Chronic Myelogenous Leukemia
Hydroxyurea is indicated in the treatment of resistant chronic myelogenous leukemia (CML). Hydroxyurea is an alternative drug for the palliative treatment of chronic-phase CML in patients who cannot undergo allogeneic bone marrow or stem cell transplantation, which is the only therapy known to be curative for this leukemia; interferon alfa, with or without cytarabine, is a preferred therapy in such patients. Unlike interferon alfa, hydroxyurea has not been associated with prolonged cytogenetic response (i.e., suppression of Philadelphia chromosome-positive cells) in patients with Philadelphia chromosome-positive CML. Hydroxyurea is superior to busulfan for the palliative treatment of CML; in a randomized trial, patients receiving hydroxyurea experienced prolonged median survival and less toxicity compared with those receiving busulfan.
Hydroxyurea is an alternative agent for the palliative treatment of the accelerated phase of CML. Hydroxyurea also is used to reduce the white blood cell count prior to bone marrow transplantation or initiation of interferon alfa therapy.
Sickle Cell Anemia
Hydroxyurea is used in the palliative treatment of sickle cell anemia generally in patients with recurrent moderate to severe painful crises occurring on at least 3 occasions during the preceding 12 months and is designated an orphan drug by the US Food and Drug Administration for this use. Hydroxyurea is employed in patients with sickle cell anemia in an attempt to increase fetal hemoglobin (Hb F) synthesis and thus potentially reduce sickling of red blood cells and prevent associated clinical sequelae (e.g., painful crises). Therapy with the drug in this condition is not curative, and any beneficial effect will be maintained only as long as an effective regimen of hydroxyurea is continued. In addition, hydroxyurea therapy in patients with sickle cell anemia is prophylactic, and therefore the drug has no role in the treatment of a crisis in progress.
Because hydroxyurea is a cytotoxic agent, the possible risks of therapy with the drug, including long-term risks such as secondary neoplasms (e.g., leukemia), should be weighed carefully against the potential benefits in treating a nonmalignant disease such as sickle cell anemia. In assessing the benefit versus risk, it should be recognized that clinical efficacy to date has been evidenced principally by amelioration of the clinical course (e.g., reduction in painful crises), and the long-term effect, if any, on progression of organ damage and mortality remains to be elucidated. Reversal of previously documented splenic dysfunction has been reported in 2 patients with sickle cell anemia treated with long-term hydroxyurea therapy and may indicate a possible effect of the drug on disease-induced organ damage.
Prophylactic hydroxyurea therapy may not be appropriate for all patients with sickle cell anemia, and evidence of clinical benefit to date has been established principally in patients with severe, recurrent painful episodes. In addition, current evidence suggests that patients with minimal or no increase in hemoglobin F concentrations after an adequate trial of hydroxyurea are not candidates for continued (i.e., long-term) therapy with the drug.
Hematologic Response Trials
Early studies on the effects of hydroxyurea in patients with sickle cell anemia evaluated the hematologic response to treatment, the doses required to produce the responses, and the incidence and severity of myelosuppression associated with the drug. Patients considered responders to therapy exhibited substantial increases in Hb F concentrations, resulting from increased populations of F cells and F reticulocytes, increased concentrations of Hb F per F cell, and/or increased F-cell survival. Increases in median corpuscular volume and median corpuscular hemoglobin also were noted in patients responding to hydroxyurea therapy. Initial dosages of hydroxyurea administered in these studies ranged from 3-50 mg/kg daily. Patient response to hydroxyurea therapy exhibited marked variability in terms of drug-induced increases in Hb F concentrations, and the dose of drug and duration of treatment necessary to produce a hematologic response. Although these early studies were not designed to specifically determine the efficacy of hydroxyurea in ameliorating clinical manifestations of the disease, there also was some evidence of potential clinical benefit from treatment.
Clinical Efficacy Trials
Clinical efficacy of hydroxyurea in ameliorating manifestations of sickle cell anemia has been established to date principally by the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), which was a well-designed, placebo-controlled study of the drug's efficacy in reducing the frequency of painful crises in adults with moderate to severe sickle cell anemia who had a history of 3 or more such crises per year. Hydroxyurea produced a 46% reduction in the annual rate of painful crises, with a median of 2.5 or 4.6 crises per year being experienced by patients receiving hydroxyurea or placebo, respectively. When only crises severe enough to result in hospitalization were considered, patients experienced a median of 1 or 2.5 crises per year, respectively. Patients receiving hydroxyurea also developed fewer episodes of chest syndrome (56 versus 101), a life-threatening complication of sickle cell anemia characterized by chest pain, fever, prostration, and pulmonary infiltrates on chest radiographs, and fewer patients required blood transfusions (55 versus 79) than those receiving placebo. Median times to development of the first and second vaso-occlusive crises were 2.76 versus 1.35 months and 6.58 versus 4.13 months in patients receiving hydroxyurea or placebo, respectively. There was no evidence of effect on mortality, stroke, or hepatic sequestration in this study. However, because interim analysis of data from the study indicated important beneficial effects of hydroxyurea in the management of sickle cell anemia, the trial's Data Safety and Monitoring Board recommended that the study be terminated 4 months earlier than the proposed scheduled end date. As a result, the study was stopped, clinical investigators at the participating centers were notified of the safety and efficacy of hydroxyurea in the treatment of sickle cell anemia, patients who had been receiving placebo were immediately offered therapy with the drug, and the National Heart, Lung, and Blood Institute issued a clinical alert regarding potential benefits of hydroxyurea in the treatment of sickle cell anemia. Because the study ended early, only 134 of 299 patients enrolled had completed the 2-year follow-up.
The MSH trial did not address the reversibility of chronic organ damage induced by sickle cell disease, and it currently is unknown whether inhibition of sickling could affect such preexisting lesions. When the study ended, total hemoglobin concentrations, MCV, Hb F concentrations, and proportion of F cells were higher, and the leukocyte, platelet, reticulocyte, and dense cell counts were lower, in the hydroxyurea-treated patients compared with those receiving placebo. Differences between the hydroxyurea and placebo groups in MCV and F-cell production were apparent within 8 weeks of treatment onset,reached a peak at approximately 40 weeks, and then declined. In patients with sickle cell anemia treated with hydroxyurea, fetal hemoglobin (HbF) increases 4-12 weeks following the start of treatment; however, a correlation between HbF or F-cell concentrations and reduced frequency of sickle cell crises has not been clearly demonstrated. In the MSH, the dose-related cytoreductive effect of hydroxyurea (particularly on neutrophils) correlated strongly with reduced crisis frequency.
Use in Children, Pregnancy, and Other Considerations
Safety and efficacy of hydroxyurea in children younger than 18 years of age with sickle cell anemia were not assessed in the multicenter study. In addition, although there was no evidence of adverse effect on pregnancy outcome in this study, hydroxyurea currently is not recommended for use in patients with sickle cell anemia who are likely to become pregnant; therapy with the drug also is not recommended for those unwilling or unable to follow instructions regarding such therapy or give informed consent stating their willingness to comply with given instructions.
Hydroxyurea has been used in the palliative treatment of polycythemia vera, including use as an adjunct to intermittent phlebotomy. The drug has been employed effectively for its cytoreductive (myelosuppressive) effects to reduce the excess production of platelets and red blood cells and control associated abnormal hematologic indices (e.g., hematocrit) in this condition and thus potentially prevent clinical sequelae such as thrombotic and hemorrhagic complications. Reduction in platelet counts generally occurs more rapidly than control of hematocrit, although at least 80% of patients appear to respond with reduced platelet counts and control of hematocrit within 12 weeks after initiating therapy with the drug.
Therapy with hydroxyurea for polycythemia vera is not curative, and any beneficial effect of the drug will be maintained only as long as an effective regimen of hydroxyurea is continued. If the drug is discontinued, unmaintained remissions usually are of short duration, with thrombocytosis commonly recurring within 7-10 days in patients with high pretreatment platelet counts. Because hydroxyurea is a cytotoxic agent, the possible risks of therapy with the drug, including long-term risks such as secondary neoplasms (e.g., leukemia), should be weighed carefully against the potential benefits in treating a myeloproliferative disorder such as polycythemia vera. Optimum therapy for the management of polycythemia vera has not been established, but drug therapy generally has been reserved for patients whose disease could not be adequately controlled by intermittent phlebotomy alone (i.e., those requiring cytoreductive therapy) or in whom phlebotomy has become impractical or has been associated with thrombotic or other complications. When hydroxyurea is used as an adjunct to phlebotomy, phlebotomy requirements are reduced. In addition, hydroxyurea-induced cytoreduction may be useful in providing symptomatic relief of severe pruritus that is unresponsive to antihistamines and/or phlebotomy in some patients and also may decrease symptomatic splenomegaly. Studies are ongoing to further define the potential risks and benefits and role of various therapies, including drug therapies (e.g., hydroxyurea, interferon alfa), in the management of polycythemia vera.
Adjunctive Therapy for HIV Infection
Because the results of randomized trials have shown inconclusive benefit and serious, including fatal, toxicity, the use of hydroxyurea as an adjunct to antiretroviral therapy for HIV infection is not recommended. Hydroxyurea has been used investigationally as an adjunct to certain antiretroviral drug regimens to enhance antiretroviral activity in the treatment of HIV infection. Early data reporting efficacy of hydroxyurea for this use was derived mostly from uncontrolled studies involving short-term follow-up of small numbers of patients, many of whom had early-stage HIV infection and were treatment-naive; limited data were available from controlled clinical trials. Further study in randomized trials has not clearly demonstrated the benefit of hydroxyurea as an adjunct to HIV therapy. Because of a lack of data from large, randomized, multicenter clinical trials and the potential for serious, sometimes fatal, toxicity, the use of hydroxyurea as a component of combination therapy for HIV infection is not recommended.
Serious toxicity, including fatal and nonfatal pancreatitis, hepatotoxicity (in some cases leading to fatal hepatic failure), and peripheral neuropathy (sometimes severe), has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral agents. One randomized trial was terminated when 3 patients receiving the hydroxyurea-containing regimen died from pancreatitis. Clinical trends and risk analysis indicate an increased risk of peripheral neuropathy in patients receiving hydroxyurea in combination with didanosine and stavudine. Other risks associated with the use of hydroxyurea as an adjunct to antiretroviral therapy in HIV infection, including persistent cytopenias, teratogenic effects, and long-term adverse effects such as secondary neoplasms (e.g., leukemia), also must be considered. The risk of hydroxyurea-induced neutropenia is of particular concern in patients with HIV infection, and some experts have recommended that hydroxyurea not be administered to patients with a baseline absolute neutrophil count (ANC) of less than 1700/mm.
The addition of hydroxyurea to a regimen of didanosine and stavudine or didanosine alone results in moderately enhanced antiretroviral activity. In a small randomized trial involving mostly treatment-naive patients with HIV infection, the addition of hydroxyurea 500 mg twice daily versus placebo to didanosine and stavudine was associated with a greater decrease in plasma HIV-1 RNA levels and a greater proportion of patients with undetectable viremia (defined as plasma HIV-1 RNA less than 200 copies/mL) over a 12-week period. At the end of 12 weeks, the study was unblinded, and patients receiving placebo who had plasma HIV-1 RNA greater than 200 copies/mL were given the option of adding hydroxyurea to their regimen. At a 2-year follow-up, patients receiving hydroxyurea in addition to didanosine and stavudine experienced more toxicity, including nausea and vomiting, fatigue, and peripheral neuropathy, and were more likely to discontinue the treatment than those receiving didanosine and stavudine; most patients in the study stopped the treatment to switch to other regimens containing protease inhibitors. When patients previously treated with a regimen of indinavir, zidovudine, and lamivudine were kept on the same regimen or switched to a regimen of didanosine, stavudine, and indinavir, with or without hydroxyurea (600 mg twice daily), patients receiving the hydroxyurea-containing regimen experienced the highest rate of treatment failure, principally because of drug-related toxicity.
Although hydroxyurea appears to enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors, such as didanosine, and initially produce greater suppression of the plasma viral load, it also is associated with a decrease in the median CD4 T-cell count. The lack of consistent increase, or eventual decrease, in CD4 T-cell counts may be related to the cytostatic activity and lymphopenic effects of hydroxyurea. The long-term clinical outcome of adding hydroxyurea to antiretroviral regimens is unknown.
The optimum dosage and dosing schedule for hydroxyurea were not established. In the study that was terminated because of 3 deaths from pancreatitis, patients received a higher dose of hydroxyurea (600 mg twice daily) than the typical dose used in previous studies (500 mg twice daily). In a 12-week pilot study among patients receiving chronic didanosine therapy for advanced HIV infection, a greater reduction in plasma viremia was observed with the addition of hydroxyurea 500 mg twice daily versus hydroxyurea 500 mg once daily. In a phase II dosing study, a higher dosage of hydroxyurea (1500 versus 1000 mg daily) administered with didanosine in treatment-naive or previously treated patients with HIV infection was associated with similar efficacy but greater toxicity, particularly neutropenia.
Hydroxyurea acts on a cellular enzyme that is less likely to mutate compared with viral enzymes that typically mutate to confer drug resistance, and suppression of HIV in response to didanosine in combination with hydroxyurea has been observed despite the onset of known genotypic mutations associated with didanosine resistance. Continued suppression of plasma HIV-1 RNA levels has been reported at 1-year follow-up in some patients receiving hydroxyurea and didanosine. Viral rebound did not occur up to 1 year following suspension of all antiretroviral therapy in 2 patients with high baseline CD4 T-cell counts who achieved suppression of HIV-1 RNA levels in plasma and lymph nodes during 1 year of treatment with hydroxyurea and didanosine; this finding suggests that the combination of hydroxyurea and didanosine exerts anti-HIV activity in resting lymphocytes and macrophages, an important reservoir of HIV. Hydroxyurea is thought to contribute to the inhibition of HIV replication by enhancing the activity of nucleoside reverse transcriptase inhibitors (
see Pharmacology: Antiviral Effects), and hydroxyurea monotherapy is not effective for the treatment of HIV infection.
Use of hydroxyurea as an adjunct to antiretroviral therapy for HIV infection generally is not recommended; if further study is undertaken to explore the possible role of hydroxyurea in this condition (e.g., salvage regimens, therapy for early-stage disease), patients must be closely monitored for potentially serious toxicity.
Hydroxyurea has been used for the treatment of cervical cancer; however, other agents are considered more effective for the treatment of this neoplasm.
Hydroxyurea mainly has been used as a radiation sensitizer, but evidence from randomized trials indicates that other agents, particularly cisplatin (used alone or in combination), are superior to hydroxyurea for concomitant use with radiation therapy for the treatment of locally advanced cervical cancer. () Limited evidence from a small randomized trial of patients with advanced cervical cancer suggests that cisplatin-based chemotherapy is superior to hydroxyurea, which has minimal activity as a single agent in the treatment of metastatic or recurrent cervical cancer.
Head and Neck Cancer
Hydroxyurea has been used in combination with radiation therapy for local control of primary squamous cell (epidermoid) carcinoma of the head and neck, excluding the lip.
Although hydroxyurea also is labeled for use in the treatment of melanoma and recurrent, metastatic, or inoperable ovarian cancer, other agents are preferred for the treatment of these neoplasms. (See and .)
Hydroxyurea has been used in the treatment of psoriasis and is reportedly beneficial in the treatment of hypereosinophilic syndrome that does not respond to corticosteroid therapy.