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Clinical Updates

Sélim Aractingi, MD, PhD

Hydroxyurea: an Old Drug for New Dermatologists

Selim Aractingi

Tuesday, August 10, 2010

Hydroxyurea (HU; called hydroxycarbamide in the UK) was launched on the market in the 1960s and was initially given to patients with various malignancies, such as melanoma and ovary carcinoma but usually for chronic myeloid leukemia, as well as other indications such as psoriasis. It is now nearly always prescribed to patients with myeloproliferative disease, more recently called myeloproliferative neoplasia, and rarely those with sickle cell disease or hypereosinophilic syndrome. It acts as an antimetabolite that leads to inhibition of DNA replication. Because it is an oral drug, it is given as first-line treatment, and is prescribed for long periods in elderly populations, the probability that dermatologists will have to manage cutaneous reactions is very high. In this Expert Opinion article, such skin events are categorized as being either benign or severe.

Benign Adverse Reactions to HU Almost Always Occur

There is a wide range of benign skin lesions that can occur either early or late after treatment with HU. The best data on their incidence come from a series in which patients treated with HU were systemically examined by a dermatologist.1,2 Skin atrophy and dryness develops in 55% of treated cases. It is usually moderate but can eventually evolve into a true ichthyosis. This cutaneous atrophy may then induce a variable degree of pruritus. Alopecia is found in up to 18% of cases. Again, the severity is usually moderate, but could, in some cases, be a cause of dose reduction or even withdrawal in females. Discussion about this should occur on a case-by-case basis with hematologists. Oral mucosa may also be affected: unique or multiple aphthous lesions or, more rarely, stomatitis occurs in 10% of HU-treated cases. Lesions may be painful and are, similar to other chemotherapy-induced aphthae, rather difficult to treat. All of these reactions are dose dependent and result from direct reduction of epidermal/epithelial proliferation by HU. Hyperpigmentation develops in 26-30% of treated recipients. Its incidence is higher in patients with a dark phototype, and usually occurs years after the initiation of HU therapy. It largely affects sun-exposed areas, such as the hands and face, but can also involve non-sun-exposed sites, such as the palms, nails, and mucosa. It can even be diffuse. Here too, the consequence of such a reaction depends on the patient's personality; for example, if they are very sensitive to their external appearance, as is the case in some populations, such changes may be a cause of psychosocial disturbance. Finally, lichen planus-like lesions may occur. These are usually restricted to specific areas of the body, such as the upper limbs and hands. The most typical lichenoid HU-induced lesions are infiltrated erythemato-squamous plaques located on the dorsum of the hand joints, resembling cutaneous dermatomyositis (DM).3 Although these plaques strongly evoke DM, there is never muscle disease. The incidence of DM is high, developing in 22% of patients after a mean delay of 5 years. However, it does not require any change in the HU regimen. The mechanism of these pigmentary or lichenoid changes currently remains unknown.

Severe Adverse Reactions to HU Should Be Recognized Early and Managed Adequately

Leg Ulcers

There are several important points to highlight concerning leg ulcers as a complication of HU therapy. First, the frequency of leg ulcers is high, as series data show that it can occur in 9% to 32% of patients. It is also a late complication, developing after a mean delay of 5 years (range, 0.5-13 years).4-7 Second, these ulcers, which can be unique or multiple, are extremely painful. More particularly, these HU-induced ulcers are identical to ulcers induced by myeloproliferative disorders themselves (eg, polycythemia vera or thrombocytemia). Therefore, one cannot - based on either a questionnaire or physical examination - discriminate whether an ulcer results from HU toxicity or is disease related. The only accepted criteria for diagnosis of HU-induced ulcers is evolution towards skin healing after HU withdrawal, knowing that any such improvement may require up to 3 months. In summary, when leg ulcers develop, the hypothesis that they are drug induced needs to be investigated through withdrawal testing, unless another confounding cause is present. The pathogenesis of induced ulcers is unknown and may rely either on a direct cytotoxic effect on keratinoytes or on reduced red blood cell deformability.

Skin Cancers

HU therapy frequently induces actinic keratosis (AK) and sometimes skin squamous cell carcinoma; this effect is related to HU impairment of DNA natural repair after UV damage (TT dimers). The incidence of precancerous lesions (eg, AK) is high, occurring in 51% of cases, whereas the incidence of carcinoma varies between 3% and 11%.8-11 As for many of the adverse reactions to HU, the delay until occurrence is prolonged, reportedly between 3 and 9 years after initiation of HU treatment. It is therefore mandatory to advise HU-treated patients to avoid sun exposure and also to have their whole skin examined once a year, similar to organ transplant recipients. Of note, cancerous lesions may be multiple and sudden in their appearance. Metastasis has been reported, as have oral cancers. The question of what attitude to adopt concerning HU therapy in patients with AK or skin squamous cell carcinoma remains unanswered, but the development of invasive skin cancers should reasonably lead to HU withdrawal, except in very particular cases. Development of multiple AKs should also lead to a discussion about the benefit/risk balance in the affected patient. In contrast, isolated AK does not affect HU maintenance.

Conclusion

Several series have shown that nearly 100% of HU-treated patients develop cutaneous reactions. These may be benign but, depending on the particular patient, can severely affect quality of life. Some reactions, however, are severe and indicate a switch from HU to other drug alternatives. HU-treated patients should have their skin examined yearly after several years of treatment.

References

  1. Salmon-Ehr V, Leborgne G, Vilque JP, Potron G, Bernard P. Secondary cutaneous effects of hydroxyurea: prospective study of 26 patients from a dermatologic consultation. Rev Med Int. 2000;21:30-34.
  2. Dumont-Wallon G, Milpied-Homsi B, Morineau N, Harousseau J-L, Stalder J-F. [Effets secondaires cutanéomuqueux de l'hydroxyurée: étude prospective sur 27 patients]. Hématologie. 2006;12:262-266.
  3. Senet P, Aractingi S, Porneuf M, Perrin P, Duterque M. Hydroxyurea-induced dermatomyositis-like eruption. Br J Dermatol. 1995;133:455-459.
  4. Randi ML, Ruzzon E, Tezza F, Luzzatto G, Fabris F. Toxicity and side effects of hydroxyurea used for primary thrombocythemia. Platelets. 2005;16:181-184.
  5. Sirieix ME, Debure C, Baudot N, et al. Leg ulcers and hydroxyurea: forty-one cases. Arch Dermatol. 1999;135:818-820.
  6. Best PJ, Daoud MS, Pittelkow MR, Petitt RM. Hydroxyurea-induced leg ulceration in 14 patients. Ann Intern Med.  1998;128:29-32.
  7. Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005;353:33-45.
  8. Brash DE, Ziegler A, Jonason AS, et al. Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion. J Invest Dermatol Symp Proc. 1996;1:136-142.
  9. Snyder RD. The role of deoxynucleoside triphosphate pools in the inhibition of DNA-excision repair and replication in human cells by hydroxyurea. Mutat Res. 1984;131:163-172.
  10. Najean Y, Rain JD. Treatment of polycythemia vera: the use of hydroxyurea and pipobroman in 292 patients under the age of 65 years. Blood. 1997;90:3370-3377.
  11. Sanchez-Palacios C, Guitart J. Hydroxyurea-associated squamous dysplasia. J Am Acad Dermatol. 2004;51:293-300.
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