Description

Inclusion Criteria:

• Understand the research and sign a written informed consent form;
• Be newly diagnosed with AML according to WHO 2022 criteria without prior treatment;
• Be ineligible for intensive chemotherapy (IC) or unwilling to undergo IC. Ineligibility for IC is defined as meeting any of the following criteria:
• Age ≥ 60 years; or
• Age 18-59 years with ≥1 of the following:
• Eastern Cooperative Oncology Group (ECOG) performance status ≥2 at screening;
• Severe heart failure (congestive heart failure requiring treatment or myocardial infarction history with ejection fraction ≤50%);
• Severe pulmonary dysfunction (DLCO ≤65%, FEV1 ≤65%, dyspnea at rest, or oxygen dependence);
• Severe renal insufficiency requiring dialysis;
• Child-Pugh B or C cirrhosis, or hepatic impairment with total bilirubin >1.5×ULN;
• Mental illness requiring inpatient psychiatric treatment;
• Any comorbidity deemed by physician to contraindicate IC.

Exclusion Criteria:

• Diagnosis of:
• AML arising from chronic myeloid leukemia (CML);
• Myeloid sarcoma;
• Acute promyelocytic leukemia (APL);
• Presence of FLT3-ITD mutations;
• Active malignancies (except adequately treated carcinoma in situ or basal cell carcinoma) within 2 years prior to Cycle 1 Day 1 (C1D1);
• Major surgery or systemic anticancer therapy within 28 days before C1D1;
• Known hypersensitivity to:
• Active pharmaceutical ingredients: cladribine, homoharringtonine, cytarabine, venetoclax, azacitidine;
• Any excipients in study drug formulations;
• GI conditions impairing oral drug absorption:

•Dysphagia, short-gut syndrome, gastroparesis, or related disorders;

• Uncontrolled active infection;
• Controlled infection permitted if:
• Afebrile (<38°C) and hemodynamically stable (SBP >90 mmHg, HR <100 bpm) for ≥72 hours pre-C1D1;
• On non-interacting antimicrobial regimen;
• Active HBV/HCV infection (Chronic carriers require PI approval with viral load monitoring);
• HIV-positive patients receiving HAART;
• Pregnancy/lactation or refusal of contraception:

•Negative serum β-hCG within 24h pre-C1D1;

• Psychiatric disorders or social circumstances compromising protocol compliance;

Concomitant Medication-Related

• Prior AML-directed therapy except:
• Cytoreduction for hyperleukocytosis per institutional guidelines (hydroxyurea, leukapheresis);
• Supportive growth factors;
• BCL-2 inhibitor therapy within 2 years prior to C1D1;
• Strong/moderate CYP3A4 inducers or inhibitors within 14 days before C1D1.

  TREATMENT

Therapeutic Regimen:

1. Induction Phase (4 alternating cycles):

Participants will receive 4 cycles of alternating therapy:

• VA Cycle:
• Venetoclax 400 mg PO daily on Days 1-28
• Azacitidine 75 mg/m² SC/IV daily on Days 1-7
• Low-dose CHA Cycle:
• Cladribine 5 mg/m² IV daily on Days 1-3
• Homoharringtonine 1 mg/m² IV daily on Days 1-5
• Cytarabine 20 mg SC every 12 hours on Days 1-10 Alternating sequence: VA → CHA → VA → CHA → VA → CHA → VA → CHA The interval between the two cycles is 2 weeks, and the interval between the two alternations is 4 weeks. 2. Maintenance Phase (24 months):

Following induction, participants will receive:

• Venetoclax 400 mg PO daily on Days 1-28
• Azacitidine 75 mg/m² SC/IV daily on Days 1-7 Repeated every 28 days for 24 cycles. The interval between the two cycles is 2 weeks.

Study Endpoints:

Primary Endpoint MRD negativity rate after two cycles of alternating VA/CHA therapy Definition: Proportion of patients achieving MRD-negative status (≤0.1% leukemic blasts by flow cytometry) at completion of the second alternating round.

Secondary Endpoints

1. Composite complete remission (CRc) rate Definition: Proportion achieving CR or CRi per ELN 2022 criteria at at the end of the first (cycle 2) and second (cycle 4) alternating round
2. Overall response rate (ORR) Definition: Proportion achieving PR or better (CR/CRh/CRi/MLFS/PR) per IWG criteria at the end of the first (cycle 2) and second (cycle 4) alternating round
3. Overall survival (OS) Definition: Time from enrollment to death from any cause, assessed up to 4 years (censored at last follow-up for survivors)
4. Disease-free survival (DFS) Definition: Time from the date of first response until the date of relapse or death from any cause, whichever came first, assessed up to 4 years
5. MRD-negative DFS (DFS-MRD) Definition: Time from the date of first MRD-negative status until the date of MRD-positive， relapse or death from any cause, whichever came first, assessed up to 4 years
6. Event-free survival (EFS) Definition: Time from enrollment until the date of treatment failure, relapse or death from any cause, whichever came first, assessed up to 4 years
7. Treatment-emergent adverse events (TEAEs) Definition: Incidence of CTCAE v6.0-graded AEs from day 1 of treatment to study completion, an average of 2 years

Withdrawal Policies:

Subjects will be discontinued from the study if any of the following occur:

1. Unacceptable toxicity:
   • Grade ≥3 non-hematologic or Grade 4 hematologic adverse events persisting >14 days despite supportive care
   • Complications preventing protocol compliance per investigator assessment 2. Lack of therapeutic benefit:
   • Failure to achieve PR after 1 alternating cycle
   • Failure to achieve CR/CRi after 2 alternating cycles
   • Persistent MRD positivity (>0.1% by flow cytometry) after 4 alternating cycles 3. Allogeneic hematopoietic stem cell transplantation (allo-HSCT)
   • Planned or emergent allo-HSCT at any point during study 4. Loss to follow-up:
   • ≥2 consecutive missed visits without contact 5. Subject-initiated withdrawal:
   • Voluntary request by subject or legally authorized representative 6. Non-compliance:
   • Protocol deviation rate >30% affecting safety/efficacy assessments 7. Investigator-determined withdrawal:
   • Any condition jeopardizing subject welfare or data integrity