The observations of Dr. Kennedy and Disla and colleagues are interesting but deserve further comment. Kennedy and colleagues had performed many of the seminal clinical studies examining the activity and use of hydroxyurea. Their 1975 report did not specifically identify the distinctive painful leg ulcers that develop in patients receiving long-term hydroxyurea therapy [1]. We recently reported our findings on the lichenoid, dermatomyositis-like skin changes resulting from hydroxyurea therapy, changes similar to Kennedy and colleagues' initial observations [1, 2]. Most of the patients with leg ulcers that resulted from hydroxyurea did not have the atrophic, lichenoid changes reported by Kennedy and coworkers and us [1, 2]. These skin findings seem to represent separate pathologic processes with distinctive comorbidity factors leading to lichenoid changes or leg ulcers.

When hydroxyurea is chosen as a therapeutic agent in myeloproliferative disorders, daily dosage is the textbook standard. To our knowledge, the intermittent dosage schedule described by Kennedy (his [4]) has not been evaluated in a controlled manner. The largest series on intermittent dosage reported on 45 patients with various types of cancer [3]; the mean duration of therapy was only 6 months. In our patients with painful ulcers, the mean duration was 6 years.

We agree with Disla and colleagues' comment that leg ulcers in the setting of hydroxyurea therapy may be multifactorial. For patients receiving hydroxyurea who develop leg ulcers, other important comorbid, predisposing factors should also be evaluated for and treated accordingly. In some cases, as they observe, ulceration may not be due primarily to hydroxyurea. We specifically excluded patients with ulcers that may have been caused by other conditions. The hemoglobin level of Disla and colleagues' patient was not controlled, which raises the possibility of viscosity as a contributing factor. Associated thrombocythemia may cause ulceration [4], but any vascular studies done on their patient were not mentioned. However, if other conditions causing leg ulceration are treated successfully but ulcers persist, hydroxyurea is the likely offending agent and discontinuation of this therapy is often necessary. Occasionally, as observed with two of our patients, decreasing the dosage may result in substantial improvement in or resolution of leg ulcers. The chronic, lichenoid, atrophic changes of skin induced by hydroxyurea invariably require cessation of therapy with the agent and respond more slowly after discontinuation [2].