Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1479-1480
CORRESPONDENCE
Successful Healing of Hydroxyurea-Related Leg Ulcers With Topical
Granulocyte-Macrophage Colony-Stimulating Factor
 |
LETTER |
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 
-interferon (-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 -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.
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.
Fabio Stagno
Patrizia Guglielmo
Ugo Consoli
Paolo Fiumara
Mario Russo
Rosario Giustolisi
University of Catania
Catania,
Italy
| |
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