JNCCN 360 - CLL - Novel BCL2 Inhibitor Under Study in Resistant CLL and Other Blood Cancers
Novel BCL2 Inhibitor Under Study in Resistant CLL and Other Blood Cancers
According to Sikander Ailawadhi, MD, of the Mayo Clinic, Jacksonville, Florida, and colleagues, lisaftoclax offers a “user-friendly” daily ramp-up schedule for patients with relapsed or refractory chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and other hematologic malignancies. At the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract 7502), the results of this first-in-human, phase I trial were presented, indicating this BCL2 inhibitor may be well tolerated with doses up to 1,200 mg per day.
Patients had relapsed or refractory CLL or SLL (n = 15); multiple myeloma (n = 6); follicular lymphoma (n = 5); Waldenström’s macroglobulinemia (n = 4); and either acute myeloid leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, myelodysplastic syndromes, or hairy cell leukemia (n = 1 each). They were administered daily lisaftoclax at doses ranging from 20 to 1,200 mg.
No dose-limiting toxicities were reported. The maximum tolerated dose was not reached; no laboratory or clinical tumor-lysis syndrome was observed in this population. Neutropenia (22.9%), anemia (17.1%), fatigue (28.6%), diarrhea (17.1%), and nausea (11.4%) were the most frequently reported treatment-related adverse events of any grade. The most common treatment-related adverse events higher than grade 3 were neutropenia (14.3%), thrombocytopenia, leukopenia, lymphopenia, fatigue, and nausea (2.9% of patients each). In patients with CLL or SLL, grades 3 and 4 neutropenia (13.3%) and thrombocytopenia (6.7%) were reported.
The objective response rate was 85.7% in patients with relapsed or refractory CLL or SLL. Reductions in the absolute lymphocyte count were observed with doses as low as 20 mg. Based on the preliminary pharmacokinetic profile, exposures increased with doses from 20 to 1,200 mg. BH3 profiling showed that lisaftoclax rapidly triggered changes in the BCL2 complex in samples from patients with CLL or SLL; this was found to be consistent with clinical reductions in absolute lymphocyte counts.