Recurrence of Hydroxyurea-induced Leg Ulcer After Discontinuation of Treatment

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Hydroxyurea (HU) is a hydroxylated derivative of urea that has been recognized since 1960 as effective against cancer (1). It is an inhibitor of cellular DNA synthesis, and it promotes cell death in the S phase of the cell cycle through inhibition of the enzyme ribonucleotide reductase (2). The most common indications for HU therapy are chronic myeloid leukaemia and other myeloproliferative disorders (3, 4) such as essential thrombocythemia (5) and polycythemia vera (PV) (6). Cutaneous side-effects, such as alopecia, diffuse hyperpigmentation, scaling, lichen planus-like lesions, poikiloderma, atrophy of the skin and subcutaneous tissues, and nail changes, can occur during the treatment with HU (7–9). The occur-rence of painful leg ulcers represents another rare and incompletely characterized complication that has been described in patients with myeloproliferative diseases receiving high-dose long-term HU treatment (10). While the mode of action of HU on bone marrow elements is well established, its effects on actively proliferating epit-helial cells remain less described (11). Poor response to traditional local and systemic therapy is a typical feature of HU-induced leg ulcers, and discontinuation of the drug is often required to achieve complete wound healing (6, 8). Cessation of the drug usually improves the skin ulcer; although, in some cases, the ulcer remains and additional therapies, such as skin grafting, are needed (12). We report here the first case of a leg ulcer that recurred even after discontinuation of HU treatment. CASe rePorTThe patient was an 82-year-old Japanese male who had been diagnosed with PV 9 years before and had been treated only with phlebotomy and an anti-platelet agent for several years. Due to splenomegaly and elevated blood cell counts, HU therapy was started 3 years ago at a dosage of 1 g daily for a month, followed by 1.0 or 1.5 g daily for 28 months. A good clinical response was achieved. However, the patient developed painful ulcers on the left second toe after two years of HU treatment.He visited our outpatient clinic and was diagnosed with an HU-induced skin ulcer. HU was discontinued, topical application of sulfadiazine silver was performed, an oral antibiotic (cefdinir) was administered, and the ulcer epithelialized. However, a new ulcer appeared on the left lateral malleolar area 46 days after cessation of HU and gradually enlarged in size. The patient was admitted to our hospital for treatment of the ulcer.examination revealed a 48 × 56 mm ulcer with yellow necrotic tissue and marginal erythematous oedema (Fig. 1). Laboratory examination revealed a white blood cell count of 11.6×10