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

Jessica A Pollard, Elissa Furutani, Shanshan Liu, Erica Esrick, Laurie E Cohen, Jacob Bledsoe, Chih-Wei Liu, Kun Lu, Maria Jose Ramirez de Haro, Jordi Surrallés, Maggie Malsch, Ashley Kuniholm, Ashley Galvin, Myriam Armant, Annette S Kim, Kaitlyn Ballotti, Lisa Moreau, Yu Zhou, Daria Babushok, Farid Boulad, Clint Carroll, Helge Hartung, Amy Hont, Taizo Nakano, Tim Olson, Sei-Gyung Sze, Alexis A Thompson, Marcin W Wlodarski, Xuesong Gu, Towia A Libermann, Alan D'Andrea, Markus Grompe, Edie Weller, Akiko Shimamura, Jessica A Pollard, Elissa Furutani, Shanshan Liu, Erica Esrick, Laurie E Cohen, Jacob Bledsoe, Chih-Wei Liu, Kun Lu, Maria Jose Ramirez de Haro, Jordi Surrallés, Maggie Malsch, Ashley Kuniholm, Ashley Galvin, Myriam Armant, Annette S Kim, Kaitlyn Ballotti, Lisa Moreau, Yu Zhou, Daria Babushok, Farid Boulad, Clint Carroll, Helge Hartung, Amy Hont, Taizo Nakano, Tim Olson, Sei-Gyung Sze, Alexis A Thompson, Marcin W Wlodarski, Xuesong Gu, Towia A Libermann, Alan D'Andrea, Markus Grompe, Edie Weller, Akiko Shimamura

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.

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Flow diagram of study population. Includes patients screened, enrolled, and determined to be eligible for protocol treatment.
Figure 2.
Figure 2.
Hematologic parameters at baseline and maximum response following metformin treatment. (A) Hemoglobin. (B) Platelet count. (C) Absolute neutrophil count. (D) Mean corpuscular volume. (E) Absolute reticulocyte count.

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Source: PubMed

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