Hydroxyurea

Hydroxyurea (HU) is a potent inhibitor of the enzyme ribonucleotide diphosphate reductase and prevents DNA synthesis. This drug was first used in the PVSG-08 trial, initiated in 1977, to find a safer agent to prevent the early thrombosis associated with phlebotomy alone. Fifty-one patients were enrolled into this study, all receiving HU and its efficacy and safety were compared retrospectively to the 194 patients previously enrolled into the PVSG-01 phlebotomy arm.21 Following the first 7 years of follow-up, there was a marked reduction in the number of thrombotic events (PVSG-08, 9.8 percent vs. PVSG-01, 32.8 percent, p = .009) in the HU-treated patients.108 These results were updated with longer follow-up (a median of 8.6 years and maximum follow-up of over 15 years) for the development of acute leukemia and myelofibrosis. The incidence of acute leukemia was low in patients treated with HU at 5.9 percent and did not differ significantly from those treated with phlebotomy alone in PVSG-01 (1.5 percent, p = .18) nor did the incidence of myelofibrosis (PVSG-08, 7.8 percent vs. PVSG-01,11.2 percent, p = .28).15 More recently HU has been compared with the agent pipobroman, which has a structure similar to alkylating agents but acts more like an antimetabolite. This randomized study of 269 patients less than 65 years old observed no difference in overall survival, rate of thrombotic complications, and actuarial incidence of progression to leukemia.18 The efficacy with which HU reduces thrombotic complications in PV has been confirmed in further studies.9,18,109

HU is tolerated extremely well by most patients, with gastrointestinal upset the most commonly reported side effect. Occasionally it can cause skin ulceration, classically of the ankles over the malleoli, with biopsy showing a nonspecific, usually leukocytoclastic vasculitis. HU does not damage DNA in the manner of alkylating agents or 32P, but may interfere with effective DNA repair and, accordingly, there is legitimate concern over its leukemogenic potential. HU is increasingly used in patients with sickle cell disease (SCD), where it increases the proportion of HbF within circulating erythrocytes and ameliorates this disorder. Use in young patients for a disorder without intrinsic malignant potential has prompted a recent review of its mutagenic and carcinogenic potential.110 Acquired mutations were measured in the peripheral blood mononuclear cells of adults with MPD and SCD treated with HU, from children with SCD treated with HU, and from normal age-matched, untreated controls. In adult patients there was a low mutation rate that was no different from that observed in controls.

A number of studies of MPD patients have raised the possibility that treatment with HU results in a 5 to 10 percent risk of leukemic transformation. However, these studies were small, nonrandomized, or included patients who had received HU together with other cytotoxic agents. Najean and Rain18 reported an actuarial risk of acute leukemia of 5 percent after 10 years of follow-up and 10 percent after 13 years of follow-up in patients treated with HU, but the latter figure is subject to very wide confidence intervals since only 15 percent of patients remained under observation at 13 years. A study of 201 patients with ET who had received HU alone reported a 3.5 percent risk of leukemic transformation after a median follow-up of over 8 years.111 There is therefore no evidence to suggest that treatment with HU alone results in a significant increase in leukemic transformation, but anxieties over the theoretical possibility have prompted the evaluation of other agents felt to be less genotoxic.

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Responses

  • SELAM
    Is hydroxy urea use in treatment of multiple myeloma?
    10 months ago

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