At a recent Annual Meeting of the American Society of Hematology (ASH), a prospective study conducted by Prof. Yi Luo’s team at The First Affiliated Hospital, Zhejiang University School of Medicine was selected for oral presentation. The study focused on MRD-positive acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT), evaluating the efficacy and safety of preemptive azacitidine plus venetoclax (Ven+Aza) therapy.
During the meeting, Hematology Frontier invited Associate Chief Physician Lizhen Liu, the study’s first author, to interpret the research findings, and Prof. Yi Luo to provide in-depth expert commentary, aiming to offer new insights for clinical practice and future research.
Investigator’s Perspective
Associate Chief Physician Lizhen Liu
This study aimed to evaluate the efficacy and safety of preemptive Ven+Aza therapy in AML and MDS patients after allo-HSCT. Although allo-HSCT remains a potentially curative treatment—particularly for high-risk patients—post-transplant relapse remains one of the leading causes of mortality, underscoring the importance of relapse prevention and early intervention.
Recent advances in measurable residual disease (MRD) monitoring, including multicolor flow cytometry, quantitative PCR (qPCR), and digital PCR (dPCR), have enabled more sensitive and dynamic post-transplant surveillance. In this study, Ven+Aza therapy was initiated immediately upon MRD positivity, and its clinical efficacy was systematically assessed.
Compared with previously reported post-transplant preemptive strategies—such as azacitidine monotherapy or donor lymphocyte infusion (DLI)—the Ven+Aza regimen demonstrated higher response rates, better tolerability, and lower relapse rates. The incidence of severe graft-versus-host disease (GVHD) was relatively low; only two patients discontinued treatment due to severe GVHD, suggesting a manageable and controllable safety profile, particularly when compared with DLI.
Multivariate analysis identified AML1-ETO and MLL fusion positivity, as well as MDS as the primary diagnosis, as factors associated with poorer responses to preemptive therapy. For patients with these characteristics, future treatment strategies may require combination approaches, such as incorporating DLI or targeted agents (e.g., menin inhibitors), to further improve treatment outcomes.
Expert Commentary
Prof. Yi Luo
This prospective phase II study evaluated venetoclax combined with azacitidine as preemptive therapy in MRD-positive AML and MDS patients following allo-HSCT. Post-transplant relapse remains the principal cause of treatment failure in high-risk AML, and outcomes are generally poor once overt hematologic relapse occurs.
By implementing MRD-guided preemptive intervention, this study aimed to induce earlier MRD negativity, thereby improving long-term survival. The results showed that patients who achieved MRD-negative remission after Ven+Aza therapy experienced significantly improved progression-free survival.
However, the study also revealed that certain subgroups—such as patients harboring AML1-ETO or MLL fusion genes, or those who remained MRD-positive after three to four treatment cycles—continued to face a high risk of subsequent hematologic relapse, with limited long-term benefit.
Future efforts should focus on further optimizing precision-based treatment strategies, particularly through target-driven combination therapies and multimodal approaches, to improve disease-free survival in these ultra–high-risk patient populations.
Study Abstract
Abstract 1061
Azacitidine Combined with Venetoclax as Preemptive Therapy for AML/MDS After Allogeneic Hematopoietic Stem Cell Transplantation: A Prospective Phase II Study
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the only curative option for acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS); however, post-transplant relapse remains a major clinical challenge. Systematic monitoring of measurable residual disease (MRD) enables detection of subclinical leukemia prior to overt relapse, allowing timely preemptive intervention. Given the established efficacy of venetoclax-based regimens in newly diagnosed AML, this prospective study evaluated MRD-guided venetoclax plus azacitidine (Ven+Aza) as preemptive therapy to prevent relapse (ClinicalTrials.gov: NCT04809181).
Patients with AML or advanced MDS who achieved complete remission after allo-HSCT underwent prospective MRD screening using multicolor flow cytometry (MFC) and donor chimerism analysis. Molecular MRD was assessed using qPCR or dPCR for leukemia-specific fusion genes or mutations. Patients with high baseline WT1 or EVI1 expression were monitored using bone marrow mRNA levels.
MRD positivity was defined as:
- LAIPs ≥0.1% by MFC; or
- Fusion gene level >0.1%; or
- WT1 expression >0.6%; or
- Mutation positivity (NPM1 ≥2%; other mutations >1% by qPCR or >0.2% by dPCR).
Upon MRD detection, immunosuppressive therapy was tapered and discontinued. All patients received azacitidine (75 mg/m², days 1–7) plus venetoclax (400 mg, days 1–14) every 4–8 weeks for up to six cycles. Treatment was discontinued in cases of intolerance, grade II–IV acute GVHD, severe chronic GVHD, or disease progression after two cycles.
Primary response was defined as LAIPs <0.01% or ≥1-log reduction/clearance of molecular markers; secondary response as partial reduction not meeting primary criteria.
A total of 44 patients were enrolled (median age 47 years, range 17–66), including 30 AML (68.2%) and 13 MDS (29.5%) cases. Haploidentical transplantation was performed in 81.8% of patients. The median time from transplantation to treatment initiation was 286 days.
After one treatment cycle, the major response rate was 62.8%. By the third cycle, the overall response rate peaked at 81.4%. With a median follow-up of 549 days, the 2-year cumulative incidence of relapse was 46.4%. Two-year overall survival, progression-free survival, and non-relapse mortality were 73.5%, 48.6%, and 4.9%, respectively.
Multivariate Cox analysis identified response to Ven+Aza as a strong protective factor for progression-free survival (HR = 0.02, P < 0.001), whereas WT1 positivity and MDS diagnosis were associated with inferior outcomes.
Grade 3–4 adverse events were mainly hematologic and reversible with supportive care. The incidence of acute and chronic GVHD was clinically manageable.
Conclusion: Preemptive venetoclax plus azacitidine is a safe and effective strategy for preventing disease progression in MRD-positive AML/MDS patients after allo-HSCT.
Expert Profiles
Prof. Yi Luo
The First Affiliated Hospital, Zhejiang University School of Medicine
MD, Professor, Chief Physician, PhD Supervisor Deputy Director, Bone Marrow Transplantation Center Zhejiang Provincial High-Level Innovative Health Talent
Deputy Head, HSCT Group, Chinese Society of Hematology Standing Committee Member, Zhejiang Society of Hematology Committee Member, Chinese Anti-Cancer Association (Hematologic Malignancies) Extensive experience in HSCT clinical and translational research; recipient of multiple national and provincial science awards; first or corresponding author in Blood, Leukemia, AJH, BJH, BMT, BBMT, among others.
Associate Chief Physician Lizhen Liu
The First Affiliated Hospital, Zhejiang University School of Medicine
MD, Master’s Supervisor Vice Chair, Young Committee, Hematology & Lymphoma Branch, Zhejiang Anti-Cancer Association Committee Member, HSCT Committee, China Primary Health Care Foundation
