In a registrational Phase II study of 72 evaluable patients with relapsed/refractory CLL/SLL after BTK inhibitor exposure, lisaftoclax monotherapy delivered a 62.5% objective response rate with a median progression-free survival of 23.89 months at a median follow-up of 22.01 months. Minimal residual disease negativity was observed in 21.8% of peripheral blood assessments, and 6 of 11 evaluable patients achieved bone marrow MRD negativity. The safety profile was dominated by hematologic grade ≥3 events, with no tumor lysis syndrome and no treatment-related deaths reported. Separately, in a Phase I/II combination study with azacitidine, lisaftoclax produced a 40.4% ORR and 29.8% CR rate in relapsed/refractory AML/MPAL, and a 29.2% ORR with 20.8% CR in venetoclax-exposed R/R AML/MPAL. In newly diagnosed higher-risk MDS/CMML, the ORR reached 80% with 40% CR and 40% marrow CR. No DLTs were observed; the most common grade ≥3 TEAEs included neutropenia (41.7%) and febrile neutropenia (35.0%).
The American Society of Hematology accepted the lisaftoclax monotherapy readout for an oral presentation and the azacitidine combination for a poster, signaling Ascentage Pharma’s intent to broaden the BCL-2 footprint beyond its China approval in BTKi-exposed CLL/SLL. The Phase II dataset is positioned to reinforce the company’s domestic label. It underpins a global push now centered on four registrational Phase III programs across CLL/SLL, AML, and higher-risk MDS. The program is unfolding alongside olverembatinib’s late-stage development, giving Ascentage multiple hematology catalysts as it works to establish a U.S. and EU presence.
Strategically, the company is advancing a two-track thesis: monotherapy viability in post-BTK CLL/SLL and combination potential where venetoclax resistance is eroding outcomes in AML/MDS. The absence of TLS in the Phase II experience is noteworthy operationally, as BCL-2 inhibitors often carry monitoring and ramp-up burdens that strain site capacity and inpatient resources. In AML/MDS, showing activity in a venetoclax-exposed population addresses a growing pain point for sponsors and clinicians; however, converting single-arm signals into a differentiated label in the U.S. will likely require randomized evidence and clarity on durability and survival in defined subgroups.
For sites and CROs, Lisaftoclax’s global Phase III footprint means near-term protocol flow across CLL/SLL and myeloid malignancies with added complexity around prior BTKi exposure, MRD sampling, and cytopenia management. The potential to minimize TLS logistics could reduce onboarding friction and monitoring intensity, particularly in community settings, but hematologic toxicity will still drive resource planning and transfusion support. Regulators have already coordinated on the MDS study clearance across the FDA, EMA, and China’s CDE, hinting at an accelerated multi-region dialogue if Phase III signals hold. Diagnostics and central lab vendors should expect increased demand for standardized MRD readouts as sponsors seek regulatory-grade minimal disease endpoints in CLL/SLL.
The next set of milestones will test whether the Phase II CLL/SLL outcomes translate into broader, more heterogeneous Phase III populations and whether the azacitidine combination shows an advantage over entrenched venetoclax-based regimens, particularly after prior venetoclax exposure. Watch for durability beyond two years, outcomes in TP53-aberrant and complex karyotype cohorts, and any movement toward U.S. expedited pathways contingent on Phase III readouts. Operationally, keep an eye on how protocols codify TLS mitigation, hospitalization requirements, and MRD assessment schedules—areas that may determine site uptake as much as efficacy does.
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.
