Lisaftoclax (APG-2575), a Novel BCL-2 Inhibitor, in Combination with Azacitidine in Treatment of Patients with Myelodysplastic Syndrome (MDS)

• Published in: Blood 2024-11, Vol.144, p.3202-3202
• Main Authors: Wang, Huafeng, Wei, Xudong, Liang, Yang, Weng, Jianyu, He, Wenjuan, Chang, Chunkang, Chen, Suning, Ma, Hongbing, Chen, Zi, Men, Lichuang, Liu, Lihui, Tian, Xiaohong, Zhang, Zhang, Cong, Danhua, Yang, Dajun, Zhai, Yifan, Jin, Jie
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-205371

Introduction Hypomethylating agents (HMAs) remain the standard of care in MDS. In the event of HMA failure/resistance, new therapeutic options are needed. Preclinical data have shown that novel, investigational BCL-2 inhibitor lisaftoclax synergistically induces apoptosis when combined with an HMA. Here, we present follow-up safety and efficacy data from a phase 1b/2 clinical trial evaluating lisaftoclax combined with azacitidine in adults (≥ 18 years) with MDS. Methods Patients with higher-risk MDS (IPSS-R score > 3.5; blasts > 5%), including those with treatment-naïve (TN) or relapsed or refractory (R/R) disease, were enrolled. Lisaftoclax alone at an assigned dose (400, 600, or 800 mg) was administered orally once daily from Days 1 to 14 and combined with azacitidine (75 mg/m2/day) on Days 1 to 7 in repeated 28-day cycles. A daily ramp-up was used before the first cycle to prevent tumor lysis syndrome (TLS). The primary objectives of the study were to assess the efficacy and safety of this combination in patients with MDS and establish the recommended phase 3 dose for lisaftoclax. Complete response (CR) and marrow CR rates were evaluated in accordance with 2006 International Working Group (IWG) criteria. Results As of July 1, 2024, a total of 49 patients were enrolled: 8 had R/R MDS (lisaftoclax 600 mg [n = 5] and 800 mg [n = 3]) and 41 had TN MDS (lisaftoclax 400 mg [n = 16], 600 mg [n = 16], and 800 mg [n = 2]). The median (range) age was 66 (22-83) years, and 55.1% of patients were male. IPSS-R risk categories were as follows: intermediate (12/49 [24.5%]), high (24/49[49.0%]), and very high (13/49 [26.5%]). Among 39 patients with genetic mutational profile data, 9 (23.1%) had TP53 mutations; 11 (28.2%), TET2 mutations; 10 (25.6%), ASXL1 mutations; and 10 (25.6%), RUNX1 mutations. At baseline, 70.8% (34/48) of patients reported grade ≥ 3 anemia; 54.2% (26/48), grade ≥ 3 neutropenia; and 45.8% (22/48), grade ≥ 3 thrombocytopenia. All patients treated with lisaftoclax combined with azacitidine reported treatment-emergent adverse events (TEAEs), of which 93.8% were grade ≥ 3 AEs and 35.4% serious AEs. Common grade ≥ 3 nonhematologic TEAEs (≥ 10% incidence) included pneumonia (24.4%) and hypokalemia (10.2%). Common grade ≥ 3 hematologic TEAEs included leukocyte count decreased (75.5%), neutropenia (69.4%), thrombocytopenia (65.3%), anemia (24.5%), and febrile neutropenia (18.4%). Grade ≥ 3 infections (system-organ-class) were reported in 46.9% of patients