Hydroxyurea-induced skin ulcerations in patients with chronic myeloproliferative disorders.

Abstract

461 HYDROXYUREA (HU) is a hydroxylated derivative of urea used in the treatment of myeloproliferative disorders and acute myelogenous leukemia. It inhibits cellular DNA synthesis and promotes cell death in the S phase of the cell cycle through its action on the enzyme ribonucleotide reductase, an essential enzyme to DNA synthesis (1). HU is well tolerated with a relatively low toxicity profile. Side effects may be systemic or restricted to skin and mucous membranes. Dermatological adverse effects are underestimated because they are usually benign. These include alopecia, xerosis, diffuse hyperpigmentation, brown-nail discoloration, fixed drug eruption, stomatitis, acral erythema and scaling eruptions, photosensitization, skin tumors on UV-light-exposed areas, dermatomyositis-like dermatitis, lichen planus-like dermatitis, and painful leg ulcerations (2). We report 6 patients in whom cutaneous leg ulcers developed while receiving HU. Their characteristics are summarized in Table 1. The reported incidence of adverse reactions varies from 10 to 35% and leg ulcers have been described in less than 0.1% of patients (3). Since the first description by Montefusco et al. in 1986, HU-related leg ulcers have been reported following chronic therapeutic doses. The first lesions usually observed after 0.7–7 years (4). There was no relationship between sex ratio, age, duration of treatment, and daily dose, neither with the appearance, worsening, and regressions of the lesions and nor with the complementary therapy received for the control of the haematological disease (5). The most common site of ulcers is on legs, mainly located near the malleoli, but they were occasionally found over the tibia, on feet, and on calves (1). The clinical feature of our cases is the early appearance of lesions in older patients. All of them developed extensive and progressive skin changes with ulceration on malleoli, calves, or hands (see Fig. 1). Ulcers were extremely painful and fibrous with violaceous macules, edema surrounding them, and thin periulcerous skin. Histology of vascular changes showed leukocytoclastic vasculitis, perivascular lymphocytic inflammation, formation of thrombus, swelling of the endothelial cells, and thickening of the vascular walls (6). The pathogenesis remains poorly understood and probably leg ulcers are often multifactorial. Microvascular circulatory disturbance in myeloproliferative disorders includes erytromelalgia, Raynaud’s phenomenon, digital ischemia, acrocyanosis, blue toe syndrome, livedo reticularis, cutaneous ulcers, or necrotic purpura (7). Besides, HU causes cumulative toxicity on the basal layer of epidermis producing cutaneous atrophy and impaired wound healing (8). Furthermore, the megaloblastic erythrocyte changes, which occur in almost all patients taking HU, may be a pathogenic factor. Macroerytrocytosis can be considered as an acquired blood dyscrasia and similar leg ulcers have long been known to occur with certain hereditary blood dyscrasias, such as sickle cell anemia, thalassemia, and spherocytosis (9). The megaloblastic erythrocytes may circulate poorly through the capillary network and may lead to cutaneous anoxia and subsequent ulceration after minor trauma (10). Therefore, it has been suggested that repeated mechanical injury accounts for the ulceration occurring in areas of common trauma. The risk appears to be higher in elders, particularly if they had mechanical injuries, vessel abnormalities, or peripheral edema (11). No major vascular disease to account for the persistent