Metformin Inhibits DNMT3A Clonal Hematopoiesis in Acute Leukemia: A Single-Arm Clinical Study
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Rate of major molecular response based on the variant-allele frequency (VAF) of DNMT3A R882 mutation at 6-month follow-up
研究概览
简要总结
This is a prospective, single-arm clinical study evaluating the efficacy and safety of metformin in inhibiting DNMT3A R882-driven clonal hematopoiesis (CH) in patients with acute leukemia (AL) who are in remission and under follow-up. Patients with DNMT3A R882 mutation (VAF ≥5%) will receive oral metformin for 6 months, with dosage gradually increased to 2000 mg/day. The primary endpoint is the proportion of patients with effective decline in DNMT3A R882 mutation VAF at 6 months. Secondary endpoints include VAF decline at 3 months, relapse-free survival (RFS) at 6 and 12 months, overall survival (OS), cumulative incidence of relapse (CIR), cumulative remission-phase mortality, and adverse event rates. Planned enrollment: 32 participants.
详细描述
Clonal hematopoiesis (CHIP) involves hematopoietic stem cells (HSCs) acquiring mutations like DNMT3A R882, conferring a proliferative advantage and increasing risks of hematologic malignancies and inflammatory diseases. No effective interventions exist currently. Preclinical studies show that DNMT3A R882 mutations enhance mitochondrial respiration and oxidative phosphorylation (OXPHOS) in hematopoietic stem/progenitor cells (HSPCs), which is essential for their competitive advantage. Metformin, at clinical doses, inhibits the electron transport chain (ETC) complex I, reducing OXPHOS and selectively diminishing the advantage of mutant HSPCs. Mechanisms include restoring epigenetic stability by elevating methylation potential (SAM/SAH ratio), reversing hypomethylation in differential methylation regions (DMRs), and normalizing H3K27me3 histone modifications.
In mouse and humanized models, metformin suppresses clonal expansion of DNMT3A R882 mutant cells. Based on metformin's 60-year safety profile in diabetes treatment, this study tests its potential in AL patients with persistent DNMT3A R882 CH post-remission. Metformin may reduce risks like secondary tumors and diabetes in these patients.
Study intervention: Oral metformin starting at 500 mg twice daily, titrated to 500 mg three times daily or 1000 mg twice daily (or maximum tolerated dose), up to 2000 mg/day, taken with meals for 6 months.
Efficacy assessment: Next-generation sequencing (NGS) for DNMT3A R882 VAF at 0, 3, and 6 months.
- Major response: For VAF >20%, absolute decline ≥10%; for VAF ≤20%, relative decline ≥50%.
- Partial response: For VAF >20%, absolute decline 5-10%; for VAF ≤20%, relative decline 25-50%.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 14 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients diagnosed with acute leukemia based on bone marrow morphology, immunology, and genetics, per WHO 2022 or ICC criteria.
- •Patients in complete remission follow-up phase with DNMT3A R882 mutation clonal hematopoiesis, VAF ≥5%.
- •Age ≥14 years, any gender
- •Laboratory requirements (within 7 days before treatment):
- •Total bilirubin ≤1.5 × upper limit of normal (ULN) for age.
- •AST and ALT ≤2.5 × ULN for age.
- •Serum creatinine <2 × ULN for age.
- •Cardiac enzymes <2 × ULN for age.
- •Ejection fraction within normal range by echocardiogram (ECHO).
- •Signed informed consent: By patient (≥18 years) or legal guardian/relative (<18 years or if beneficial for condition).
排除标准
- •Patients with diabetes receiving other medications
- •Known allergy to metformin
- •Deemed unsuitable by investigator
研究组 & 干预措施
Metformin Treatment Arm
Dosage: Start at 500 mg twice daily, titrate to 2000 mg/day (e.g., 500 mg three times daily or 1000 mg twice daily), based on tolerance.
干预措施: Metformin (Drug)
结局指标
主要结局
Rate of major molecular response based on the variant-allele frequency (VAF) of DNMT3A R882 mutation at 6-month follow-up
时间窗: up to 6 months
An effective decline in VAF is defined as an absolute reduction of ≥10% when the baseline variant-allele frequency is greater than 20%; a relative reduction of ≥50% when the baseline variant-allele frequency is ≤20%. Variant-allele frequency is tested in bone-marrow samples via next-generation sequencing (NGS).
DNMT3A R882 Mutation VAF at 6 Months
时间窗: up to 6 months
Effective decline defined as: For baseline VAF \>20%, absolute decline ≥10%; for VAF ≤20%, relative decline ≥50%. Measured via NGS.
次要结局
- Rate of major molecular response based on the variant-allele frequency (VAF) of DNMT3A R882 mutation at 3-month follow-up(up to 3 months)
- Rate of Overall Response of DNMT3A R882 Mutation VAF at 3 Months(up to 3 months)
- Rate of Overall Response of DNMT3A R882 Mutation VAF at 6 Months(up to 6 months)
- Relapse-Free Survival (RFS) Rate at 6 Months(up to 6 months)
- DNMT3A R882 Mutation VAF at 3 Months(up to 3 months)
- Relapse-Free Survival (RFS) Rate at 12 Months(up to 12 months)
- Overall Survival (OS) Rate(Up to 12 months)
- Cumulative Incidence of Relapse (CIR)(Up to 12 months)
- Cumulative Remission-Phase Mortality Rate(Up to 12 months)