T-cell malignancies with anti-CD19 chimeric antigen receptor T-cell therapy

TO THE EDITOR:

On 28 November 2023, the US Food and Drug Administration announced an investigation into the risk of T-cell malignancies after autologous chimeric antigen receptor (CAR) T-cell therapies.¹ Among those, the CD19-directed therapies axicabtagene ciloleucel (axi-cel) and brexucabtagene autoleucel (brexu-cel) are 2 of the earliest approved CAR T-cell therapies. Axi-cel and brexu-cel have demonstrated clinically meaningful long-term efficacy along with manageable safety profiles in patients with B-cell malignancies.^2,3 Notably, epidemiological studies demonstrate there is an increased risk of T-cell malignancies occurring among patients with malignancies of B-cell origin compared with the general population (supplemental Table 1).⁴ The cumulative incidence of T-cell malignancies occurring after B-cell malignancies is dependent on the initial diagnosis (supplemental Tables 2-4). To characterize the specific risk of T-cell malignancies after the administration of axi-cel or brexu-cel, we reviewed events reported in the Gilead Global Safety Database, which includes safety data from clinical trials, postauthorization studies, and spontaneous reports to the database (supplemental Methods).

As of 16 February 2024, 17 578 patients had received axi-cel and 3336 had received brexu-cel (Table 1). Upon review of the Gilead Global Safety Database cumulative to 5 March 2024, there were 13 subsequent malignancies of T-cell origin among patients who received axi-cel, for an overall reporting rate of 0.07% (n = 13/17 578; Tables 1-2). This rate was consistent with the clinical trial incidence of T-cell malignancies reported after axi-cel, namely 0.1% (n = 1/905; Table 1). The median time to onset of these subsequent T-cell malignancies was 12.2 months (range, 1.8-58.5). No T-cell malignancies were reported among patients who received brexu-cel (Table 1). Four of the 13 cases of T-cell malignancies had sufficient tumor biopsy and/or blood sample availability for molecular analysis, including the detection of the CAR transgene. None of the cases demonstrated causality, with CAR detected at frequencies near or below the limit of detection in each case (Table 2).

Overall, T-cell malignancies reported after axi-cel were rare (none reported with brexu-cel), and the reporting rate was consistent with the background risk among patients with B-cell malignancies. At present, a causal relationship between T-cell malignancies and treatment with axi-cel or brexu-cel is not established. The benefit-risk profile for both therapies in their respective approved indications continues to be positive.

Underestimation of subsequent malignancies is possible because of variable reporting in the postauthorization setting. Ongoing reporting of any new T-cell malignancy after CAR T-cell therapy and access to tumor biopsy samples can help ensure an accurate and appropriate risk assessment.

Most of the data reported here are from the postauthorization setting (ie, institutional review board study approval is not applicable). For data reported in the context of clinical trials, the studies were approved by the institutional review board at each study site, and all patients treated in that setting provided written informed consent.

Acknowledgments: The authors thank all individuals in Clinical Development, Real World Evidence, and Medical Affairs departments from Kite, a Gilead company who contributed to the data for this publication. Medical writing assistance was provided by Danielle Fanslow of Nexus Global Group Science, supported by funding from Kite, a Gilead company.

Funding was provided in full by Kite, a Gilead company.

Contribution: L.J.M. and F.N. designed the research; L.J.M., J.B.W., R.R.S., and F.N. performed the research and analyzed the data; and all authors contributed to the writing of the manuscript.

Conflict-of-interest disclosure: L.J.M. reports employment at Kite, a Gilead company; and stock or other ownership in Gilead Sciences. J.B.W. reports employment with Kite, a Gilead company; and stock or other ownership in Gilead Sciences. R.R.S. reports employment with Kite, a Gilead company; stock or other ownership in Gilead Sciences; and patents, royalties, and other intellectual property from Atara and Kite. F.N. reports former employment with Kite, a Gilead company; stock or other ownership in bluebird bio, Gilead Sciences, and 2seventy bio; and other relationship with Kite.

Correspondence: Lisa J. Martin, Kite, a Gilead company, 2400 Broadway, Santa Monica, CA 90404; email: lmartin5@kitepharma.com.