On March 5, 2021, the CD19-directed genetically modified autologous T-cell immunotherapy axicabtagene ciloleucel was granted accelerated approval for treatment of adults with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy.^1,2

Axicabtagene ciloleucel is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus [brexucabtagene autoleucel] REMS Program.

Supporting Efficacy Data

Approval was based on findings from the single-arm, multicenter, phase II ZUMA-5 trial (ClinicalTrials.gov identifier NCT03105336).² Patients with a history of central nervous system disorders or autoimmune disease requiring systemic immunosuppression were ineligible for the study. 

In the trial, 123 patients with relapsed or refractory disease after two or more lines of systemic therapy, including the combination of an anti-CD20 monoclonal antibody and an alkylating agent, underwent leukapheresis. Of these patients, 120 received axicabtagene ciloleucel as a single intravenous (IV) infusion with a target of 2 × 10⁶ anti-CD19 chimeric antigen receptor (CAR) T cells/kg (maximum permitted dose = 2 × 10⁸ cells) following lymphodepletion. The lymphodepleting regimen consisted of cyclophosphamide at 500 mg/m² and fludarabine at 30 mg/m² given on the fifth, fourth, and third days before axicabtagene ciloleucel. Among the 120 patients who received treatment, the 81 consecutive patients included in the primary efficacy analysis had at least 9 months of potential follow-up from the date of first response.

The main efficacy measures were objective response rate and duration of response, as determined by an independent review committee. Among the 81 patients, an objective response was observed in 74 patients (91%, 95% confidence interval [CI] = 83%–96%), with complete remission in 49 (60%). The median time to response was 1 month. The median duration of response was not reached (95% CI = 20.8 months to not estimable; range = 0.0 to 25.0+ months); rates of continued remission at 12 and 18 months were 76.2% and 74.2% among responders. Among all 123 patients who underwent leukapheresis, an objective response was observed in 110 (89%, 95% CI = 83%–94%), with complete remission in 76 (62%).

How It Works

Axicabtagene ciloleucel is a CD19-directed genetically modified autologous T-cell immunotherapy that binds to CD19-expressing cancer cells and normal B cells. Following anti-CD19 CAR T-cell engagement with CD19-expressing target cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signaling cascades that lead to T-cell activation, proliferation, acquisition of effector functions, and secretion of inflammatory cytokines and chemokines, resulting in killing of CD19-expressing cells.

How It Is Used

The target dose of axicabtagene ciloleucel is 2 × 10⁶ CAR-positive viable T cells/kg, with a maximum of 2 × 10⁸ CAR-positive viable T cells. A lymphodepleting regimen of cyclophosphamide at 500 mg/m² and fludarabine at 30 mg/m² is given on the fifth, fourth, and third days before axicabtagene ciloleucel infusion. Patients should be premedicated with oral acetaminophen at 650 mg and IV or oral diphenhydramine at 12.5 mg approximately 1 hour before infusion. Prophylactic use of systemic corticosteroids should be avoided because it may interfere with the activity of axicabtagene ciloleucel.

Axicabtagene ciloleucel should not be given to patients with active infection or inflammatory disorders. Infusion of the drug carries risk of cytokine-release syndrome and neurologic toxicities. Tocilizumab and emergency equipment must be available prior to infusion and during the recovery period. The agent must be administered at a certified health-care facility. Patients should be monitored at least daily for 7 days at the certified health-care facility following infusion 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.

Product labeling provides detailed instructions on management of cytokine-release syndrome and neurologic toxicities, including the use of tocilizumab and corticosteroid treatment for grades 1 to 4 cytokine-release syndrome and for grades 2 to 4 neurologic toxicity concurrent with or not concurrent with cytokine-release syndrome. Nonsedating antiseizure medicines (eg, levetiracetam) should be considered for seizure prophylaxis for any grade ≥ 2 neurologic toxicities.

Safety Profile

The most common adverse events of any grade (incidence ≥ 20%) in patients with non-Hodgkin lymphoma receiving axicabtagene ciloleucel in clinical trial have been cytokine-release syndrome, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, febrile neutropenia, nausea, infections–pathogen unspecified, decreased appetite, chills, diarrhea, tremor, musculoskeletal pain, cough, hypoxia, constipation, vomiting, arrhythmias, and dizziness.

Safety data are from 146 patients with relapsed or refractory indolent non-Hodgkin lymphoma who received axicabtagene ciloleucel in the ZUMA-5 study. The most common adverse events of any grade (incidence ≥ 20%) were fever (85%), cytokine-release syndrome (84%), hypotension (51%), encephalopathy (49%), fatigue (49%), headache (45%), infections–pathogen unspecified (45%), tachycardia (44%), febrile neutropenia (41%), musculoskeletal pain (40%), nausea (40%), tremor (31%), chills (29%), diarrhea (29%), constipation (28%), decreased appetite (26%), cough (25%), vomiting (24%), hypoxia (23%), arrhythmia (21%), and dizziness (20%). The most common grade ≥ 3 adverse events included febrile neutropenia (41%), encephalopathy (16%), infections–pathogen unspecified (14%), fever (8%), cytokine-release syndrome (8%), pneumonia (8%), and hypoxia (8%). The most common grade 3 or 4 laboratory abnormalities were neutropenia (92%), leukopenia (92%), thrombocytopenia (35%), anemia (30%), hypophosphatemia (25%), and lymphopenia (22%).

Serious adverse events occurred in 48% of patients, with those occurring in more than 2% of patients including febrile neutropenia, encephalopathy, fever, cytokine-release syndrome, infections–pathogen unspecified, pneumonia, hypoxia, and hypotension. Tocilizumab treatment was required in 75 patients (51%). Fatal adverse events occurred in 1% of patients, including cytokine-release syndrome and fungal infection.

Axicabtagene ciloleucel has boxed warnings for cytokine-release syndrome, including fatal and life-threatening reactions, and neurologic toxicity, including fatal and life-threatening reactions. Severe or life-threatening cytokine-release syndrome should be treated with tocilizumab or tocilizumab and corticosteroids. Neurologic toxicity has been observed to occur concurrently with cytokine-release syndrome or after resolution of the syndrome. Patients should be monitored for neurologic toxicities. Those with neurologic toxicity should receive supportive care and/or corticosteroids as needed. Axicabtagene ciloleucel is available only through a REMS program called the Yescarta and Tecartus REMS program.

Axicabtagene ciloleucel also has warnings/precautions for hypersensitivity reactions; serious infections; prolonged cytopenias, including grade ≥ 3 cytopenias for several weeks following infusion; hypogammaglobulinemia; secondary malignancies; and effects on the ability to drive and use machines. Complete blood cell counts should be monitored. Patients should be monitored for hypogammaglobulinemia and receive replacement therapy when needed. Secondary malignancies should be reported to Kite at 1-844-454-KITE (5483). Patients should refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 8 weeks after treatment. 

REFERENCES

1. U.S. Food and Drug Administration: FDA grants accelerated approval to axicabtagene ciloleucel for relapsed or refractory follicular lymphoma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-axicabtagene-ciloleucel-relapsed-or-refractory-follicular-lymphoma. Accessed March 17, 2021.

2. Yescarta (axicabtagene ciloleucel) suspension for intravenous infusion prescribing information, Kite Pharma, Inc, March 2021. Available at https://www.gilead.com/-/media/files/pdfs/medicines/oncology/yescarta/yescarta-pi.pdf. Accessed March 17, 2021.