On August 30, 2017, tisagenlecleucel (Kymriah) was granted regular approval for the treatment of patients up to age 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.^1,2 Tisagenlecleucel is the first chimeric antigen receptor (CAR) T-cell immunotherapy approved by the U.S. Food and Drug Administration. It is available only through a restricted program under a risk evaluation and mitigation strategy. 

The anti–interleukin 6 receptor monoclonal antibody tocilizumab (Actemra) was concurrently approved for the treatment of patients aged ≥ 2 years with cytokine-release syndrome, which can occur with CAR T-cell therapy.^1,3 

Supporting Efficacy Data 

APPROVAL OF TISAGENLECLEUCEL was based on a trial in 63 evaluable patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients with prior hematopoietic stem cell transplantation. Patients received a single intravenous dose of tisagenlecleucel within 2 to 14 days after completing lymphodepleting chemotherapy with fludarabine at 30 mg/m2 daily for 4 days and cyclophosphamide at 500 mg/m2 daily for 2 days. Patients had a median age of 12 years (range = 3–23 years), 35 were male, 46 were white, and 6 had primary refractory disease. 

Confirmed overall remission on independent central review occurred in 52 patients (83%), including complete remission in 40 (63%) and complete remission with incomplete hematologic recovery in 12 (19%). All patients with confirmed complete remission or complete remission with incomplete hematologic recovery tested negative for minimal residual disease by flow cytometry. The median remission duration was not reached (range = 1.2 to 14.1+ months). 

In an analysis of data from clinical trials of CAR T-cell therapy, 69% of patients with severe or life-threatening cytokine-release syndrome showed resolution of that complication within 2 weeks following one or two doses of tocilizumab. 

How It Works 

TISAGENLECLEUCEL CONSISTS of autologous T cells collected in a leukapheresis procedure. The T cells are genetically modified with a transgene encoding a CAR protein that allows them to identify and eliminate CD19-expressing normal and malignant cells. After binding to CD19-expressing cells, the CAR transmits a signal to promote T-cell expansion, activation, target cell elimination, and persistence of the tisagenlecleucel T cells. 

Interleukin (IL)-6 is a pleiotropic proinflammatory cytokine produced by a variety of cell types including T and B cells, lymphocytes, monocytes, and fibroblasts. By binding to soluble and membrane-bound IL-6 receptors, tocilizumab inhibits IL-6–mediated signaling. 

How It Is Used 

TISAGENLECLEUCEL IS PREPARED from autologous blood collected by leukapheresis. It is for autologous, intravenous use only. 

One tisagenlecleucel treatment course consists of fludarabine and cyclophosphamide lymphodepleting chemotherapy followed by infusion of tisagenlecleucel. Tisagenlecleucel is provided in a single-dose unit containing CAR-positive viable T cells based on the patient’s weight reported at the time of leukapheresis. The dose is 0.2 to 5.0 106 CAR-positive viable T cells per kg body weight for patients weighing ≤ 50 kg and 0.1 to 2.5 108 CAR-positive viable T cells for patients weighing > 50 kg. 

Lymphodepleting chemotherapy consists of intravenous fludarabine at 30 mg/m2 daily for 4 days and intravenous cyclophosphamide at 500 mg/m2 daily for 2 days starting with the first dose of fludarabine. The tisagenlecleucel infusion should occur 2 to 14 days after the completion of lymphodepleting chemotherapy. The infusion rate is 10 to 20 mL per minute, adjusted for smaller children and smaller volumes. The volume in the infusion bag ranges from 10 to 50 mL. 

Due to a high risk for cytokine-release syndrome, tocilizumab and emergency equipment must be available prior to infusion and during the recovery period. Detailed instructions for management of cytokine-release syndrome are provided in the product labeling. Tisagenlecleucel infusion should be delayed in patients with unresolved serious adverse reactions (including pulmonary reactions, cardiac reactions, or hypotension) from preceding chemotherapies, active uncontrolled infection, active graft-vs-host disease, or worsening of leukemia burden following lymphodepleting chemotherapy. Patients should be premedicated with acetaminophen and diphenhydramine or another H1-antihistamine approximately 30 to 60 minutes prior to infusion. Corticosteroids should not be used at any time except in the case of a life-threatening emergency. 

Tisagenlecleucel contains human cells genetically modified with a lentivirus. Local biosafety guidelines applicable for handling and disposal of such products should be followed. The product may pose a risk of transmitting infectious viruses to health-care professionals handling the product. Universal precautions to avoid potential transmission of infectious diseases should be employed when handling the product. 

Safety Profile 

THE MOST COMMON adverse events of any grade observed in 68 patients receiving tisagenlecleucel were cytokine-release syndrome (79%), hypogammaglobulinemia (43%), infections with an unspecified pathogen (41%), pyrexia (40%), decreased appetite (37%), headache (37%), encephalopathy (34%), hypotension (31%), and bleeding episodes (31%). 

Grade 3 or 4 adverse events occurred in 84% of patients; the most common were cytokine-release syndrome (49%), hypotension (22%), viral infectious disorders (18%), hypoxia (18%), infections with unspecified pathogens (16%), pyrexia (15%), and decreased appetite (15%). All patients experienced neutropenia, anemia, and thrombocytopenia, with neutropenia and thrombocytopenia commonly persisting for several weeks. Other grade 3 or 4 laboratory abnormalities included increased aspartate transaminase (28%), hypokalemia (27%), increased alanine transaminase (21%), and increased bilirubin (21%). 

The median time to onset of cytokine-release syndrome was 3 days (range = 1–22 days). Of the 54 patients with cytokine-release syndrome, 27 (50%) received tocilizumab, with 7 (13%) receiving 2 doses, 3 (6%) receiving 3 doses, and 14 (26%) receiving corticosteroids. The median time to resolution of cytokine-release syndrome was 8 days (range = 1–36 days). 

Serious adverse events included cytokine-release syndrome, sometimes fatal and sometimes associated with disseminated intravascular coagulation with intracranial hemorrhage; prolonged cytopenias; infection; cardiac failure; and cardiac arrest. Death occurred in 11 patients treated with tisagenlecleucel, with 2 patients dying within 30 days of infusion; 1 died with cytokine-release syndrome and progressive leukemia, and 1 had resolving cytokine-release syndrome with abdominal compartment syndrome, coagulopathy, and renal failure when an intracranial hemorrhage occurred. Seven deaths were considered disease-related. 

Tisagenlecleucel has boxed warnings for cytokine-release syndrome and neurologic toxicities. Risk factors for severe cytokine-release syndrome are high preinfusion tumor burden (> 50% blasts in bone marrow), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and inflammatory processes. Severe or life-threatening cytokine-release syndrome should be treated with tocilizumab. Patients should be monitored for neurologic events. 

Tisagenlecleucel also carries warnings/precautions for hypersensitivity reactions, serious infections, prolonged cytopenias, hypogammaglobulinemia, secondary malignancies, and effects on the ability to drive and use machines. ■

REFERENCES 

1. U.S. Food and Drug Administration: FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. Available at www.fda. gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm574154.htm. Accessed September 6, 2017. 

2. Kymriah (tisagenlecleucel) suspension for intravenous infusion prescribing information, Novartis Pharmaceuticals Corp, August 2017. Available at www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM573941.pdf. Accessed September 6, 2017. 

3. Actemra (tocilizumab) injection prescribing information, Genentech Inc, August 2017. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2017/125276s114lbl.pdf. Accessed September 6, 2017.