Patients and families should understand that the effects of hydroxyurea are not immediate. Laboratory changes occur over the first few weeks, typically with a rise in MCV and a concomitant fall in the ANC and absolute reticulocyte count (ARC). As the hydroxyurea dose is escalated toward MTD, changes also become evident in the peripheral blood smear: macrocytosis without polychromasia, fewer sickled forms, more target cells, and lower numbers of circulating neutrophil and reticulocytes. Fig. 1 illustrates typical changes in the laboratory profile and peripheral blood smear of a young patient with SCA who initiates hydroxyurea with dose escalation to MTD. Beneficial effects on %HbF are not necessarily evident early in treatment, reaching maximum effects only after 6–12 months of treatment [8].

At each visit, compliance and especially medication adherence must be emphasized. Each missed daily dose allows erythropoiesis to occur without the “influence” of hydroxyurea, so represents a missed opportunity to ameliorate the disease. Responses are sustained as long as adherence is maintained. Downward trends in MCV and HbF, or upward trends in ANC and ARC, often reveal problems with adherence. Periodic review of the peripheral blood smear with the patient and family can be helpful in promoting adherence [11].

When administered orally once a day, hydroxyurea treatment is very well tolerated with little short-term toxicity. Mild cytopenias, especially of granulocytes and reticulocytes, are expected and actually should be considered therapeutic goals of treatment. If cytopenias are ever excessive, counts recover quickly after a temporary treatment hold, typically one week. Patients typically require a complete blood count with reticulocytes every month during initial dose escalation, but monitoring can be reduced to every 2–3 months once a stable MTD is established. Mild gastrointestinal symptoms can occur but usually abate following adjustment of daily dosing, e.g., giving the dose before bedtime. Dermatological changes including melanonychia and hyperpigmentation do occur but are cosmetic only. Other toxicities such as hair loss, rash, skin ulcers, and hepatic or renal dysfunction are exceedingly rare, if they occur at all in this patient population.

Hydroxyurea research in SCA is now approaching 30 years of experience (Fig. 2). In 1984 the first proof-of-principle study was reported [5], followed by prospective Phase I/II studies in adults [13], then children [8] and finally infants [10]. The landmark Phase III Multicenter Study of Hydroxyurea trial was published in 1995; this randomized placebo-controlled trial proved the clinical efficacy of hydroxyurea for the prevention of pain, ACS, transfusion, and hospitalization of adults with SCA [7].

Two major NIH-sponsored clinical trials involving hydroxyurea have been recently completed. In the Phase III infant hydroxyurea trial (BABY HUG, ClinicalTrials.gov NCT00006400), infants with SCA between 9–18 months old were recruited without regard to clinical severity, and randomized either to daily hydroxyurea (20 mg/kg/d) or placebo for 24 months of treatment. Although the primary study endpoints (prevention of organ dysfunction) were not met, secondary study endpoints of reduced pain, dactylitis, acute chest syndrome, transfusions, and hospitalizations were all significantly lower in the hydroxyurea treatment arm [9]. Based on these findings, the authors concluded that hydroxyurea can now be considered for all young patients with SCA.

A second major NIH-funded study was Stroke With Transfusions Changing to Hydroxyurea (SWiTCH, NCT00122980), which treated children with documented stroke and iron overload either with standard treatment (transfusions and chelation) or alternative treatment (hydroxyurea and phlebotomy) to prevent secondary stroke and better manage iron overload. This study was stopped early due to a failure of the alternative treatment arm to improve iron overloading between phlebotomy and chelation; at the time of study closure there was a stroke imbalance of 10% on hydroxyurea versus 0% on transfusions [14]. Additional lessons learned from the SWiTCH trial include the severe vasculopathy and clinical fragility present among most children with SCA and previous stroke, and the difficulty of a composite primary study endpoint in a multicenter randomized clinical trial.

Several NIH-funded clinical trials involving hydroxyurea for patients with SCA are currently underway. The first is TCD With Transfusions Changing to Hydroxyurea (TWiTCH, NCT01425307), where children with abnormal Transcranial Doppler velocities who receive chronic transfusions will be randomized either to standard treatment (continued transfusions) or alternative treatment (hydroxyurea). The primary endpoint is change in TCD velocity and this study is currently enrolling patients in the US and Canada. The second study is Sparing Conversion to Abnormal TCD Elevation (SCATE, NCT01531387), where children with conditional TCD velocities will be randomized either to standard treatment (observation) or alternative treatment (hydroxyurea) to prevent increases (conversion) to the abnormal threshold of greater or equal to 200 cm/s. This study includes clinical sites in the US, Jamaica, and Brazil and patient enrollment is ongoing. The Hydroxyurea Study of Long-Term Effects (HUSTLE, NCT00305175) continues to gather information on the pharmacokinetics and pharmacogenetics of hydroxyurea treatment for children with SCA, as well as the long-term effects of hydroxyurea on organ function. Finally, the BABY HUG cohort is now being following prospectively in a follow-up study (NCT00890396), to help determine the long-term risks and benefits of hydroxyurea treatment when initiated at an early age.

Potential long-term toxicities continue to be of great concern and should be monitored in all patients with SCA who receive hydroxyurea therapy. To date, no increase in stroke, myelodysplasia, or carcinogenicity has been detected in SCA patient cohorts, now reaching 15–20 years of exposure for some treated adults and 10–15 years for treated children. Regarding the rare case reports of malignancy developing in patients on hydroxyurea, the background cancer rate in SCA must be considered [15] to prevent undue concern or ill-advised associations. Deleterious effects of hydroxyurea on fertility are suggested but not proven, in particular the effects on sperm production. However, clinical experience suggests no effect on fertility of either men or women with SCA. Similarly, teratogenicity is a theoretical risk has not been observed clinically, but a recent report from an adult cohort is reassuring with respect to pregnancy outcomes [16]. While most clinicians still recommend avoidance of pregnancy or conception while receiving hydroxyurea therapy, limited data indicate no adverse effects. In the setting of a pregnant woman with SCA on hydroxyurea, the risks of continuing hydroxyurea must be weighed carefully against the risks of discontinuing an effective treatment in a high-risk pregnancy.

From the standpoint of long-term benefits, the profile of hydroxyurea therapy is encouraging. Numerous studies document sustained laboratory and clinical benefits for patients who remain adherent, with improved growth/development in young patients. Two recent long-term adult studies (USA and Greece) have documented improved survival of patients with SCA and hydroxyurea exposure [17,18]; improved mortality on hydroxyurea provides an even more compelling reason to consider treatment for all affected patients.

Despite the accumulated evidence for benefits of hydroxyurea in children with SCA of all ages, there are scant data regarding its use in developing countries where the burden is greatest [19]. With over 300,000 babies born with sickle cell disease worldwide each year, the opportunity to provide the only disease-modifying treatment should be a high priority. However, the safety and feasibility of hydroxyurea treatment in the setting of co-morbidities such as general malnutrition, vitamin and micronutrient deficiencies, and infections (malaria, helminthes) have not been assessed.

While it is tempting to consider hydroxyurea suitable for current use in developing countries, especially in Africa, a careful assessment of its risks and benefits is warranted, ideally through prospective studies such as the proposed Realizing Effectiveness Across Continents with Hydroxyurea (REACH) pilot trial. As countries in Africa develop newborn screening programs to identify SCA, the widespread use of hydroxyurea may prove to be a useful treatment to help ameliorate the disease in resource-limited settings.

An important area of future investigation is to explain the observed phenotypic variability of the hydroxyurea response. The ability to tolerate different doses of hydroxyurea is variable among patients, as is the HbF response. Recent investigation has suggested that pharmacokinetic differences exist as well as pharmacogenetic influences [20].

Another critical knowledge gap exists because almost all of the available data relate to patients with SCA (i.e., HbSS or HbS/β⁰-thalassemia); experience with HbSC and HbS/β⁺-thalassemia is limited to anecdotes and small series, and extrapolations to these patient populations should not be assumed. Prospective studies involving HbSC are badly needed, since clinicians are increasingly using hydroxyurea in this patient population. Although HbF does not have a clear benefit for patients with HbSC, the additional salutary effects such as lower WBC and reduced cellular adhesion may provide therapeutic benefits. Measurements of blood viscosity may prove useful in clinical trials involving HbSC patients, since increases in the hemoglobin concentration from hydroxyurea are common and could potentially be deleterious.