This prospective, open-label, multicenter phase Ib trial will evaluate the safety, tolerability, and RP2D of the VAM regimen (liposomal mitoxantrone + azacitidine \[AZA\] + venetoclax \[VEN\]) in elderly or unfit patients with newly diagnosed AML. A standard 3+3 dose escalation will enroll 12-30 patients, testing liposomal mitoxantrone at 8, 12, 16, and 20 mg/m². VEN duration (9 vs. 14 days) will be determined at the 8 mg/m² dose level, after which only liposomal mitoxantrone will be escalated while AZA and VEN will remain fixed.
Induction therapy will consist of up to two 28-day cycles. Responders achieving CR/CRi/MLFS will be eligible for up to 4 consolidation cycles (total ≤6 cycles), after which they will proceed to maintenance with either AZA+VEN or observation.
Diagnosis of acute myeloid leukemia (AML) according to the WHO 2022 or ICC criteria, excluding acute promyelocytic leukemia (APL).
No prior therapy for AML, except hydroxyurea for the management of hyperleukocytosis.
Age ≥ 75 years;
ECOG performance status 0-3.
Acute promyelocytic leukemia (APL)..
Active central nervous system (CNS) leukemia.
Prior targeted therapy or chemotherapy for AML, excluding hydroxyurea.
Uncontrolled active infection.
Single group
Liposome Mitoxantrone
DrugLiposome Mitoxantrone: 8, 12, 16, and 20 mg/m², administered by intravenous drip (ivgtt) on day 1, every 4 weeks
Venetoclax
DrugVenetoclax(9 days): 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-9, administered orally (po), every 4 weeks Venetoclax(14 days): 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-14, administered orally (po), every 4 weeks
Azacitidine
DrugAzacitidine: 75 mg/m², administered subcutaneously (sc) on days 1-7, every 4 weeks
Dose-Limiting Toxicity (DLT)
To evaluate the safety, tolerability, and RP2D of the VAM regimen in newly diagnosed elderly/unfit AML patients.
Incidence of treatment-related adverse events
The safety of the drug was evaluated by NCI-CTC AE 5.0 standard which including hematologic and non-hematologic toxicity
Composite complete remission (CRc) rate
Proportion of patients with complete remission (CR), complete remission with incomplete hematologic recovery (CRi) or morphologic leukemia-free state (MLFS)
Complete remission (CR) rate
Proportion of patients with complete remission (CR)
Complete remission with incomplete hematologic recovery (CRi) rate
Proportion of patients with complete remission with incomplete hematologic recovery (CRi)
Morphologic leukemia-free state (MLFS) rate
Proportion of patients with morphologic leukemia-free state (MLFS)
Event-free survival (EFS)
It is defined as the time from the start of study treatment to the occurrence of induction failure or disease progression or death from any cause (whichever occurs first)
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