Robert M. Petitt

Hydroxyurea-Induced Leg Ulceration in 14 Patients

Hydroxyurea therapy has been recognized as an effective treatment for cancer since 1960 [1]. The most common indications for this therapy are chronic myeloproliferative disorders and acute myelogenous leukemia. Hydroxyurea has also been used to treat various solid tumors, including primary brain tumors, head and neck cancers, renal cell carcinoma, and breast cancer [2]. Less commonly, it is used as a radiosensitizer, for the management of sickle-cell anemia, for the treatment of psoriasis, and to inhibit viral replication in HIV disease [3-6]. Dermatologic side effects of hydroxyurea are fairly common and include hyperpigmentation, scaling, erythema and desquamation of the face and hands, and partial alopecia [7]. A less well-described and less well-characterized complication is leg ulcers. We present clinical observations documenting a strong association between hydroxyurea therapy and cutaneous ulceration of the legs. Retrospective review of the medical records of patients registered at the Mayo Clinic, Rochester, Minnesota, identified 14 patients who had leg ulcers related to hydroxyurea therapy. Case Reports Patient 1 A 69-year-old man with a history of polycythemia vera and an associated transient ischemic attack received 1.5 g of hydroxyurea daily. After 3 years of continuous therapy, he developed a painful, indolent ulcer of the right posterior calf. Various topical wound dressings, enzymatic debridement, and oral antibiotics failed to heal the ulcer. When the hydroxyurea dosage was increased to 2 to 2.5 g/d, the ulcer increased in size to 3 3 cm. Hydroxyurea treatment was discontinued when its association with the ulcer was identified. The ulcer healed over the course of 3.5 months, and the patient had no further difficulties until 3 years later, when hydroxyurea treatment was restarted by a physician who was not convinced of the original diagnosis of hydroxyurea-induced cutaneous ulceration. Four months after therapy was reinitiated, the patient developed multiple painful ulcers on both ankles (Figure 1). Treatment was again discontinued, and the cutaneous ulcers completely resolved within 6 months. Figure 1. Hydroxyurea-induced ulcer. Top. Bottom. Patient 2 A 41-year-old woman with an undifferentiated myeloproliferative disorder and a history of portal venous thrombosis had received hydroxyurea therapy for 9 years without complications, but she developed an extremely painful ulcer over the left lateral malleolus while she was receiving 1.5 g of hydroxyurea daily. Treatment with pentoxifylline, aspirin, warfarin, and leg elevation was unsuccessful. Hydroxyurea therapy was subsequently discontinued, and anagrelide therapy was initiated. The ulcer resolved within 2 months. Several months later, hydroxyurea therapy was restarted at a dosage of 1.5 g/d because of gastrointestinal intolerance of anagrelide. Cutaneous ulcers developed within 4 months and persisted for the ensuing 4 years while the patient was receiving hydroxyurea therapy. Results Fourteen patients with hydroxyurea-induced leg ulcerations were identified through review of the medical records of 115 patients with various myeloproliferative diseases and leg ulcers who had been treated with hydroxyurea during the previous 16 years (1980 to 1995). This period extended back beyond the first report of hydroxyurea-associated leg ulcers, which was published in 1986 [8]. It would have been preferable to identify all patients treated with hydroxyurea at our institution, but this was not possible because our clinical database does not index patients by medication use. Detailed medical histories of 8 women and 6 men, including the 2 patients described above, were reviewed. The Table 1 summarizes the clinical and morphologic features and clinical course of hydroxyurea-related skin ulcers in these 14 patients. The average age of patients at diagnosis was 65 years (range, 41 to 74 years). Hydroxyurea was administered to treat polycythemia vera (5 patients), essential thrombocythemia (2 patients), agnogenic myelogenous metaplasia (2 patients), chronic granulocytic leukemia (4 patients), and an incompletely characterized myeloproliferative disorder (1 patient). One patient had diabetes mellitus, and 6 had hypertension. Noninvasive arterial and venous vascular studies were done in 7 patients, and no specific vascular causes were identified that might explain the persistent ulcers. Table 1. Clinical Findings in Hydroxyurea-Related Leg Ulcers in 14 Patients Cutaneous ulcers were typically located near the malleoli but were occasionally found over the tibia, on the dorsal aspect of the feet, and on the calves. Of the 18 malleolar ulcers in our 14 patients, 10 (55.6%) were over the medial malleolus and 8 (44.4%) were over the lateral malleolus. A representative cutaneous ulceration is shown in the top panel of the (Figure 1). The ulcers were usually extremely painful. Multiple ulcers were seen in 9 patients (64%). When treatment was discontinued, the hydroxyurea dosage ranged from 1 to 2.5 g/d. The average cumulative dose of hydroxyurea before ulcers developed was 3.2 kg (range, 1.4 to 5.5 kg). The duration of hydroxyurea treatment ranged from 2 to 15 years (mean, 6.1 years). The cutaneous ulcers completely resolved in 12 patients after cessation of hydroxyurea treatment. Two patients had skin grafting to expedite healing. Patient 4 had an indolent ulcer for 1 year, after which time the hydroxyurea dosage was decreased from 1.5 to 0.5 g/d. Ulcer healing ensued within 5 months. Patient 8 also had improvement after the hydroxyurea dosage was decreased from 2 to 1 g/d. However, this dosage was subsequently increased to 2.5 g/d. The original ulcer markedly worsened over the ensuing 4 months, and new ulcers appeared over both malleoli. Hydroxyurea treatment was discontinued. A fatal myocardial infarction that occurred 2 weeks later prevented further assessment. Discussion Hydroxyurea is typically well tolerated and has a relatively low toxicity profile [9]. However, substantial cutaneous side effects have been seen; these include diffuse hyperpigmentation, brown discoloration of nails, acral erythema, photosensitization, fixed drug eruption, alopecia, oral ulceration, and stomatitis [9]. A poikilodermatous dermatomyositis-like skin eruption with atrophy, erythema, and scaling has also been reported [7]. Another ill-defined dermatologic side effect is cutaneous ulceration during hydroxyurea administration. Montefusco and colleagues [8] described 17 patients who had hydroxyurea-related leg ulcers and found complete resolution (14 patients) or marked improvement (3 patients) after hydroxyurea therapy was discontinued. Another study [10] described 4 patients with hydroxyurea-induced skin ulcers that eventually resolved with diligent wound care. We describe 14 patients in whom cutaneous leg ulcers developed while the patients were receiving long-term treatment with hydroxyurea. Our findings indicate that even with meticulous wound care, resolution of the ulcers usually requires discontinuation of hydroxyurea treatment. Extensive attempts to initiate wound healing before discontinuation of treatment included the use of topical and systemic antibiotic therapy, pentoxifylline, hyperbaric oxygen, warfarin, prednisone, Unna vascular boots, and topical wound dressings. None offered significant clinical benefit. Several mechanisms of action have been described for hydroxyurea, including inactivation of the enzyme ribonucleotide reductase with subsequent inhibition of cellular DNA synthesis and cell death in S phase [11]. In the skin, basal keratinocytes are the most actively replicating cells of the epidermis, and damage to keratinocytes by cytotoxic chemotherapeutic agents is one of the most common pathologic alterations seen in chemotherapy-induced reactions [12]. With sustained damage to basal keratinocytes, epidermal atrophy may become prominent [7]. Hydroxyurea has other effects on mammalian cells, including damage due to free-radical nitroxide intermediates and inhibition of DNA repair [11]. Hydroxyurea-induced cutaneous ulcers often occur over the malleoli. One explanation for this localization may be mechanical injury and trauma. In addition, the latency to onset, indolent behavior, and eventual healing after therapy is discontinued all suggest that the mechanism for cutaneous toxicity involves chronic and progressive but reversible cytologic damage. 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 [11]. Histologic examination shows nondiagnostic changes. A typical histologic photomicrograph of a hydroxyurea-induced ulcer is shown in the bottom panel of the (Figure 1). At the ulcer border, pseudoepitheliomatous hyperplasia and epidermal spongiosis are seen. In the dermis, endothelial cell swelling, edema, and thickening of blood vessel walls are prominent. Perivascular lymphocytic inflammation without vasculitis is common. In chronic lesions, focal hyalinization of blood vessel walls and intraluminal deposition of fibrinoid material directly beneath the ulceration are seen. These findings resemble the cutaneous occlusive vasculopathy seen in livedoid vasculitis. At later stages, dermal fibrosis develops. No consistent correlation between the dose or duration of hydroxyurea therapy and the occurrence of ulcers has been reported previously [8]. On the other hand, although we observed the development of ulcers over a range of hydroxyurea dosages, the extent and size of the ulcers did correlate with the amount of hydroxyurea administered in two patients. One patient had resolution of the ulcers when the dosage was decreased to 500 mg/d. In addition, long-term hydroxyurea therapy lasting at least 2 to 3 years was generally required before the ulcers occurred. The clinical experience summarized here confirms and further cl

Essential Thrombocythemia in Young Adults

Essential thrombocythemia is typically a disorder of adults in the sixth or seventh decade of life and is characterized by frequent thrombohemorrhagic complications. In young patients, the optimal management of complications is controversial. We studied 56 young adults (33 female and 23 male patients) with a diagnosis of essential thrombocythemia. The mean duration of follow-up was 4.68 years. The mean platelet count at diagnosis was 1,328,000/mm3. Platelet aggregation studies in 21 patients demonstrated hypoaggregation to epinephrine; spontaneous platelet aggregation was present in 4. At diagnosis, 39 patients were asymptomatic, and thrombocytosis was discovered incidentally. Throughout follow-up (up to 20 years), 24 patients remained asymptomatic. Thrombotic complications developed in 24 patients; they were life-threatening in only 3. The most common vaso-occlusive symptoms were migraine headache (in 12 patients) and erythromelalgia (in 3). Minor hemorrhagic complications occurred in six patients, and none was life-threatening. Serious complications (one cerebral and two myocardial infarctions) occurred in three patients, all of whom recovered. Two deaths occurred, neither of which was attributable to essential thrombocythemia. The treatment regimens used were chemotherapy in 9 patients, antiaggregating agents in 7, radioactive phosphorus in 1, the newer platelet-lowering agent anagrelide in 10, and only observation in 29. No treatment-related acute leukemias developed. This series of young patients with essential thrombocythemia, the largest to date, demonstrates a low incidence of life-threatening complications and a favorable long-term prognosis. Therapeutic recommendations should remain conservative, and potential leukemogens should be avoided unless serious complications develop. Anagrelide may be useful in young patients with thrombocythemia who are symptomatic.

The effects of anagrelide on human megakaryocytopoiesis

Anagrelide, an inhibitor of platelet aggregation, decreases the number of platelets in normal subjects and in patients with myeloproliferative disorders. We describe studies aimed at discovering the general mechanism(s) by which anagrelide acts. We examined three hypotheses: (1) anagrelide shortens platelet survival, (2) anagrelide inhibits the proliferation of megakaryocytic‐committed progenitor cells (CFU‐M), and (3) anagrelide inhibits maturation of megakaryocytes. We observed that anagrelide did not shorten platelet survival. Proliferation of CFU‐M in vivo was not affected by anagrelide, although high concentrations of anagrelide inhibited CFU‐M in vitro. In‐vivo and in‐vitro anagrelide altered the maturation of megakaryocytes, causing a decrease in their size and changing other morphometric features. We conclude that anagrelide decreases the number of platelets primarily by interfering with the maturation of megakaryocytes.

Autosomal Dominant Familial Mediterranean Fever-Like Syndrome With Amyloidosis

We report a pedigree in which a syndrome that resembled familial Mediterranean fever occurred in four family members over three successive generations. All four patients had systemic amyloidosis. Typically, patients with familial Mediterranean fever show an autosomal recessive inheritance pattern. The disorder commonly afflicts Sephardic Jews, Arabs, and persons of Turkish descent. Colchicine therapy dramatically reduces the attack rate of serositis. The family described herein is unique because of their European ethnicity and the autosomal dominant inheritance pattern. Unlike typical familial Mediterranean fever, colchicine had no influence on the attacks and did not prevent amyloidosis in the three patients who received this treatment.

Multiple Skin Cancers Associated With Hydroxyurea Therapy

The association of multiple cutaneous cancers and long-term use of hydroxyurea is now being recognized. In this article, we describe the development of multiple skin tumors in two patients who were receiving hydroxyurea therapy. These cases illustrate the late onset of subsequent skin cancers despite discontinuation of therapy. As hydroxyurea continues to have a prominent role in the treatment of myeloproliferative diseases, clinicians must be aware of the increased risk of multiple skin cancers and use preventive and skin cancer screening practices in patients with these diseases.

Prognostic significance of computed tomography of the brain in thrombotic thrombocytopenic purpura

We studied the prognostic value of computed tomography (CT) of the brain for neurologic morbidity in patients with thrombotic thrombocytopenic purpura. On review of Mayo Clinic records for 1975 through 1985, we found 32 patients with thrombotic thrombocytopenic purpura, 20 of whom had undergone CT of the brain during their hospitalization. Despite major neurologic symptoms and signs, normal CT findings were associated with complete neurologic recovery. Seventy percent of patients with normal results of CT of the brain recovered and had no neurologic deficits, whereas 80% of patients with CT abnormalities died or had permanent neurologic sequelae. A review of the literature supports these conclusions. Thus, we suggest that CT of the brain be done in any patient with thrombotic thrombocytopenic purpura and neurologic deficits. Regardless of the severity of neurologic involvement, normal CT findings should encourage continued vigorous treatment of the patient because a normal scan supports the possibility of full clinical recovery.

Vinblastine-Loaded Platelets for Autoimmune Hemolytic Anemia

Excerpt Treatment of autoimmune hemolytic anemia with corticosteroids (1), splenectomy (2), immune suppression (3), and plasma exchange (4), serially or in combination, often yields partial or shor...