Lisaftoclax: A Promising Bcl-2 Inhibitor in Combination Therapies for Relapsed/Refractory CLL

Live from ASH 2024 | Ascentage Pharma's Bcl-2 Inhibitor Lisaftoclax in Combinations Demonstrates Potential Clinical Benefit in Patients with Prior Exposure to Venetoclax

At the 66th American Society of Hematology (ASH) Annual Meeting, Ascentage Pharma presented promising data on lisaftoclax, a Bcl-2 inhibitor, in combination with other therapies for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who had prior exposure to venetoclax. The study demonstrated that lisaftoclax, when combined with accelerated ramp-up and then with either acalabrutinib or rituximab, showed activity and safety in patients with CLL.

The study included 47 patients who were heavily pretreated and had been exposed to Bruton tyrosine kinase (BTK) inhibitors. The patients were treated with lisaftoclax at doses ranging from 100 to 800 mg daily, with a median follow-up period of 14.06 months. The median age of the patients was 58 years, with 68.1% being male.

The study found that 76.6% of patients experienced grade 3/4 treatment-emergent adverse events (TEAEs), and 27.7% had serious adverse events (SAEs). Common TEAEs included decreased neutrophil, platelet, and leukocyte counts, anemia, hypertriglyceridemia, hyperuricemia, hypokalemia, diarrhea, and hyperbilirubinemia. Notably, no significant new or unmanageable safety findings were observed in combination therapies.

The median time to first response was 2.07 months, with an overall response rate (ORR) of 73.3% and a complete response (CR)/complete response with incomplete marrow recovery (CRi) rate of 24.4%. The rate of CR/CRi seemed to be dose-dependent, with higher rates observed at higher doses. Additionally, one patient in the 400-mg cohort achieved a CR after a dose escalation to 600 mg.

Minimal residual disease (MRD) negativity was observed in 7 of 18 (38.9%) patients tested with peripheral blood MRD assessment, and 4 of 6 (66.7%) patients tested negative for MRD with MRD assessment of bone marrow. Median progression-free survival (PFS) was 18.53 months, and median overall survival (OS) was not reached. OS at 12 and 30 months was 94.8% and 86.3%, respectively.

The combination of lisaftoclax with acalabrutinib or rituximab may offer a viable treatment option for patients with relapsed/refractory CLL who have prior exposure to venetoclax. The study demonstrated the potential synergistic effects of combining lisaftoclax with other therapies, contributing to enhanced clinical benefits. Further research is needed to confirm these findings and establish the most effective dosage and combination regimen for lisaftoclax in patients with prior exposure to venetoclax.