This is a single institution, open-label, single arm pilot study of Metformin in patients with Fanconi Anemia (FA) and cytopenias with the primary endpoint of hematologic response. This study will also assess safety, tolerability, and the biologic effects of Metformin in patients with FA.

Inclusion Criteria:

• Age > 6 years and ≤35 years

• Lansky/Karnofsky performance status ≥ 50% for patients ≥16 years of age and Lansky ≥ 50% for patients <16 years of age (see Appendix A)

• Diagnosis requirement

• Participants must have a clinical diagnosis of Fanconi Anemia.

  • Participants must have confirmed diepoxybutane-mitomycin C (DEB/MMC) stress testing to document diagnosis of Fanconi Anemia.
  • Patients must have at least one of the following cytopenias: Hemoglobin <10g/dL; Platelets <100k/uL; Absolute neutrophil count <1000/uL

• Participants must have normal organ function as defined below:

  • Hepatic Function : Total bilirubin ≤ 1.5 x upper limit of normal for age; alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 135 U/L
  • Renal Function: A serum creatinine based on age/gender as follows:

Age Maximum Serum Creatinine (mg/dL) Male Female

1. to < 2 years 0.6 0.6
2. to < 6 years 0.8 0.8

6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4

≥ 16 years 1.7 1.4

AND

• Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal

• Normal cardiac status as documented clinically, otherwise they will need an echocardiogram prior to enrollment
• Serum bicarbonate must be >17.
• Participants of child-bearing or child-fathering potential must agree to use adequate contraception (hormonal birth control; intrauterine device; double barrier method; or total abstinence) throughout their participation, including up until 30 days after last dose of Metformin.
• Patients must be able to swallow pills.
• Ability to understand and/or the willingness of the patient (or parent or legally authorized representative, if minor) to provide informed consent, documented using an institutionally approved informed consent procedure

Exclusion Criteria:

• Patients must not have undergone prior bone marrow transplantation.
• Patients must not have very severe aplastic anemia at the time of enrollment which would require bone marrow transplantation (as defined by at least 2 out of the following 3: Absolute Neutrophil Count (ANC) <200k/uL, platelets <20k/uL, absolute reticulocyte count <40k/uL).
• Patients must not be taking any other concurrent medications to improve their hematopoiesis such as androgens or growth factors such as Granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), or thrombopoietin (TPO) mimetics. There is a one month wash-out period for prior therapies including androgens.
• Pregnant participants will not be entered on this study given that the effects of Metformin on the developing human fetus are unknown.
• Breastfeeding mothers are not eligible because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Metformin.
• Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to Metformin.
• Patients must not have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients must not have prior history of symptomatic hypoglycemia over the past year or hypoglycemia with glucose <50mg/dL on screening and baseline laboratory assessments.
• Patients must not have type 1 diabetes mellitus.
• Patients must abstain from alcohol as part of this study.
• Patients must not have a diagnosis of myelodysplastic syndrome or leukemia, or other concurrent malignancy undergoing treatment.
• Patients must not have vitamin B12 deficiency.
• Patients must not have Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency.

Study enrollment through 30 days after completion of treatment, up to 7 months