Lisaftoclax Demonstrates 62.5% Response Rate in BTK-Refractory CLL/SLL Patients
核心洞察
Lisaftoclax monotherapy achieved a 62.5% overall response rate and median progression-free survival of 23.89 months in heavily pretreated patients with relapsed/refractory chronic lymphocytic leukemia (搜索)/small lymphocytic lymphoma (搜索) who had failed BTK (搜索) inhibitors.
The phase 2 registrational study enrolled 77 patients with high-risk factors, including 42.9% with complex karyotype and 39% with del(17p)/TP53 (搜索) mutations, representing an ultra-high-risk population.
The BCL-2 (搜索) inhibitor demonstrated a manageable safety profile with no tumor lysis syndrome reported, supporting its conditional approval in China in July 2025.
Lisaftoclax, a novel BCL-2 (搜索) inhibitor developed by Ascentage Pharma (搜索), demonstrated significant clinical activity in heavily pretreated patients with relapsed/refractory chronic lymphocytic leukemia (搜索)/small lymphocytic lymphoma (搜索) (CLL/SLL) who had failed Bruton tyrosine kinase (BTK (搜索)) inhibitors, according to results from a pivotal phase 2 registration study presented at the 67th American Society of Hematology Annual Meeting.
The study enrolled 77 patients who met dual criteria of prior refractory, relapsed, or intolerance to both BTK (搜索) inhibitors and immunotherapy, or had high-risk factors such as del(17p)/TP53 (搜索) mutation or chromosomal complex karyotype. Among 72 evaluable patients, lisaftoclax achieved an overall response rate of 62.5% with a median progression-free survival of 23.89 months (95% CI, 13.01–not reached).
High-Risk Patient Population
The study population represented a particularly challenging cohort of CLL/SLL patients. At baseline, 42.9% had chromosomal complex karyotype, 39% had del(17p)/TP53 (搜索) mutation, and 53.2% had unmutated immunoglobulin heavy chain variable (IGHV). Among patients with complex karyotype, 63.6% had high karyotypic complexity with 5 or more aberrations, and 63.6% also had del(17p) or TP53 mutation.
"In our study, CK accounted for 42.9% of the total population. Patients with the del(17p)/TP53 (搜索) mutation accounted for 39.0% of the population, which was higher than that observed in prior studies. This represents true BTK (搜索) inhibitor failure and a refractory population," said Kenshu Zhou, MD, of the Henan Cancer Hospital in Zhengzhou, China, who presented the data.
The median patient age was 63.0 years, 59.7% were male, and patients had received a median of 3 previous therapies. Eighty-seven percent were refractory to BTK (搜索) inhibitors.
Efficacy Outcomes
At the data cutoff of July 25, 2025, with a median follow-up of 22.01 months, the median time to first response was 3.68 months and the median duration of response was 18.53 months (95% CI, 14.75–not reached). The 12-month progression-free survival rate was 66.4% (95% CI, 53.1%–76.7%).
Minimal residual disease negativity was observed in 21.8% of patients in peripheral blood and 54.5% in bone marrow among evaluable patients. The 30-month overall survival rate was 78.0% (95% CI, 66.1%–86.2%) with median overall survival not reached.
Subgroup analyses revealed the impact of high-risk genetic features on outcomes. In patients with del(17p)/TP53 (搜索) mutation, the median progression-free survival was 11.2 months versus 29.6 months in patients without this mutation or complex karyotype (HR, 5.0; P = 0.018). In patients with high complex karyotype, the median progression-free survival was 12.9 months versus 25.7 months in those without high complex karyotype (HR, 2.7; P = 0.001).
Safety Profile
The treatment demonstrated a manageable safety profile. Most treatment-related adverse events were grade 1 or 2, with grade 3/4 instances including neutropenia (27.3%), thrombocytopenia (16.9%), anemia (9.1%), and pneumonia (3.9%). Notably, no cases of tumor lysis syndrome or drug-related deaths were reported.
"Lisaftoclax monotherapy showed significant efficacy in heavily treated patients with relapsed/refractory CLL/SLL with a favorable safety profile and no TLS observed," Zhou noted.
Regulatory Status and Development
Based on these results, lisaftoclax received conditional approval from China's National Medical Products Administration in July 2025 for the treatment of adult patients with CLL/SLL who have previously received at least one systemic therapy, including BTK (搜索) inhibitors.
Ascentage Pharma (搜索) is currently conducting four global registrational Phase III studies to evaluate lisaftoclax in multiple indications. These include the FDA-cleared GLORA study in combination with BTK (搜索) inhibitors in patients with CLL/SLL, the GLORA-2 study in newly diagnosed CLL/SLL patients, the GLORA-3 study in elderly and unfit patients with acute myeloid leukemia (搜索), and the GLORA-4 study in patients with higher-risk myelodysplastic syndrome (搜索).
Clinical Significance
Professor Keshu Zhou emphasized the clinical importance of these findings: "These patients represent an ultra-high-risk subgroup with very poor prognosis. The overall results from the study show that Lisaftoclax monotherapy achieved encouraging deep and durable responses in heavily pretreated patients who had received multiple lines of treatment, especially those who had high-risk factors such as complex karyotype."
Zhou compared lisaftoclax favorably to venetoclax, another BCL-2 (搜索) inhibitor, noting its significant efficacy in heavily pretreated patients, short half-life, and absence of drug-drug interactions with BTK (搜索) inhibitors or CD20 monoclonal antibodies.
The study represents a significant advance for patients with BTK (搜索)-refractory CLL/SLL, particularly those with high-risk genetic features who have limited treatment options and poor prognosis with existing therapies.