Prospective evaluation of venetoclax combined with CLAG regimen in relapsed/refractory acute myeloid leukemia: A multicenter, randomized controlled, open-lable, phase II Trial

Abstract

Abstract CLAG (cladribine + cytarabine + G-CSF) based regimen is recommended for the salvage treatment of relapsed/refractory (RR) acute myeloid leukemia (AML). Recent study showed that venetoclax (Ven) combined with CLAG-based regimen had promising efficacy and well toleration in the frontline treatment of AML[1]. Our real-world study indicated Ven+CLAG might excel CLAG in the salvage treatment of RR-AML[2]. Here we performed a multicenter, prospective, randomized controlled, open-lable, phase II trial (NCT06763666) to compare the efficacy and safety of Ven+CLAG and CLAG in the RR-AML. As our previous study[2], patients in the control group took CLAG treatment, as follow, cladribine 5mg/m2, day 1-5, cytarabine 1g/m2, day 1-5, G-CSF 300ug per day, day 0-5. Patients in the experimental group took Ven+CLAG treatment. CLAG regimen was the same as the control group, and Ven was taken 400mg per day, from day 2-8. The primary endpoint was the rate of composite complete remission (CRc). Up to June 2025, 79 patients, with a median age of 38 (range, 18-65) years, were randomized into the experimental (n=41) and control (n=38) groups. After the salvage treatment, 31(75.6%) patients in the experimental group acquired CRc, significantly higher than the control group did (18(47.4%) obtained CRc, P=0.010). Also, the rates of overall response (85.4% vs 52.6%, P=0.002) and measurable residual disease (MRD)-negative (51.2% vs 28.9%, P=0.044) were remarkably different between the two groups. Subgroup analysis showed that patients with primary refractory disease, prior venetoclax/HMAs, ELN 2022-high risk, or MECOM-rearrangement had significantly higher CRc rate with Ven+CLAG treatment compared to CLAG . With a median follow-up of 4.5(IQR 2.0-8.0) months, patients in the experimental group had significantly better survival than the control group did (estimated 1 year overall survival 80.8%±8.8% vs 57.4%±10.1%, P=0.028). Adverse events including all grade and grade 3/4, also early mortality, occurred at similar frequencies in the two groups. In summary, our ongoing study demonstrated Ven combined with CLAG might significantly improve the outcome of the patients with RR-AML, with well toleration. Key words: CLAG, Venetoclax, salvage therapy, relapsed/refractory, acute myeloid leukemia Reference Kadia TM, Reville PK, Borthakur G, etal. Venetoclax plus intensive chemotherapy with cladribine, idarubicin, and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a cohort from a single-centre, single-arm, phase 2 trial. Lancet Haematol. 2021; 8(8): e552-e561. Zhang Y, Yin Z, Yao Z, Xu D, Jiang X, Nie X, Chen D, Zhou H, Shi P, Liu H, Liu Q, Yu G. Venetoclax added to CLAG regimen might improve the outcome of patients with relapsed/refractory acute myeloid leukemia. Ther Adv Hematol. 2025;16: