Alternating venetoclax+azacitidine and low-dose cladribine+homoharringtonine+cytarabine for 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 whether alternating venetoclax + azacitidine with low-dose cladribine + homoharringtonine + cytarabine can help people aged ≥60 or otherwise unfit with newly diagnosed AML become MRD negative and achieve better disease control.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 25 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: First Affiliated Hospital of Zhejiang University (Academic / other)
• Drugs / interventions: chemotherapy
• Locations: 5 sites (Beijing, Beijing Municipality and 4 other locations)
• Trial ID: NCT07172204 on ClinicalTrials.gov

What this trial studies

This single-arm, multi-center phase II study enrolls adults with newly diagnosed AML who are ineligible for intensive chemotherapy, mainly age ≥60 or those with significant comorbidities. Participants receive four alternating 28-day induction cycles of venetoclax + azacitidine (VA) and low-dose cladribine + homoharringtonine + cytarabine (CHA), followed by up to 24 cycles of maintenance VA. The primary endpoint is the rate of minimal residual disease (MRD) negativity after two alternating cycles, with secondary endpoints including composite complete remission rate, overall survival, and treatment-emergent adverse events. The regimen is intended to overcome venetoclax resistance and improve depth of response in patients who cannot tolerate intensive chemotherapy.

Who should consider this trial

Good fit: Ideal candidates are adults with newly diagnosed AML who are ineligible for intensive chemotherapy—typically age ≥60 or younger patients with significant comorbidities or poor performance status.

Not a fit: Patients with excluded diagnoses such as acute promyelocytic leukemia (APL), those with FLT3-ITD mutations, active uncontrolled infections, or other major exclusion criteria are unlikely to qualify for or benefit from this regimen.

Why it matters

Potential benefit: If successful, this regimen could increase MRD-negative remissions and extend disease control for older or unfit AML patients who cannot receive intensive chemotherapy.

How similar studies have performed: Venetoclax plus azacitidine has shown benefit in older or unfit AML in prior studies, but alternating that backbone with low-dose CHA is a novel approach with limited prior data.

Eligibility criteria

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;

Where this trial is running

Beijing, Beijing Municipality and 4 other locations

• Beijing Chao-Yang Hospital, Capital Medical University — Beijing, Beijing Municipality, China (Recruiting)
• Shenzhen University General Hospital — Shenzhen, Guangdong, China (Recruiting)
• the First Affiliated Hospital of Soochow University — Suzhou, Jiangsu, China (Recruiting)
• the Second Affiliated Hospital of Nanchang University — Nanchang, Jiangxi, China (Recruiting)
• Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine — Hangzhou, Zhejiang, China (Recruiting)

Study contacts

• Principal investigator: Jie Dr. Sun, M.D, Ph.D — Bone Marrow Transplantation Center of The First Affiliated Hospital, Zhejiang University School of Medicine
• Study coordinator: Jie Sun

Conditions Intensive Chemotherapy Unfit; Newly Diagnosed Acute Myeloid Leukemia; Age ≥60; Acute Myeloid Leukemia; Venetoclax; alternating; Homoharringtonine; Cladribine