Long-term propylthiouracil use and acute myeloid leukemia: A case report and review of the literature

Abstract

Dear Editor, We report a 31-year-old female who had been administered propylthiouracil for 15 years and shortly after delivery developed acute myeloid leukemia with complex karyotype, including a rare t(2;21) translocation. We discuss here the potential mechanisms by which this drug could have contributed to leukemia and review the literature for propylthiouracil-related hematological disorders. Acute Myeloid Leukemia (AML) has very few welldefined chemical triggers. Chronic drug use has been associated with increased AML risk, but no definitive evidence is available yet. Many drugs have in vitro leukemogenicity, and for some of them, literature exists reporting causal association with AML in patients. Thionamide-type thyroid peroxidase inhibitors are commonly used to treat primary hyperthyroidism. Despite the fact that methimazole (MMI) is the drug of choice, many patients develop side effects such as hepatitis, cholestatic jaundice, splenomegaly, and lupus-like syndrome, in addition to mild and common side effects like granulocytopenia, pruritus, urticaria, and maculopapular or papular eruption [1], so that they are then shifted to the older drug of this class, 6-n-propylthiouracil (PTU), originally used as a measure of taste genetics. In addition, in comparison with MMI, PTU has a shorter duration of action and has significantly less transfer across the placenta and into breast milk, making PTU the preferred antithyroid agent for pregnant women. PTU can induce antigranulocyte cytoplasm antibodies [2, 3], as well as antinuclear antibodies [4]. Since its approval by the Food and Drug Administration in 1947, PTU has been associated with many hematological adverse events [5], including granulocytopenia, agranulocytosis [6], and eosinophilia [7]. Thionamides resemble the methyltetrazole-thiol leaving group of certain cephalosporin antibiotics, and both thionamides and cephalosporins have been found to inhibit the vitamin-K-dependent gamma-carboxylation of glutamic acid in vitro [8]: actually, PTU has been associated with hypoprothrombinemia [9], disseminated intravascular coagulation [10], and acute thrombocytopenic purpura [11]. Most importantly, PTU has been associated with bone marrow aplasia [12, 13] and AML [14, 15]. AML itself is favored by immunosuppression. We report here on a patient who had been on PTU for 15 years and who developed AML shortly after delivery. A previously healthy, 31-year-old female was admitted at our division because of sudden onset of ecchymoses and a complete blood count showing leukocytosis and thrombocytopenia. A peripheral blood smear suggestive for AML was confirmed by bone marrow aspiration and trephine biopsies. Immunohistochemistry and immunophenotyping showed acute myelomonoblastic leukemia (FAB M4). Cytogenetics on bone marrow leukocytes showed a complex karyotype with two abnormal clones, one with t(2;21) and another with both t(3;16) and del8p. At past medical history, she reported only having been diagnosed with primary hyperthyroidism at age 16, which was initially treated with MMI. Because of drug intolerance, she was then shifted to PTU 25 mg daily po, a drug that she took for 15 years before AML diagnosis. At that time, she had just been pregnant, having an uncomplicated delivery 4 months before the onset of AML. Ann Hematol (2008) 87:233–235 DOI 10.1007/s00277-007-0369-4