By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved the first cell-based gene therapy for the treatment of acute lymphoblastic leukemia (ALL). This genetically engineered anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is created by reprogramming a patient’s own T cells using a lentiviral-vector, resulting in T cells that target leukemia cells that exhibit CD19 on the surface. Tisagenlecleucel is marketed as Kymriah.


Tisagenlecleucel is indicated 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.1


A single-dose unit contains 0.2-5.0 × 106 CAR-positive viable T cells per kg of body weight for patients ≤ 50 kg, or 0.1-2.5 × 106 CAR-positive T cells for patients > 50 kg.1 The dose is administered through IV infusion. Premedication with acetaminophen and an H1 antihistamine are recommended. The expanded use of tocilizumab (an anti-interleukin-6 receptor antagonist) has been approved by the FDA to treat CAR T-cell-induced severe or life-threatening cytokine release syndrome (CRS).2


Tisagenlecleucel is the first effective cell-based gene therapy to be approved for ALL. Once administered, it is present in the blood and bone marrow beyond two years.1 This enhanced persistence may be associated with more durable remission.3


Serious adverse reactions have been associated with tisagenlecleucel administration, including CRS (79% with 49% grade 3/4), neurological toxicity (e.g., headache, encephalopathy; 65% with 18% grade 3/4), serious infections (59% with 35% grade 3/4), and hypogammaglobulinemia (43%).1,2 Patients may need to receive immunoglobulin replacement for an indefinite period following treatment.1 Treated patients may develop secondary malignancies or recurrence of their leukemia.1 Tisagenlecleucel only targets CD19. It does not target other antigens expressed on B cells, such as CD22 and CD123.3-5 Patients may relapse with CD19-negative disease. There is a potential for manufacturing failure occurring in up to 9% of cases.


Tisagenlecleucel is prepared from the patient’s peripheral blood mononuclear cells obtained by leukapheresis. A transgene is introduced via a lentivirus vector to express a CD19-directed chimeric antigen receptor and activated with anti-CD3/CD28 antibody-coated beads. CD19 exists on most precursor B-cell ALL tumor cells. The modified T cells feature three components: extracellular antigen-recognition domain, signaling/activation domain (CD3 zeta) to initiate T-cell activation, and a co-stimulatory domain (4-IBB) to enhance the expansion and persistence. The efficacy of tisagenlecleucel was evaluated in a clinical trial of 63 evaluable pediatric and young adults with relapsed or refractory B-cell precursor ALL.1 The median age was 12 years (range, 3-23 years). Treatment involved lymphodepleting chemotherapy (fludarabine 30 mg/m2 daily for four days and cyclophosphamide 500 mg/m2 daily for two days), followed by a single dose of tisagenlecleucel. Efficacy endpoints were complete remission within three months after infusion, the duration of remission, and proportion of subjects with remission and minimal residual disease (MRD) < 0.01% by flow cytometry (MRD-negative). There were two categories of complete remission (CR and CRi). CR was defined as complete remission with < 5% of blast in the bone marrow, no evidence of extramedullary disease, and full recovery of peripheral blood counts without transfusion. CRi was defined as complete remission but with incomplete blood count recovery with or without blood transfusion. With a median follow-up of 4.8 months, 40 subjects achieved CR and 12 achieved CRi. All were MRD-negative. Median onset was 29 days (range 26-31). The median duration of remission has not been reached; therefore, long-term effects (either positive or negative) are unknown.


ALL is the most common childhood cancer. Approximately 15-20% either do not respond to initial treatment or relapse. Currently, the National Comprehensive Cancer Network lists tisagenlecleucel as a treatment option for relapsed/refractory ALL in those ≤ 25 years of age.6 For those with Philadelphia chromosome-positive disease, the recommendation is for refractory disease or two or more relapses and failure of two tyrosine kinase inhibitors. For Philadelphia chromosome-negative disease, the recommendation is for refractory disease or after two or more relapses.

The efficacy of tisagenlecleucel is quite robust. For comparison, blinatumomab, a bispecific, T-cell engager that binds to CD19 and CD3 and is approved for both pediatric and adult use, produces CR of 33% in patients < 18 years of age.7 Tisagenlecleucel is available only through a restricted program under a risk evaluation and mitigation strategy. Hospitals and associated clinics that prescribe/administer this drug must be specially certified and trained to recognize and manage CRS and neurological events.1 The cost is $475,000 per treatment course. Regulators require researchers to conduct a postmarket observational study involving patients treated with this therapy.2


  1. Kymriah Prescribing Information. Novartis Pharmaceutical Corporation. August 2017.
  2. U.S. Food & Drug Administration. FDA approval brings first gene therapy to the United States. Available at: Accessed Sept. 25, 2017.
  3. Maude SL, Teachey DT, Porter DL, Grupp SA. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood 2015;125:4017-4023.
  4. Luskin MR, DeAngelo DJ. Chimeric antigen receptor therapy in acute lymphoblastic leukemia clinical practice. Curr Hematol Malig Rep 2017 Jun 27. doi: 10.1007/s11899-017-0394-x. [Epub ahead of print].
  5. Ruella M, Maus MV. Catch me if you can: Leukemia escape after CD19-directed T cell immunotherapies. Comput Struct Biotechnol J 2016;14:357-362.
  6. National Comprehensive Cancer Network. NCCN Acute Lymphoblastic Leukemia V.3.2017. Available at: Accessed Sept. 25, 2017.
  7. Blincyto Prescribing Information. Amgen Inc. July 2017.