Study Finds Comparable Risk of Secondary Malignancies in CAR T-Cell Therapy and Standard Treatments

The risk of second primary malignancy (SPM) associated with chimeric antigen receptor (CAR) T-cell therapy was found to be comparable to that of traditional standard-of-care treatments, according to findings published in Clinical Cancer Research. The study’s authors suggested that factors unrelated to CAR T-cell therapy were more strongly linked to SPM development, calling the validity of the FDA’s black-box warning into question.

The findings underscore the need for more long-term data on the relationship between CAR T-cell therapy and SPMs. Image Credit: © LELISAT - stock.adobe.com

CAR T-cell therapy is a powerful immunotherapy that harnesses a patient’s own T-cells, equipping them with artificial receptors to target specific proteins overexpressed on malignant cells. Clinical trials have shown CAR T-cell therapy to be an effective treatment with positive response rates, reduced hospitalization needs, and lower toxicity risks. However, reports submitted to the FDA in November 2023 raised concerns about a potential link between SPMs and CAR T-cell therapy, which led to the issuance of black-box warnings for all BMCA- or CD19-directed CAR T-cell therapies, identifying T-cell malignancies as a serious adverse effect.^1-3

Since the warning, many researchers and clinicians have questioned the basis of the reported data, arguing that factors like patient age, follow-up duration, type of CAR T-cell therapy, initial diagnosis, and prior treatments may have been overlooked. To clarify the association between CAR T-cell therapy and SPMs, researchers at Memorial Sloan Kettering Cancer Center conducted a systematic review and meta-analysis of data from 18 clinical trials and 7 real-world studies involving patients with multiple myeloma (MM) and various types of lymphoma. They searched the MEDLINE, Embase, and CENTRAL (Cochrane) databases to identify SPM cases and classify their origin, using random-effect models to analyze SPM point estimates.⁴

Their analysis included 5,517 patients with large B-cell lymphoma (3,614), multiple myeloma (1,362), indolent lymphoma (425), and mantle-cell lymphoma (116), of whom 326 had developed SPMs. The most common SPMs were hematologic malignancies (37%), solid tumors (27%), and non-melanoma skin cancers (16%). Notably, the T-cell malignancies that prompted the FDA’s warning accounted for only 1.5% of cases.⁴

With a median follow-up of 21.7 months, the data revealed that 5.8% of patients treated with CAR T-cell therapy developed an SPM (95% CI 4.7-7.2). The study also found that SPM risk was influenced by treatment setting, follow-up duration (P = .009), and the number of prior treatment lines, with higher SPM rates observed in patients who had undergone multiple lines of therapy (8.7% vs. 5.7%, P = .13).⁴

"We showed through meta-regression modeling in a large patient cohort that factors unrelated to CAR T-cell therapy were the primary drivers of SPM development," Kai Rejeski, MD, from Memorial Sloan Kettering Cancer Center, said in an interview with MedPage Today. "Specifically, patients with longer follow-up, more extensive prior treatment, and those treated in clinical trials—where follow-up is more rigorous—were at higher risk."⁵

The findings underscore the need for more long-term data on the relationship between CAR T-cell therapy and SPMs, as well as a deeper understanding of the factors contributing to their development. CAR T-cell therapy is a life-saving option for many patients, and improving knowledge of its risks is essential to enhancing outcomes for those with multiple myeloma or lymphoma.

REFERENCES

1. Blood test may predict car t-cell therapy outcomes for patients with multiple myeloma. Pharmacy Times. July 26, 2024. Accessed September 13, 2024. https://www.pharmacytimes.com/view/blood-test-may-predict-car-t-cell-therapy-outcomes-for-patients-with-multiple-myeloma

2. Fda investigating serious risk of t-cell malignancy following bcma-directed or cd19-directed autologous chimeric antigen receptor (car) t cell immunotherapies. FDA. November 28, 2023. Accessed September 13, 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

3. Fda requires boxed warning for t cell malignancies following treatment with bcma-directed or cd19-directed autologous chimeric antigen receptor (car) t cell immunotherapies. FDA. April 18, 2024. Accessed September 13, 2024. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-requires-boxed-warning-t-cell-malignancies-following-treatment-bcma-directed-or-cd19-directed

4. Tix I, Alhomoud M, Shouval R, et al. Second primary malignancies after CAR T-cell therapy: A systematic review and meta-analysis of 5,517 lymphoma and myeloma patients. Clin Cancer Res. September 11, 2024. doi:10.1158/1078-0432.CCR-24-1798

5. Second malignancy risk with car t-cell therapy on par with other treatments. MedPage Today. September 11, 2024. Accessed September 13, 2024. https://www.medpagetoday.com/hematologyoncology/othercancers/111911?xid=nl_mpt_DHE_2024-09-11&mh=6d2b5f4f91352444bdf817a9c17750bc&utm_source=Sailthru&utm_medium=email&utm_campaign=Daily%20Headlines%20Evening%202024-09-11&utm_term=NL_Daily_DHE_dual-gmail-definition