This study aims to evaluate the efficacy and safety of mitoxantrone hydrochloride liposome, subcutaneous cytarabine and G-CSF combined with venetoclax (CMG+Ven) versus azacitidine combined with venetoclax (VA) in the treatment of adult myelodysplastic syndrome IB2 (MDS-IB2) and newly diagnosed secondary or elderly AML.
Patients with secondary AML (S-AML) and elderly AML have an extremely poor prognosis due to advanced age, multiple comorbidities, and unfavorable cytogenetic abnormalities. Traditional intensive chemotherapy is associated with low remission rates and substantial toxicity. Myelodysplastic syndrome with excess blasts-2 (MDS-IB2) carries a very high risk of transformation to AML, and its management is similar to that of AML. Although venetoclax, a BCL-2 targeted agent, combined with azacitidine (VA regimen) has revolutionized the treatment paradigm for AML patients unfit for intensive chemotherapy, the VA regimen provides insufficient depth of remission in patients eligible for chemotherapy and is difficult to administer at full dosage and full course, highlighting an urgent need for optimization. Mitoxantrone hydrochloride liposome is an improved formulation of conventional mitoxantrone. Through liposomal encapsulation and polyethylene glycol modification, it exhibits a prolonged half-life and enhanced tumor targeting, while significantly reducing cardiac toxicity and other non-hematologic toxicities. Our center's previous exploratory study demonstrated that mitoxantrone hydrochloride liposome combined with cytarabine, G-CSF, and venetoclax (CMG+Ven) achieved a composite complete remission (CRc) rate of 72.6% and an MRD-negative rate of 75.6% in patients with newly diagnosed secondary or elderly AML. Furthermore, compared with the VA regimen, CMG+Ven significantly increased the MRD-negative rate and shortened hospital stay, showing promising clinical potential. Therefore, the investigators designed a prospective, multicenter, randomized controlled trial. The study plans to enroll 168 adult patients with clinically confirmed MDS-IB2 and newly diagnosed secondary or elderly AML. Participants will be randomly assigned in a 1:1 ratio to receive one of the following induction treatments: 1) mitoxantrone hydrochloride liposome, subcutaneous cytarabine, and G-CSF combined with venetoclax (CMG+VEN), or 2) azacitidine combined with venetoclax (VA). The primary endpoint is the composite complete remission (CRc) rate following induction therapy.
Study Type
INTERVENTIONAL
Allocation
Mitoxantrone Hydrochloride Liposome: 15 mg/m², administered by intravenous drip (ivgtt) on day 1
Cytarabine: 10 mg/m², administered subcutaneously (H) every 12 hours (q12h) on days 1-7
G-CSF: 5 μg/kg, administered subcutaneously (H) starting from day 0, and discontinued when WBC ≥ 20×10\^9/L
Proportion of Participants With Composite Complete Remission (CRc = CR + CRh + CRI) in Induction Therapy (Assessed via European LeukemiaNet [ELN] 2022 Criteria)
Number of participants achieving composite complete remission (CRc), defined as complete remission (CR) + complete remission with partial hematologic recovery (CRh) + complete remission with incomplete hematologic recovery (CRI), assessed at the end of each 28-day cycle (up to 2 cycles) using European LeukemiaNet \[ELN\] 2022 criteria.
Time frame: At the end of each cycle (each cycle is 28 days), up to 2 cycles
Proportion of Participants With Objective Response (ORR = CRC + Morphologic Leukemia-Free State [MLFS] + Partial Remission [PR]) in Induction Therapy (Assessed via European LeukemiaNet [ELN] 2022 Criteria)
Number of participants achieving objective response (ORR), defined as composite complete remission (CRC) + morphologic leukemia-free state (MLFS) + partial remission (PR), assessed at the end of each 28-day cycle (up to 2 cycles) using European LeukemiaNet \[ELN\] 2022 criteria.
Time frame: At the end of each cycle (each cycle is 28 days), up to 2 cycles
Proportion of CRc-Achieving Participants With Measurable Residual Disease (MRD) Negativity (Assessed via Flow Cytometry Testing Per ELN 2022 Criteria)
Number of participants who achieved CRc and had MRD negativity, assessed at the end of each 28-day cycle (up to 2 cycles) using flow cytometry testing per European LeukemiaNet \[ELN\] 2022 criteria.
Time frame: At the end of each cycle (each cycle is 28 days), up to 2 cycles
Overall Survival (OS) Time (From Treatment Day 1 to Date of Death From Any Cause)
Time from day 1 of treatment to date of death from any cause, measured for all participants in the study, up to 1 year after the last enrolled participant's enrollment date.
Time frame: Up to 1 years after the date of the last enrolled participants
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RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
168
Venetoclax: 100 mg on day 2, 200 mg on day 3, and 400 mg on days 4-10, administered orally (po)
Venetoclax: 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-21 or 3-28, administered orally (po)
Azacitidine: 75 mg/m\^2, administered subcutaneously (H) on days 1-7.
Relapsed-Free Survival (RFS) Time (From CRc Achievement to Hematologic Relapse or Death From Any Cause)
Time from date of achieving CRc to date of hematologic relapse or death from any cause, measured only for participants who achieved CRc, up to 1 year after the last enrolled participant's enrollment date.
Time frame: Up to 1 years after the date of the last enrolled participants
Event-Free Survival (EFS) Time (From Treatment Day 1 to Treatment Failure, Hematologic Relapse From CRc, or Death From Any Cause [Whichever Occurs First])
Time from day 1 of treatment to date of treatment failure, hematologic relapse from CRc, or death from any cause (whichever occurs first), measured for all participants in the study, up to 1 year after the last enrolled participant's enrollment date.
Time frame: Up to 1 years after the date of the last enrolled participants
Incidence of Treatment-Emergent Adverse Events (Assessed via Common Terminology Criteria for Adverse Events [CTCAE] v5.0)
Number of participants with treatment-emergent adverse events, assessed via Common Terminology Criteria for Adverse Events \[CTCAE\] v5.0, from day 1 of treatment to 28 days after the last dose.
Time frame: From day 1 of treatment to 28 days after the last dose
Exploratory Biomarker Profiling (Including Genetic Mutations, Gene Expression Profiles, and Molecular Markers in Blood/Bone Marrow)
Assessment of exploratory biomarkers (including genetic mutations, gene expression profiles, and molecular markers) in blood or bone marrow, to explore association with treatment response/resistance/prognosis in AML, at baseline and end of each 28-day cycle (up to 2 cycles).
Time frame: Baseline, end of each cycle (up to 2 cycles)