Venetoclax, cladribine plus low-dose cytarabine for relapsed/refractory Acute Myeloid Leukemia: A multicenter, randomized phase II Study

Abstract Introduction: Relapse or refractory acute myeloid leukemia (R/R AML) is a highly heterogeneous disease with poor prognosis. Current conventional reinduction regimens, such as FLAG-ida and MEC, yield remission rates of 30%–50% and a two-year survival rate of only 27%. Venetoclax, a BCL-2 inhibitor, has shown promise in combination with hypomethylating agents (azacitidine or decitabine) or low-dose cytarabine, achieving a reinduction rate of approximately 40%. Additionally, cladribine-based regimens have demonstrated synergistic effects with cytarabine, with remission rates exceeding 50%. To explore more effective treatment options for R/R AML, we designed a multicenter, randomized controlled trial comparing the reinduction efficacy of MEC versus a novel combination of venetoclax, cladribine, and low-dose cytarabine (CAV). Here, we present the interim analysis of this ongoing clinical trial (NCT05657639). Methods: This randomized, controlled, multicenter study evaluated the efficacy and safety of CAV compared to MEC. Eligible patients were randomized 1:1 to receive either CAV (cladribine 5 mg/m2/day, cytarabine 20mg q12h, venetoclax 100mg d1, 200 d2, 400 mg/day from day 3 to day 21) or MEC (mitoxantrone 8mg/m2 d1-5, etoposide 100mg/m2 d1-5, cytarabine 1g/m2 d1-5). The primary endpoint of the study was overall response rate (ORR), the secondary endpoints of the study were adverse events (AEs), overall survival (OS) and event free survival (EFS). Bone marrow evaluation was performed after the blood cell count recovery or within 14 days after treatment completion. Results: From October 2022 to July 2025, a total of 55 R/R AML patients were enrolled and randomly assigned, 30 to the CAV group and 25 to the MEC group. Baseline characteristics were relatively balanced between groups. 28 (50.9%) of 55 patients were male and 27 (49.1%) were female. The median age was 49.5 years (range 15-66) and 51 years (range 30-68) in the CAV group and MEC group, respectively. Overall, 10 (22%) of patients had a high-risk stratification, including 43.3% in the CAV and 20% in MEC group. ORR (CR/CRh/CRi/MLFS) was 53.3% (16/30) in the CAV group and 32.0% (8/25) in the MEC group (P=0.11). CR was achieved in 30% and 4%, respectively. Notably, in the venetoclax-naïve subgroup, CAV achieved a significantly superior ORR of 66.7% (10/15) versus 32% (8/25) with MEC (P=0.03). While the 1-year overall survival rate was 67.1% in the MEC group, it was not yet reached in the CAV group. Following treatment, 34.5% (19/55) patients underwent allogeneic hematopoietic stem cell transplantation. Seven patients died because of disease progression, four patients died of infection. Grade ≥3 hematologic toxicities were similar in both treatment groups, with neutropenia reported in 100% in both groups. The commonest grade≥3 nonhematologic toxicities in the CAV and MEC groups were pneumonia (10% vs 20%), sepsis (3% vs 28%). Conclusion: Our findings demonstrate that the CAV regimen represents an effective and well-tolerated salvage therapy for R/R AML, particularly in venetoclax-naïve patients who achieved significantly superior response rates. These promising results warrant further validation in larger prospective studies to confirm the regimen's efficacy.