A novel therapy combining the investigational BCL-2 inhibitor lisaftoclax with azacitidine has demonstrated encouraging efficacy and safety among participants with higher-risk myelodysplastic syndrome (MDS), according to a phase 1b/2 trial.
Hypomethylating agents, such as azacitidine, are the standard-of-care treatment for MDS. MDS, in particular higher-risk MDS, poses significant challenges for clinicians due to limited treatment options after hypomethylating agent therapy failure. Preclinical studies have suggested that lisaftoclax enhances the pro-apoptotic effects of azacitidine. Dr. Huafeng Wang, Zhejiang University, Hangzhou, China, and colleagues assessed the safety and efficacy of a combination therapy of lisaftoclax and azacitidine in a phase 1b/2 trial (NCT04501120).1
The trial enrolled 49 adults with treatment-naive or relapsed and refractory higher-risk MDS. Participants received oral doses of lisaftoclax of 400, 600, or 800 mg daily (days 1–14) combined with azacitidine (75 mg/m² daily, days 1–7) in 28-day cycles. A dose ramp-up phase was included to minimize tumor lysis syndrome risk.
In eight participants with relapsed and refractory MDS, the overall response rate (ORR) was 75% (95% CI, 34.9-96.8), with a complete response (CR) rate of 12.5%. Among 40 efficacy-evaluable treatment-naive participants, the ORR was 77.5% (95% CI, 61.5-89.2), with a CR rate of 25% per International Working Group (IWG) 2006 criteria. For the 23 efficacy-evaluable treatment-naive participants treated with 600 mg lisaftoclax and azacitidine, the ORR was 73.9%, with a CR rate of 30.4%. The composite CR rate was 69.6% in this group, based on the updated IWG 2023 criteria.
All participants presented with treatment-emergent adverse events (TEAEs), of which 93.8% were grade ≥3 AEs and 35.4% were serious AEs. The most common TEAEs were decreased leukocyte count (75.5%), neutropenia (69.4%), and thrombocytopenia (65.3%). Besides these, no tumor lysis syndrome or 60-day mortality cases were reported, and dose reductions were only required for 8.2% of participants. Treatment-related adverse events were reported by 95.9% of participants, of which 87.8% were grade ≥3 and 28.6% were serious AEs with manageable delays and minimal need for dose modifications.
In this study, the combination of lisaftoclax and azacitidine was safe and effective for participants with higher-risk MDS, a group with limited treatment options. The observed activity among participants with treatment-naive and relapsed and refractory MDS supports this combination as a promising candidate for further trials.
Reference
- Wang H, Wei X, Liang Y, et al. Lisaftoclax (APG-2575), a novel BCL-2 inhibitor, in combination with azacitidine in treatment of patients with myelodysplastic syndrome (MDS). Abstract #3202. Presented at the American Society of Hematology Annual Meeting; December 7-10, 2024; San Diego, California.