Exploratory Study of Venetoclax, Homoharringtonine, Azacitidine Plus G-CSF for Newly Diagnosed AML (VHAG)

A Prospective, Multicenter, Exploratory Study of Venetoclax, Homoharringtonine, and Azacitidine Combined With G-CSF in Elderly or Unfit Patients With Newly Diagnosed Acute Myeloid Leukemia

This study is a single-arm, prospective, multi-center exploratory clinical trial. A total of 61 patients with newly diagnosed acute myeloid leukemia (AML) who are not suitable for intensive chemotherapy will be enrolled. The Simon two-stage design will be adopted to control the type I and type II errors, with the minimum acceptable composite remission rate of 65% and a power of 80%.

Prior to treatment, subjects will undergo screening within 28 days, including bone marrow aspiration, genetic testing, ECOG performance status assessment, and organ function evaluation. Data will be recorded in Excel and subject to unified quality control. During the treatment period, G-CSF (granulocyte colony-stimulating factor) will be administered subcutaneously as appropriate, and supportive care such as antiemetic and hydration therapy will be provided routinely.

For patients who achieve remission, individualized consolidation therapy will be given: those eligible for transplantation will undergo allogeneic hematopoietic stem cell transplantation; those who can tolerate moderate-intensity treatment will receive consolidation with medium-dose cytarabine first, followed by 4 cycles of VHAG regimen consolidation. Patients with FLT3 mutations will receive additional targeted therapy during consolidation.

Safety assessment will be conducted in accordance with the NCI-CTCAE Version 5.0. For grade 4 hematological toxicity or severe non-hematological toxicity, the treatment dose will be adjusted or the treatment will be suspended. Severe adverse events will be reported in a timely manner, and all research-related data will be retained for at least 10 years in accordance with relevant regulations.

According to the detailed inclusion and exclusion criteria, first-line induction therapy: VHAG regimen Venetoclax 100 mg on day 2, 200 mg on day 3, 400 mg on days 4-10; Homoharringtonine 1 mg/m² on days 1-7; Azacitidine 75 mg/m² on days 1-7; G-CSF 5 μg/kg subcutaneously starting on day 0;G-CSF to be discontinued if WBC ≥ 30 × 10⁹/L.

One cycle every 4 weeks, for a total of 2 cycles.Patients who achieve CR/CRi/MLFS/PR after the first cycle will receive one additional cycle of the same regimen for consolidation(venetoclax 400 mg on days 1-7 in the second course).

Subsequent treatment After achieving remission, re-evaluate tolerability comprehensively based on age, performance status, comorbidities, and other factors.

Patients eligible for transplantation will undergo allogeneic hematopoietic stem cell transplantation.

Transplant-ineligible patients:

Those tolerable to intensive chemotherapy may receive1-2 courses of intermediate-dose cytarabine consolidation,followed by 4 courses of VHAG consolidation.

Those intolerant to intensive chemotherapy will continue6 courses of VHAG consolidation.

Patients with FLT3 mutations in the intermediate- or high-risk groups may receive combination therapy with a FLT3 inhibitor during consolidation.

Endpoints Primary endpoint: Composite complete remission rate (CRc: CR + CRi)

Secondary endpoints:

Overall response rate (ORR: CR + CRi + MLFS + PR) Overall survival (OS) Relapse-free survival (RFS) Rate of measurable residual disease (MRD) negativity Safety Hematologic and non-hematologic toxicities (NCI CTCAE version 5.0) Exploratory biomarker evaluation

Inclusion Criteria:

• The patient has fully understood the study, voluntarily participated, and signed the informed consent form (ICF).
• Newly diagnosed acute myeloid leukemia (AML) confirmed by bone marrow morphology, immunophenotyping, cytogenetics, and/or molecular biology testing, in accordance with the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (2022 edition).
• No prior systemic therapy for AML (including induction, consolidation, or maintenance therapy).
• Patients judged unfit for standard cytarabine plus anthracycline induction chemotherapy due to age or comorbidities.
• Short-term use of hydroxyurea or low-dose cytarabine before enrollment to control hyperleukocytosis is permitted.
• Age ≥ 75 years, or age 18-74 years with any of the following comorbidities:
• ECOG performance status 2-3
• History of congestive heart failure, left ventricular ejection fraction (LVEF) ≤ 50%, or chronic stable angina
• Diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 65% predicted, or forced expiratory volume in 1 second (FEV1) ≤ 65% predicted
• Creatinine clearance 30-45 mL/min (≥ 30 and < 45)
• Moderate hepatic impairment: total bilirubin > 1.5 × ULN and ≤ 3 × ULN
• Other comorbidities deemed unfit for standard chemotherapy by the investigator
• Estimated survival time ≥ 12 weeks.
• For patients aged ≥ 75 years: ECOG performance status 0-2.
• For patients aged 18-74 years: ECOG performance status 0-3.
• Creatinine clearance ≥ 30 mL/min (calculated by the Cockcroft-Gault formula).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN).
• Total bilirubin ≤ 1.5 × ULN; may be relaxed to ≤ 3 × ULN in patients with leukemic hepatic infiltration.
• For patients < 75 years old, total bilirubin ≤ 3 × ULN.

Exclusion Criteria:

• Acute promyelocytic leukemia (APL).
• History of prior myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia, myelofibrosis, etc.
• Prior receipt of hypomethylating agents, venetoclax (VEN), or systemic chemotherapy for myelodysplastic syndromes (MDS).
• Prior receipt of any investigational drug or device therapy for MDS/AML.
• Concurrent participation in another clinical trial.
• AML with central nervous system (CNS) involvement confirmed by imaging or cerebrospinal fluid examination.
• Positive HIV antibody during the screening period.
• Positive HBsAg or HCV antibody with a high-sensitivity viral load above the lower limit of detection within 3 months (excluding those who are cured or with persistent low-level replication).
• Ingestion of grapefruit, grapefruit juice, Seville oranges, star fruit, or their products within 72 hours prior to the first dose.
• Chronic respiratory failure requiring long-term oxygen therapy.
• Presence of severe cardiac, hepatic, renal, endocrine, metabolic, immune, neurological, or psychiatric disorders.
• History of hypersensitivity to the study drug (including azacitidine excipients).
• Impaired drug absorption due to malabsorption syndrome, short bowel syndrome, or other conditions affecting oral drug absorption.
• Active tuberculosis or other severe infections requiring intravenous anti-infective therapy for ≥7 days.
• Presence of a second malignancy within 2 years prior to enrollment, excluding cured carcinoma in situ of the cervix or breast, completely resected basal cell carcinoma or localized squamous cell carcinoma of the skin, or localized malignancies cured by surgery and requiring no further follow-up.
• The investigator judges that the patient is otherwise ineligible to participate in this study.