Introduction Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) have poor prognoses. Venetoclax plus hypomethylating agent AZA is approved for certain patients with AML, but most have resistance or intolerance, warranting additional therapies for post-venetoclax relapsed/refractory (R/R) AML. Lisaftoclax, a novel, oral, investigational small-molecular BCL-2 inhibitor, has shown enhanced treatment responses when combined with AZA in preclinical and clinical studies. The aim of this study was to assess the safety and efficacy of lisaftoclax plus AZA for hematologic malignancies.

Methods APG2575AU101, a phase 1b/2, multicenter, open-label trial (initiated on July 30, 2021), enrolled patients diagnosed with histologically confirmed R/R AML, mixed phenotype acute leukemia (MPAL), chronic myelomonocytic leukemia (CMML), or R/R higher-risk (HR) MDS (by 2016 WHO classification) for which no available standard therapies were indicated or expected to elicit a durable response. These comprised patients with ND or R/R disease, including prior venetoclax treatment. In part 1, oral lisaftoclax (200-800 mg QD) plus AZA was administered to assess DLTs and MTD. In part 2, lisaftoclax (200/400/600 mg QD) over 28 or 14 days of 28-day cycles was administered with standard-dose AZA. Outcome measures included DLT (by NCI CTCAE v5.0) assessed within the first 28-day cycle of study treatment, MTD, RP2D, overall response rate (ORR), and overall survival (OS).

Results As of the data cutoff date, July 1, 2025, 103 patients were enrolled, including 63 with AML/MPAL (n = 56 R/R) and 40 with HR MDS/CMML (n = 25 R/R). Median (range) age was 71.0 (23-89) years, 58.2% of patients were male, and 28 (27.2%) had prior venetoclax exposure (all in the R/R AML/MPAL group). Treatment duration ranged from 2.0 (1-15) cycles (median 3.7 [0-17] months) in the R/R AML/MPAL group to 5.0 (1-21) cycles (median 6.5 [1-22] months) in the ND HR MDS/CMML group. No DLTs occurred. Grade ≥ 3 TEAEs (>5%) included neutropenia (41.7%), febrile neutropenia (35.0%), thrombocytopenia (26.2%), anemia (17.5%), sepsis (10.7%), pneumonia (6.8%) and white blood cell count decreased (5.8%). Serious AEs (>5%) included febrile neutropenia (31.1%), sepsis (9.7%), and pneumonia (6.8%). In patients with R/R AML/MPAL treated with lisaftoclax for 28 (n = 36) or 14 days (n = 11), respective ORRs were 38.9% and 45.5%, with respective complete response (CR) rates of 27.8% and 36.4%. In 24 efficacy-evaluable patients with venetoclax-refractory AML/MPAL, the ORR was 29.2% (7/24), and the CR (CR + CR with incomplete blood count recovery + marrow CR) rate was 20.8% (5/24). Among 18 patients with baseline peripheral blood mononuclear cell (PBMC) samples tested for NGS-based gene mutation analysis, 8 (44.4%) achieved CR, which demonstrated the highest TP53 (55.6%, 10/18) mutation, followed by TET2 (44.4%, 8/18), and 38.9% (7/18) patients exhibited both DNMT3A and RUNX1 mutations. Differential analysis of genes with mutations in ≥ 2 patients demonstrated increased CSF3R, SRSF2, and EZH2 mutations in the response group, suggesting their association with better treatment outcomes. Analysis of paired PBMC samples from baseline and end-of-treatment (EOT) from 7 patients demonstrated a significant increase in IDH2 mutation of 37.5% in EOT samples compared to 11.1% in baseline samples, irrespective of the clinical response. In addition, newly acquired mutations TEK, CHEK2, ABCB1, GNAS, and PMS2 were detected in patients either with or without responses in EOT samples, suggesting that they emerged during treatment. In 15 efficacy-evaluable patients with ND HR MDS/CMML, the ORR was 80.0%, with CR 40.0% and marrow CR 40.0%. Respective median (95% CI) OS values were (1) 7.6 (4.7-8.4) and 11.3 (3.9-13.4) months in patients with R/R AML/MPAL and R/R HR MDS/CMML; (2) 6.3 (3.1-NE) months in those with ND AML/MPAL; and (3) not reached (13.0-NE) in those with ND HR MDS/CMML.

Conclusions Lisaftoclax in combination with AZA provides a potential treatment option for HR MDS or AML. Lisaftoclax has shown promise to overcome venetoclax resistance in patients with these conditions. Most of the mutations detected in EOT samples were related to the RTK–RAS–MAPK pathway of gene regulation, indicating that tumors may commonly exhibit adaptive responses to treatment pressure, involving both reactivation of signaling pathways and resistance reprogramming. ClinicalTrials.gov ID: NCT04964518.

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2025
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