Repurposing Metformin As a Leukemia-preventive Drug in CCUS and LR-MDS

Patients are eligible to be included in WP1 if they meet all of the following criteria: Inclusion criteria: * A diagnosis of: * LR-MDS according to the revised international prognostic scoring system (IPSS-R), i.e., very low- or low-risk disease (IPSS-R score ≤3) in addition to a bone marrow blast percentage \<5 OR * CCUS defined as the presence of somatic mutation(s) or cytogenetic abnormality not diagnostic of MDS or any other malignancy in the context of persistent cytopenia (\>6 months) with other common causes of cytopenia ruled out in the setting of bone marrow morphology that is not diagnostic of MDS or any other malignancy, and hematolytic conditions have been ruled out. Peripheral blood cytopenia is defined as hemoglobin (hgb) \<11.3 g/dL (7 mmol/L) in women and hgb \<12.9 g/dL (8 mmol/L) in men, platelet count \<150 x 109/L, or neutrophil count \<1.8 x 109/L * Menopause, if being a female, defined as females \>45 years of age who have experienced amenorrhea for minimum 12 months, without any other obvious pathological or physiological cause * ≥18 years of age * Written informed consent * Willingness to comply with mandatory aspects of the protocol * Ability to swallow pills Exclusion criteria: * Any prior treatment with metformin * A diagnosis of diabetes mellitus * Therapeutic radiation, immunosuppressive therapy (with the exception of corticosteroids), or chemotherapy within the past year * Treatment with granulocyte colony-stimulating factor within the past 30 days * Prior therapy with hypomethylating agents (i.e., azacitidine, decitabine) * eGFR \<45 mL/min * Performance status according to the Eastern Cooperative Oncology Group \>2 * Other active malignancy within the past five years * Uncontrolled comorbidity including impaired hepatic function (total serum bilirubin \>1.5 × upper limit of the normal range (ULN), serum alanine transaminase \>3 × ULN), chronic hepatitis with decompensated cirrhosis, disabling psychiatric disease, severe neurologic disease, uncontrolled metabolic disease, or severe cardiac disease (NYHA class 3-4) An eGFR calculation performed up to one month prior to inclusion may be used to assess renal function. If such an assessment is not available, it is performed at screening. Healthy volunteers are eligible to be included in WP0 if they meet all of the following criteria: Inclusion criteria: * Healthy individuals matched on age, sex, and BMI, if possible, to individual patient participants in WP1 * Written informed consent * Willingness to comply with mandatory aspects of the protocol Exclusion criteria: * Use of metformin within the past 3 years * A diagnosis of diabetes mellitus, rheumatological disorders, autoimmune diseases or other inflammatory disorders, celiac disease, inflammatory bowel disease, or other gastrointestinal disorders or symptoms * Treatment with immunosuppressive drugs (with the exception of corticosteroids) or chemotherapy within the past year or antibiotics within the past 6 months * Any contraindications to MRS