FDA official says CAR-T ‘incredibly beneficial’ despite secondary malignancy risk
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Benefits of chimeric antigen receptor T-cell therapy far outweigh the risks involved, including secondary T-cell malignancies, according to Peter Marks, MD, PhD, director of the FDA’s Center for Biologic Evaluation and Research.
The FDA issued a safety advisory for patients receiving CAR-T regarding T-cell malignancies at the end of November, but Marks said only 22 cases out of more than 27,000 individuals treated had been reported by the end of 2023.
“Make no mistake, the overall risk-benefit profile [for CAR-T] is still incredibly beneficial,” Marks said during the Alliance for Regenerative Medicine state of the industry briefing on cell and gene therapy on Monday. “For all of the approved uses, we don’t have any concerns with continued use of these products.”
Marks discussed the positive survival curves for children and young adults with acute lymphoblastic leukemia and adults with non-Hodgkin lymphoma and the “low amounts of toxicity” they have.
“It doesn’t salvage everyone, which means we can always do better, but it’s really quite remarkable,” he said.
Marks said CAR-Ts have risks, including cytokine release syndrome, cell-mediated encephalopathy syndrome, immune effector cell-associated neurotoxicity syndrome, low blood counts, transient heart dysfunction and low immunoglobulin levels, but explained those are “generally manageable.”
As for T-cell malignancies, CAR-Ts appear to be associated despite limited data.
“Although sequencing is not available for all of them, in at least a few of the cases we know that the CAR construct is in the malignant clone, which really suggests that there was probably an association there,” Marks said. “And the onset of these was soon enough after the administration in some cases that it does look like there’s a causal relationship.”
Healio reported in November that the FDA said multiple approved agents in the class produced T-cell malignancies, including 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).
However, Marks believes CAR-Ts still perform better than the alternative.
“We did put out a safety alert — yes, it’s going to require follow-up — but again, I think one has to step back and remember as the hematologist/oncologist, the other way to try to salvage people is to give them combination chemotherapy with cytotoxic agents that have secondary malignancy rates measured in the low percent range,” he said. “This is a risk-benefit balance.”