Tisagenlecleucel: First Gene Therapy Ever Approved

On August 30, 2017, the United States Food and Drug Administration (U.S. FDA) granted regular approval to tisagenlecleucel (Brand Name – Kymriah, manufactured by Novartis Pharmaceuticals Corp.) for the treatment of patients up to the age of 25 years with B-cell precursor acute lymphoblastic leukaemia (ALL – a type of blood cancer) that is either relapsing (went into remission, then came back) or refractory (did not go into remission with other leukaemia treatments).

Overview of ALL:

ALL is a cancer of the bone marrow and blood, in which abnormal lymphocytes (a type of white blood cells) are produced instead of the normal ones. It is the most common childhood cancer in the U.S. according to the National Cancer Institute. Approximately 3100 patients of age 20 years or less are diagnosed with ALL every year. ALL can be either T- or B-cell (types of lymphocytes) origin, with B-cell the most common. Tisagenlecleucel has been approved for use in paediatric and young adult patients with relapsed or refractory B-cell precursor ALL, which occurs in an estimated 15-20 percent of patients.

Tisagenlecleucel Mechanism of Action:

Tisagenlecleucel is the first chimeric antigen receptor (CAR) T-cell immunotherapy approved by the FDA. Tisagenlecleucel is a customized treatment formulated using patient’s own T-cells. It consists of autologous T-cells which are collected by a leukapheresis procedure (a laboratory procedure in which white blood cells are separated from the blood and the remainder is infused back to the circulation) from the patient. The collected T-cells are genetically modified with a lentivirus to include a new gene. Modified T-cells are infused back to the patient as a treatment to deadly disease. This new gene triggers production of CAR protein which directs the T-cells to target and eliminate leukaemia cells that have a specific antigen (CD19) on their surface. This results in decreased burden of leukaemia cells.

Clinical Trial Results that led to drug’s approval:

The safety and efficacy of tisagenlecleucel was demonstrated in a multicentre clinical trial involving 63 paediatric and young adult patients with relapsed or refractory B-cell precursor ALL. All participants received recommended weight-based dose of tisagenlecleucel. The most common adverse reactions were cytokine release syndrome (CRS), which was observed in 79% patients. Overall remission rate of 83 percent was achieved within three months of treatment.

In above clinical trial among the patients who experienced CRS, 69 percent of patients had complete resolution of CRS within two weeks following tocilizumab treatment. This observation led to expanded FDA approval of tocilizumab to treat CAR T-cell-induced severe or life-threatening CRS in patients 2 years of age or older.

Adverse Events observed with Tisagenlecleucel:

Tisagenlecleucel Treatment may be associated with severe adverse events. The most common and most severe adverse reaction reported was CRS, which is a systemic response to the activation and proliferation of CAR T-cells causing high fever and flu-like symptoms.  Other commonly observed severe adverse events include neurological events, serious infections, low blood pressure (hypotension), acute kidney injury, fever, and decreased oxygen (hypoxia). A total of 11 deaths were reported, of which 2 deaths occurred within 30 days of treatment administration.

Additional FDA Requirements for Tisagenlecleucel treatment:

Tisagenlecleucel is approved under a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU) due to the risk of CRS and neurological events. The FDA further requires that hospitals and their associated clinics that dispense Tisagenlecleucel be specially certified, tocilizumab is available for immediate administration, and staff involved in the prescribing, dispensing, or administering of Tisagenlecleucel are trained to recognize and manage CRS and neurological events. The patients should be informed of the signs and symptoms of CRS and neurological toxicities and should promptly return to the treatment site if they develop fever or other adverse reactions after receiving Tisagenlecleucel treatment. Novartis is also required to conduct a post-marketing observational study involving patients treated with Tisagenlecleucel.

Scope of Tisagenlecleucel in India:

Fortunately, the mortality rate of leukaemia in India is less than that in western countries. The average mortality rate of leukaemia in India has decreased by 4.6% since 1990, and is 0.2% a year currently. Considering the other options currently available for treatment of ALL and cost of Tisagenlecleucel, it can be predicted that this drug will not gain much popularity in India in recent future. It is estimated that single administration of Tisagenlecleucel will costs around $500,000.


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