Metformin for Treating Cytopenias in Children and Young Adults With Fanconi Anemia
abstract
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Access this abstract nowFanconi anemia (FA), a genetic disorder affecting DNA repair, is characterized by bone marrow failure and cancer susceptibility. In FA mouse models the biguanide metabolic agent metformin improves blood counts and delays tumor development. We conducted a single institution pilot study of metformin in non-diabetic patients with FA to assess feasibility and tolerability of metformin treatment and to determine whether metformin could improve blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin <10g/dL, platelet count <100K cells/µL, or an absolute neutrophil count <1K cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5), and 8/14 were male (57%). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; one subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions due to toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response (HR) based on modified MDS IWG criteria was observed in 4 of 13 evaluable patients (30.8%, 90% CI:11.3 to 57.3). Median time to response was 84.5 days (range 71-128). 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. We conclude that metformin is safe and tolerable in non-diabetic patients with FA and may provide therapeutic benefit.
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Metformin for Treatment of Cytopenias in Children and Young Adults with Fanconi Anemia
Blood Adv 2022 May 02;[EPub Ahead of Print], J Pollard, E Furutani, S Liu, EB Esrick, LE Cohen, JR Bledsoe, CW Liu, K Lu, MJ Ramírez, J Surrallés, MM Malsch, A Kuniholm, A Galvin, M Armant, AS Kim, K Ballotti, LA Moreau, Y Zhou, DV Babushok, F Boulad, C Carroll, H Hartung, A Hont, TA Nakano, TS Olson, SK Sze, AA Thompson, MW Wlodarski, X Gu, TA Libermann, AD D'Andrea, MCP Grompe, E Weller, A ShimamuraFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Pollard and colleagues should be commended on their efforts to investigate a new treatment approach for Fanconi anemia (FA), an inherited bone marrow failure syndrome with limited treatment options, using the readily available oral biguanide metformin. Although allogeneic hematopoietic stem cell transplantation remains a cornerstone therapy for FA, treatments aimed at improving the underlying deficiencies in hematopoiesis, associated endocrinopathies, and preventing secondary malignancies remain an area of need.
In this single-institution, open-label, investigator-initiated pilot study, 14 patients underwent a planned 6-month treatment with metformin (maximum dose, 1000–2000 mg daily, dependent on the participant's age). The study population was predominantly pediatric or consisted of adolescent to young adult patients (median age, 9.4 years); all patients had an absolute neutrophil count greater than 500 cells per mL.
Treatment with metformin was well-tolerated. No grade 3 or 4 adverse events occurred, and 86% of patients (n = 12) completed the planned 6 months of therapy. Encouragingly, treatment resulted in a hematologic response (defined as the per modified MDS IWG criteria) in 30.8% of the patients (n = 4) after a median period of 84.5 days. Responses were observed across several cell lineages (even in the sole RBC transfusion–dependent patient at the time of study enrollment) and were durable. No patient lost response or experienced relapse. Only 3 patients had evidence of mild insulin resistance at baseline, of whom 2 demonstrated improvement in their insulin resistance parameters following metformin therapy.
Although limited by a small sample size, the authors further sought to characterize the biological impact of metformin in FA. No change in the bone marrow cellularity was observed following metformin treatment. Increased myeloid and erythroid colony–forming cell numbers were observed in a minority of patients (2 of 4 non-responding patients); chromosomal breakage, albeit not statistically significant, was decreased in treated patients exposed to mitomycin C and diepoxybutane. Biological pathway analysis revealed downregulation of the inflammatory and cytokine/cytokine receptor pathways in addition to type 1 diabetes mellitus pathways. Clonal evolution while on therapy was uncommon. Only 1 patient had dynamic clonal changes identified by cytogenetic analysis during the study period (potentially as a consequence of the relatively short study duration).
These results reported by Pollard et al are noteworthy. Future investigative efforts, including a larger population of patients with FA, are welcomed to confirm these preliminary findings, identify biomarkers predictive of metformin response (the current sample size precluded any definitive correlative analyses), and assess responses in patients with more severe FA. Furthermore, as the authors noted — a longer duration of metformin treatment and ongoing prospective follow-up may aid in assessing the impact of prolonged metformin use on hematopoiesis and associated secondary malignancies in the disease requiring additional treatment strategies.