Adding a BCL-2 Inhibitor to BTK Inhibitor Therapy—Can Lisaftoclax Close the Gap for High-Risk CLL?

For patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have been on Bruton tyrosine kinase inhibitor (BTKi) therapy for a year or more without achieving a complete response, what comes next? Residual disease and the potential risk of BTKi resistance leave this population at meaningful risk for early progression, underscoring the critical need for strategies that can deepen responses before resistance takes hold.

Introducing BCL-2 Inhibitors

BTK inhibitors work by blocking B-cell receptor (BCR) signaling but they don't address all pathways that drive CLL survival. BCL-2 inhibitors take a different route, targeting the apoptotic machinery of cancer cells through a BCR-independent mechanism. The combination of these 2 approaches forms the scientific rationale behind this trial.

Lisaftoclax (APG-2575; Ascentage Pharma) is a selective, oral BCL-2 inhibitor with a short half-life of 4 to 6 hours, allowing for once-daily dosing. Already approved in China as a second-line CLL therapy, lisaftoclax has demonstrated overall response rates of 67% in relapsed/refractory CLL and 62.5% in BTKi-refractory disease—including patients with high-risk features such as del(17p) and TP53 mutations. When combined with acalabrutinib (Calquence; AstraZeneca Pharmaceuticals LP), response rates exceeded 97%, and the combination demonstrated a favorable tolerability profile, providing early evidence that the combination is both active and manageable.

The GLORA Trial

The global, multicenter, open-label, randomized phase 3 registrational GLORA study (NCT06104566) is investigating lisaftoclax as a monotherapy for adults with CLL/SLL who, after at least 12 months of BTKi monotherapy across up to 3 lines of therapy, have neither a complete response nor progressive disease. This partial response plateau represents a window of opportunity to deepen responses before resistance takes hold.

Eligible patients must also have at least 1 high-risk feature, such as del(17p)/TP53 mutation, unmutated IGHV, or complex karyotype with 5 or more abnormalities, or have measurable residual disease with lymph nodes of 2.5 cm or larger. Patients with prior BCL-2 inhibitor exposure or Richter transformation are excluded.

Study Design

Approximately 440 patients will be randomized to receive either lisaftoclax plus their physician’s choice of BTKi (acalabrutinib, zanubrutinib [Brukinsa; BeiGene], or ibrutinib [Imbruvica; Janssen Biotech]) or to continue BTKi monotherapy. Patients in the investigational arm undergo a 5-day oral lisaftoclax ramp-up to 400 mg once daily, then continue in 28-day cycles until progression or unacceptable toxicity. Randomization is stratified by del(17p)/TP53 mutation status.

The primary end point is progression-free survival (PFS) by independent review committee per 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, with overall survival as the key secondary end point. Additional end points include investigator-assessed PFS, overall response rate, duration of response, minimal residual disease negativity, and safety.

Looking Ahead

Enrollment is actively ongoing across 126 sites in 18 countries. If lisaftoclax plus BTKi succeeds in deepening responses and prolonging PFS in this high-risk population, it could establish a new combination strategy for patients with historically limited options.

REFERENCE

Davids MS, Ailawadhi S, Musuraca G, et al. A global multicenter, open-label, randomized, phase 3 registrational study of lisaftoclax (APG-2575) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): GLORA trial in progress. Presented at: 2026 ASCO Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract TPS7101.