Introduction
Chimeric Antigen Receptor (CAR) T-cell therapy is an immunotherapeutic approach that has proven efficacy in multiple hematologic malignancies. CAR T-cell therapy requires the initial extraction of the patient’s T cells through leukapheresis, which are sent to a manufacturing lab for genetic modification. After viral transduction, these T cells will express a surface receptor, the CAR, which will allow the identification and elimination of cells that express the presented antigen. Prior to infusion, the patient is expected to undergo lymphodepleting chemotherapy to enhance T-cell expansion. To date, the FDA has approved six CAR T-cell therapies for use in refractory/relapsed B-cell malignancies and multiple myeloma. Four CD-19 targeted CAR T-cell products have been approved including axicabtagene ciloleucel (Yescarta®), tisagenlecleucel (Kymriah®), lisocabtagene maraleucel (Breyanzi®), and brexucabtagene autoleucel (Tecartus®) for B-cell malignancies, as well as two B-cell maturation antigen (BCMA) targeted therapies including idecabtagene vicleucel (Abecma®) and ciltacabtagene autoleucel (Carvykti®) for the treatment of multiple myeloma. While every agent is different, all six CAR T-cell therapies share class-specific adverse effects of cytokine-release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), B-cell aplasia, and hypogammaglobulinemia to varying extents.
In November 2023, the FDA announced their investigation of reports of T-cell lymphomas from clinical trials and post-marketing adverse event data sources for CAR T-cell immunotherapies1. In January 2024, the FDA issued Safety Labeling Change notification letters for the manufacturers of all six agents to update the labels to include the following: “T-cell malignancies have occurred following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies. Mature T-cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes”2.
Available Data
While limited information has been disclosed, news reports quote the FDA stating their investigation of 22 reports of T-cell malignancies. Data is currently available for 14 of these cases, among which T-cell malignancies have developed within two years after administration of the CAR T-cells, with roughly half of the cases occurring within the first year following treatment. It is also worth noting that the CAR transgene has been detected among three different cases, which may indicate that the administered therapy may have played a role in the development of the T-cell malignancies3. Some published data is also available for a few individual cases.
In December 2023’s American Society of Hematology (ASH) Annual Meeting, an abstract on a CAR positive T-cell lymphoma following ciltacabtagene autoleucel therapy for relapsed refractory multiple myeloma was presented. The abstract presented the case of a 51-year-old male who had achieved a stringent complete response, followed by a diagnosis of T-cell lymphoma from a nasal facial plaque 5 months post-infusion. Following plaque and lymph node biopsy, 90% to 100% of the cells were positive for the CAR construct and a monoclonal sequence in 91% of all T cells, which is not natural. While the newly developed lymphoma is not due to the activation of a gene expected to lead to T-cell lymphoma, the T-cell lymphoma may have been potentially driven by genetic mutations, which may have existed in the form of a clone before ciltacabtagene autoleucel manufacturing4.
Similarly, recent data from the University of Pennsylvania displayed a review of 449 patients who have received commercial CAR T-cell therapies. Among all patients, 16 (3.6%) developed secondary primary malignancies, of which 5 (1.1%) were hematologic, including a single case of T-cell lymphoma with axicabtagene ciloleucel that did not carry the CAR transgene5.
Another ASH abstract matched B-cell lymphoma patients treated at Stanford with either CD19-targeted CAR T-cell or hematopoietic cell transplantation who have achieved durable remissions and investigated the mechanisms causing adverse events, including clonal hematopoiesis, which refers to a disproportional proliferation of peripheral blood cells from a single hematopoietic progenitor. Among 21 patients from the CAR T-cell group, 18 (86%) had evidence of somatic mutations in genes associated with clonal hematopoiesis. These clones were detected pre- and post-infusion of the CAR in 90.1% of the cases, having expanded post-infusion. The clinical significance of these clonal expansions remains undetermined6.
Overall, the 20 cases that have been identified through the FDA Adverse Events Reporting System (FAERS) originate from an estimated 30,000 patients who have received CAR T-cell therapy in the United States7. While the reported number of cases is relatively low, one cannot properly estimate the accuracy of reporting such cases, given the voluntary nature of reporting, or the potential reporting bias of a T-cell malignancy that may be more likely to be reported to the FDA than cases of other types of cancer. Similarly, data from the National Cancer Institute Surveillance, Epidemiology, and End Results Program (SEERS) database estimates that patients with B-cell lymphomas are at a 4.7-fold higher risk of developing T-cell lymphoma than otherwise healthy patients8.
Impact on Current Practice
In their news release on January 23, 2024, the FDA stated that “the overall benefits of these products continue to outweigh their potential risks for their approved uses”9. At the moment, the number of reported cases of T-cell lymphomas remains relatively low, and the benefit CAR T-cell therapies can provide outweighs the potential risk, especially when compared to the alternative of combination chemotherapy. The CAR T-cell products have been initially approved with a requirement of a 15-year long-term follow-up to assess the long-term safety and risk of secondary neoplasms.
The FDA now recommends life-long monitoring for new malignancies and encourages reporting such events to the manufacturer to proceed with obtaining patient samples for testing for the presence of the CAR transgene9. In conclusion, CAR T-cell therapy still plays a major role in cancer treatment and its role is expected to expand further while we remain vigilant for any alarming adverse event.
References:
1.Center for Biologics Evaluation and Research. FDA investigating serious risk of T-cell malignancy. U.S. Food and Drug Administration. November 28, 2023. Accessed February 9, 2024. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous.
2.Center for Biologics Evaluation and Research. 2024 safety and Availability Communications. U.S. Food and Drug Administration. January 19, 2024. Accessed February 9, 2024. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/2024-safety-and-availability-communications.
3.Verdun N, Marks P. Secondary cancers after chimeric antigen receptor T-cell therapy. N Engl J Med. 2024;390(7):584-586. doi:10.1056/nejmp2400209
4.Harrison SJ, Nguyen T, Rahman M, et al. Car+ T-cell lymphoma post Ciltacabtagene Autoleucel therapy for relapsed refractory multiple myeloma. Blood. 2023;142(Supplement 1):6939-6939. doi:10.1182/blood-2023-178806.
5.Ghilardi G, Fraietta JA, Gerson JN, et al. T-cell lymphoma and secondary primary malignancy risk after commercial car T-cell therapy. Nat Med. Published online January 24, 2024. doi:10.1038/s41591-024-02826-w.
6.Hamilton MP et al. CAR19 Therapy Drives Expansion of Clonal Hematopoiesis and Associated Cytopenias. ASH Annual Meeting & Exposition 2023. https://ash.confex.com/ash/2023/webprogram/Paper182522.html.
7.Levine BL, Pasquini MC, Connolly JE, et al. Unanswered questions following reports of secondary malignancies after CAR-T cell therapy. Nat Med. 2024;30(2):338-341. doi:10.1038/s41591-023-02767-w
8.Chihara D, Dores GM, Flowers CR, Morton LM. The bidirectional increased risk of B-cell lymphoma and T-cell lymphoma. Blood. 2021;138(9):785-789. doi:10.1182/blood.2020010497.
9.FDA roundup: January 23, 2024. U.S. Food and Drug Administration. January 23, 2024. Accessed February 9, 2024. https://www.fda.gov/news-events/press-announcements/fda-roundup-january-23-2024.
