Risk for second primary malignancies no greater with CAR-T than other standard therapies
Click Here to Manage Email Alerts
Key takeaways:
- Rates of second primary malignancies after CAR-T and other standard treatment strategies appeared comparable.
- Extent of prior therapy and longer follow-up time are independent risk factors for second primary malignancies.
Patients who received chimeric antigen receptor T-cell therapy did not exhibit increased risk for second primary malignancies compared with those who received other standard treatments, according to a systematic review and meta-analysis.
Risk for second primary malignancies after CAR-T increased for patients who had at least three prior lines of therapy, those who had longer follow-up and those treated in clinical trials.
“These results, to an extent, question the FDA’s class-wide warning,” study co-author Kai Rejeski, MD, visiting investigator and research fellow on the adult bone marrow transplant service at Memorial Sloan Kettering Cancer Center, told Healio. “CAR T-cell therapy represents a transformative immunotherapy and has changed the treatment landscape of multiple B-cell malignancies. We hope that the calculated estimates can guide conversations with patients receiving CAR T-cell therapies, highlighting that there does not seem to be an increased risk relative to other treatment strategies that are offered in similar refractory disease settings.”
Background and methods
The FDA has approved six CAR-T products for the treatment of hematologic malignancies — idecabtagene vicleucel (Abecma, Bristol Myers Squibb, 2seventy bio), lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb), ciltacabtagene autoleucel (Carvykti; Janssen, Legend Biotech), tisagenlecleucel (Kymriah, Novartis), brexucabtagene autoleucel (Tecartus, Kite Pharma/Gilead Sciences) and axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead Sciences).
These products have improved outcomes for many patients but have also been associated with adverse events, such as cytokine release syndrome and neurotoxicity.
The FDA issued a safety advisory about second malignancies in November 2023 and required a boxed warning for CAR-T products in January.
One study showed 4.3% of CAR-T-related adverse events reported to the FDA have been second primary malignancies, most of which have been myeloid neoplasms.
“Patients are reading this in the news and, appropriately, asking questions to providers,” Rejeski said in a press release. “We need to understand the potential risks but, at the same time, we need to interpret the data cautiously and contextualize it for our patients.”
Rejeski and colleagues used multiple databases to conduct a systematic review and meta-analysis of studies that evaluated FDA-approved CAR-Ts for treatment of lymphoma or multiple myeloma.
The analysis included 18 clinical trials (n = 1,991) and seven real-world studies (n = 3,526).
Most patients had large B-cell lymphoma (65.5%). The majority of studies evaluated axicabtagene ciloleucel (14 reports), lisocabtagene maraleucel (8) or tisagenlecleucel (8).
The frequency and distribution pattern of second primary malignancies following CAR-T served as the primary endpoint.
Results and next steps
Median follow-up was 21.7 months (range, 6.6-65.4).
Researchers determined 5.8% of patients developed a second primary malignancy. The second primary malignancy rate did not significantly differ based on cancer type or CAR-T product.
Results showed higher risk for second primary malignancies among patients with longer follow-up (greater than vs. less than median, 8.5% vs. 4.2%; P < .001), more heavily pretreated patients (at least three lines vs. two lines or less, 8.7% vs. 5.7%); and those treated in clinical trials vs. real-world settings (7.3% vs. 4.6%; P = .04).
Five trials evaluated CAR-T vs. other standard-of-care treatments. The rate of second primary malignancies did not differ significantly between treatment approaches in those trials.
Hematologic cancers accounted for more than one-third (37%) of second primary malignancies, whereas solid tumors accounted for 27% and non-melanoma skin cancers accounted for 16%. T-cell malignancies accounted for 0.09%, and only one of those cases had a positive CAR transgene result.
“Ultimately, the low frequency of T-cell malignancies, the small proportion of CAR-positive cases, and the inconclusive evidence regarding the pathogenetic significance of CAR vector insertion question the significant media attention that has followed the announcement of the FDA warning label,” Rejeski told Healio. “Nonetheless, we believe that the reporting of long-term adverse events, including second primary malignancies and T-cell lymphomas, remains pivotal in this vulnerable patient population.”
Researchers acknowledged study limitations, including heterogeneity regarding follow-up and patient populations among different studies, missing data on some second primary malignancies and lack of individual patient information.
“Future research should focus on figuring out if there is a true mechanistic link between CAR T-cell therapy and second primary malignancies, considering the roles of prior therapies, immune suppression and genomic instability,” Rejeski told Healio. “Additionally, there is a need for large-scale, long-term studies to better understand patient-individual risk factors of second primary malignancies across diverse patient populations. It remains to be determined if moving CAR-T therapies to earlier treatment lines, resulting in less exposure to cytotoxic chemotherapies before CAR-T, impacts the subsequent development of second primary malignancies.”
References:
- Risk of secondary cancers after CAR-T therapy may be similar to risk after other cancer treatments (press release). Available at: https://www.aacr.org/about-the-aacr/newsroom/news-releases/risk-of-secondary-cancers-after-car-t-therapy-may-be-similar-to-risk-after-other-cancer-treatments/. Published Sept. 11, 2024. Accessed Sept. 11, 2024.
- Tix T, et al. Clin Cancer Res. 2024;doi10.1158/1078-0432.CCR-24-1798.
Collapse
Read more about
Click Here to Manage Email Alerts