Risk of Secondary Cancers After CAR T Therapy May Be Similar to Risk After Other Cancer Treatments, Findings Suggest 

The study, published in an AACR journal, comes after an FDA warning regarding the potential for secondary malignancies after CAR T cells are used for B-cell lymphoma or multiple myeloma. 

Patients who receive CAR T-cell therapy for B-cell lymphoma or multiple myeloma are no more likely to develop a second primary cancer than patients who received other standard-of-care therapies, according to a study published in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR).  

The study follows a directive from the U.S. Food and Drug Administration (FDA) requiring CAR T-cell therapies to carry a warning that patients who use them may develop new T-cell cancers unrelated to their B-cell lymphoma or multiple myeloma. The FDA decision was based largely on reports from clinical trials and from a federal reporting system for side effects.  

Kai Rejeski, MD, senior author of the study and a visiting investigator and research fellow in the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center, said the study was a systematic review and meta-analysis of clinical trials and other studies that provided data on the occurrence of second primary malignancies (SPMs). 

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.    

“These data do not suggest that there is an increased risk of SPMs relative to other standard-of-care therapies,” Dr. Rejeski said. “I worry that the warning labels may intimidate patients who receive this therapy, which may not be entirely founded.”  

When assessing the risk of SPMs, 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, Dr. Rejeski noted.    

“Patients are reading this in the news and, appropriately, asking questions to providers,” Dr. 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.”    

Dr. Rejeski and colleagues reviewed data from 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.    

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.    

Dr. Rejeski said 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, Dr. Rejeski said. An increased risk with longer follow-up time may indicate a survivorship bias, he added, 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,” Dr. Rejeski said. “I would strongly caution against withholding this therapy because of the miniscule risk of developing T-cell malignancies.”  

More work is needed 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, Dr. Rejeski said. Accurate reporting of SPMs across long-term follow-up periods, especially in clinical trials, will be helpful, he said.  

“We still need to be vigilant in understanding this adverse event, and that means we need to have clear reporting standards,” Dr. Rejeski said.

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.