In a registrational Phase II study of 77 patients with BTK inhibitor–refractory relapsed/refractory CLL/SLL, lisaftoclax monotherapy delivered a 62.5% objective response rate among 72 evaluable patients, with a median progression-free survival of 23.89 months at a 22.01-month median follow-up. The cohort was heavily pretreated and enriched for adverse biology, including 42.9% with complex karyotype, 39% with del(17p)/TP53 mutations, and 53.2% with unmutated IGHV. Peripheral blood MRD negativity was achieved in 21.8% of patients, and among 11 evaluable patients with bone marrow assessments, 54.5% were MRD negative. No tumor lysis syndrome or treatment-related deaths were reported; the most frequent grade ≥3 treatment-related events were expected cytopenias.
The core development: Ascentage Pharma presented the data as an oral at ASH from a China-based, single-arm registrational trial (NCT05147467) in patients who had failed BTK inhibitors and were refractory to, relapsed on, or intolerant of immunochemotherapy, or ineligible for it. These results underpinned China’s NMPA approval of lisaftoclax in July 2025 for adults with previously treated CLL/SLL, including prior BTKi exposure. The company is now prosecuting a global program with four Phase III studies spanning CLL/SLL, AML, and higher-risk MDS, including an FDA-cleared study in CLL/SLL combining lisaftoclax with BTK inhibitors in patients with suboptimal BTKi response.
Strategically, the readout advances Ascentage’s bid to position lisaftoclax as a next-generation BCL-2 option in the post-BTKi setting while it builds out combination and frontline strategies. The absence of TLS in a high-risk population is notable for a class where initiation logistics often drive site burden and patient management complexity. The signal of durable monotherapy efficacy in ultra–high-risk cytogenetics is the clinical hook; the operational hook is a potential easing of inpatient monitoring and lab intensity if the TLS profile holds in broader use. The counterweight is that the dataset is single-arm and China-centric, and the bar for global adoption remains comparison against entrenched venetoclax-based regimens.
For sites and CROs, lisaftoclax’s profile, if replicated, could recalibrate startup and monitoring requirements in CLL trials that typically revolve around TLS mitigation, serial labs, and potential inpatient ramp-up. Even with conservative protocols, a lower TLS incidence could translate into fewer hospitalization requirements, simplified schedules, and reduced pharmacy coordination. At the same time, trials in BTKi-refractory, genomically adverse CLL demand robust central cytogenetics and MRD infrastructure, adding assay complexity and turnaround-time pressure. Sponsors will also be competing for a finite pool of BTKi-refractory, venetoclax-naïve patients, making eligibility definitions and prior therapy caps pivotal to recruitment velocity.
In the competitive and regulatory context, differentiation from venetoclax will require randomized evidence, not only on efficacy and safety, but on real operational advantages. Activity in venetoclax-exposed patients would be a decisive wedge; the current readout does not address this. FDA and EMA will scrutinize durability beyond 24 months, subgroup consistency across high-risk genetics, contemporaneous SOC controls, and MRD as a supportive, not primary, endpoint. Multi-regional enrollment and manufacturing comparability will be prerequisites for any bridging strategy from China to U.S./EU labels.
What to watch next are the global Phase III CLL programs, especially outcomes in patients with suboptimal BTKi response and any head-to-head or SOC-controlled designs that benchmark against venetoclax-based therapy. Operationally, look for how initiation is handled in Western studies—outpatient vs inpatient, lab cadence, and real-world TLS rates—and whether protocols evolve to reflect a different risk profile. Key risks include cytopenia management in combinations, competition for a narrow BTKi-refractory population, and the unanswered question of efficacy post-venetoclax. If lisaftoclax can substantiate TLS sparing and durable control in controlled settings, it could shift both sequencing logic and site workload in CLL.
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.
