Fludarabine Plus Melphalan Versus Addition of Venetoclax to Fludarabine/Melphalan Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in AML/MDS Patients Aged > 50 Years: a Multicenter, Randomized, Phase 3 Trial

March 16, 2026 updated by: First Affiliated Hospital of Zhejiang University

Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) serves as a curative treatment modality for the vast majority of patients with hematological malignancies. Historically, due to the relatively high treatment-related mortality rate associated with Allo-HCT, this therapy was primarily administered to younger patients. However, the median age at onset of most hematological malignancies falls within the elderly population. For instance, the median ages at onset of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) are 68 and 77 years, respectively. In recent years, with the advancement of transplantation techniques and the application of Reduced-intensity Conditioning (RIC) regimens, a growing number of elderly patients have undergone Allo-HCT. Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) indicate that in 2017, 31% of patients who received Allo-HCT were aged over 60 years, and 6% were over 70 years old. Over the past decade, the number of elderly patients undergoing Allo-HCT has increased significantly.

Given that most elderly patients cannot tolerate conventional myeloablative conditioning regimens, RIC regimens based on Fludarabine (Flu) combined with Busulfan (Bu), or Fludarabine (Flu) combined with Melphalan (Mel) are currently widely used in elderly patients undergoing Allo-HCT. Nevertheless, the post-transplant relapse rate remains as high as 30%-55%, and the long-term GVHD-free and Relapse-free Survival (GRFS) rate fluctuates between 21% and 59%, suggesting that the efficacy of transplantation needs to be further improved. Further comparison of the commonly used RIC regimens in elderly patients-namely Flu+Bu (2-day), Flu+Bu (4-day) and Flu+Mel-has demonstrated that the Flu+Mel regimen yields superior transplantation outcomes over the Flu+Bu regimens.

At present, the optimal RIC regimen for elderly patients with hematological malignancies has not yet been clearly defined. The selection of transplantation conditioning regimens for elderly patients should strike a balance between reducing non-relapse mortality and decreasing post-transplant relapse. Over the past 20 years, an increasing number of targeted drugs acting on specific cellular signaling pathways, anti-apoptotic proteins, epigenetic regulators, and monoclonal antibodies have been introduced into clinical practice, thereby revolutionizing the treatment landscape of hematological malignancies. These novel targeted therapies not only bring hope of achieving remission to patients with hematological tumors resistant to traditional chemotherapy, but also the combined application of novel drugs and Allo-HCT is bound to fundamentally transform the overall technical system of hematopoietic stem cell transplantation. Venetoclax is a potent and selective oral inhibitor targeting the BH3 domain of the anti-apoptotic protein Bcl-2. In 2018, the FDA approved Venetoclax as a first-line induction chemotherapy agent for elderly AML patient's ineligible for intensive chemotherapy, with a complete remission rate of up to 67% and favorable tolerability¹¹. Preclinical studies using Allo-HCT animal models have confirmed that the addition of a Bcl-2 inhibitor to RIC regimens can promote donor cell engraftment, reduce the incidence of GVHD, without impairing the graft-versus-leukemia (GVL) effect¹². In recent years, clinical trials have reported the efficacy and safety of the conditioning regimen combining Venetoclax with Flu+Bu in patients with myeloid malignancies undergoing Allo-HCT. Our research center has demonstrated the favorable safety profile and promising long-term survival outcomes of the Venetoclax plus Flu+Mel conditioning regimen in a phase II clinical trial involving patients aged over 50 years with AML/MDS undergoing Allo-HCT (2024 EBMT Poster B093; 2025 EBMT Poster B126). However, the long-term superiority of this novel regimen over the conventional Flu+Mel conditioning regimen remains to be clarified.

Therefore, based on the existing findings from clinical studies and Allo-HCT animal model research, we hypothesize that incorporating Venetoclax into the Fludarabine+Melphalan conditioning regimen for elderly patients undergoing Allo-HCT is expected to improve long-term post-transplant survival and further enhance the transplantation efficacy in this patient population.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Patients aged over 50 years diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who met the inclusion and exclusion criteria were enrolled in this study. Stratified by age (< 60 years vs. ≥ 60 years) and disease type (AML vs. MDS), the patients were randomly assigned to two groups: the control group, which received the conditioning regimen of fludarabine plus melphalan; and the experimental group, which received the conditioning regimen of venetoclax combined with fludarabine and melphalan.

  1. Conditioning Regimen for the Experimental Group 1) Venetoclax: 400 mg/day, days -8 to -2. (Note: If fluconazole is co - administered for antifungal prophylaxis during the transplantation conditioning period, the dose of Venetoclax should be reduced to 50% of the standard dose (i.e., 200 mg/day). If voriconazole or posaconazole is used for antifungal prophylaxis, the dose of Venetoclax should be reduced to 25% of the standard dose (i.e., 100 mg/day).) 2) Fludarabine (Flu): 30 mg/m²/day, days -7 to -3. 3) Melphalan (Mel) dose, adjusted according to the patient's age:

    1. For patients aged < 60 years: 140 mg/m²/day, day -2.
    2. For patients aged 60 ≤ age < 70 years: 120 mg/m²/day, day -2.
    3. For patients aged ≥ 70 years: 100 mg/m²/day, day -2.

  2. Conditioning Regimen for the Control Group 1) Fludarabine (Flu): 30 mg/m²/day, days -7 to -3. 2) Melphalan (Mel) dose, adjusted according to the patient's age:

    1. For patients aged < 60 years: 140 mg/m²/day, day -2.
    2. For patients aged 60 ≤ age < 70 years: 120 mg/m²/day, day -2.
    3. For patients aged ≥ 70 years: 100 mg/m²/day, day -2.

Study Type

Interventional

Enrollment (Estimated)

186

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • China
      • Chongqing, China
        • Recruiting
        • Second Affiliated Hospital of Army Medical University (Xinqiao Hospital)
        • Contact:
      • Hangzhou, China
        • Recruiting
        • The Second Affiliated Hospital, Zhejiang University School of Medicine
        • Contact:
      • Hangzhou, China
        • Recruiting
        • Sir Run Run Shaw Hospital Zhejiang University School of Medicine
        • Contact:
      • Hangzhou, China
        • Recruiting
        • The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine)
        • Contact:
      • Hangzhou, China
        • Recruiting
        • Zhejiang Provincial Peoples's Hospital
        • Contact:
      • Ningbo, China
        • Recruiting
        • The Affiliated People's Hospital of Ningbo University
        • Contact:
      • Ningbo, China
        • Recruiting
        • The First Affiliated Hospital of Ningbo University
        • Contact:
      • Shanghai, China
        • Recruiting
        • Shanghai General Hospital (Shanghai First People's Hospital)
        • Contact:
          • Xianmin Song
      • Wenzhou, China
        • Recruiting
        • The First Affiliated Hospital of Wenzhou Medical University
        • Contact:
    • Fujian
      • Fuzhou, Fujian, China
        • Recruiting
        • The First Affiliated Hospital of Fujian Medical University
        • Contact:
    • Guangdong
      • Guangzhou, Guangdong, China
        • Recruiting
        • Nanfang Hospital Southern Medical University
        • Contact:
          • Li Xuan
    • Henan
      • Zhengzhou, Henan, China
        • Recruiting
        • The First Affiliated Hospital of Zhengzhou University
        • Contact:
    • Hubei
      • Wuhan, Hubei, China
        • Recruiting
        • Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
        • Contact:
          • Linghui Xia
    • Hunan
      • Changsha, Hunan, China
    • Jiangsu
      • Nanjing, Jiangsu, China
        • Recruiting
        • Jiangsu Province Hospital (The First Affiliated Hospital of Nanjing Medical University)
        • Contact:
    • Shandong
      • Jinan, Shandong, China
        • Recruiting
        • Qilu Hospital of Shandong University
        • Contact:
          • Xinguang Liu
    • Zhejiang
      • Hangzhou, Zhejiang, China, 311121
        • Recruiting
        • The first Affiliated Hospital, Zhejiang University School of Medicine
        • Contact:
      • Hangzhou, Zhejiang, China
        • Recruiting
        • Zhejiang Cancer Hospital & Hangzhou Institute of Medicine, Chinese Academy of Sciences
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Aged > 50 years;
  2. Confirmed as acute myeloid leukemia (AML) in remission prior to transplantation, myelodysplastic syndrome (MDS; IPSS: Intermediate-2, high; or IPSS-R: Intermediate, high, very high; or IPSS-M: moderate-high, high, and very high), or myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) by morphology, immunology, cytogenetics and molecular biology (MICM) typing;
  3. Having an eligible donor and scheduled to undergo allogeneic hematopoietic stem cell transplantation (Allo-HCT) from a related or unrelated donor;
  4. Karnofsky Performance Score ≥ 70;
  5. Eastern Cooperative Oncology Group (ECOG) Performance Status < 3;
  6. Expected survival time > 12 weeks;
  7. Voluntarily signing the informed consent form and being able to understand and comply with all study requirements.

Exclusion Criteria:

  1. Complicated with severe cardiac insufficiency with a left ventricular ejection fraction (EF) < 60%; or complicated with severe arrhythmia, and assessed by the investigator as unable to tolerate the intensive conditioning regimen;
  2. Complicated with severe pulmonary insufficiency (obstructive and/or restrictive ventilatory disorder), and assessed by the investigator as unable to tolerate the intensive conditioning regimen;
  3. Complicated with severe liver function impairment, with liver function indicators (alanine aminotransferase [ALT], total bilirubin [TBIL]) exceeding 3 times the upper limit of normal (ULN); and assessed by the investigator as unable to tolerate the intensive conditioning regimen;
  4. Complicated with severe renal insufficiency, with serum creatinine (Cr) exceeding 2 times the upper limit of normal (ULN); or with a 24-hour creatinine clearance rate (Ccr) < 50 ml/min, and assessed by the investigator as unable to tolerate the intensive conditioning regimen;
  5. Suffering from severe active infection prior to transplantation, and assessed by the investigator as unable to tolerate the intensive conditioning regimen;
  6. Having a history of allergic reactions or severe adverse reactions to the drugs involved in the conditioning regimen, and assessed by the investigator as ineligible for enrollment;
  7. Other reasons for ineligibility assessed by the investigator.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: FM
Fludarabine and Melphalan
Drug: Fludarabine and Melphalan

FM conditioning regimen:

  1. Fludarabine (Flu): 30 mg/m²/day, days -7 to -3.

  2. Melphalan (Mel) dose, adjusted according to the patient's age:

    1. For patients aged < 60 years: 140 mg/m²/day, day -2.
    2. For patients aged 60 ≤ age < 70 years: 120 mg/m²/day, day -2.
    3. For patients aged ≥ 70 years: 100 mg/m²/day, day -2.
Experimental: VFM
Venetoclax in combination with fludarabine and melphalan
Drug: Venetoclax in combination with fludarabine and melphalan

VFM Conditioning Regimen:

  1. Venetoclax: 400 mg/day, days -8 to -2. (Note: If fluconazole is co - administered for antifungal prophylaxis during the transplantation conditioning period, the dose of Venetoclax should be reduced to 50% of the standard dose (i.e., 200 mg/day). If voriconazole or posaconazole is used for antifungal prophylaxis, the dose of Venetoclax should be reduced to 25% of the standard dose (i.e., 100 mg/day).
  2. Fludarabine (Flu): 30 mg/m²/day, days -7 to -3.

  3. Melphalan (Mel) dose, adjusted according to the patient's age:

    1. For patients aged < 60 years: 140 mg/m²/day, day -2.
    2. For patients aged 60 ≤ age < 70 years: 120 mg/m²/day, day -2.
    3. For patients aged ≥ 70 years: 100 mg/m²/day, day -2.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
GVHD-free and Relapse-free Survival (GRFS)
Time Frame: 2-year
the time from the date of transplantation to the first occurrence of any of the following events: development of grade Ⅲ-Ⅳ acute graft-versus-host disease (aGVHD); development of moderate to severe chronic graft-versus-host disease (cGVHD); disease relapse or progression; death from any cause.
2-year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival (OS)
Time Frame: 2-Year
The time from the date of transplantation to death from any cause.
2-Year
Progression-free Survival (PFS)
Time Frame: 2-Year
The time from the date of transplantation to disease relapse, progression, or death from any cause.
2-Year
Non-relapse Mortality (NRM)
Time Frame: 2-year
The time from the date of transplantation to death from non-relapse causes, with disease relapse considered as a competing event.
2-year
Cumulative Incidence of Relapse (CIR)
Time Frame: 2-year
Bone marrow blasts/immature cells > 5%, presence of blasts in peripheral blood, or occurrence of extramedullary leukemia; death without relapse is considered as a competing event.
2-year
Chronic Graft-versus-host Disease (cGVHD)
Time Frame: 2-year
Based on the 2014 NIH Diagnostic and Grading Criteria for Chronic GVHD.
2-year
Acute Graft-versus-host Disease (aGVHD)
Time Frame: 100-day
Based on the 2016 Diagnostic and Grading Criteria for Acute GVHD by Harris et al.
100-day
Immune Reconstitution (IR)
Time Frame: 2-year
Recovery status of peripheral blood T, B, NK cell subsets and immunoglobulin levels.
2-year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

First Affiliated Hospital of Zhejiang University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

March 1, 2026

Primary Completion (Estimated)

January 31, 2030

Study Completion (Estimated)

June 30, 2030

Study Registration Dates

First Submitted

February 2, 2026

First Submitted That Met QC Criteria

February 2, 2026

First Posted (Actual)

February 9, 2026

Study Record Updates

Last Update Posted (Actual)

March 17, 2026

Last Update Submitted That Met QC Criteria

March 16, 2026

Last Verified

January 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ZJU-HSCT-VFM

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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