Results come amid the FDA's review of chimeric antigen receptor (CAR) T-cell therapy.
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.”
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:
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
Patients With MG Report Higher Azathioprine Discontinuation vs Other Immunosuppressants
May 15th 2024Survey data from over 200 patients showed that treatment discontinuation was lower for those taking mycophenolate or methotrexate than for those taking azathioprine for their myasthenia gravis (MG).
Read More
Frameworks for Advancing Health Equity: Urban Health Outreach
May 9th 2024In the series debut episode of "Frameworks for Advancing Health Equity," Mary Sligh, CRNP, and Chelsea Chappars, of Allegheny Health Network, explain how the Urban Health Outreach program aims to improve health equity for individuals experiencing homelessness.
Listen
Bleeds and Resource Use in Hemophilia B: Retrospective Observational Study
May 15th 2024This real-world US study describes individuals with hemophilia B who experience bleeds despite factor replacement therapy and quantifies the associated comorbidity and health care resource utilization burden.
Read More
Patients With MG Report Higher Azathioprine Discontinuation vs Other Immunosuppressants
May 15th 2024Survey data from over 200 patients showed that treatment discontinuation was lower for those taking mycophenolate or methotrexate than for those taking azathioprine for their myasthenia gravis (MG).
Read More
Frameworks for Advancing Health Equity: Urban Health Outreach
May 9th 2024In the series debut episode of "Frameworks for Advancing Health Equity," Mary Sligh, CRNP, and Chelsea Chappars, of Allegheny Health Network, explain how the Urban Health Outreach program aims to improve health equity for individuals experiencing homelessness.
Listen
Bleeds and Resource Use in Hemophilia B: Retrospective Observational Study
May 15th 2024This real-world US study describes individuals with hemophilia B who experience bleeds despite factor replacement therapy and quantifies the associated comorbidity and health care resource utilization burden.
Read More
2 Commerce Drive
Cranbury, NJ 08512