To the Editor:

Hydroxyurea (HU) is a cytoreductive agent commonly used in the treatment of chronic myeloproliferative disorders. HU is usually well tolerated; however, long-term HU therapy has been associated with cutaneous side effects, such as alopecia, diffuse hyperpigmentation, erythema, skin atrophy, and nail changes.1 Painful skin ulcers have been also reported and their treatment modalities mainly consisted of HU discontinuation,2-4 which was generally followed by the complete or almost complete healing.5 We report here a successful treatment of HU-related leg ulcers with topical granulocyte-macrophage colony-stimulating factor (GM-CSF) in 4 patients affected by chronic myeloid leukemia (CML), whose clinical features are shown in Table 1. Diagnosis of CML was confirmed by both cytogenetic (Ph+chromosome) and molecular (bcr-abl) findings. All of the patients, after a preliminary cytoreduction of peripheral leukemic burden with HU, were assigned to receive conventional therapy with α-interferon (α-IFN), and 3 of them were also enrolled in a clinical trial of the Italian Cooperative Study Group on CML.6 However, because of adverse side effects caused by α-IFN,7 we first had to reduce and then to stop it in all patients. They were then reverted to chemotherapy with HU, which was administered at a mean daily dosage of 2 g to maintain complete hematological response. After a mean time of 29.7 months (range, 19 to 37 months), we noticed the appearance of painful perimalleolar skin ulcers. Ulcers appeared with an erythematous border, whereas the epidermidis was replaced by a fibrinous exudate and the dermis scattered by necrotic areas. Skin biopsies of the ulcerated lesions showed in all cases an histologic picture compatible with small vessel vasculitis. Circulating immune complexes were not detectable and doppler-fluximetry was always found in normal range.

Table 1.

Patients’ Clinical and Laboratory Characteristics at Skin Ulcers’ Onset

Patient No. Age/Sex Time From Diagnosis (mo)HU Therapy Duration (mo) WBC (109/L)PLT (109/L) LDH (U/L) SplenomegalyHepatomegaly
1  68/M  54  27  73.5  728 1,155  No  Yes  
2  62/M  75  36  29.8  264 184  No  No  
3  65/F  54  37  26.5  1,086 968  Yes  Yes  
4  44/F  50  19  40.0  312 1,286  Yes  Yes 
Patient No. Age/Sex Time From Diagnosis (mo)HU Therapy Duration (mo) WBC (109/L)PLT (109/L) LDH (U/L) SplenomegalyHepatomegaly
1  68/M  54  27  73.5  728 1,155  No  Yes  
2  62/M  75  36  29.8  264 184  No  No  
3  65/F  54  37  26.5  1,086 968  Yes  Yes  
4  44/F  50  19  40.0  312 1,286  Yes  Yes 

Abbreviations: WBC, white blood cell count; PLT, platelet count; LDH, lactate dehydrogenase.

Because GM-CSF has been reported to be effective in either preventing and reducing drug-induced mucositis or decreasing the healing period in cut and burn wounds,8 we tried a topical GM-CSF treatment after obtaining patients’ informed consent. Briefly, GM-CSF (Mielogen 150; Schering Plough, Milan, Italy) was diluted in sterile water for injection up to 5 μg/mL, and every 1 mL was dispensed in a sterile syringe and stored at 4°C until a maximum of 15 days. Skin ulcers were then douched twice a day, dried up to 20 minutes, and dressed. All patients received GM-CSF treatment for 2 weeks, with the exception of 1 patient (no. 2) who needed 2 further weeks of therapy. Topical GM-CSF was able to heal the cutaneous lesions and none of the patients required discontinuation of HU therapy.

It is noteworthy that 1 patient (no. 1) also experienced local treatment with granulocyte colony-stimulating factor (G-CSF) without any lesion improvement, whereas topical GM-CSF administration healed it. However, 2 months later, this patient entered CML blastic transformation and developed a second skin malleolar ulcer that this time showed only a partial response to an additional GM-CSF treatment.

The appearance of HU-related skin ulcers represents a serious clinical problem for CML patients in long-term continuous treatment. In the past, we have observed several CML patients with HU-related cutaneous lesions who have been unsuccessfully treated with a variety of approaches such as topical antibiotics, subcutaneous calcium-heparin injections, and hemoreologic drugs. Furthermore, the incidence of HU-related cutaneous lesions was not lowered by reducing the schedule of HU administration, suggesting a close correlation with HU cumulative dose. Long-term cytoreductive therapy could play a pivotal role in affecting endothelial cells’ function, therefore leading to vascular sufference and tissue-organ damage. In this context, we have also found abnormally high vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) serum levels in these 4 CML patients.9 

The mechanisms through which GM-CSF acts are not yet clarified. It might be hypothesized that its promoting activity on both recruitment and proliferation of monocytes and macrophages could modulate the in situ production of cytokines such as interleukin-1, tumor necrosis factor, and macrophage colony-stimulating factor, which, in turn, can affect the healing process.

Therefore, in the search for alternative remedies for HU-related skin ulcers, our preliminary experience would suggest that topical GM-CSF therapy may be helpful in the management of these common skin lesions when discontinuation of HU treatment is not advisable.

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