Dr Bhat on the Limitations of Current Treatments for Double-Refractory CLL

“There are a limited [number of] effective [treatment] options for dual-refractory CLL. [Patients] usually have acquired mutations, which make current treatments ineffective, and the disease [typically] progresses very quickly, requiring prompt treatment. The overall outlook for these patients is poor.”

Seema A. Bhat, MD, an associate professor in the Division of Hematology within the Department of Internal Medicine at The Ohio State University (OSU), as well as a hematologist-oncologist in the Leukemia and Hematologic Malignancies Program at OSU Comprehensive Cancer Center—James, discussed the current prognosis and treatment paradigm for patients with double-refractory chronic lymphocytic leukemia (CLL).

Patients with CLL who have relapsed on or are refractory to covalent BTK inhibitors, BCL-2 inhibitors, and/or anti-CD20 monoclonal antibodies have a limited number of effective treatment options, Bhat began. These patients often develop acquired mutations that decrease the efficacy of currently available treatments, and their disease often progresses rapidly, necessitating prompt treatment, she emphasized, adding that these patients generally have a poor prognosis. Moreover, agents such as PI3K inhibitors are associated with limited efficacy as well as adverse effects that may prohibit their use in select patients, she said.

There are 2 currently FDA-approved treatments for patients with double-refractory CLL, Bhat continued. The noncovalent BTK inhibitor pirtobrutinib (Jaypirca) was granted accelerated approval in 2023 for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL) who have received 2 or more prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. This regulatory decision was supported by findings from the phase 1/2 BRUIN trial (NCT03740529), in which patients who received pirtobrutinib (n = 108) achieved an overall response rate of 72% (95% CI, 63%-80%); all responses were partial. Additionally, the CD19-directed CAR T-cell therapy lisocabtagene maraleucel (Breyanzi) received accelerated approval in 2024 for the same indication. This approval was backed by data from the phase 1/2 TRANSCEND CLL 004 study (NCT03331198), in which patients who received liso-cel (n = 65) achieved a complete response rate of 20% (95% CI, 11.1%-31.8%).