In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On May 1, 2018, tisagenlecleucel (Kymriah), a CD19-directed genetically modified autologous T-cell immunotherapy, was granted approval for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL)–not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.^1,2 Tisagenlecleucel is not indicated for the treatment of patients with primary central nervous system lymphoma. Due to the serious risks of cytokine-release syndrome and neurologic toxicities, tisagenlecleucel is approved with a Risk Evaluation and Mitigation Strategy.

Supporting Efficacy Data

Approval was based on the findings of the single-arm multicenter, phase II JULIET trial in adults with relapsed or refractory DLBCL and DLBCL after transformation from follicular lymphoma.^2,3 Eligible patients had to have received at least two prior lines of therapy, including an anthracycline and rituximab (Rituxan), or relapsed following autologous hematopoietic stem cell transplantation. Patients received a single infusion of tisagenlecleucel following completion of lymphodepleting chemotherapy.

Among 68 evaluable patients, the median age was 56 years (range = 22–74 years), 71% were male, 90% were white, 4% were Asian, and 3% were black or African American; 78% had primary DLBCL–not otherwise specified and 22% had DLBCL following transformation from follicular lymphoma (17% high-grade), and 44% had undergone prior autologous hematopoietic stem cell transplantation. The median number of prior therapies was 3 (range = 1–6), 56% had refractory disease, and 44% relapsed after their last therapy. Lymphodepleting therapy was received by 90% (66% fludarabine and 24% bendamustine), the median time from leukapheresis and cryopreservation to tisagenlecleucel infusion was 113 days (range = 47–196 days), the median dose was 3.5 × 10⁸ chimeric antigen receptor (CAR)-positive viable T cells (range = 1.0 to 5.2 × 10⁸ cells), and 73% of patients received treatment in the inpatient setting.

Among 68 evaluable patients, objective response, as assessed by independent review committee, was observed in 34 patients (50%), with a complete response seen in 22 patients (32%). With median follow-up of 9.4 months, the median duration of response was not reached (range = 1.5+ to 11.3+ months) among patients with a complete response and 3.4 months (range = 0.03+ to 11.3+ months) in those with a partial response.

How It Works

Tisagenlecleucel is a CD19-directed genetically modified autologous T-cell immunotherapy that involves reprogramming a patient’s own T cells with a transgene encoding a CAR to identify and eliminate CD19-expressing malignant and normal cells. The CAR consists of a murine single-chain antibody fragment that recognizes CD19 and is fused to intracellular signaling domains from 4-1BB (CD137) and CD3 zeta. The CD3-zeta component is critical for initiating T-cell activation and antitumor activity, whereas 4-1BB enhances the expansion and persistence of tisagenlecleucel. Upon binding to CD19-expressing cells, the CAR transmits a signal to promote T-cell expansion, activation, target cell elimination, and persistence of the tisagenlecleucel cells.

How It Is Used

Tisagenlecleucel is for autologous use only. It is provided as a single-dose for infusion containing a suspension of CAR-positive viable T cells. Adult patients are given 0.6 to 6.0 × 10⁸ CAR-positive viable T cells.

Lymphodepleting chemotherapy consists of fludarabine at 25 mg/m² intravenously (IV) daily for 3 days and cyclophosphamide at 250 mg/m² IV daily for 3 days starting with the first dose of fludarabine. An alternative regimen consists of bendamustine at 90 mg/m² daily for 2 days if a patient experienced previous grade 4 hemorrhagic cystitis with cyclophosphamide or demonstrates resistance to a previous cyclophosphamide-containing regimen. Tisagenlecleucel should be infused 2 to 11 days after completion of the lymphodepleting chemotherapy. Lymphodepleting chemotherapy can be omitted if a patient’s white blood cell count is ≤ 1 × 10⁹/L within 1 week prior to infusion. Tisagenlecleucel contains human cells genetically modified with a lentivirus. Local biosafety guidelines applicable for handling and disposal of such products should be followed.

Since it poses serious risk for cytokine-release syndrome and neurologic toxicities, tisagenlecleucel should be administered at a certified health-care facility. Patients should be monitored two to three times during the first week following infusion at the certified health-care facility for signs and symptoms of cytokine-release syndrome and neurologic toxicities. Patients should be instructed to remain within proximity of the certified health-care facility for at least 4 weeks following infusion. Due to the risk of cytokine-release syndrome, tocilizumab (Actemra) for cytokine-release syndrome treatment and emergency equipment must be available prior to infusion and during the recovery period. Detailed instruction for management of cytokine-release syndrome is provided in the product labeling. Severe or life-threatening cytokine-release syndrome should be treated with tocilizumab or tocilizumab and corticosteroids. Patients should be monitored for neurologic symptoms and provided supportive care as needed.

Patients should be premedicated with acetaminophen and diphenhydramine or another H1-antihistamine approximately 30 to 60 minutes prior to infusion. Prophylactic use of systemic corticosteroids should be avoided, since it may interfere with the activity of 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-versus host disease, or worsening of the leukemia burden following lymphodepleting chemotherapy.

Safety Profile

Among 106 patients receiving tisagenlecleucel in the JULIET trial, the most common adverse events of any grade were cytokine-release syndrome (74%), infection-pathogen unspecified (42%), pyrexia (34%), diarrhea (31%), nausea (27%), fatigue (26%), hypotension (26%), edema (23%), and headache (21%). The most common grade 3 or 4 adverse events were infection-pathogen unspecified (25%), cytokine-release syndrome (23%), febrile neutropenia (17%), encephalopathy (11%), and hypotension (8%). The most common grade 3 or 4 laboratory abnormalities were lymphopenia (94%), neutropenia (81%), leukopenia (77%), anemia (58%), thrombocytopenia (54%), and hypophosphatemia (24%).

Tisagenlecleucel has boxed warnings for cytokine-release syndrome, including fatal and life-threatening reactions, and neurologic toxicities, which may be severe or life-threatening. Patients should be monitored for neurologic symptoms and provided supportive care as needed. Tisagenlecleucel is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS).

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

REFERENCES

1. U.S. Food and Drug Administration: FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm606540.htm. Accessed May 9, 2018.

2. Kymriah (tisagenlecleucel) suspension for intravenous infusion prescribing information, Novartis Pharmaceuticals Corp, May 2018. Available at https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kymriah.pdf. Accessed May 9, 2018.

3. Schuster SJ, Bishop MR, Tam CS, et al: Primary analysis of Juliet: A global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. 2017 ASH Annual Meeting. Abstract 577.