Registry Data Inconclusive on Risk of Secondary Primary Malignancy After CAR T, Authors Say

Data in the FDA’s adverse events (AEs) registry do not offer “conclusive evidence” that patients receiving chimeric antigen receptor (CAR) T-cell therapy face higher risk of developing a secondary primary malignancy (SPM), according to authors who performed the analysis.

Their findings appear today in the journal Blood, the official journal of the American Society of Hematology (ASH). Many studies that led to approval of the 6 CAR T-cell products on the market today were presented at ASH’s annual meeting.

On November 28, 2023, the FDA announced it was investigating reports of serious risk of T-cell malignancy among patients who had received either BCMA-directed CAR T-cell therapy for multiple myeloma or CD19-directed autologous CAR T-cell therapy for various types of lymphoma.

The action required some manufacturers to add a black box warning to their products, and an FDA advisory committee hearing is set for March 15 to discuss the 2 therapies used to treat multiple myeloma, ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel).

The authors writing in Blood examined the data reported to the FDA Adverse Event Reporting System (FAERS) and found that T-cell malignancies following CAR T-cell therapy represent just 0.1% of all reports made to the system.

SPMs were reported in 536 of the 12,394 AE reports following CAR T-cell therapy made to FAERS, with myeloid and T-cell neoplasms more frequently noted. Although SPMs following CAR T were found in 4.3% of AE reports, the authors said, “this percentage only reflects the likelihood of reporting SPMs to the FDA.”

Gene therapy | Image Credit: ipopba - stock.adobe.com

The authors note that patients are typically heavily pretreated prior to receiving CAR T-cell therapy for relapsed or refractory B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and multiple myeloma. The investigators noted the following:

• Patients receiving axicabtagene ciloleucel (axi-cel, Yescarta) and tisagenlecleucel (tisa-cel, Kymriah) accounted for most of the AE reports (51.7% [277/536] and 33.0% [177/536], respectively)
• The most frequent SPMs by high-level group term were leukemias (62.1% [333/536]), which the authors said represented 2.7% (333/12,394) of all reports involving CAR T
• Myelodysplastic syndromes was the most frequently cited type of leukemia (38.8% [208/536]; 1.7% [208/12,394]), followed by acute myeloid leukemias (19.8% [106/536]; 0.9% [106/12,394]) and 2 cases of T-cell large granular lymphocytic leukemia
• Skin neoplasms were the second most frequent SPM (10.1% [54/536]; 0.4% [54/12,394]); these cases included nonmelanoma skin neoplasms (7.8% [42/536]; 0.3% [42/12,394]) and skin melanomas (2.2% [12/536]; 0.1% [12/12,394])
• Hematopoietic neoplasms excluding leukemias and lymphomas were reported in 26 of the 536 cases (4.9%), or 0.2% of all AE reports (26/12,394)
• Nervous system tumors were reported in 21 of the 536 cases (3.9%), or 0.2% of all AE reports, and respiratory neoplasms were reported in 20 cases, also for 0.2% of all AE reports

T-cell non-Hodgkin lymphomas comprised 17 of 536 cases (3.2%), including 12 anaplastic large T-cell lymphomas (7 from tisa-cel, 3 from axi-cel, and 2 from cilta-cel); also, there were 3 peripheral T-cell lymphoma cases (1 each following tisa-cel, cilta-cel, and lisocabtagene maraleucel [liso-cel]).

There was 1 angioimmunoblastic T-cell lymphoma (axi-cel), and 1 enteropathy-associated T-cell lymphoma (cilta-cel). Of the 17 cases, there were 8 deaths, 4 cases of hypogammaglobulinemia, 3 cases of cytokine release syndrome, 2 each of hemophagocytic lymphohistiocytosis and neurotoxicity.

The analysis showed higher odds of reporting MDS with axi-cel, tisa-cel, liso-cel, ide-cel, and cilta-cel; tisa-cel and cilta-cel, with higher odds of reporting acute myeloid leukemia; and tisa-cel, with higher odds of reporting anaplastic large T-cell lymphomas. The authors reviewed SPM reporting in the clinical trial for each therapy while noting that SPMs “have been extensively documented in survivors of hematologic malignancies.”

Elevated reporting odds of myeloid neoplasms were seen in 5 of the 6 approved CAR T products, and the authors wrote that a recent study found a shorter onset to myeloid neoplasms following CAR T compared with stem cell transplant. However, cytogenetic and clonal abnormalities were often preexisting in patients before CAR T, “suggesting a clonal evolution of existing treatment-related clonal hematopoiesis.”

Genetic sequencing of 19 cases of T-cell malignancies associated with cilta-cel and liso-cel has been “inconclusive,” where the introduction of the therapy was the driver of the SPM.

The authors wrote that although the FAERS database “remains a valuable resource for identifying AEs not captured during clinical studies…it has limitations such as duplicate report submissions, missing information, inability to establish causal relationships, and underreporting or overreporting based on AE severity.”

Also, they wrote, the fact that the database does not record the total number of prescribed products is a significant challenge.

Reference

Elsallab M, Ellithi M, Lunning MA et al. Second primary malignancies after commercial CAR T cell therapy of FDA adverse events reporting system (FAERS). Blood. Published online March 14, 2024. doi:10.1182/blood.2024024116