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 acute lymphocytic leukemia (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 out 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 complete remission (CR) or CR with incomplete blood count recovery.
The most common adverse events (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%).
Most symptoms appear within one to 22 days following infusion of tisagenlecleucel, according to Novartis, the drug’s manufacturer. There may be an increased risk of infection for a prolonged period because the CD19 target antigen is also present on normal B cells. To further evaluate the long-term safety of tisagenlecleucel, Novartis is required to conduct a post-marketing observational study.
Because of the risk of CRS and neurologic events, the drug was approved with a Risk Evaluation and Mitigation Strategy; under this designation, hospitals and clinics that dispense tisagenlecleucel must be trained in proper prescribing, dispensing, and administering of the drug, as well as recognizing and managing CRS and neurologic events. Certified hospitals and clinics also are required to have protocols in place to ensure that tisagenlecleucel is given to patients only after verification that tocilizumab is available for immediate administration.
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.