In a Phase Ib/II study of 103 patients with myeloid malignancies, lisaftoclax plus azacitidine delivered an overall response rate of 43.2% and a complete remission rate of 31.8% among 44 evaluable patients with relapsed/refractory AML or MPAL. In the venetoclax-exposed relapsed/refractory subgroup (n=22), responses persisted with a 31.8% ORR and 22.7% CR rate. Newly diagnosed high-risk MDS/CMML patients (n=15) saw an 80% ORR, split evenly between complete remissions and marrow CRs. Median overall survival was 7.6 months in relapsed/refractory AML/MPAL and 11.3 months in relapsed/refractory high-risk MDS/CMML; OS was 6.3 months in newly diagnosed AML/MPAL and not reached in newly diagnosed high-risk MDS/CMML. No dose-limiting toxicities were reported; grade ≥3 cytopenias were the leading adverse events, including neutropenia (41.7%), febrile neutropenia (35.0%), thrombocytopenia (26.2%), and anemia (17.5%).
The company presented these results at ASH 2025, positioning lisaftoclax, a Bcl-2 inhibitor already approved in China for CLL/SLL, as a potential option for newly diagnosed high-risk MDS/CMML and for patients with prior venetoclax exposure across AML/MPAL and MDS/CMML. The multi-cohort trial (NCT04964518) included dose-escalation and expansion phases and used azacitidine as the backbone across newly diagnosed and relapsed/refractory settings.
Strategically, the signal in venetoclax-exposed disease is the fulcrum. With venetoclax firmly entrenched in frontline AML and advancing in MDS, sponsors face a growing pool of patients who relapse on or cannot tolerate the class, with few effective salvage options. Ascentage is testing whether another Bcl-2 inhibitor can recapture apoptotic sensitivity post-venetoclax and do so without exacerbating class-limiting toxicities. The absence of dose-limiting toxicities in this dataset underpins that narrative, even as high-grade cytopenias remain a reality of the mechanism and backbone. The company’s broader registrational posture in AML and MDS suggests a two-track plan: carve out a clear clinical niche in venetoclax-exposed salvage while trying to establish frontline relevance in high-risk MDS and elderly/unfit AML where azacitidine combinations dominate.
For sites and CROs, the operational implications are straightforward but nontrivial. Accrual in venetoclax-exposed relapsed/refractory AML is feasible given rising prevalence, but these patients are clinically fragile, with infection risk and cytopenia management driving resource utilization. Monitoring for tumor lysis and marrow suppression will dictate scheduling, transfusion support, and hospitalization patterns similar to current Bcl-2 practice. The mixed-diagnosis design offers broad access but creates heterogeneity that regulators will expect to be resolved via randomized, indication-specific Phase 3 studies. Vendors supporting central pathology, MRD assessment, and transfusion independence endpoints should anticipate expanded roles if the program pivots to registrational endpoints beyond CR.
What’s next hinges on trial design discipline and regulatory positioning. To displace or coexist with venetoclax in frontline MDS or AML, randomized evidence against azacitidine plus venetoclax will be the bar; to secure a post-venetoclax label, a well-powered study versus physician’s choice with OS, durability, and transfusion metrics will carry weight. The 31.8% ORR in venetoclax-exposed relapsed/refractory disease is encouraging but small and needs durability and survival substantiation. Safety scalability as enrollment expands will be scrutinized, particularly infection rates and dose intensity over time. Watch for protocol details from the ongoing Phase 3 GLORA studies in AML and high-risk MDS, clarity on biomarker or resistance-enrichment strategies, and any signal that regulators are open to an approval pathway anchored in the venetoclax-exposed population. If Ascentage can confirm efficacy post-venetoclax with manageable cytopenias and preserve dose delivery, it could define a salvage space; without that, head-to-head displacement in earlier lines will be a higher, costlier hill to climb.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
