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The FDA granted for pretreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), drugmaker Bristol Myers Squibb announced on Thursday.

A CD19-directed cellular therapy, liso-cel becomes the first CAR-T product specifically for CLL/SLL; the one-time infusion is indicated for patients with relapsed or refractory disease following two or more prior therapies, including both a BCL-2 inhibitor such as venetoclax (Venclexta) and a Bruton's tyrosine kinase (BTK) inhibitor such as ibrutinib (Imbruvica), acalabrutinib (Calquence), or zanubrutinib (Brukinsa).

Findings from the phase I/II TRANSCEND CLL 004 study supported the approval. Among patients with relapsed or refractory CLL/ SLL in the single-arm, open-label trial, 45% (95% CI 32.3-57.5) responded to treatment, including complete responses in 20% (95% CI 11.1-31.8). The median duration of response reached 35.3 months overall and was not reached among complete responders, a group that had high rates of minimal residual disease negativity in the blood (100%) and bone marrow (92.3%).

"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 investigator Tanya Siddiqi, MD, of City of Hope National Medical Center in Duarte, California. This approval "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."

CLL is one of the most common forms of leukemia, with an estimated 18,740 cases diagnosed last year and 4,490 deaths, . While BCL-2 and BTK inhibitors are highly effective initial treatments for patients requiring therapy, no standard of care exists for patients who fail on both of these agents.

Liso-cel's new indication comes following FDA's investigation into reports of T-cell malignancies associated with CAR-T products. As a result, the agency in January required boxed warnings about the risks of these cancers on all CAR T-cell therapies. Research shows these malignancies to be extremely rare, however, representing following treatment with CAR T-cell therapy in the FDA Adverse Event Reporting System.

Other boxed warnings for liso-cel include cytokine release syndrome (CRS) and neurologic toxicities, though most of these events among the 89 patients who received liso-cel in TRANSCEND CLL 004 were considered low grade, and no deaths due to either toxicity were reported. Overall, 83% of the patients had CRS (grade 3 in 9%) and 46% had neurologic toxicities (grade 3 in 20% and grade 4 in one case).

As a condition of the accelerated approval in CLL/SLL, further confirmatory evidence will be required to show clinical benefit. Liso-cel is also approved for large B-cell lymphoma and follicular lymphoma.

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