The U.S. Food and Drug Administration (FDA) has approved tisagenlecleucel (Kymriah) for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL).

The historic action makes Novartis Pharmaceutical’s CAR-T cell treatment the first gene therapy available in the United States. (Gilead just negotiated to buy Kite Pharma, which also has a CAR-T therapy under review.) The announcement ushers in a new approach to the treatment of cancer and other serious and life-threatening diseases by using the patient’s own modified T-cells to fight disease.

“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, M.D. “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. At the FDA, we’re committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving.”

The therapy is approved for patients up to 25 years for ages with B-cell precursor ALL that is refractory or in second or later relapse.

Each dose is a personalized treatment using the patient’s T-cells. After being collected, the T-cells are genetically modified to include a new gene that contains a specific protein that directs the T-cells to target and kill the leukemia cells that have a specific antigen on the surface.  Once modified, the cells are infused back into the patient to kill the cancer cells.

The treatment has an overall remission rate with of 83 percent within three months of treatment.

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

Boxed warning and REMS

Though effective, tisagenlecleucel has the potential to cause severe side effects. According to the announcement, it carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T-cells causing high fever and flu-like symptoms, and for neurological events. Both CRS and neurological events can be life-threatening. Other severe side effects of tisagenlecleucel include serious infections, low blood pressure (hypotension), acute kidney injury, fever, and decreased oxygen (hypoxia).

Most symptoms appear within one to 22 days following infusion of tisagenlecleucel. Since the CD19 antigen is also present on normal B-cells, and tisagenlecleucel will also destroy those normal B cells that produce antibodies, there may be an increased risk of infections for a prolonged period of time.

The FDA also expanded the approval of Actemra (tocilizumab) to treat CAR T-cell-induced severe or life-threatening CRS in patients 2 years of age or older. In clinical trials in patients treated with CAR-T cells, 69 percent of patients had complete resolution of CRS within two weeks following one or two doses of Actemra.

Because of the risk of CRS and neurological events, tisagenlecleucel is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring that hospitals and their associated clinics that dispense tisagenlecleucel be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of tisagenlecleucel are required to be trained to recognize and manage CRS and neurological events. Additionally, the certified health care settings are required to have protocols in place to ensure that tisagenlecleucel is only given to patients after verifying that tocilizumab is available for immediate administration.

To further evaluate the long-term safety, Novartis is also required to conduct a post-marketing observational study involving patients treated with tisagenlecleucel.

The FDA granted tisagenlecleucel Fast Track, Priority Review and Breakthrough Therapy designations.