Homoharringtonine, Lisaftoclax, and Azacitidine for AML After Venetoclax-Based Therapy Failure

A Multi-Center, Prospective, Open-Label, Single-Arm Study of Homoharringtonine Combined With Lisaftoclax and Azacitidine in Patients With Acute Myeloid Leukemia After Failure of Venetoclax-Based Therapy

Venetoclax (Ven) resistance is common in the treatment of acute myeloid leukemia (AML). Patients with Ven resistance have poor response and survival, except those with specific targeted therapy. Whether we could use new BCL-2 inhibitors to replace Ven and combine with the agents which have been shown to enhance the antilekeumia effect of BCL-2 inhibitors, to overcome Ven resistance? This is unknown up until now. This multi-center, prospective, open-label, single-arm study will evaluate the efficacy and safety of homoharringtonine combined with lisaftoclax and azacitidine (HLA) as salvage therapy for adults with AML after failure of a Ven-containing regimen. Ven treatment failure is defined as no response after at least two consecutive cycles of a Ven-containing regimen or relapse during continued, protocol-compliant Ven-based therapy after a prior response. The study plans to enroll 73 participants. The primary endpoint is the overall response rate after two treatment cycles. Secondary endpoints include complete remission (CR), CR with incomplete blood count recovery (CRi), measurable residual disease (MRD) negativity, survival and relapse, and treatment-related adverse events.

Venetoclax-based regimens are widely used in acute myeloid leukemia, but patients who do not respond or who relapse during continued venetoclax therapy have poor outcomes and limited low-intensity treatment options. Lisaftoclax is a selective BCL-2 inhibitor with clinical activity in myeloid malignancies, including preliminary activity in patients previously exposed to venetoclax. Prior preclinical and clinical work by the study group suggests that homoharringtonine may enhance the antileukemic activity of BCL-2 inhibitor-based therapy.

Participants will receive the HLA regimen in 28-day cycles. Homoharringtonine will be administered at 1 mg/m^2 by intravenous infusion on Days 1-7. Lisaftoclax will be administered orally at 200 mg on Day 1, 400 mg on Day 2, and 600 mg on Days 3-14. Azacitidine will be administered at 75 mg/m^2 by subcutaneous injection on Days 1-7. When concomitant use of a strong CYP3A4 inhibitor is required, the lisaftoclax dose will be reduced to 200-400 mg/day.

Response will be assessed using blood counts, bone marrow morphology, and measurable residual disease testing. Bone marrow assessment is planned around Day 14 or Day 28 of each salvage cycle. Participants who achieve complete remission, complete remission with incomplete hematologic recovery, or a morphologic leukemia-free state may proceed to allogeneic hematopoietic stem cell transplantation when feasible or receive further protocol-directed therapy. Participants with partial response or no response after the first cycle may receive a second HLA cycle. Participants with no response after reassessment following the second cycle will discontinue study treatment.

The study will evaluate overall response after two cycles, additional remission outcomes, measurable residual disease negativity, overall survival, relapse-free survival, duration of response, relapse, and safety. Exploratory whole-genome sequencing, RNA sequencing, targeted next-generation sequencing, and single-cell sequencing will be used to characterize biological correlates of response and investigate mechanisms of venetoclax resistance and response to the HLA regimen.

Inclusion Criteria:

1. Diagnosis of acute myeloid leukemia according to the World Health Organization classification.
2. Age 18 years or older.
3. Failure after venetoclax exposure, defined as either no response after at least 2 consecutive cycles of a venetoclax-containing regimen or disease relapse during continued, protocol-compliant treatment with a venetoclax-containing regimen after a prior response.
4. Creatinine clearance of at least 30 mL/min.
5. Alanine aminotransferase less than 5 times the upper limit of normal and bilirubin less than 3 times the upper limit of normal.
6. Life expectancy of at least 3 months.
7. Able to receive oral lisaftoclax.
8. Able to understand and comply with protocol procedures and willing to provide written informed consent.

Exclusion Criteria:

1. Acute promyelocytic leukemia.
2. Acute myeloid leukemia with central nervous system involvement.
3. Acute myeloid leukemia with FLT3, IDH1/2, or NPM1 mutations or MLL rearrangement for which could be treated with a corresponding targeted inhibitor.
4. Other clinically significant uncontrolled conditions, including but not limited to an uncontrolled or active systemic viral, bacterial, or fungal infection; chronic hepatitis B virus or hepatitis C virus infection requiring treatment; or a concurrent second malignancy requiring active treatment.
5. Known hypersensitivity to any study drug.
6. Active human immunodeficiency virus infection.
7. Pregnant or breastfeeding.
8. Any condition that, in the investigator's opinion, makes the patient unsuitable for enrollment.