The chronic use of hydroxyurea (HU) in some oncologic and non-oncologic diseases (psoriasis, sickle cell anemia) can be accompanied by side effects, both systemic and mucocutaneous. The most severe adverse events known in HU therapy are leg ulcers and cutaneous carcinomas. At skin level may also appear: xerosis, persistent pruritus, skin color changes (erythema, hyperpigmentation), cutaneous atrophy. Likewise, oral ulcerations and stomatitis may occur at mucosal level. Hair damage can be expressed through alopecia and nail damage through melanonychia and oncycholysis. First case, a 63-year-old woman with severe psoriasis vulgaris and chronic granulocytic leukemia, with 5 years of HU therapy, was admitted to hospital for submammary and palmoplantar ulcers, superinfected with methicillin-resistant
Hydroxyurea (HU) is a urea hydroxylated derivate used for nearly 60 years as a chemotherapeutic agent, effective in the treatment of certain neoplasias: Hematological (chronic myeloid leukemia resistant to treatment), inoperable brain, kidney, breast, cervical and cutaneous cancers (squamous cell carcinoma, malignant melanoma). Besides, HU can also be used in the treatment of non-neoplastic diseases (sickle cell anemia, psoriasis, HIV infection) (
In terms of pharmacokinetics, HU is intestinally absorbed, metabolized by the liver and urinary excreted (
The anti-neoplastic mechanism of action is not fully elucidated. Some studies indicate that HU interferes with DNA synthesis without interfering with RNA or protein synthesis. Although it has numerous sites of action, it most likely inhibits the incorporation of thymidine into DNA by its direct action and also the free tyrosyl radical residue (the catalytic center of ribonucleotide diphosphate reductase, the enzyme which catalyzes the transformation of ribonucleotides into deoxyribonucleotides). HU is an inhibitor of the S phase of the cellular cycle, determining cell sequestration in G1-S phase, decreasing cell progression rate in S phase, and/or determining accumulation of cells in S phase as a result of DNA synthesis inhibition (
Studies conducted on animals have shown that the cytotoxic effects of HU are limited to the tissues with high cellular proliferation rates and the effects are noticeable in cells with active synthesis of DNA (
HU also presents a number of systemic side effects, of which the most important are hematological (pancytopenia or cytopenia on certain hematological lines), gastrointestinal (dyspeptic syndromes), neurological (headache, vertigo, hallucinations, seizures), renal (hyperuricemia, renal lithiasis).
Skin reactions occur in 10-30% of patients chronically treated with HU. The most common are pruritus, facial and acral erythema and xeroderma, skin hyperpigmentation, leg ulcers and stomatitis. Exacerbation of post-radiotherapy erythema (in case of associated radiotherapy), affection of the nails (melanonychia, onycholysis, blue lunula), skin atrophy and alopecia may also occur.
The increasing number of new therapies used to stabilize oncological diseases determines the increment of the common mucocutaneous side effects in dermatological practice. The greatest use of HU in the hospital is in hemato-oncology clinic. Most frequently we have controllable side effects, only with compensatory dermatological therapy. Rarely, in selected cases, the severity of the skin manifestations requires the discontinuation of HU therapy. We present two cases with severe skin adverse events (leg, submammary and palmoplantar ulcers) in patients undergoing chronic HU treatment for chronic granulocytic leukemia (CGL), respectively primary thrombocythemia, which required the discontinuation of HU therapy and the modification of oncological therapy.
A 63-year-old female patient with type 2 diabetes, chronic venous insufficiency (venous ulcer epithelized in 2016), severe psoriasis vulgaris since 2001 with many episodes of erythroderma, treated with Methotrexate then with Acitretin, was diagnosed with CGL (2012) for which HU treatment was followed for 5 years. For CGL, the patient initially followed a treatment with Imatinib which was not tolerated due to severe thrombocytopenia. After 2 months she presented with multiple palmoplantar and submammary, painful, bleeding ulcers, which progressively aggravated with depth extensions (
Laboratory investigations showed moderate anemia (Hb 9.3 g/dl, Ht 27.7%), inflammatory syndrome (ESR 63 mm/h), superinfection of ulcers with MRSA
In order to control the adverse events of the skin, the hematologist recommended a temporary discontinuation of HU. Superinfection of ulcers was treated with Cefuroxime 3 g/day. Topical treatment of ulcers was performed with disinfection and application of epithelizing agents. The xerosis was controlled with emollients. In evolution, the ulcers slowly epithelialized and the skin texture improved (
A 72-year-old female, diagnosed in 2014 with primary thrombocytemia (treated with Thromboreductin 2.5 mg/day and HU 500 mg/day for 3 years) was admitted for giant, necrotic leg ulcers, extremely painful, appeared in the previous 2 months. A well-defined, pruriginous, erythematous plaques covered with squamo-crusts, edema (
On admission we had an underweight patient (body mass index 18.3 kg/m²), with a kyphoscoliotic thorax, with abolished vesicular murmur in the right lung base and with slightly elevated blood pressure (160/80 mmHg). The laboratory investigations showed a hypochromic macrocytic anemia (Hb 9.6 g/dl, Ht 30, l1%), leukocytosis with neutrophilia (L 24.440/mm³, Ne 89.6%), mild thrombocytosis (Tr 484000/mm³). The bacteriological exam of the ulcer identified a triple association of germs [
Due to the triple association of germs and pulmonary congestive process, we decided to start the treatment with Cefuroxime 3 g/day, 10 days, with probiotics, antimycotics, analgesics and diuretics. The therapeutic approach regarding the ulcers was a classical one with disinfectants and silver nitrate epithelizing creams. Hematologist decided to discontinue the HU administration and increasing the dose of Thromboreductin, which allowed a slow epithelialization of ulcers (
Both patients or their family gave written inform consent for publication.
Leg ulcers appear in approximately 9% of patients who receive high doses of HU, administered chronically. Chaine
Leg ulcers occur by reducing tissue viability when the chemotherapeutic agent disrupts the S phase of the cellular cycle. HU inhibits DNA synthesis, damaging the basal keratinocytes and disruption of collagen production (
In the first case, after 5 years, the HU therapy induced the occurrence of ulcers with particular submammary and acral disposition and marked cutaneous xerosis and melanonychia. In this case, the HU therapy was beneficial in psoriasis evolution with the disappearance of psoriatic lesions after 1 year of treatment. Even if the patient had experienced challenging, hardly manageable episodes of psoriasis erythroderma in the past, before taking HU, over the last 4 years she has not had any psoriasis lesions (she reached PASI 0-absolut psoriasis area and severity index). In psoriasis the interconnections between the immune system, the nervous system (expressed by stress that triggers the first or the new episodes of skin lesions) and the skin are very complex (
Oakley (
The mucocutaneous and nail hyperpigmentation induced by chronic HU therapy is due to genetic predisposition, photosensitivity with focal stimulation of melanocytes and cytotoxic effect on the nail bed and matrix. A plausible hypothesis is that the activation of melanocytes inducted by drugs increased the production of melanin (
The nail changes that may occur are longitudinal nail bands with varying pigmentation intensity, usually on a few nails, especially those on the hand. In specialized literature only 4 cases were reported in which nail damage was observed in all 20 nails in the same patient (
Rarely, in the course of chronic therapy with HU, dermatomyositis-like lesions, skin carcinomas (squamous cell carcinomas, rarely basal cell carcinoma) (3%) (
In conclusion, in over 1 year of HU treatments, the mucocutaneous adverse effects are frequent. The mechanism by which these side effects occur is not fully known. In the presented cases, the mucocutaneous manifestations secondary to chronic HU therapy were leg ulcers with particular localizations (submammar, palmoplantar), xeroderma, skin atrophy, melanonychia. In the first case, the beneficial effect of HU on the evolution of psoriatic disease should be mentioned, obtaining PASI absolute after 1 year of treatment. In the cases presented by us, leg ulcers and those with particular localization (palmoplantar and submammary) occurred after 5 years, respectively, 3 years of HU therapy initiation. The healing process required HU discontinuation, association of systemic antibiotics for superinfected ulcers, and topical epithelizing treatment.
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No funding was received.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
GMI and MR contributed in the conception and design of the study, analysis and interpretation of patient data, manuscript drafting and critical revision of the manuscript for important intellectual content. AO contributed in the data acquisition, analysis and interpretation of patient data, manuscript drafting and design of the study. All authors read and approved the final manuscript.
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The patients or their family gave written inform consent for publication.
The authors declare that they have no competing interests and they have no financial relationships to disclose.
Submammary, palmoplantar and radiocarpian ulcers on admission.
At 3-month follow up (epithelization of ulcers, improving xerosis, persistence of melanonychia).
(A) Giant, superinfected ulcers with secondary cellulitis on admission. (B) A 1-month ulcer follow-up (reduction in size, reduction of fibrino-purulent exudate and cellulite healing).