells. This modification enables the T cells to find and eliminate cancer cells once reintroduced into the patient's bloodstream.

However, in November 2023, the FDA issued a warning regarding the risk of secondary T-cell malignancies in patients who received treatment with CAR T-cell therapy. Some manufacturers were required to add a boxed warning to their CAR T-cell therapy’s prescribing information.

Study Methods and Results

In the recent analysis, the investigators sought to evaluate the prevalence of T-cell malignancy reporting to the FDA Adverse Event Reporting System following CAR T-cell therapy. 

“When compared [with] similar drugs, we observed a slight increase in reporting certain secondary [malignancies] to the FDA after CAR T-cell products,” explained lead study author Magdi Elsallab, MD, PhD, a researcher at Massachusetts General Hospital.

The investigators identified 12,394 adverse event reports associated with CAR T-cell therapy in the FDA Adverse Event Reporting System database. Among the reports, 4.3% (n = 536) of them listed second primary malignancies among other adverse events. Among the 536 reports, 51.7% and 33% of them were associated with the specific use of CAR T-cell products axicabtagene ciloleucel and tisagenlecleucel, respectively.

The investigators discovered that the most common second primary malignancies observed with CAR T-cell therapy were leukemias (2.7%) followed by skin cancers (0.4%). Further, they identified 17 instances of T-cell non-Hodgkin lymphomas in the Adverse Event Reporting System—the majority of which were anaplastic large T-cell lymphomas—and two cases of large granular T-cell leukemia. The investigators noted that they identified 19 total T-cell malignancies in the reports. 


Although the investigators uncovered second primary malignancies in the FDA’s Adverse Event Reporting System, they were unable to establish causation based on the data provided by the agency. According to the American Cancer Society, patients undergoing cancer treatment may face an elevated risk of developing secondary malignancies as a result of several common treatments, including chemotherapy and radiation. 

“Patients receiving CAR T-cell therapy are often heavily pretreated with other drugs, which can also contribute to the development of secondary [malignancies],” explained Marcela Maus, MD, PhD, an attending physician at Massachusetts General Hospital. “At this point, the risk of secondary [malignancies] after CAR T-cell therapy cannot be definitively attributed to the CAR T cells, [since] all of these patients received multiple prior chemotherapy agents that are known to elevate the risk of secondary [malignancies],” she underscored. 

The investigators indicated that because the Adverse Event Reporting System relies on voluntary reporting of adverse events, duplicate submissions from providers, patients, and manufacturers may have occurred. Additionally, the lack of data on the total number of CAR T-cell therapies prescribed may have made it challenging to estimate the incidence of adverse events such as second primary malignancies across all CAR T-cell therapy use.

“We will continue to monitor the data released by the FDA to learn more about CAR T-[cell therapy]–associated risks. However, it's crucial to stress that the benefits of CAR T-cell therapies still outweigh the risks for the approved indications,” concluded Dr. Elsallab.

Disclosure: For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.