On March 14, the U.S. Food and Drug Administration (FDA) granted accelerated approval to lisocabtagene maraleucel (Breyanzi), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for the treatment of adults with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least two prior lines of therapy (including a Bruton’s tyrosine kinase [BTK] inhibitor and a B-cell lymphoma 2 [BCL2] inhibitor). This indication approval is based on response rate and duration of response; continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
CLL and SLL are among the most common types of B-cell lymphoma. Treatments for people living with CLL or SLL primarily consist of targeted therapies including BTK and BCL2 inhibitors. However, patients often experience relapse or become refractory after early-line treatment with these therapies, and there is no established standard of care for patients with double-class–exposed CLL or SLL. After relapsing or becoming refractory to these therapies, patients have few options and poor outcomes, including lack of durable complete responses.
TRANSCEND CLL 004
The phase I/II, open-label, single-arm TRANSCEND CLL 004 study (ClinicalTrials.gov identifier NCT03331198) was the first pivotal multicenter trial to evaluate a CAR T-cell therapy in patients with relapsed or refractory CLL or SLL. The phase I dose-escalation portion of the study assessed the safety and recommended dose for the subsequent phase II expansion cohort. The phase II portion of the study is evaluating lisocabtagene maraleucel at the recommended dose from the phase I monotherapy arm. The primary endpoint of the phase II portion of the study is complete response rate, including complete remission with incomplete bone marrow recovery, based on independent review committee according to the International Workshop on Chronic Lymphocytic Leukemia 2018 guidelines.
The complete response rate associated with lisocabtagene maraleucel was 20% (95% confidence interval [CI] = 11.1%–31.8%). Among patients who achieved a complete response, median duration of response was not reached (95% CI = 15 months to not reached) at the time of data cutoff. Among all responders (overall response rate = 45%; 95% CI = 32.3%–57.5%), median duration of response was 35.3 months (95% CI = 12.4 months to not reached). High rates of undetectable measurable residual disease (MRD) were observed across patients treated with lisocabtagene maraleucel who achieved a complete response, with an undetectable MRD rate of 100% in the blood (95% CI = 75.3%–100%) and 92.3% in the bone marrow (95% CI = 64%–99.8%).
“CLL and SLL are currently considered incurable diseases with few treatment options in the relapsed setting that can confer complete responses, something that has historically been associated with improved long-term outcomes,” said Tanya Siddiqi, MD, lead investigator of TRANSCEND CLL 004 and Associate Professor, Division of Lymphoma, City of Hope National Medical Center. “The FDA approval of lisocabtagene maraleucel in relapsed or refractory CLL and SLL after treatment with prior BTK inhibition and BCL2 inhibition is a remarkable breakthrough, shifting the treatment paradigm from continuous therapy with sequential regimens to overcome drug resistance to a one-time personalized T-cell–based approach that has the potential to offer patients complete and lasting remission.”
Among 89 patients in the study treated with lisocabtagene maraleucel, occurrences of cytokine-release syndrome and neurologic events were mostly low-grade. Any-grade cytokine-release syndrome occurred in 83% of patients, with grade 3 cytokine-release syndrome occurring in 9% of patients. No grade 4 or 5 cytokine-release syndrome events were reported. Any-grade neurologic events were reported in 46% of patients, with grade 3 neurologic events reported in 20% of patients, and one case of a grade 4 neurologic event reported. No grade 5 neurologic events were observed.
In patients with relapsed or refractory CLL or SLL, lisocabtagene maraleucel is delivered through a treatment process that culminates in a one-time infusion with a single dose containing 90 to 110 x 106 CAR-positive viable T cells. Lisocabtagene maraleucel has boxed warnings regarding cytokine-release syndrome, neurologic toxicities, and secondary hematologic malignancies.
