First CAR T-Cell Therapy for Pediatric Leukemia Gains FDA Approval

The U.S. Food and Drug Administration (FDA) approved the chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel for the treatment of pediatric and young adult patients with B-cell precursor ALL that is refractory or in second or later relapse. This is the first gene therapy available in the U.S. and is “ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases,” the FDA said.

“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” said FDA Commissioner Scott Gottlieb, MD. “New technologies such as gene and cell therapies hold … the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses.”

The safety and efficacy of tisagenlecleucel (a CD19-directed CAR T-cell therapy) were demonstrated in the open-label, phase II ELIANA trial, which included 63 pediatric and young adult patients (age range = 3-23 years) with relapsed or refractory B-cell precursor ALL. At three months after infusion, 52 patients (83%) achieved CR or CR with incomplete blood count recovery.

The most common AEs (occurring in >20% of patients) were cytokine release syndrome (CRS), hypogammaglobulinemia, infections (pathogens unspecified), pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, and delirium.

The drug carries a boxed warning for CRS and neurologic events. Forty-nine percent of patients in the trial experienced grade 3 or 4 CRS, and 18 percent of patients experienced grade 3 or 4 neurologic events within eight weeks of treatment. There were no incidents of cerebral edema, and the most common neurologic events were encephalopathy (34%), headache (37%), delirium (21%), anxiety (13%), and tremor (9%).

Because of the risk of CRS and neurologic events, the drug was approved with a Risk Evaluation and Mitigation Strategy.

“The approval of CAR T-cell therapy for pediatric leukemia marks an important shift in the blood cancer treatment paradigm. … This is a potentially curative therapy in patients whose leukemia is unresponsive to other treatments and represents the latest milestone in the shift away from chemotherapy toward precision medicine,” said Kenneth Anderson, MD, president of the American Society of Hematology, in a news release. “While the importance of CAR-T cannot be overstated, this approval only pertains to a small population of children. More research is needed to make this therapy more effective for a broader population, to reduce the severe side effects that patients experience during treatment, and ultimately to find a broader application beyond blood cancers.”

On the same day as the approval, the FDA expanded the indication for tocilizumab, a monoclonal antibody to treat CAR T-cell–induced, severe or life-threatening CRS in patients ≥2 years of age. In clinical trials of patients treated with CAR T cells, 69 percent of patients had complete resolution of CRS within two weeks following one or two doses of tocilizumab.

Sources: U.S. Food and Drug Administration news release, August 30, 2017; Novartis news release, August 30, 2017.

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