Bottom Line: The frequency of second primary malignancies (SPMs) arising in cancer survivors following treatment with CAR T-cell therapy was statistically comparable to the frequency of SPMs following other standard-of-care therapies, according to a systematic review and meta-analysis.
Journal in Which the Study was Published: Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR)
Author: Kai Rejeski, MD, a visiting investigator and research fellow in the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center.
Background: In January 2024, the U.S. Food and Drug Administration (FDA) required labeling information for all currently available CAR T-cell therapies to include a boxed warning advising prescribers and patients of the potential risks of a secondary cancer arising after CAR T treatment. Specifically, the boxed warnings alert patients to the possibility of developing new T-cell cancers unrelated to the B-cell lymphoma or multiple myeloma for which the patients received CAR T.
The decision was based largely on data from the FDA Adverse Event Reporting System. However, some researchers have expressed concerns that the data may possess inherent biases, including reporting bias, Rejeski explained. When assessing SPM risk, it is important to account for confounders such as age and follow-up duration, the type of CAR T therapy received, the patient's initial diagnosis, or other types of treatment the patient may have been given before CAR T, Rejeski noted.
"Patients are reading this in the news and, appropriately, asking questions to providers," Rejeski said. "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."
How the Study was Conducted: Rejeski and colleagues performed a systematic review and meta-analysis of clinical studies in which adult patients with lymphoma or multiple myeloma received one of the six currently approved CAR T-cell therapies: idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), ciltacabtagene autoleucel (Carvykti), tisagenlecleucel (Kymriah), brexucabtagene autoleucel (Tecartus), or axicabtagene ciloleucel (Yescarta). To meet inclusion criteria, studies must have provided data on SPM occurrence for the entire follow-up period, which ranged from 6.6 months to 65.4 months. The final selection included 18 clinical trials and seven real-world studies consisting of a combined 326 SPMs in 5,517 patients.
Results: After a median follow-up of 21.7 months, 5.8% of patients developed an SPM. The researchers did not find any significant differences in SPM rates between patients with different cancer types or between patients who received different CAR T-cell products.
Studies in which patients had received a median of more than three lines of therapy before CAR T reported a significantly higher risk of SPMs than studies in which patients received fewer than three prior lines of therapy. Similarly, the rate of SPMs was 4.2% among studies with a follow-up time below the median of 21.7 months and 8.5% among studies with a follow-up time above the median.
Out of 326 SPMs identified in this analysis, hematologic malignancies, including myelodysplastic syndrome and acute myeloid leukemia, accounted for the largest proportion of SPMs at 37%. Five cases were T-cell malignancies, a rate of 0.09% across the entire study population. In three of these cases, the malignant T cells were tested to determine if they contained the CAR transgene (an indicator that the malignancy may have arisen from CAR-edited cells), and one case tested positive.
Four of the clinical trials included in the study assessed the outcomes of patients treated with CAR T therapy in comparison to a standard-of-care regimen. In a total of 1,253 patients across these studies, the rate of SPMs was 5% among patients treated with CAR T and 4.9% among patients treated with the standard of care, a difference that was not statistically significant.
Author's Comments: "These data do not suggest that there is an increased risk of SPMs relative to other standard-of-care therapies," Rejeski said. "I worry that the warning labels may intimidate patients who receive this therapy, which may not be entirely founded."
Rejeski further explained that the study's data may help identify specific factors that increase the risk of SPMs for patients who receive CAR T. For instance, the increased incidence of SPMs with increasing lines of prior treatment may reflect cumulative damage caused by several previous therapies, Rejeski said. He also stated that an increased risk with longer follow-up time may indicate a survivorship bias, meaning more patients may be developing SPMs because they are living long enough to do so.
"CAR T therapy is the first treatment in more than 20 years to show an overall survival benefit compared to the standard of care in refractory large B-cell lymphoma," Rejeski said. "I would strongly caution against withholding this therapy because of the miniscule risk of developing T-cell malignancies."
Rejeski emphasized that more work will be necessary to understand the specific contributions of CAR T-cell therapy to the development of SPMs and to better estimate each patient's risk on an individual level. He stressed that accurate reporting of SPMs across long-term follow-up periods, especially in clinical trials, will help tremendously with such research.
"We still need to be vigilant in understanding this adverse event, and that means we need to have clear reporting standards," Rejeski said.
Study Limitations: Limitations of this study include the heterogeneity of the included data sets, as well as a lack of patient-level data about comorbidities and prior treatments that may influence an individual's risk of SPM.
Funding & Disclosures: Funding for this study was provided by the School of Oncology of the German Cancer Consortium, the Walter Benjamin Fellowship by the German Research Foundation, Arnold Ventures, the Else Kröner Forschungskolleg within the Munich Clinician Scientist Program, the Bruno and Helene Jöster Foundation, the "CAR-T Control" translational group within the Bavarian Center for Cancer Research, and the National Cancer Institute of the National Institutes of Health. Rejeski has received research funding from Kite/Gilead; is a consultant for Kite/Gilead and Bristol Myers Squibb/Celgene; has received honoraria from Kite/Gilead, Bristol Myers Squibb/Celgene, and Novartis; and has received travel support from Kite/Gilead and Pierre Fabre.
