VA Induction and Bridging Transplantation for Hypoplastic/Secondary AML

Under the traditional intensive chemotherapy model, patients with hypoplastic or secondary acute myeloid leukemia (AML) often have poor bone marrow reserve and prolonged post-chemotherapy cytopenia, leading to high early mortality, low remission rates, and short median survival. To address this, the use of venetoclax combined with a hypomethylating agent (the VA regimen) as induction therapy significantly improves complete remission (CR) and overall survival (OS). Subsequent bridging to allogeneic hematopoietic stem cell transplantation (allo-HSCT) as consolidation further enhances OS and relapse-free survival (RFS). This combined strategy demonstrates a clear synergistic effect: the VA regimen effectively increases the transplantation rate, and for patients with relapsed/refractory (R/R) AML, a low-intensity regimen followed by bridging transplantation is non-inferior to traditional intensive chemotherapy, achieving a "1+1>2" therapeutic benefit. Therefore, the investigators conducted a prospective study to evaluate the efficacy and safety of VA regimen induction followed by allo-HSCT in patients with hypoplastic and secondary AML.

Inclusion criteria

• Age ≥18 years.
• Previously untreated acute myeloid leukemia (AML) diagnosed according to the 2022 ELN guidelines. Patients with isolated extramedullary disease (i.e., no evidence of AML in bone marrow or peripheral blood) are not eligible.
• Bone marrow biopsy demonstrating cellularity <20% or concurrent myelofibrosis; Or a prior history of an antecedent hematologic disorder, radiotherapy/chemotherapy-related history, or presence of myelodysplasia-related changes (AML-MRC according to WHO-HEAM5).
• The patient is deemed suitable for allogeneic hematopoietic stem cell transplantation as assessed by the treating physician.
• Adequate organ function, defined as follows: a. Good liver function: serum total bilirubin ≤2.0 × upper limit of normal (ULN); if considered due to Gilbert's disease or leukemia, serum total bilirubin <3.0 × ULN. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤3.0 × ULN, unless considered due to leukemia. b. Good renal function: serum creatinine ≤2.0 × ULN or creatinine clearance >30 mL/min calculated using the Cockcroft-Gault formula. c. No history of chronic lung disease and no dyspnea. Otherwise, documented diffusing capacity of the lung for carbon monoxide ≤40% (adjusted for hemoglobin if available) and forced expiratory volume in 1 second/forced vital capacity ≥50%.
• ECOG performance status score 0-2.
• Ability to understand and voluntarily sign informed consent.
• Women of childbearing potential must have a negative serum pregnancy test before initiation of study treatment.

Exclusion criteria

• Prior treatment for AML, except non-cytotoxic therapy given to stabilize disease.
• White blood cell count ≥10×10⁹/L, or presence of proliferation-associated gene mutations such as FLT3.
• Favorable risk group according to the 2022 ELN prognostic stratification, e.g., t(8;21), inv(16)/t(16;16), NPM1 mutation, or CEBPA bZIP in-frame mutation.
• No suitable stem cell donor available.
• Acute promyelocytic leukemia (APL).
• Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia.
• Life-threatening immediate complications of leukemia, such as uncontrolled bleeding, hypoxic pneumonia, sepsis, and/or disseminated intravascular coagulation (DIC). Expected survival <12 weeks.
• Prior allogeneic hematopoietic stem cell transplantation for a hematologic disorder.
• Current use of strong CYP3A4 inducers or narrow-therapeutic-window CYP3A4 substrates; enrollment is allowed only if these drugs can be switched to alternatives ≥5 half-lives before the first dose of study treatment.
• Active, uncontrolled systemic fungal, bacterial, or viral infection despite appropriate antibiotic, antiviral, or other therapy.
• Known infection with human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) or hepatitis C virus (HCV) that cannot be controlled by therapy.
• Another active malignancy, unless the patient has been disease-free for ≥5 years before initiation of study treatment. However, patients with the following history/concurrent conditions or similar indolent cancers are eligible: Basal cell or squamous cell carcinoma of the skin Carcinoma in situ of the cervix Carcinoma in situ of the breast Prostate cancer found incidentally on histology.
• Significant active cardiac disease within 6 months before initiation of study treatment, including New York Heart Association (NYHA) Class III or IV congestive heart failure, myocardial infarction, unstable angina, and/or stroke.
• Uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure >100 mmHg).
• Dysphagia, short-bowel syndrome, gastroparesis, or other conditions that limit oral intake or gastrointestinal absorption.
• Known history of progressive multifocal leukoencephalopathy (PML).
• Known hypersensitivity to any component of venetoclax or azacitidine.
• Female patient who is pregnant or breastfeeding.
• Any other medical or psychological condition that, in the investigator's opinion, could interfere with the patient's ability to sign informed consent or participate in the study.