Metformin Inhibits DNMT3A Clonal Hematopoiesis in Acute Leukemia
For patients and families
In plain language
An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.
- What is being studied
- The protocol lists: Metformin.
- Who it may be relevant to
- Registry conditions: DNMT3A Gene Mutation. Basic parameters: from 14 years · All.
- What needs checking
- Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
- Where it takes place
- Center list to be confirmed — check the primary protocol.
- Next step
- Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →
Unsure about the terms? Read our patient guide →
Official title
Metformin Inhibits DNMT3A Clonal Hematopoiesis in Acute Leukemia: A Single-Arm Clinical Study
Overview
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: 30 participants.
Detailed description
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%.
Safety monitoring: Close monitoring of liver/kidney function, especially in patients ≥60 years or with renal impairment, due to lactic acidosis risk.
Data management uses electronic case report forms (eCRF). Statistical analysis includes intention-to-treat (ITT) and per-protocol (PP) sets, with Kaplan-Meier for survival, t-tests, Wilcoxon rank-sum, chi-square, and Cox proportional hazards models.
Interventions
- Drug Metformin
Start at 500 mg twice daily, titrate to 2000 mg/day for 6 months
Primary outcome measures
- DNMT3A R882 Mutation VAF at 6 Months [Time frame: up to 6 months]
Secondary outcome measures (6)
- DNMT3A R882 Mutation VAF at 3 Months [Time frame: up to 3 months]
- Relapse-Free Survival (RFS) Rate at 6 Months [Time frame: up to 6 months]
- Relapse-Free Survival (RFS) Rate at 12 Months [Time frame: up to 12 months]
- Overall Survival (OS) Rate [Time frame: Up to 12 months]
- Cumulative Incidence of Relapse (CIR) [Time frame: Up to 12 months]
- Cumulative Remission-Phase Mortality Rate [Time frame: Up to 12 months]
Eligibility criteria
Inclusion criteria
- 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).
Exclusion criteria
- Patients with diabetes receiving other medications
- Known allergy to metformin
- Deemed unsuitable by investigator
Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.
Healthy volunteers: No
Study design
- Allocation
- N/A
- Model
- Single group
- Masking
- Open label
- Primary purpose
- Treatment
Study locations
Center list to be confirmed — check the primary protocol.
Identifiers
NCT: NCT07188740 · IIT2025104