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

• Lisafotoclax (Drug): Oral investigational BCL-2 inhibitor, administered in two phases: 1. LDH induction/consolidation phase (28-day cycles): * Cycle 1: 200 mg on day 1, 400 mg on day 2, 600 mg on days 3-28; * Cycle 2 and beyond: 600 mg once daily on days 1-28. 2. LD maintenance phase (28-day cycles): 600 mg once daily on days 1-14.
• Decitabine (Drug): Intravenous hypomethylating agent, administered at 15 mg/m²/day via intravenous infusion over 3 hours on days 1-3 of each 28-day cycle, used in both LDH induction/consolidation and LD maintenance regimens.
• Homoharringtonine (Drug): Intraversible alkaloid anti-leukemia agent, administered at 1 mg/m²/day via intravenous infusion over 2 hours on days 1-7 of each 28-day cycle, used exclusively in the LDH induction/consolidation phase of the study.

Primary outcomes

• Composite Complete Response Rate (CRc) [Up to 2 cycles of LDH induction/consolidation therapy (approximately 56 days)]: The proportion of participants who achieve composite complete remission (CRc), defined as the combination of complete remission (CR), complete remission with incomplete hematologic recovery (CRi), and morphologic leukemia-free state (MLFS) after 1-2 cycles of LDH induction/consolidation therapy.

Secondary outcomes

• Event-Free Survival (EFS) [Up to 12 months after the last patient is enrolled]: The time from the first dose of study treatment to the first occurrence of disease progression, relapse, or death from any cause.
• Complete Response Rate (CR) [Up to 2 cycles of LDH therapy (approximately 56 days)]: The proportion of participants who achieve complete remission (CR), defined as <5% bone marrow blasts, no evidence of extramedullary disease, and recovery of peripheral blood counts (ANC ≥1.0×10⁹/L, platelets ≥100×10⁹/L) after 1-2 cycles of LDH therapy.
• Overall Response Rate (ORR) [Up to 2 cycles of LDH therapy (approximately 56 days)]: The proportion of participants who achieve any response (CR + CRi + MLFS + partial remission \[PR\]) after 1-2 cycles of LDH induction/consolidation therapy.
• Time to Response (TTR) [Up to 2 cycles of LDH therapy (approximately 56 days)]: The time from the first dose of study treatment to the first documentation of any response (CR, CRi, MLFS, or PR).
• Duration of Response (DOR) [Up to 12 months after the last patient is enrolled]: The time from the first documentation of response (CR, CRi, MLFS, or PR) to the first occurrence of disease progression, relapse, or death from any cause.
• Overall Survival (OS) [Up to 12 months after the last patient is enrolled]: The time from the first dose of study treatment to death from any cause.

Other outcomes

• Minimal Residual Disease (MRD) Negative Rate [Up to 2 cycles of LDH therapy (approximately 56 days)]: The proportion of participants who achieve undetectable MRD in bone marrow (by flow cytometry or molecular testing) after 1-2 cycles of LDH induction/consolidation therapy.
• Rate of Bridging to Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) [Up to 3 months after achieving MRD negativity]: The proportion of participants who proceed to allogeneic hematopoietic stem cell transplantation after achieving MRD-negative status with LDH induction/consolidation therapy.

Sex: All, ages: 18 Years to 75 Years

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.