On February 5, 2021, lisocabtagene maraleucel was approved for the 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 (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.1,2 Lisocabtagene maraleucel is not indicated for the treatment of patients with primary central nervous system lymphoma.
Lisocabtagene maraleucel is a CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapy. It consists of autologous T cells that are genetically modified to produce a CAR protein, allowing the T cells to identify and eliminate CD19-expressing normal and malignant cells.
Lisocabtagene maraleucel is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.
Supporting Efficacy Data
Approval was based on findings from the single-arm, multicenter TRANSCEND trial (ClinicalTrials.gov identifier NCT02631044).2,3 In the trial, 192 evaluable patients received lisocabtagene maraleucel at a dose of 50 to 110 × 106 CAR-positive viable T cells given 2 to 7 days following completion of lymphodepleting chemotherapy; lymphodepleting chemotherapy consisted of fludarabine at 30 mg/m2/d and cyclophosphamide at 300 mg/m2/d concurrently for 3 days. Patients with a history of central nervous system disorders (eg, seizures or cerebrovascular ischemia) or autoimmune disease requiring systemic immunosuppression were ineligible for the trial.
Median patient age was 63 years (range = 18–86 years); 69% were male; and 84% were White, 6% Black, and 4.7% Asian. The median number of prior therapies was three (range = 1–8); diagnoses were de novo DLBCL in 53%, DLBCL transformed from indolent lymphoma in 25%, high-grade B-cell lymphoma in 14%, primary mediastinal large B-cell lymphoma in 7%, and follicular lymphoma grade 3B in 1.0%. Overall, 64% had disease refractory to last therapy, 53% had primary refractory disease, 37% had prior hematopoietic stem cell transplantation, and 2.6% had central nervous system involvement.
Efficacy was based on complete response rate and duration of response as assessed by an independent review committee using 2014 Lugano criteria. An objective response was observed in 141 patients (73%, 95% confidence interval [CI] = 67%–80%), with a complete response in 104 (54%, 95% CI = 47%–61%). The median time to first response was 1 month. Median duration of response was 16.7 months (95% CI = 5.3 months to not reached; range = 0.0+ to 23.5+ months). Among patients with a complete response, median duration of response was not reached (95% CI = 16.7 months to not reached; range = 0.7+ to 23.5+ months), with response lasting ≥ 6 months in 65% and ≥ 9 months in 62% of responders. Among patients with a partial response, median duration was 1.4 months (95% CI = 1.1–2.2 months; range = 0.0+ to 22.8+ months).
How It Works
CAR binding to CD19 expressed on the cell surface of tumor and normal B cells induces activation and proliferation of CAR T cells, release of proinflammatory cytokines, and cytotoxic killing of target cells. Lisocabtagene maraleucel is a CD19-directed genetically modified autologous cell immunotherapy administered as a defined composition to reduce variability in CD8-positive and CD4-positive T cell dose. The CAR is composed of an FMC63 monoclonal antibody–derived single-chain variable fragment (scFv), IgG4 hinge region, CD28 transmembrane domain, 4-1BB (CD137) co-stimulatory domain, and CD3 zeta activation domain. CD3 zeta signaling is critical for initiating activation and antitumor activity; 4-1BB (CD137) signaling enhances T cell expansion and persistence of lisocabtagene maraleucel.
How It Is Used
Lisocabtagene maraleucel must be administered at a REMS-certified health-care facility. Patients should be monitored daily at a certified health-care facility during the first week following infusion for signs and symptoms of cytokine-release syndrome and neurologic toxicities. Patients should be instructed to remain within proximity of the facility for at least 4 weeks following infusion and should refrain from driving or hazardous activities for 8 weeks.
The recommended regimen is a single dose containing 50 to 110 × 106 CAR-positive viable T cells with a 1:1 ratio of CD4 and CD8 components, administered by intravenous (IV) infusion at 2 to 7 days after completion of lymphodepleting chemotherapy. Lymphodepleting chemotherapy consists of fludarabine at 30 mg/m2/d and cyclophosphamide at 300 mg/m2/d for 3 days.
To minimize the risk of infusion reactions, patients should be premedicated with acetaminophen (650 mg) and diphenhydramine (25–50 mg IV or orally) or another H1-antihistamine 30 to 60 minutes prior to treatment. Prophylactic use of systemic corticosteroids should be avoided since they may interfere with the activity of lisocabtagene maraleucel.
Prescribing information provides detailed instructions on management and treatment of cytokine-release syndrome and neurologic toxicity by toxicity grades 1 to 4, including use of tocilizumab, corticosteroids, and antiseizure medications.
Safety data are from a total of 268 patients who received lisocabtagene maraleucel in the TRANSCEND trial. The most common adverse events of any grade (≥ 20%) were fatigue (48%), cytokine-release syndrome (46%), musculoskeletal pain (37%), nausea (33%), headache (30%), encephalopathy (29%), infections-pathogen unspecified (29%), decreased appetite (28%), diarrhea (26%), hypotension (26%), tachycardia (25%), dizziness (24%), cough (23%), constipation (23%), abdominal pain (21%), vomiting (21%), and edema (21%). Overall, neurologic toxicity of any grade occurred in 35% and was grade ≥ 3 in 12%. The most common grade ≥ 3 adverse events were infections–pathogen unspecified (16%), bacterial infectious disorders (5%), hypertension (4.5%), and cytokine-release syndrome (4.1%). The most common grade 3 or 4 laboratory abnormalities were neutropenia (76%), thrombocytopenia (39%), anemia (23%), hypofibrinogenemia (15%), and hypophosphatemia (13%). Prolonged grade 3 or 4 cytopenias occurred in 31% of patients.
Serious adverse events occurred in 46% of patients, with those occurring in > 2% of patients consisting of cytokine-release syndrome, encephalopathy, sepsis, febrile neutropenia, aphasia, pneumonia, fever, hypotension, dizziness, and delirium. Fatal adverse events occurred in 4% of patients.
Lisocabtagene maraleucel has boxed warnings for cytokine-release syndrome, including fatal and life-threatening reactions, and neurologic toxicities, including fatal and life-threatening reactions. It should not be administered to patients with active infection or inflammatory disorders. Neurologic toxicities have occurred concurrently with cytokine-release syndrome, after cytokine-release syndrome resolution, and in the absence of cytokine-release syndrome. Lisocabtagene maraleucel is available only through a restricted program under a REMS called the BREYANZI REMS.
Lisocabtagene maraleucel also has warnings/precautions for hypersensitivity reactions, serious infections, prolonged cytopenias (grade ≥ 3 cytopenias for several weeks following treatment), hypogammaglobulinemia, secondary malignancies, and effects on the ability to drive and use machines. Patients should have complete blood counts monitored. Patients should be monitored for hypogammaglobulinemia and considered for immunoglobulin replacement therapy.
Lisocabtagene maraleucel is not recommended for women who are pregnant, and pregnancy that occurs after infusion should be discussed with the treating physician. There is no information regarding the presence or effects of lisocabtagene maraleucel in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for treatment and any potential adverse effects on the breastfed infant from treatment or from the underlying maternal condition.
1. U.S. Food and Drug Administration: FDA approves lisocabtagene maraleucel for relapsed or refractory large B-cell lymphoma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-lisocabtagene-maraleucel-relapsed-or-refractory-large-b-cell-lymphoma. Accessed March 1, 2021.
2. Breyanzi (lisocabtagene maraleucel) suspension for intravenous infusion prescribing information, February 2021, Juno Therapeutics, Inc., a Bristol-Myers Squibb Company. Available at https://www.fda.gov/media/145711/download. Accessed March 1, 2021.
3. Abramson JS, Palomba ML, Gordon LI, et al: Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet 396:839-852, 2020.