A 75-year-old man with splenic marginal zone lymphoma had been treated by fludarabine. The 3 first courses were very well tolerated, with no cytopenia. To treat diabetes mellitus, metformin was added at day 6 after the beginning of the fourth course of fludarabine treatment. He had previously been briefly treated with metformin a few months before. Four days later, at day 10, haemogram revealed severe neutropenia (neutrophils: 0.7 g/l). Neutrophil count continued to decrease reaching 0.283 g/l at day 17. A bone marrow aspirate was performed and showed very active granulopoiesis with maturation arrest at the promyelocyte stage. Metformin was discontinued on day 22 (16 days after reintroduction) and neutropenia promptly reversed during next week with 1.9 g/l (day 29). Direct and indirect granulocyte immunofluorescence test were used to detect anti-neutrophil autoantibodies. The antibodies were related to metformin and were detectable by granulocyte agglutination test and the monoclonal antibody-specific immobilization of granulocyte antigens assay. A possible explanation is the fludarabine–metformin combination, since fludarabine could deplete regulator T-lymphocytes and lead to the emergence of metformin-induced anti-neutrophil antibodies.
Auto-immune neutropenia Fludarabine Metformin Splenic marginal zone lymphoma
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Meyer O, Gaedicke G, Salama A. Demonstration of drug-dependent antibodies in two patients with neutrophenia and successful treatment with granulocyte-colony-stimulating factor. Transfusion. 1999;39:527–30.PubMedCrossRefGoogle Scholar
Thieblemont C, Felman P, Callet-Bauchu E, Traverse-Glehen A, Salles G, Berger F et al. Splenic marginal-zone lymphoma: a distinct clinical and pathological entity. Lancet Oncol. 2003;4:95–103.PubMedCrossRefGoogle Scholar
Humphrey CA, French A, Morris TC. Prospective in vitro testing for drug-induced neutropenia in a patient requiring anti-malarial prophylaxis: confirmation of findings on exposure of patient to drug. Clin Lab Haematol. 1990;12:31–6.PubMedGoogle Scholar
Gamberale R, Galmarini CM, Fernandez-Calotti P, Jordheim L, Sanchez-Avalos J, Dumontet C, et al. In vitro susceptibility of CD4+ and CD8+ T cell subsets to fludarabine. Biochem Pharmacol. 2003;66:2185–91.PubMedCrossRefGoogle Scholar
Van Den Neste E, Delannoy A, Feremans W, Ferrant A, Michaux L. Second primary tumors and immune phenomena after fludarabine or 2-chloro-2′-deoxyadenosine treatment. Leuk Lymphoma. 2001;40:541–50.CrossRefGoogle Scholar