Alternating Regimen of VA and Low-dose CHA in the Treatment of Unfit Newly Diagnosed AML

The Efficacy and Safety of VA Alternating With Low-dose CHA in the Treatment of Newly Diagnosed Unfit AML: a Prospective, Multi-centers, Single Arm Phase II Study

This phase II trial tests how well VA alternating with low-dose CHA works in treating unfit patients with newly diagnosed acute myeloid leukemia (AML). This is a prospective, multi-centers, single arm phase II study aimed to overcome VEN resistance and achieve greater MRD negative rate, providing better control of treatment for unfit AML.

This clinical study protocol investigates a novel treatment for newly diagnosed Acute Myeloid Leukemia (AML) patients ineligible to receive intensive chemotherapy (IC). Eligibility is defined as age ≥60 or age 18-59 with significant comorbidities. Key exclusions include specific AML subtypes including Acute promyelocytic leukemia (APL); FLT3-ITD mutations and active infections. The Intervention is a two-phase regimen. The Induction Phase consists of four alternating 28-day cycles of Venetoclax + Azacitidine (VA) and low-dose Cladribine + Homoharringtonine + Cytarabine (CHA). This is followed by a Maintenance Phase of 24 cycles of VA therapy. The Primary Endpoint is the rate of Minimal Residual Disease (MRD) negativity after two alternating cycles. Secondary Endpoints include composite complete remission rate, overall survival, and incidence of treatment-emergent adverse events. Clear Withdrawal Criteria are defined for situations involving unacceptable toxicity, lack of therapeutic benefit, or patient/investigator decision.

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;

• or unwilling to undergo IC. Ineligibility for IC is defined as meeting any of the following criteria:

• Age ≥ 60 years

• Age 18-59 years but ineligible for intensive chemotherapy (IC) , meet ≥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) or 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;
• Prior AML-directed therapy except: cytoreduction for hyperleukocytosis per institutional guidelines (hydroxyurea, leukapheresis); supportive growth factors;