Lisaftoclax Monotherapy Achieves Significant Responses and PFS in R/R CLL/SLL

Lisaftoclax, a BCL-2 inhibitor, demonstrated a significant overall response rate (ORR) of 62.5% and a progression-free survival (PFS) of 23.89 months (95% CI, 13.01–not reached [NR]) with a tolerable safety profile in heavily treated patients with relapse/refractory chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), according to findings of a phase 2 pivotal registration study (NCT05147467).¹

At the data cutoff of July 25, 2025, among 72 evaluable patients, the median time to first response was 3.68 months (range, 1.81–11.14) and the median duration of response was 18.53 months (95% CI, 14.75–NR).¹ The median follow-up period was 22.01 months (range, 0.80–38.0).

The 12-month PFS rate was 66.4% (95% CI, 53.1%–76.7%). The 30-month overall survival (OS) rate was 78.0% (95% CI, 66.1%–86.2%) and the median OS was NR.

“Further, minimal residual disease [MRD] negativity in peripheral blood was observed in 21.8% of patients and 54.5% in bone marrow,” Kenshu Zhou, MD, of the Henan Cancer Hospital in Zhengzhou, China, said during a presentation of the data at the 67th American Society of Hematology Annual Meeting and Exposition in Orlando, Florida.¹

Study Design

A total of 77 patients were enrolled if they met the dual criteria of prior refractory, relapsed, or intolerance to both Bruton tyrosine kinase (BTK) inhibitors and immunotherapy or had high-risk factors such as del(17p)/TP53 mutation or chromosomal complex karyotype (CK).

Eligible patients received lisaftoclax on a daily ramp-up schedule to reach the target dose of 600 mg once a day administered every 28 days in a dosing cycle. The primary end point was ORR, and secondary end points were complete response, PFS, time to response, OS, and safety.

Baseline Characteristics

At baseline, patient median age was 63.0 years (range 37–84), 59.7% were male, and had been treated with a median of 3 previous therapies (range, 1–10). Patients had an ECOG status of 0 to 1 (68.8%) or 2 (31.2%).

Eighty-seven percent were refractory to BTK inhibitors and 39% had del(17p)/TP53 mutation, 53.2% had unmutated immunoglobulin heavy chain variable (IGHV), and 42.9% had CK.

Among patients with CK (n = 33), 63.6% had high CK with 5 or more aberrations and 21 (63.6%) also had del(17p) of TP53 mutation.

In patients with del(17p)/TP53 mutation, the median PFS was 11.2 months vs 29.6 months in patients without this mutation or CK (HR, 5.0; P =.018). In patients with high CK, the median PFS was 12.9 months vs 25.7 months in those without high CK (HR, 2.7; P =.001).

“In our study, CK accounted for 42.9% of the total population. Patients with the del(17p)/TP53 mutation accounted for 39.0% of the population, which was higher than that observed in prior studies.^2,3 This represents true BTK inhibitor failure and a refractory population,” Zhou said.

Regarding safety, most treatment-related adverse events (TRAEs) were grade 1 or 2, although there were grade 3/4 instances of neutropenia (27.3%), thrombocytopenia (16.9%), anemia (9.1%), and pneumonia (3.9%) reported. “There were no cases of tumor lysis syndrome [TLS] or drug-related deaths reported,” Zhou continued.

Zhou further compared the agent with another BCL-2 inhibitor, venetoclax (Venclexta), noting significant efficacy in heavily pretreated patients with CLL/SLL, a short half-life, and the absence of drug-drug interactions with BTK inhibitors or CD20 monoclonal antibodies.

“Lisaftoclax monotherapy showed significant efficacy in heavily treated patients with relapsed/refractory CLL/SLL with a favorable safety profile and no TLS observed,” Zhou said. “The agent received a conditional approval in China in July 2025,” Zhou concluded.

REFERENCES

1. Zhou K, Wang T, Niu T, et al. Results of a registrational Phase 2 study of lisaftoclax monotherapy for treatment of patients (pts) with Relapsed/Refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who had failed Bruton’s tyrosine kinase inhibitors (BTKis). Presented at: 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, Florida. Abstract 88.

2. Ghia P, Pluta A, Wach M, et al. ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol; 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355

3. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332. doi:10.1056/NEJMoa2211582