Efficacy and Safety of Lisafotoclax Plus Decitabine and Homoharringtonine in Venetoclax/Azacitidine Pretreated AML Patients

A Multi-Center, Prospective, Single-Arm, Phase 2 Clinical Study on the Efficacy and Safety of Lisafotoclax Combined With Decitabine and Homoharringtonine in Patients With Acute Myeloid Leukemia Previously Treated With Venetoclax Combined With Azacitidine Regimen

This is a multi-center, prospective, single-arm, phase 2 clinical study conducted in China to evaluate the efficacy and safety of Lisafotoclax combined with Decitabine and Homoharringtonine in patients with acute myeloid leukemia (AML) who have failed or are intolerant to prior treatment with Venetoclax plus Azacitidine.

Eligible participants must be at least 18 years old, have a confirmed diagnosis of AML according to WHO 2016 criteria, and have an ECOG performance status of 0-2. Participants will receive oral Lisafotoclax in combination with intravenous Decitabine and Homoharringtonine according to the study protocol.

The primary objective is to assess the overall response rate (ORR) after induction treatment. Secondary objectives include evaluating complete remission (CR) rate, event-free survival (EFS), overall survival (OS), and the incidence of adverse events (AEs) and serious adverse events (SAEs). Participants will be followed for up to 12 months after the last patient is enrolled to collect long-term efficacy and safety data.

This study has been approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine and will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice (GCP).

Inclusion Criteria

• Age ≥18 years old.

• Diagnosis of acute myeloid leukemia (AML), not otherwise specified (non-acute promyelocytic leukemia [APL]), confirmed by WHO 2022 5th edition criteria.

• Evidence of treatment failure after prior venetoclax + azacitidine (VA) regimen, defined as either:

  1. VA intolerance: Treatment discontinuation due to ≥Grade 3 non-hematologic toxicity or persistent ≥Grade 4 hematologic toxicity;
  2. VA treatment failure:

• Primary resistance: No partial remission (PR) after 1-2 cycles of VA induction therapy;

• Molecular persistence/progression: ≥1 log increase or persistent positivity of driver gene mutations (e.g., FLT3-ITD, IDH1/2, NPM1) by quantitative PCR or NGS compared to best response;

• Hematologic relapse: ≥5% bone marrow blasts or extramedullary leukemia after prior CR/CRi.

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

• Adequate organ function within 7 days prior to study initiation:

• Liver: Total bilirubin ≤1.5×ULN; AST/ALT ≤2.5×ULN;

• Kidney: Serum creatinine ≤1.5×ULN or CrCl ≥50 mL/min;

• Heart: Left ventricular ejection fraction (LVEF) ≥50%.

• Ability to provide written informed consent and comply with study procedures. Exclusion Criteria

• Diagnosis of acute promyelocytic leukemia (APL) or Philadelphia chromosome-positive AML.

• Prior treatment with any BCL-2 inhibitor other than venetoclax as part of VA regimen.

• Active central nervous system (CNS) leukemia involvement.

• Uncontrolled systemic active infection.

• Known HIV infection, or active hepatitis B or C.

• New York Heart Association (NYHA) Class III-IV heart failure, unstable angina, myocardial infarction within 6 months, or severe arrhythmia.

• Other active uncontrolled malignancy.

• Severe gastrointestinal disease affecting drug absorption.

• Pregnant or breastfeeding individuals; fertile patients refusing effective contraception during study and 6 months after last dose.

• Known hypersensitivity to any component of LDH or LD regimens.

• Any other condition judged by investigator to interfere with study conduct or patient safety.