The U.S. Food and Drug Administration has approved tisagenlecleucel (Kymriah), a first-of-its-kind chimeric antigen receptor T-cell (CAR T) therapy, for the treatment of children and young adults up to age 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

The FDA also expanded the approval of tocilizumab (Actemra) to treat CAR T cell–induced severe or life-threatening cytokine release syndrome (CRS), which is a potentially life-threatening side effect of tisagenlecleucel, in patients aged 2 years or older; tocilizumab was shown to resolve CRS within 2 weeks after 1-2 doses in 69% of patients.

Tisagenlecleucel will carry a boxed warning regarding the CRS risk. Additionally, due to the CRS risk and risk of neurological events, the approval requires a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use, according to an FDA press release.

Special certification will be required for hospitals and associated clinics that dispense tisagenlecleucel. As part of certification, staff will be trained in the prescribing, dispensing, or administering of the therapy, and to recognize and manage CRS and neurological events.

Novartis, the maker of tisagenlecleucel, will be required to conduct postmarketing observational study.

The historic approval of tisagenlecleucel, the first-ever gene therapy approved in the United States, follows a recommendation from the FDA’s Oncologic Drugs Advisory Committee (ODAC), which in July unanimously voted in favor of approval, with one temporary voting member calling the therapy the “most exciting thing I have seen in my lifetime, and probably since the introduction of ‘multiagent total cancer care,’ as it was called then, for treatment of childhood leukemia.”

Indeed, FDA commissioner Scott Gottlieb, MD, said the approval marks the entry to a “new frontier in medical innovation.”

“New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses,” he said in the press statement.

Tisagenlecleucel is a genetically modified autologous T-cell immunotherapy involving customized treatment created using a patient’s own T cells. The T cells are genetically modified to include a chimeric antigen receptor that directs the T cells to target and kill leukemia cells with CD19 surface antigen, and are then infused back into the patient.

In a phase 2 clinical trial, the overall remission rate with tisagenlecleucel therapy was 83% in 63 children and young adults with relapsed/refractory B-cell precursor ALL for whom at least two prior lines of therapy had failed; the therapy was granted Fast Track, Priority Review, and Breakthrough Therapy designations.

“Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease,” Peter Marks, MD, director of the FDA’s Center for Biologics Evaluation and Research said in the press statement. “Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that shows promising remission and survival rates in clinical trials.”

At its meeting in July, the FDA ODAC agreed nearly unanimously that the risk mitigation plan put forward by Novartis, including planned 15-year follow-up and other mitigation measures, would be adequate for detecting serious consequences of CAR T-cell therapy.


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