Japanese Journal of Clinical Oncology 30:159-162 (2000)
© 2000 Foundation for Promotion of Cancer Research
A Case of Bilateral Heel Ulcers Associated with Hydroxyurea Therapy for Chronic Myelogenous Leukemia
Departments of 1Hematology and 2Dermatology, Jichi Medical School, Tochigi, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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Bilateral heel skin ulcers developed in a 50-year-old male in the chronic phase of chronic myelogenous leukemia who had been receiving hydroxyurea (HU) therapy for 3 years. Histological examination showed perivascular lymphocytic inflammation without vasculitis. After interruption of HU administration, the heel ulcers were completely resolved within 2 months. The clinical course strongly suggested that the heel ulcers were induced by long-term HU therapy.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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Hydroxyurea (HU) has been recognized as an effective agent for treating cancer since 1960 (1). The most common indications for hydroxyurea therapy are chronic myeloproliferative disorders and acute myelogenous leukemia. As to dermatological side-effects, long-term daily therapy was associated with usual dermatitis characterized by atrophy of the skin, hyperpigmentaion, alopecia, scaling and nail changes (2). Here we describe a case of bilateral heel ulcers associated with HU therapy for chronic myelogenous leukemia (CML). The first report of HU-related leg ulcers was described in 1986. Up to the present, five cases of leg ulcers due to HU therapy for CML have been documented in Japan and some cases in other countries have also been reported. These cases are reviewed in this paper.
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CASE REPORT |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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A 50-year-old male was referred to the Department of Hematology in our hospital for evaluation of leukocytosis in August 1994 and was diagnosed as having chronic myelogenous leukemia (CML) in the chronic phase by neutrophilia without disturbance of maturity, 100% positivity of Philadelphia chromosome (Ph) and splenomegaly. The patient was initially treated with interferon (rIFN alfa-2b) at a dose of 6 x 106 U/day for 10 days and 9 x 106 U/day for 9 days. However, mental depression occurred as a neurotoxic adverse effect and the treatment with IFN was discontinued. White blood cell (WBC) counts were controlled between 4000 and 12 000/µl by daily oral administration of HU at a dosage of 1–2 g/day from August 24th, 1994. Brownish pigmentation on the right heel, which was very painful, appeared in October 1997. One month later, similar pigmentation appeared on the left heel and the lesions gradually developed into ulcers without other dermatological lesions. The patient was referred to the Department of Dermatology and was admitted on January 13th, 1998. Ulcers due to HU were suspected and alprostadil (PGE1) was administered intravenously at a dose of 5µg/body from January 26th. However, the symptoms did not improve and the patient was referred to the Department of Hematology on January 29th for alternative therapy to replace HU.
The patient’s height was 174 cm and weight 70 kg. Physical examination did not reveal any abnormalities except for mild splenomegaly. Ulcers with partial pigmentations around them were located on both heels (left 40 x 50 mm, right 30 x 40 mm) (Fig. 1). The patient had no dermatological symptoms except for leg ulcers. The peripheral blood data were red blood cell count 274 x 104/µl, hemoglobin 12.5 g/dl, platelet count 15.8 x 104/µl and white blood cell count 6.7 x 103/µl with a differential of 2.0% blasts, 1.0% promyelocytes, 8.0% myelocytes, 1.0% metamyelocytes, 1.0% band forms, 34.0% segmented neutrophils, 19.0% basophils, 13.0% lymphocytes and 21.0% monocytes. Biochemical serum values showed lactic dehydrogenase (LDH) of 842 IU/l and C-reactive protein of <0.1 mg/dl. Examination of bone marrow showed 29.7 x 104 nucleated cells/µl with a differential of 10.6% blasts, 33.6% promyelocytes, 12.8% myelocytes, 3.6% metamyelocytes, 10.8% band forms, 11.0% segmented neutrophils, 1.4% eosinophils, 1.0% basophils, 1.4% lymphocytes, 1.8% plasmacytes, 1.0% monocytes and 0.4% erythroblasts. Chromosomal analysis revealed 100% positivity of Ph without any additional abnormalities. Histological examination of the heel skin showed perivascular lymphocytic infiltration without vasculitis (Fig. 2) and thickening of blood vessel walls (Fig. 3) throughout the whole dermis.
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After the interruption of HU administration on January 29th, the ulcers began to epithelialize within a few days and healed completely early in March. As to the state of CML, we failed to control it by busulfan at a dose of 4 mg/body for 14 days and consequently managed it by cytarabine ocfosfate at a dose of 200 mg/body for 6 days, carboquone at a dose of 3 mg/body for 6 days and ranimustine at a dose of 50 mg/body for 3 days. On May 3rd, the patient was discharged and was maintained in chronic phase by the administration of ranimustine at a dose of 100 mg/body biweekly. However, blastic crisis occurred 1 year after development of the ulcers.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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In the present case, the heel ulcers were considered to be caused by HU since the ulcers healed immediately after interruption of HU administration and the patient did not have any disease associated with angiopathic changes, such as diabetes mellitus. Dermatitis associated with long-term HU therapy, which was characterized by atrophy of the skin, hyperpigmentation, alopecia, scaling and nail changes, was reported by Kennedy et al. in 1975 (2). The first report of HU-related skin ulcers was by Stahl and Silber in 1985 (3). Five cases of HU-related leg ulcers have so far been reported in Japan (4,5). Here we describe a case of bilateral heel ulcers associated with HU therapy for CML. The ulcers, including those in our case, tend to be located below the ankles. One possible reason for this is that these regions are subjected to pressure daily and can be grazed by footwear. Best et al. suggested that leg ulcers are caused by both chronic cytotoxicity of HU and a tendency for the legs to be easily injured (6). HU converts a free radical nitroxide in vivo and inhibits DNA repair (7). Cellular injury accumulates to the extent that repair mechanisms can no longer regenerate viable, normal-functioning epidermis, stromal cells or endothelium and tissue damage and ulcers therefore develop (7).
Table 1 summarizes the clinical features and pathological findings of 20 patients with CML and leg ulcers who were treated with HU. These data were obtained by a MEDLINE search of the National Library of Medicine database. The average age at the time of diagnosis was 60 years (range, 45–73 years). The daily dose of HU was 0.5–2.5 g/day and the average period of therapy before formation of ulcers was 2.6 years (range, 1–7 years). 75% of the patients had bilateral leg ulcers.
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Histologically, perivascular lymphocytic infiltration and swelling of vessel walls without vasculitis have mainly been reported recently (Table 1). However, even after complete healing of the ulcer, the patients felt pain on the scars of the ulcers during platelet transfusion. This suggests that the pathogenesis is related to ischemia due to intravascular thrombosis.
In the present case, it was difficult to determine the effect of PGE1 because of the very short time from the start of PGE1 administration until the interruption of HU therapy. Although PGE1 had been administered for 28 days, it had no effect at least 3 days after the start of administration.
Blastic crisis occurred 1 year after developing ulcers, but the relation between the ulcers and blastic crisis is unclear.
It has been reported that two cases developed ulcers on re-starting HU treatment in patients with polycythemia vera and myeloproliferative disorder (6). The results of this study indicate that HU administration should be interrupted to allow for healing of ulcers.
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FOOTNOTES |
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+ For reprints and all correspondence: Shigehiko Imagawa, Department of Hematology, Jichi Medical School, Minamikawachi-machi, Tochigi 329-0498, Japan. E-mail: simagawa@jichi.ac.jpAbbreviations: HU, hydroxyurea; CML, chronic myelogenous leukemia; IFN, interferon; Ph, Philadelphia chromosome; PGE1, prostaglandin E1 (alprostadil)
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REFERENCES |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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Received September 30, 1999; accepted November 18, 1999.
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