FDA Approves First CAR T-Cell Therapy for Pediatric and Young Adult Patients With B-Cell Precursor ALL

Key Points

  • The safety and efficacy of tisagenlecleucel were demonstrated in the phase II multicenter ELIANA clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within 3 months of treatment was 83%.
  • The FDA today also expanded the approval of tocilizumab to treat CAR T-cell–induced severe or life-threatening cytokine-release syndrome in patients 2 years of age or older.
  • Because of the risk of cytokine-release syndrome and neurologic events, tisagenlecleucel is being approved with a risk evaluation and mitigation strategy, which includes elements to ensure safe use.
  • The FDA is requiring that hospitals and their associated clinics that dispense tisagenlecleucel be specially certified.

Today, the U.S. Food and Drug Administration (FDA) issued what it has called a “historic action,” making the first gene therapy available in the United States. The FDA approved tisagenlecleucel (Kymriah) for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL).

“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.”

Tisagenlecleucel, a cell-based gene therapy, is approved in the United States for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.

Tisagenlecleucel is a genetically modified autologous T-cell immunotherapy. Each dose of tisagenlecleucel is a customized treatment created using an individual patient’s own T cells. The patient’s T cells are collected and sent to a manufacturing center, where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor, or CAR) that directs the T cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.

ALL can be of either T- or B-cell origin, with the B-cell type being the most common. Tisagenlecleucel is approved for use in pediatric and young adult patients with B-cell ALL, and is intended for patients whose cancer has not responded to or has returned after initial treatment, which occurs in an estimated 15% to 20% of patients.

“Tisagenlecleucel 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, MD, PhD, Director of the FDA’s Center for Biologics Evaluation and Research (CBER). “Not only does tisagenlecleucel 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.”

Trial Results and Side Effects

The safety and efficacy of tisagenlecleucel were demonstrated in the phase II multicenter ELIANA clinical trial involving 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within 3 months of treatment was 83%.

Treatment with tisagenlecleucel has the potential to cause severe side effects. It carries a boxed warning for cytokine-release syndrome—which is a systemic response to the activation and proliferation of CAR T cells causing high fever and flu-like symptoms—and for neurologic events. Both cytokine-release syndrome and neurologic events can be life-threatening.

Other severe side effects of tisagenlecleucel include serious infections, hypotension, acute kidney injury, fever, and hypoxia. Most symptoms appear within 1 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 today also expanded the approval of tocilizumab (Actemra) to treat CAR T-cell-induced severe or life-threatening cytokine-release syndrome in patients 2 years of age or older. In clinical trials in patients treated with CAR T cells, 69% of patients had complete resolution of cytokine-release syndrome within 2 weeks following one or two doses of tocilizumab.

Risk Evaluation and Mitigation Strategy

Because of the risk of cytokine-release syndrome and neurologic events, tisagenlecleucel is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to ensure safe use. 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 cytokine-release syndrome and neurologic 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. The REMS program specifies that patients be informed of the signs and symptoms of cytokine-release syndrome and neurologic toxicities following infusion—and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with tisagenlecleucel.

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

Prior Designations

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

The tisagenlecleucel application was reviewed using a coordinated, cross-agency approach. The clinical review was coordinated by the FDA's Oncology Center of Excellence, while CBER conducted all other aspects of review and made the final product approval determination.

The FDA granted approval of tisagenlecleucel to Novartis Pharmaceuticals Corp and granted the expanded approval of tocilizumab to Genentech Inc.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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