olverembatinib + lisaftoclax + dexamethasone

A combination therapy consisting of olverembatinib (a third-generation BCR-ABL tyrosine kinase inhibitor), lisaftoclax (a BCL-2 selective inhibitor), and dexamethasone (a corticosteroid). This regimen is being investigated primarily for the treatment of relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (R/R Ph+ ALL) in children and adolescents. ## Drug Information Olverembatinib (HQP1351) is a third-generation BCR-ABL tyrosine kinase inhibitor developed by Ascentage Pharma. It targets both wild-type BCR-ABL1 kinase and a broad spectrum of BCR-ABL1 mutants, including the T315I mutation that confers resistance to first and second-generation TKIs[8]. It has been approved in China for treating adult patients with TKI-resistant chronic myeloid leukemia[8][10]. Lisaftoclax (APG-2575) is an investigational novel oral Bcl-2 selective inhibitor also developed by Ascentage Pharma[2][4]. It was recently included in the Chinese Society of Clinical Oncology (CSCO) 2025 Guidelines, marking its first recommendation in clinical practice guidelines[2][4]. The combination therapy includes dexamethasone, a corticosteroid that is commonly used in treatment regimens for leukemia. ## Clinical Development The combination is being studied in an open-label, multicenter, phase 1b study designed to explore the safety, efficacy, and pharmacokinetics of olverembatinib in combination with lisaftoclax in treating R/R Ph+ ALL in children[5]. The study protocol includes: 1. A 6-week core treatment after screening: - 2-week olverembatinib monotherapy - 4-week combination therapy with olverembatinib, lisaftoclax, and dexamethasone[5] 2. Dosing regimen: - Olverembatinib: 40mg adult equivalent dose every other day - Lisaftoclax: Ramp-up dosing of 200mg/400mg/600mg adult equivalent dose daily - Dexamethasone: 6 mg/m²/day daily[5] ## Mechanism of Action and Synergy The combination shows promising synergistic effects: 1. Olverembatinib inhibits BCR-ABL tyrosine kinase, which is crucial for the treatment of Philadelphia chromosome-positive leukemias[8]. 2. Lisaftoclax selectively inhibits BCL-2, a protein that prevents apoptosis (programmed cell death) in cancer cells[2][4]. 3. Preclinical studies have shown that olverembatinib in combination with lisaftoclax: - Synergistically inhibits proliferation and augments apoptosis in leukemia cells - Overcomes resistance to venetoclax (another BCL-2 inhibitor) in acute myeloid leukemia models[7][9] - Downregulates MCL-1 (an anti-apoptotic protein) by suppressing signaling pathways[9] 4. Dexamethasone likely enhances the anti-leukemic effects and helps manage side effects of the other medications. This combination represents a potential chemotherapy-free regimen for children with relapsed/refractory Ph+ ALL, which could offer significant clinical benefits compared to traditional chemotherapy approaches[3].

Other names

olverembatinib + APG-2575 + dexamethasone