Metformin for treatment of cytopenias in children and young adults with Fanconi anemia

Jessica A. Pollard, Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA.
Elissa Furutani, Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA.
Shanshan Liu, Biostatistics and Research Design Center, Institutional Centers for Clinical and Translational Research, Harvard Medical School, Boston, MA.
Erica Esrick, Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA.
Laurie E. Cohen, Department of Pediatrics, Harvard Medical School, Boston, MA.
Jacob Bledsoe, Department of Pathology, Boston Children's Hospital, Boston, MA.
Chih-Wei Liu, Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Kun Lu, Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Maria Jose de Haro, Joint Research Unit UAB-Sant Pau Biomedical Research Institute,Institut de Recerca Hospital de la Santa Creu i Sant Pau-IIB Sant Pau, Universitat Autònoma de Barcelona, Barcelona Spain.
Jordi Surrallés, Joint Research Unit UAB-Sant Pau Biomedical Research Institute,Institut de Recerca Hospital de la Santa Creu i Sant Pau-IIB Sant Pau, Universitat Autònoma de Barcelona, Barcelona Spain.
Maggie Malsch, Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA.
Ashley Kuniholm, Clinical Research Operations Center, Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA.
Ashley Galvin, Clinical Research Operations Center, Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA.
Myriam Armant, Trans Laboratory, Boston Children's Hospital, Boston, MA.
Annette S. Kim, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Kaitlyn Ballotti, Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA.
Lisa Moreau, Comprehensive Center for Fanconi Anemia, Dana-Farber Cancer Institute, Boston, MA.
Yu Zhou, Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA.
Daria Babushok, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA.
Farid Boulad, Pediatric Hematology-Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY.
Clint Carroll, Pediatric Hematology-Oncology, The Children's Hospital at TriStar Centennial, Nashville, TN.
Helge Hartung, Pediatric Hematology-Oncology, Children's Hospital of Philadelphia, Philadelphia, PA.
Amy Hont, Pediatric Hematology-Oncology, Children's National Medical Center, Washington, DC.
Taizo Nakano, Pediatric Hematology-Oncology, Children's Hospital Colorado, Denver, CO.
Tim Olson, Pediatric Hematology-Oncology, Children's Hospital of Philadelphia, Philadelphia, PA.
Sei-Gyung Sze, Department of Pediatrics, Maine Medical Center, Tufts University School of Medicine, Portland, ME.
Alexis A. Thompson, Pediatric Hematology-Oncology, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
Marcin W. Wlodarski, Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN.
Xuesong Gu, Beth Israel Deaconess Medical Center Genomics, Proteomics, Bioinformatics and Systems Biology Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Towia A. Libermann, Beth Israel Deaconess Medical Center Genomics, Proteomics, Bioinformatics and Systems Biology Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Alan D'Andrea, Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Markus Grompe, Oregon Stem Cell Center, Department of Pediatrics, Papé Family Institute, Oregon Health and Science University, Portland, OR; and.

Abstract

Fanconi anemia (FA), a genetic DNA repair disorder characterized by marrow failure and cancer susceptibility. In FA mice, metformin improves blood counts and delays tumor development. We conducted a single institution study of metformin in nondiabetic patients with FA to determine feasibility and tolerability of metformin treatment and to assess for improvement in blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin < 10 g/dL; platelet count < 100 000 cells/µL; or an absolute neutrophil count < 1000 cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5 ). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; 1 subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions caused by toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response based on modified Myelodysplastic Syndrome International Working Group criteria was observed in 4 of 13 evaluable patients (30.8%; 90% confidence interval, 11.3-57.3). Median time to response was 84.5 days (range 71-128 days). Responses were noted in neutrophils (n = 3), platelets (n = 1), and red blood cells (n = 1). No subjects met criteria for disease progression or relapse during treatment. Correlative studies explored potential mechanisms of metformin activity in FA. Plasma proteomics showed reduction in inflammatory pathways with metformin. Metformin is safe and tolerable in nondiabetic patients with FA and may provide therapeutic benefit. This trial was registered at as #NCT03398824.