NEW YORK – The findings from a recently published meta-analysis are adding important context about the risk of future primary cancers associated with CAR T-cell therapies.
Earlier this year, the US Food and Drug Administration required CAR T-cell therapy manufacturers to include a boxed warning in their product labels informing consumers that these treatments could put them at risk of developing second primary cancers, especially T-cell malignancies.
But in a new analysis of 18 clinical trials and seven real-world studies, researchers found that around 5.8 percent of patients who received these treatments went on to develop another primary cancer, and in most cases, these cancers weren't T-cell malignancies.
The meta-analysis, published in the journal Clinical Cancer Research on Wednesday, called into question whether the level of attention that an FDA boxed warning brings is warranted, given the low frequency of T-cell malignancies, the small proportion of CAR-positive cases, and the limited evidence of any significant CAR vector insertion in second primary cancers.
To conduct the systematic review and meta-analysis, a Memorial Sloan Kettering Cancer Center-led team of international researchers searched for studies characterizing second primary malignancies in the MEDLINE, Embase, and Cochrane CENTRAL databases. They identified studies in which lymphoma or multiple myeloma patients received one of the FDA-approved autologous CAR T-cell therapies requiring the warning labels: Bristol Myers Squibb's Abecma (idecabtagene vicleucel) or Breyanzi (lisocabtagene maraleucel); Janssen's Carvykti (ciltacabtagene autoleucel); Novartis' Kymriah (tisagenlecleucel); or Gilead Sciences' Tecartus (brexucabtagene autoleucel) or Yescarta (axicabtagene ciloleucel).
The researchers, including senior author Kai Rejeski, a research oncologist at MSK, identified about two dozen clinical and real-world studies with sufficient follow-up data on patients' long-term outcomes. Among 5,517 patients on these therapies with a median follow-up of 21.7 months, Rejeski and colleagues tallied 326 patients, or 5.8 percent, who developed second primary malignancies.
Of these second primary cancers, more than one-third were either myelodysplastic syndromes or acute myeloid leukemias. Just five cases were T-cell malignancies, which accounted for 0.09 percent of patients in the meta-analysis. Only three of these T-cell malignancy cases underwent testing to gauge the presence of CAR transgenes, an indication of whether the secondary cancers were associated with CAR T-cell therapies. They found only one case was CAR-positive.
When Rejeski and colleagues narrowed their analysis to the handful of randomized clinical trials designed with standard-of-care control arms, they found no significant difference in the rate of second primary cancers between patients receiving CAR T-cell and standard treatments. In four randomized clinical trials, 5 percent of patients who received CAR T-cell therapies developed second primary cancers, whereas the same was true for 4.9 percent of patients who received standard therapies.
Generally, patients who were heavily pretreated before receiving CAR T-cell therapy were more likely to develop second primary cancers, and the rate of these cancers tended to be highest in studies with the longest available follow-up. "These data do not suggest that there is an increased risk of second primary malignancies relative to other standard-of-care therapies," Rejeski said in a statement. "I worry that the warning labels may intimidate patients who receive this therapy, which may not be entirely founded."
Ultimately, the researchers behind the Clinical Cancer Research paper underscored the importance of studying individual cases of second primary cancers and collecting more data from patients who are followed for longer periods of time. "Future research should focus on elucidating the true mechanistic link between CAR T-cell therapy and second primary malignancies," the authors wrote, suggesting this could include studying the role of patients' prior treatments, immune suppression, and genomic instability, as well as studying how these relative treatments affect diverse patient populations.