Hydroxyurea use in sickle cell disease

INTRODUCTION — 

The major causes of morbidity and mortality in sickle cell disease (SCD) are the acute and long-term consequences of vaso-occlusion and hemolysis, many of which cannot be reversed (eg, tissue infarction, vasculopathy).

The approaches that are available for reducing these pathophysiologic processes are regular red blood cell (RBC) transfusions, medications (hydroxyurea, L-glutamine, and crizanlizumab) and stem cell therapies (hematopoietic stem cell transplantation and gene therapy).

This topic review discusses hydroxyurea therapy in SCD, including the mechanism of action, administration, dosing, and adverse effects.

Separate topic reviews discuss the following subjects:

●General management:

•Outpatient management – (See "Overview of preventive/outpatient care in sickle cell disease".)

•Inpatient management – (See "Sickle cell disease: Overview of management during hospital admission".)

•Routine pediatric care – (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

•Transition from pediatric to adult care – (See "Sickle cell disease (SCD) in adolescents and young adults (AYA): Transition from pediatric to adult care".)

●Pain management:

•Evaluation of pain – (See "Evaluation of acute pain in sickle cell disease".)

•Treatment of pain – (See "Acute vaso-occlusive pain management in sickle cell disease".)

●Other therapies:

•RBC transfusions – (See "Red blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications".)

•Pharmacologic therapies – (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease".)

•Transplantation and gene therapy – (See "Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy".)

•Investigational pharmacologic therapies – (See "Investigational pharmacologic therapies for sickle cell disease".)

The choice of preventive therapy for specific complications such as acute chest syndrome or stroke is also presented separately. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Prevention' and "Prevention of stroke (initial or recurrent) in sickle cell disease".)

MECHANISM OF ACTION

Induction of Hb F expression — Hydroxyurea causes a shift in gene expression at the beta globin locus, such that gamma globin expression is increased relative to beta globin. This results in increased production of fetal hemoglobin (Hb F; alpha2/gamma2) and decreased production of adult hemoglobin (Hb A; alpha2/beta2), the reverse of the normal fetal switch. (See "Fetal hemoglobin (Hb F) in health and disease", section on 'Hemoglobin switching and downregulation of Hb F expression'.)

Since the gamma globin chain is not affected by the sickle mutation, the overall effect in patients with SCD is to reduce the relative concentration of sickle hemoglobin (Hb S).

Hb F is the hemoglobin normally produced during fetal development and early infancy. Hydroxyurea increases Hb F production at least twofold above baseline, often much more. The concentration of Hb F per cell, the proportion of Hb F-containing cells, and the overall percentage of Hb F are all increased. The resulting decrease in the relative intracellular concentration of Hb S leads to less hemoglobin polymerization and precipitation. This is because Hb S polymerization is sensitive to intracellular concentration, and a decrease in the relative concentration of Hb S has a significant impact on RBC sickling. Hb F has properties that differ slightly from Hb A, including a slightly higher oxygen affinity, but it is well tolerated and causes no clinical problems. (See "Pathophysiology of sickle cell disease", section on 'Hb polymerization'.)

These effects reduce the formation of sickled red blood cells (RBCs). RBC lifespan is increased; hydration is improved, hemolysis is reduced, and adhesion to the vascular endothelium is lessened [1-6]. In turn, blood flow through the microcirculation improves and vaso-occlusive events are less likely to occur. This is thought to be the major mechanism by which hydroxyurea reduces vaso-occlusive events, based on observational studies in people with SCD that revealed an association between elevated HB F levels and decreased incidence of complications, as well as experimental studies in mouse models that established a protective role for Hb F [7-12].

How hydroxyurea increases Hb F production is incompletely understood. Possible mechanisms include inhibition of ribonucleotide reductase activity, epigenetic modification, changes in gene transcription, and altered intracellular and intercellular signaling [13,14].

●Inhibiting ribonucleotide reductase – Hydroxyurea can bind metals. Its primary cellular target is the ribonucleotide reductase enzymes, iron-containing enzymes that convert ribonucleoside diphosphates to deoxyribonucleotide triphosphates (dNTPs), which are used in DNA (deoxyribonucleic acid) synthesis and repair [15,16].

Ribonucleotide reductases use a free radical mechanism to catalyze the conversion to dNTPs, and hydroxyurea appears to block their function by binding the iron molecules and scavenging the free radicals [17]. The lack of available dNTPs causes cells to arrest in S-phase of the cell cycle. Eventually, cells with stalled DNA replication forks will either delay S-phase until DNA synthesis can proceed, or they will undergo cell death.

The exact mechanism by which ribonucleotide reductase inhibition induces gamma-globin expression is not understood. One possibility is that blocking DNA replication induces a degree of stress erythropoiesis that increases gamma-globin expression [18].

●Suppression of other enzymes – Hydroxyurea has been shown to suppress other enzymes such as iron-sulfur cluster-containing enzymes, but it is not clear whether there is any physiologic effect in vivo. (See "Causes and pathophysiology of the sideroblastic anemias", section on 'Iron-sulfur (Fe-S) cluster biogenesis'.)

●G protein expression – Hydroxyurea may induce expression of the small GTP-binding protein (G protein) SAR1 (secretion-associated and ras-related signaling protein), which activates gamma globin expression through c-Jun N-terminal kinase (JNK/Jun) [19,20]. Expression is increased from the G-gamma rather than the A-gamma gene [21]. These effects require active erythropoiesis, which may be suppressed by transfusion and possibly increased by erythropoietin. Alternative approaches to increasing Hb F production via these pathways are under investigation. (See "Investigational pharmacologic therapies for sickle cell disease", section on 'Increasing Hb F'.)

●Methylation changes – Studies have shown that hydroxyurea results in global hypermethylation across the genome that may affect gene transcription [22].

●Increased NO – Increased nitric oxide (NO) levels may induce Hb F transcription via genes that regulate globin gene transcription and translation, including BCL11A, a key regulator of baseline Hb F levels [23-25]. (See 'Other mechanisms' below and "Fetal hemoglobin (Hb F) in health and disease", section on 'BCL11A'.)

In addition to increasing Hb F, NO may have other beneficial effects on the vasculature. (See 'Other mechanisms' below.)

Other mechanisms — While increased Hb F levels are a major beneficial effect of hydroxyurea in SCD, other effects may also play a role in reducing vaso-occlusion and hemolysis.

●Increased NO and vasodilation – Nitric oxide (NO) is a potent vasodilator, and depletion in certain vascular beds could contribute to vaso-occlusion; increases in NO may improve blood flow in certain beds such as the pulmonary vasculature [23,26-30]. (See "Pulmonary hypertension associated with sickle cell disease", section on 'Pathogenesis'.)

Hydroxyurea may increase NO levels by different mechanisms including reducing hemolysis, which decreases free hemoglobin and reduces NO scavenging. Interaction with hems proteins increases intracellular NO production in endothelial cells and RBCs [26-29,31].

●Reticulocytopenia and improved RBC rheology – Because hydroxyurea affects cell division, it causes global myelosuppression, including neutropenia, anemia, reticulocytopenia, and thrombocytopenia. (See 'Myelosuppression' below.)

The lower reticulocyte count induced by hydroxyurea and corresponding shift to more mature RBCs may improve RBC volume, density, adhesivity, and passage through the microcirculation independent of Hb F levels [5,32-35]. This may be due in part to a reduction in the proportion of reticulocytes and young, low-density RBCs, which are particularly likely to adhere to vascular endothelium [32,36]. Effects of hydroxyurea on cellular signaling pathways may also reduce adhesion [34]. (See "Pathophysiology of sickle cell disease", section on 'Effects on the RBC'.)

●Lower WBC count and reduced interactions with vascular endothelium – Reduced white blood cell (WBC) counts and/or neutrophil adhesivity to the vascular endothelium may reduce vaso-occlusion [37]. In vitro studies have shown that neutrophils from individuals with SCD have enhanced binding to fibronectin and increased activation [38,39]. In a trial that randomly assigned individuals with SCD to hydroxyurea or placebo, lower neutrophil counts were associated with fewer pain episodes during two years of observation [40]. Interpretation is difficult because the hydroxyurea dose was titrated to the neutrophil count, and better adherence to hydroxyurea therapy led to lower neutrophil counts. (See "Pathophysiology of sickle cell disease", section on 'Inflammation'.)

INDICATIONS AND EVIDENCE FOR EFFICACY

Indications and appropriate age to start therapy — Hydroxyurea (also called hydroxycarbamide) was first approved by the US Food and Drug Administration (FDA) in 1967 as an antineoplastic drug. It was approved for adults with SCD by the FDA in 1998 and by the European Medicines Agency (EMA) in 2007 [41,42]. A formulation was approved for pediatric use in 2017, but it has been used in children with SCD for decades [43].

Hydroxyurea reduces complications and may increase life expectancy in SCD, especially in individuals with the most clinically severe genotypes (Hb SS, sickle beta⁰ thalassemia), as summarized in the table (table 1).

Hydroxyurea takes weeks to months to be effective and is used to prevent complications, not to treat them in the acute setting.

Our approach to deciding when hydroxyurea is appropriate in patients with SCD is summarized in the flowchart (algorithm 1). This approach also applies to individuals with homozygous SS, and sickle beta⁰ thalassemia, as well as a small subset of individuals with Hb SC disease, sickle-beta⁺ thalassemia, and other "milder" genotypes, when the individual's phenotype is similar to that of Hb SS or sickle beta⁰ thalassemia. Additional information is presented below, and clinical features of milder genotypes are discussed in a separate topic review. (See "Overview of compound sickle cell syndromes".)

Key indications by age group include:

●Infants 6 to 9 months – For infants 6 to 9 months with symptomatic disease (severe anemia, dactylitis, acute pain episodes), regardless of genotype, we consider hydroxyurea. This is based on indirect evidence from older children and the potential value of preserving high levels of fetal hemoglobin. Limited evidence in this age group demonstrates higher levels of total hemoglobin and lower neutrophil counts at 24 months with early initiation of hydroxyurea.

●Infants ≥9 months, children, and adolescents – For all infants ≥9 months, children, and adolescents with Hb SS or sickle beta⁰ thalassemia, we recommend hydroxyurea, regardless of disease severity. This is based on secondary endpoints from a randomized trial discussed below and is consistent with 2014 guidelines for SCD management from the National Heart, Lung, and Blood Institute (NHLBI; in the National Institutes of Health [NIH] in the United States).

For individuals in these age groups with Hb SC or sickle beta⁺ thalassemia, we individualize the decision to start hydroxyurea; unlike for individuals with Hb SS or sickle beta⁰ thalassemia, we do not start hydroxyurea in asymptomatic individuals with Hb SC disease or sickle beta⁺ thalassemia.

●Adults – For males who are taking hydroxyurea, we continue hydroxyurea therapy unless they are attempting to conceive a child in the next three months.

For females who are taking hydroxyurea, this is usually stopped when they become pregnant. Details are presented separately. (See "Sickle cell disease: Obstetric considerations", section on 'Hydroxyurea'.)

For adults not taking hydroxyurea, we start hydroxyurea if they have at least one episode of moderate to severe sickle cell acute pain or acute chest syndrome in the last 12 months, symptomatic anemia, pulmonary hypertension, chronic hypoxemia, or chronic pain impacting their quality of life. It may be reasonable to start hydroxyurea for males with episodes of priapism, adults with chronic kidney disease or proteinuria, or individuals with prior stroke if chronic transfusion therapy is not feasible.

Hydroxyurea may be omitted prior to attempted conception, as discussed separately. (See "Sickle cell disease: Obstetric considerations", section on 'Hydroxyurea'.)

●Other genotypes – Use of hydroxyurea in those with other SCD genotypes such as Hb SC disease or sickle beta⁺ thalassemia is individualized based on disease severity, which is more variable with these genotypes. (See "Overview of compound sickle cell syndromes", section on 'Hb SC disease' and "Overview of compound sickle cell syndromes", section on 'Sickle-beta thalassemia'.)

The risk-benefit ratio for hydroxyurea is most likely to be favorable for infants, children, adolescents, and adults with clinical manifestations similar to Hb SS or sickle beta⁰ thalassemia who have frequent vaso-occlusive complications, such as vaso-occlusive pain, acute chest syndrome, or priapism severe enough to require two or more clinical encounters per year.

Patients, families, and caregivers should have the opportunity to discuss potential benefits and risks, and to understand that information on some of these risks and benefits may be lacking. Supporting evidence is discussed below. (See 'Evidence for efficacy' below.)

This approach is consistent with a 2008 NIH consensus statement on use of hydroxyurea in SCD, 2014 guidelines from the NHLBI, an updated systematic review, a 2020 guidelines from the American Society of Hematology (ASH), and practices of other SCD experts [17,37,44-47]. A patient education booklet is available from ASH [48].

Hydroxyurea may be given concurrently with L-glutamine or crizanlizumab, and the benefits of the combinations appear to be greater than either agent alone. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Disease-modifying medications'.)

Evidence for efficacy — Initial evidence for the efficacy of hydroxyurea in SCD came from studies in adults; these were followed soon after by studies in children and then infants [37].

Despite the supportive evidence, many individuals with SCD who would benefit from this therapy do not receive it or are treated in a suboptimal manner. Barriers to appropriate therapy should be addressed. (See 'Eliminating barriers to appropriate therapy' below.)

Improved survival — Along with other interventions to reduce infectious complications and end-organ damage, hydroxyurea has improved survival in SCD. (See "Sickle cell disease: Overview of management during hospital admission", section on 'Survival and prognosis'.)

Evidence for improved survival comes from the following studies:

•A 2010 observational study involving 299 individuals with SCD who had >3 painful episodes per year were originally enrolled in a randomized trial (the Multicenter Study of Hydroxyurea in Sickle Cell Anemia [MSH] trial, described in greater detail below) with >17 years of follow-up reported reduced rates of death that correlated with length of hydroxyurea exposure [49,50].

•Never exposed – 5 deaths per 100 person-years

•<5 years exposure – 6.8 deaths

•5 to 10 years – 4.4 deaths

•10 to 15 years – 1.8 deaths

•≥15 years – 0 deaths

The true benefit may have been greater, as many participants assigned to placebo had subsequently switched to hydroxyurea after the short-term benefits became apparent. Additional benefits documented from the MSH trial are listed below. (See 'Reduced complications' below.)

●A 2010 prospective observational study involving 131 adults with SCD followed for five to eight years found that mortality was lower in hydroxyurea-treated individuals compared with controls (10 versus 25 percent) [51]. The survival benefit was preserved across multiple SCD genotypes (Hb SS, Hb S beta⁰ thalassemia, and Hb S beta⁺ thalassemia).

●A 2013 retrospective study involving 267 children with SCD (ages 3 to 18 years, all genotypes) treated with hydroxyurea for a median of two years found that the hydroxyurea-treated children had lower mortality compared with controls (0.5 versus 5.5 percent [95% CI 0.92-0.99]) [52].

Reduced complications — Several randomized trials and observational studies have demonstrated reduced SCD complications with hydroxyurea therapy in different age groups and SCD genotypes (table 1). These effects are most pronounced in individuals with clinically severe disease (frequent pain episodes or acute chest syndrome) and high-risk genotypes (Hb SS or Hb S beta⁰ thalassemia). Many systematic literature summaries and review articles have summarized these results [45,53,54].

●Hb SS or Hb S-beta⁰ thalassemia:

•Infants – The 2011 BABY HUG trial randomly assigned 193 infants 9 to 18 months with Hb SS or sickle beta⁰ thalassemia irrespective of clinical severity to receive hydroxyurea (20 mg/kg daily without dose escalation) or placebo for two years [55,56]. The median age at entry was 13.6 months. Primary endpoints included splenic function and glomerular filtration rate (GFR), both of which were chosen because they become abnormal in SCD early in life. Compared with controls, hydroxyurea-treated infants had a trend towards improved splenic function (assessed by cell morphology after qualitative radionucleotide scans were discontinued) and no difference in GFR. However, there were significant reductions in clinical endpoints including pain episodes (hazard ratio [HR] 0.59, 95% CI 0.42-0.83), acute chest syndrome (HR 0.36, 95% CI 0.15-0.87), dactylitis (HR 0.27, 95% CI 0.15-0.50), and constipation (HR 0.33), as well as in need for transfusions (HR 0.55). Therapy was well tolerated with no severe adverse events.

•Children – Observational studies have demonstrated similar benefits as those seen in infants and adults including reduction in painful episodes and hospitalizations [57-59]. In a cohort of 110 children treated with hydroxyurea, none had an abnormal transcranial Doppler reading (a surrogate marker for stroke risk) [60]. A small randomized trial had too few patients to assess clinical outcomes [61]. Larger studies of low versus moderate dose hydroxyurea for secondary stroke prevention as well the dose-escalated hydroxyurea over fixed-dose hydroxyurea study mentioned below add information on benefit of hydroxyurea in older children [62,63].

•Adults – The 1995 MSH (Multicenter Study of Hydroxyurea in Sickle Cell Anemia) trial randomly assigned 299 adults with Hb SS and at least three painful episodes per year to receive hydroxyurea, titrated to maximum tolerated dose or placebo for approximately two years [62]. The primary outcome was the number of painful episodes, defined as visits to a medical facility lasting >4 hours and resulting in treatment with an opioid, or another vaso-occlusive complication such as acute chest syndrome, priapism, or hepatic sequestration. Compared with controls, the hydroxyurea-treated individuals had a decrease in painful events (median annualized rate, 4.5 versus 2.5 events). The benefit persisted when crises severe enough to cause hospitalization were compared (median annualized rate, 2.4 versus 1.0). There were no differences in the rates of death, stroke, or hepatic sequestration.

Extended observation of the original MSH participants suggested a survival benefit after 9 and 17.5 years. (See 'Improved survival' above.)

A 2010 observational study in which hydroxyurea was administered to 131 adults for eight years found similar reductions in painful episodes, acute chest syndrome, hospitalizations, and mortality [51].

●Other genotypes – Demonstration of benefit is more challenging with Hb SC disease, sickle beta⁺ thalassemia, and other milder genotypes because disease manifestations are more variable and individuals with these genotypes are underrepresented in SCD clinical trials. (See "Overview of compound sickle cell syndromes", section on 'Specific compound sickle cell syndromes'.)

•Hb SC disease – Small numbers of patients with Hb SC disease have been included in general SCD studies and trials discussed above.

Studies of hydroxyurea exclusively for Hb SC disease have mostly focused on vaso-occlusive events:

-The 2025 PIVOT trial (Prospective Identification of Variables as Outcomes for Treatment) randomly assigned 212 children and adults in Ghana with Hb SC disease and a history of painful events, acute chest syndrome, hospitalizations, and retinopathy to receive hydroxyurea 20 mg/kg daily or placebo for 12 months [64]. Hydroxyurea therapy improved outcomes including fewer vaso-occlusive events (57 versus 150 per 100 person-years; incidence rate ratio [IRR] 0.38; 95% CI 0.28-0.52) and fewer hospitalizations (13 versus 31 per 100 person-years; IRR 0.42; 95% CI 0.22-0.81).

Mild cytopenias occurred in approximately one-third of participants receiving hydroxyurea. Hemoglobin increases were not significantly greater with hydroxyurea and did not require phlebotomy. There was one death in the hydroxyurea group, from acute chest syndrome and sepsis. Dose limiting toxicities were more common with hydroxyurea (33 versus 11 percent). While these results are encouraging, additional study and longer follow up is needed before hydroxyurea becomes standard therapy.

-The 2009 CHAMPS trial randomly assigned 44 individuals ≥5 years of age with Hb SC disease and at least one vaso-occlusive event (painful episode or acute chest syndrome) in the previous year to receive hydroxyurea or placebo for 2 to 10 months [65]. There were no differences in clinical events, but the sample size and study duration may have been insufficient to detect a benefit. Due to concerns about hyperviscosity syndrome caused by increased hemoglobin, pilot studies incorporating phlebotomy were performed [66,67]; additional observations suggested that therapeutic phlebotomy alone may lower the rate of vaso-occlusive events [68,69]. However, this approach is not routinely used because definitive studies are lacking and it places a high burden on patients.

-A 2016 multicenter retrospective study of 133 children and adults with Hb SC disease who were treated with hydroxyurea (average starting dose, 20 mg/kg) for a history of painful events and acute chest syndrome reported a reduction in vaso-occlusive events by 38 percent [67]. Cytopenias requiring dose-reduction or discontinuation occurred in 20 percent. Despite several limitations of the study, hydroxyurea was considered beneficial.

-Retrospective series of children and adults with Hb SC disease who were treated with hydroxyurea have also documented increases in Hb F levels and decreases in the frequency of acute pain events and hospitalization for pain [67,70].

•Sickle-beta⁺ thalassemia – There is a wide range of disease severity that may influence decisions about hydroxyurea use [51,71].

In a study of over 600 patients with various genotypes including sickle b^eta⁺ thalassemia, reduced complications were seen across all genotypes [72].

●Resource-limited settings – Hydroxyurea can be used in resource-limited settings such as sub-Saharan Africa, where SCD is common. Studies have demonstrated decreased complications from SCD and malaria. However, resources for monitoring are limited, resulting in differences in dosing (often lower, with fixed weight-based dosing). Dosing, monitoring, and supporting evidence in resource-limited settings are discussed separately. (See "Sickle cell disease in sub-Saharan Africa".)

●Stroke prevention and reduced neurocognitive deficits – Stroke prevention trials have generally shown that chronic transfusions are effective for primary and secondary prevention, although there is evidence of hydroxyurea noninferiority in a subset of individuals at high risk for a first stroke who have received chronic transfusions for ≥2 years [73]. There is also limited evidence that hydroxyurea alone can prevent progression from conditional to abnormal TCD screening results and may reduce stroke risk in patients with abnormal TCD results who do not have access to transfusion therapy [74]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Hydroxyurea in primary stroke prevention' and "Sickle cell disease in sub-Saharan Africa", section on 'Stroke'.)

Hydroxyurea may also reduce neurocognitive deficits. In a retrospective cohort of 152 patients with Hb SS or Hb S beta⁰ thalassemia, earlier initiation of hydroxyurea was associated with higher scores on neurocognitive measures [75]. This benefit was preserved even after adjustment for confounders including social vulnerability, sex, and duration of treatment. Across a variety of genotypes, patients treated with hydroxyurea demonstrated a six-point elevation in intelligence quotient (IQ) compared with untreated patients.

●Reduced retinal disease – The benefit of hydroxyurea in improving or slowing progressive proliferative retinopathy has not been proven, although some reports suggest hydroxyurea may be beneficial and associated with decreased rates of retinal thinning and may be a protective [76-79]. Prospective trials for retinal disease and hydroxyurea are needed.

Adverse effects are discussed below. (See 'Adverse effects' below.)

Other benefits

●Improved quality of life − Other potential benefits of hydroxyurea include improved quality of life and daily functioning. These in turn may translate to better school attendance and fewer days lost from work. A retrospective cohort study compared quality of life in 191 children with SCD. Those treated with hydroxyurea reported better overall health-related quality of life (HRQL) and better physical HRQL than children who did not receive hydroxyurea [80].

●Reduced risk of malaria − Hydroxyurea may also reduce the risk and/or severity of malaria. (See 'Reduced complications' above and "Sickle cell disease in sub-Saharan Africa", section on 'Malaria'.)

●Cost saving − Cost savings due to reduced clinical encounters and hospitalizations may also be seen [81,82]. In the BABY HUG trial, which randomly assigned young children to hydroxyurea versus placebo, hydroxyurea was associated with a 21 percent annual cost savings due to reduced hospitalizations [82]. A similar cost reduction was not demonstrated in the Multicenter Study of Hydroxyurea (MSH) [49,50].

Predictors of response — The Hb F response to hydroxyurea is variable and complex; there is no specific feature that can be used to determine whether an individual treated with hydroxyurea will obtain a clinical benefit or the magnitude of the benefit. Even children with low baseline percent Hb F levels can develop substantial increases in Hb F when treated at maximally tolerated doses [83]. Thus, hydroxyurea is offered to all individuals who could potentially benefit from it. (See 'Indications and appropriate age to start therapy' above.)

Predictors of response to hydroxyurea were explored in a subset of children who participated in the HUG-KIDS study, in which hydroxyurea was administered to children between 5 and 15 years of age and titrated to a maximum tolerated dose [83] (see 'Monitoring, response assessment, dose titration' below). For the 53 children who were treated at maximum tolerated dose for at least a year, the following characteristics predicted the greatest increase in percentage of Hb F, typically used as a surrogate for clinical efficacy:

●Higher baseline percent Hb F

●Higher baseline reticulocyte count

●Higher baseline WBC count

●Higher baseline hemoglobin concentration

●Higher maximally tolerated dose of hydroxyurea

●Better compliance (fewer unused pills returned at follow-up)

●Greater treatment-related increases in hemoglobin and mean corpuscular volume (MCV)

●Greater treatment-related decreases in WBC count and reticulocyte count

Baseline Hb F percentages were approximately 4 to 8 percent, and those in the top quartile of responses had Hb F percentages of approximately 21 percent [83].

Pharmacokinetic-based dosing shortened the time to titrate to the optimal dose and may lead to improved hematologic responses [84].

Some of this variability in response to hydroxyurea appears to be under genetic control, as discussed in more detail separately. (See "Fetal hemoglobin (Hb F) in health and disease", section on 'Quantitative trait loci associated with HBG expression'.)

ELIMINATING BARRIERS TO APPROPRIATE THERAPY — 

Despite the clear clinical benefits of hydroxyurea (see 'Evidence for efficacy' above), many individuals are treated with hydroxyurea in a suboptimal manner or do not receive this therapy at all [17,37,44,85-92]. This lack of hydroxyurea use has been demonstrated in large reviews such as the following:

●Children – A database review identified 7963 children with SCD in six states in the United States during the period from 2005 to 2012, representing 22,424 person-years [89]. Among all person-years, 78 percent had 0 days of hydroxyurea in a year; 3 percent had 1 to 30 days, and 20 percent had >30 days. Of those who received hydroxyurea, the average number of days' supply in a year was 189. Factors predictive of receiving hydroxyurea included younger age of the child and more frequent outpatient visits. The odds of receiving hydroxyurea did not increase over the course of the study, and in fact, it appears to have decreased in the final years.

Subsequent studies, each including >5000 children with SCD enrolled in Medicaid (government-sponsored health care in the United States) reported:

•An increase in hydroxyurea use from 14 percent in 2009 to 28 percent in 2015 [90].

•An increase from 7 percent in 2004 to 22 percent in 2019 (data limited to the state of Georgia) [92].

In a 2024 cohort of 109 children with SCD, hydroxyurea use increased from 72 percent during 2011 to 2013 up to 89 percent during 2019 to 2021 [93].

●Adults – A database review identified 2086 adults with SCD based on insurance codes identified 677 (approximately one-third) who had at least three pain-related hospitalizations or emergency department visits within a one-year period [91]. However, only 86 of these individuals with frequent painful episodes (15 percent) filled a prescription for hydroxyurea within three months of the third encounter; this percentage increased to 23 percent at one year.

A 2023 prescription database study evaluating 5022 adults with SCD reported low uptake of hydroxyurea with only 20 percent of participants filling at least one prescription for hydroxyurea in 2014 and 24 percent filling a prescription for hydroxyurea in 2021 [94].

These data suggest that significant barriers to appropriate therapy persist, even following publication of the 2014 practice guideline from the National Heart, Lung, and Blood Institute (NHLBI), which recommended hydroxyurea for all infants, children, and adolescents with SCD regardless of symptoms, as well as for adults with three or more vaso-occlusive episodes in a year [46]. The lack of hydroxyurea uptake is especially striking in adults. Evidence-based strategies are required to improve adherence to hydroxyurea in children and adults with SCD.

Several studies have defined specific and extensive barriers to appropriate administration of hydroxyurea that include obstacles related to patients, parents/families/caregivers, clinicians, and system-level obstacles. Examples include [95,96]:

●Hesitancy among members of the health care team about the safety and efficacy of hydroxyurea

●Patient concerns about carcinogenicity, teratogenicity, and other side effects

●Difficulty in adhering to daily dosing and frequent clinical and laboratory monitoring

●For children, limited access to hydroxyurea solution, which can be prepared only by specialized compounding pharmacies and may interfere with obtaining refills

●In the United States, inadequate health insurance coverage for those who live in poverty, especially with the high cost of the hydroxyurea formulation approved for children

●Misconceptions among clinicians about sickle cell pain (see "Acute vaso-occlusive pain management in sickle cell disease", section on 'Provider misperceptions that interfere with the assessment')

Additional barriers that have been identified to the widespread use of hydroxyurea in resource-limited settings. (See "Sickle cell disease in sub-Saharan Africa".)

Clinicians, researchers, and health care administrators will have to systematically address these barriers to expand access to and acceptance of hydroxyurea therapy among clinicians and for people affected by SCD.

ADMINISTRATION AND DOSING

Baseline testing — We obtain the following studies before starting hydroxyurea:

●Complete blood count (CBC) with red blood cell indices, white blood cell differential, platelet count

●Reticulocyte count

●Comprehensive metabolic panel with assessment of kidney and liver function

●Hemoglobin F (Hb F) percentage (quantitative measure)

●Pregnancy test for females of childbearing potential

The baseline mean corpuscular volume (MCV) should be noted because hydroxyurea causes macrocytosis and might mask iron, B12, or folate deficiency. If the baseline MCV is high, we check vitamin B12 and folate levels if the history is suggestive of vitamin deficiency associated with increased MCV and thyroid studies if a family history or symptoms are suggestive of thyroid disease. (See "Macrocytosis/Macrocytic anemia", section on 'Causes of macrocytosis/macrocytic anemia'.)

If the baseline MCV is low, we take a dietary history for possible iron deficiency and consider whether the patient may have alpha thalassemia trait, an established cause of low MCV values. Approximately 40 percent of unselected children with Hb SS or sickle beta⁰ thalassemia will have single alpha globin gene deletion. Thus, consistently low MCV levels are most likely related to alpha globin gene deletion. Those with acquired microcytosis should be evaluated for iron deficiency. (See "Microcytosis/Microcytic anemia", section on 'Causes of microcytosis/hypochromia'.)

Individuals with chronic kidney disease are treated with a lower initial dose of hydroxyurea. (See 'Dosing in chronic kidney disease' below.)

Initial dosing — Hydroxyurea is initiated at a low dose and gradually increased to a dose that reduces the absolute neutrophil and absolute reticulocyte counts but does not cause severe hematologic toxicity. (See 'Monitoring, response assessment, dose titration' below.)

The dose is administered as a single once-daily dose, although it can be given in divided doses if this is preferable to the patient. To improve adherence, a single hydroxyurea dose per day is recommended.

Gastrointestinal upset, a relatively common adverse effect, may improve if the dose is given at bedtime. (See 'GI side effects' below.)

A lower initial dose is used for individuals with impaired kidney function. (See 'Dosing in chronic kidney disease' below.)

Concomitant use of L-glutamine or crizanlizumab does not affect hydroxyurea dosing.

Infants and young children — For infants younger than one year of age treated with hydroxyurea who have good kidney function (creatinine clearance >60 mL/minute), we use an initial dose of 20 mg/kg per day. This starting dose was well tolerated in the BABY HUG and NOHARM trials [55,97,98].

Hydroxyurea is commercially available as an oral solution since early 2025 (brand name, Xromi; concentration, 100 mg/mL) [99]. Other available formulations include scored tablets and capsules. An oral solution can also be compounded from the commercially available capsules.

For ease of dosing, the dose can be rounded off to the nearest 2.5 mg/kg (eg, give 200 mg instead of 180 mg for a 9 kg infant, or 400 mg instead of 440 mg for a 22 kg child).

If cost and lack of access to a reliable compounding pharmacy for the oral solution are a barrier, the following may be useful:

●One formulation (brand name, Siklos) is available as 100 mg scored tablets that can be split into 50 mg increments and 1000 mg scored tablets that can be split into 250 or 500 mg increments that can be dissolved in water [43].

●For patients using capsules, the dose can be rounded to the nearest available capsule size. The capsules can be opened and mixed into a small quantity of food.

●Different doses can be used on different days of the week. For example, if the desired hydroxyurea dose is 1250 mg daily, the child can receive 1000 mg on Monday, Tuesday, Wednesday, and Thursday, and 1500 mg on Friday, Saturday, and Sunday. This averages to a weekly dose of 1250 mg/day.

Monitoring and dose titration is described below. (See 'Monitoring, response assessment, dose titration' below.)

Older children, adolescents, and adults — Individuals who are able to take hydroxyurea in pill form are given a dose in increments rounded to the nearest capsule size. Capsules are available in 200 mg, 300 mg, 400 mg, and 500 mg doses.

●The recommended initial oral dose of hydroxyurea for children with a creatinine clearance >60 mL/min is 20 mg/kg per day, rounded to the nearest 2.5 mg/kg per day.

●Adults may be started on 15 to 20 mg/kg per day with lower doses for older adults and those with normal to mildly reduced glomerular filtration rates.

Monitoring and dose titration is described below. (See 'Monitoring, response assessment, dose titration' below.)

Dosing in chronic kidney disease — Hydroxyurea is excreted by the kidney, and individuals with end-stage kidney disease or creatinine clearance <60 mL/minute may have higher exposure for a given dose.

In these individuals, we typically start at one-half the starting dose that would be used for normal kidney function (7.5 mg/kg daily rather than 15 mg/kg daily). Individuals with severe kidney disease (eGFR <15 ml/min/1.73 m²) are often started at 5 to 7.5 mg/kg daily. Smaller increments of dose titration may also be used in these individuals.

It is important to continue to monitor kidney function during dose titration. (See 'Monitoring, response assessment, dose titration' below.)

Monitoring, response assessment, dose titration — Reduction in vaso-occlusive events is the most important patient-centered clinical endpoint. Bone marrow suppression is the major dose-limiting toxicity.

Although clinical benefit is the goal, we use hematologic parameters as a surrogate for clinical benefit and an endpoint for dose titration, referred to as the maximum tolerated dose (MTD) (table 2). Hb F levels are also monitored [6]. The changes in Hb F and Hb S production are first seen in reticulocytes. It may take up to ≥3 weeks to be seen in mature RBCs and up to six months to affect clinical symptoms. The effects are completely reversible upon drug discontinuation, necessitating lifelong therapy in most cases. (See 'Can therapy be discontinued?' below.)

Monitoring is more frequent while the dose is being adjusted and continues at less frequent intervals once the individual is on a stable dose. In resource-limited settings where frequent complete blood counts (CBCs) are not an option, less intensive dosing with less frequent monitoring may be feasible and may reduce vaso-occlusive complications, including stroke. (See "Sickle cell disease in sub-Saharan Africa", section on 'Hydroxyurea'.)

There is some nuance to determining the ideal set of parameters to monitor that balances ease of use and cost with the added benefit of including more parameters. Some experts advocate hemoglobin/hematocrit and absolute reticulocyte count (ARC), as long as the additional monitoring is not a disincentive to prescribing hydroxyurea.

A 2019 pharmacokinetic model for hydroxyurea in children indicated that patients could reach maximum tolerated dose (MTD) faster using pharmacokinetic-guided dosing than with the standard increment of 5 mg/kg dose every eight weeks [84]. A separate study determined that a dose-prediction equation incorporating baseline serum creatinine, body mass index, and ARC was superior to standard dose escalation in reaching MTD more rapidly [100]. MTD was higher in the dose-prediction arm, suggesting that standard dose escalation results in falsely low MTD in very young children. Although MTD was reached more rapidly in both studies, there was no evidence of decreased morbidity from SCD.

Detailed criteria for determining eligibility for dose escalation, MTD, and toxicity are presented in the table (table 2). General principles include:

●Weight-based initial dose – The initial dose is calculated based on weight, as indicated above. (See 'Initial dosing' above.)

●Increasing the dose – The dose is increased approximately every eight weeks (range, 6 to 12 weeks) by 5 mg/kg daily, to a maximum dose of 35 mg/kg daily or 2500 mg daily, or until one or more of the MTD parameters are reached. The complete blood count (CBC) and reticulocyte count should be obtained every four weeks while the dose is being increased as the hematologic response may evolve over this period. A lower baseline absolute neutrophil count (ANC) due to the Duffy-null phenotype may affect titration of hydroxyurea to MTD; studies to address this are lacking. (See "Gene test interpretation: ACKR1 (Duffy blood group gene)", section on 'Reference ranges for Duffy-null and non-Duffy-null'.)

In individuals with a low baseline ANC, we use cautious dose escalation (eg, in 2.5 mg/kg increments each month) with monitoring, to ensure the ANC is maintained within the target range before further dose escalation. The ARC may be more useful than the ANC in establishing MTD in these individuals.

Parameters to determine MTD include any of the following:

•ANC (calculator 1) of 1500 to 3000/microL (infants with lower baseline ANC may tolerate an on-therapy ANC as low as 1000/microL)

•Absolute reticulocyte count (ARC) of 80,000 to 100,000/microL

The absolute reticulocyte count is calculated as the percent reticulocytes x RBC count (x 10⁶/microL) x 10.

•A platelet count of 80,000 to 150,000/microL

In practice, the most common parameter determining MTD is the ANC, but in some patients the target ARC will be reached before the target ANC. Reduction of the platelet count is rarely the criterion for determining MTD except in patients with splenomegaly.

People with the Duffy-null phenotype have a lower ANC on average than those without, and in these individuals, the absolute reticulocyte count may be more useful than the ANC for establishing MTD.

In one study, 80 of 120 Black children and adolescents (67 percent) had the Duffy-null phenotype [101]. The median ANC with the Duffy-null phenotype was 2820/microL, versus 5005/microL in those without. The ANC was <2000/microL in 19 of these 80 (24 percent). Another retrospective study of 187 children with SCD found the Duffy-null phenotype in over 75 percent, but the Duffy-null phenotype was not associated with lower hydroxyurea doses or increased acute SCD-related visits early in the hydroxyurea treatment course, suggesting that the Duffy-null phenotype does not affect hydroxyurea dose escalation [102].

Reticulocytopenia and worsening anemia occurs more frequently in patients with chronic kidney disease, iron deficiency, viral bone marrow suppression, or delayed hemolytic transfusion reactions [103-106]. A low ARC with anemia may be a more common reason to hold hydroxyurea in adults who are hospitalized or have significant comorbidities; it may be less common in children.

In patients with a strong hemoglobin response (hemoglobin >9 g/dL), ARC <80,000/microL is acceptable as long as the hemoglobin remains stable over several months.

●Holding the dose for significant cytopenias – If significant cytopenias develop (ANC <1000/microL, platelet count <80,000/microL), the dose is temporarily held, and the CBC rechecked once per week until the value exceeds that listed above.

•If recovery occurs within a week, hydroxyurea is then restarted at the same dose.

•If myelosuppression was prolonged or recurs, hydroxyurea is restarted at a lower previously tolerated dose (2.5 to 5 mg/kg daily less than the dose that caused hematologic toxicity).

●Hb F percentage – Routine monitoring of Hb F percentage is not necessary as it is not used to titrate the dose, although it may be checked periodically (eg, annually) to evaluate efficacy.

Most hydroxyurea responses are associated with at least a twofold increase in Hb F percentage over baseline, often much greater. Hb F >20 percent of total hemoglobin is ideal; there is no upper limit [7].

Greater increases percent Hb F or total hemoglobin (>1 g/dL) generally correlate with greater efficacy. Some studies have suggested maximal Hb F response as a surrogate for adherence, but not all individuals who adhere to therapy have a major increase in Hb F; judgement must be used [107]. (See 'Induction of Hb F expression' above and 'Lack of hematologic response' below.)

●Pregnancy test – In females of childbearing potential, a pregnancy test should be done if menses are delayed >2 weeks. Discussion about the teratogenic impact of hydroxyurea and contraception options should be discussed.

●Monitoring on stable dosing – Once the MTD is reached, monitoring is continued at less-frequent intervals. Ongoing monitoring is needed because dose effects and kidney function can change over time.

The CBC with platelet count and reticulocyte count can be measured once every three months. Liver and kidney function are evaluated as needed for ongoing monitoring of SCD (at least every 12 months, more frequently if there is known or suspected organ dysfunction). Additional monitoring may be needed if there is an intercurrent illness that might affect kidney or bone marrow function.

Can therapy be discontinued? — Hydroxyurea therapy should be continued for as long as it is tolerated and effective.

Exceptions include:

●Persistent cytopenias despite dose reductions, which can be a sign of reduced bone marrow capacity.

Other causes of cytopenias (kidney or liver disease, nutritional deficiencies, hypothyroidism) should be excluded.

●Worsening kidney function, which may increase the risk of excessive exposure due to delayed clearance of hydroxyurea, as well as of decreased erythropoiesis due to decreased erythropoietin production.

This can usually be managed by reducing the dose and sometimes by adding an erythropoiesis stimulating agent (ESA) if the primary toxicity is reticulocytopenia. (See 'Myelosuppression' below.)

●Severe cutaneous toxicity, pancreatitis, or other adverse effects that interfere with quality of life. (See 'Adverse effects' below.)

●For males, three months prior to attempting conception.

●For females who become pregnant or who are planning pregnancy in the near future. (See 'Pregnancy and breastfeeding' below.)

●Individuals who have a complication necessitating chronic (regular) transfusion therapy while taking hydroxyurea may discontinue hydroxyurea if the complication occurred despite hydroxyurea therapy. (See 'Hospitalization' below.)

ADVERSE EFFECTS — 

Adverse effects of hydroxyurea in individuals with SCD have been assessed in several studies, as summarized in the table (table 3).

Evidence from over 30 years of use in individuals with SCD has demonstrated a lack of clinically significant adverse effects on growth or development with long-term use. This includes very young children enrolled in the BABY HUG trial (ages 9 to 18 months), who had no reduction in growth or other anthropomorphic measures during two years of hydroxyurea therapy [108].

The BABY HUG trial is one of the few trials that compared fixed moderate dose hydroxyurea at 20 mg/kg/day with placebo in children with sickle cell anemia (Hb SS) [55]. Infants treated with hydroxyurea did not have significant differences from those treated with placebo in rates of severe neutropenia (absolute neutrophil count [ANC] <500/microL), thrombocytopenia (platelet count <80,000/microL), anemia (hemoglobin <7 g/dL), reticulocytopenia (absolute reticulocyte count [ARC] <80,000/microL), or abnormal liver function tests (alanine aminotransferase [ALT] >150 units/L or bilirubin >10 mg/dL).

Impact on vaccination — The package insert for hydroxyurea states that live virus vaccines should be avoided. We have not encountered any problems related to live vaccines, and we provide all routine vaccinations to individuals receiving hydroxyurea, including live virus vaccines. The benefits of reducing infections in this population of functionally asplenic individuals is likely to outweigh any risks associated with live vaccines.

The BABY HUG trial measured immunological effects of hydroxyurea including T-cell subsets, naïve and memory T-cells and antibody response to inactivated and live vaccines [109]:

●Hydroxyurea treatment resulted in lower total lymphocytes, CD4-positive T-cells, and memory T-cells; however, counts remained within the normal range for healthy children.

●Antibody responses to vaccines for pneumococcus, mumps, and rubella were unchanged, but there was a delay of 14 days in developing protective levels of measles antibody.

Myelosuppression — Hydroxyurea is relatively nontoxic, with myelosuppression as the major dose-limiting toxicity.

●For most individuals, myelosuppression is predictable, dose-dependent, and reversible [49,50,67,70].

•Myelosuppression is used to adjust hydroxyurea dosing and can be easily controlled as long as there is regular hematologic monitoring and dose reduction for severe neutropenia, anemia, or thrombocytopenia. (See 'Monitoring, response assessment, dose titration' above.)

•Some individuals have severe myelosuppression such that they are unable to tolerate even low doses of hydroxyurea. (See 'Severe myelosuppression' below.)

•Additional challenges may be seen in individuals with splenomegaly or hypersplenism.

Hyperviscosity — Hyperviscosity due to increased hemoglobin concentration is generally only a concern in individuals with milder genotypes (Hb SC disease, sickle beta⁺ thalassemia) who have higher baseline hemoglobin levels. If the hemoglobin increases to more than 12.5 g/dL, hydroxyurea may be held or the dose reduced. This limit of 12.5 g/dL is based on the targeted upper limit of hemoglobin concentration in transfused patients. Management is otherwise similar to transfusion-associated hyperviscosity. (See "Red blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications", section on 'Risk of hyperviscosity syndrome from simple transfusion'.)

Falsely elevated serum creatinine and other laboratory tests — A point-of-care device for measuring serum creatinine (the i-STAT system) used for routine testing in some clinical laboratories can give a falsely elevated creatinine measurement in patients receiving hydroxyurea [110].

Individuals receiving hydroxyurea who have a high serum creatinine on point-of-care testing should be retested using a different method to distinguish this artifact from true kidney disease. (See "Sickle cell disease effects on the kidney", section on 'Role of hydroxyurea and transfusions'.)

Hydroxyurea has also been reported to cause falsely elevated results for urea, uric acid, and lactic acid, due to analytical interference with the enzymes used to determine these values.

Hydroxyurea may falsely elevate glucose readings on certain continuous glucose monitoring (CGM) systems, with the potential for excessive dosing of insulin and resulting hypoglycemia [111]. The clinician treating diabetes should be informed of this concern. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'CGM systems'.)

GI side effects — Some individuals receiving hydroxyurea may have gastrointestinal (GI) toxicity with nausea or anorexia.

In the HUG-KIDS study, the two children with GI upset attributed to hydroxyurea had improvement in symptoms when the dose was given at bedtime.

Dermatologic effects — Skin and nail changes and leg ulcers have been described, although it is not clear whether hydroxyurea is responsible [45].

●In a cohort of 805 individuals with SCD, there was no association found between hydroxyurea use and prevalence of leg ulcers (it was neither causative of leg ulcers nor protective) [112].

●Individuals with hydroxyurea overdose have developed mucocutaneous toxicity, including:

•Erythema and soreness on the palms and soles of the hands and feet (see "Toxic erythema of chemotherapy (hand-foot syndrome)")

•Scaling

•Generalized hyperpigmentation

•Stomatitis

In such cases the dose should be stopped and supportive treatments used.

Anecdotal reports of hair thinning with hydroxyurea have been described, but there is no clear association between the two.

Pregnancy outcomes — Data on adverse pregnancy outcomes are extremely limited, and decisions regarding discontinuation (whether to discontinue, timing of stopping and restarting) must be individualized and take into account the direct risks to the fetus and mother and the indirect risks due to increased vaso-occlusive episodes and availability of other disease-modifying approaches such as chronic transfusion therapy while not taking hydroxyurea. These subjects are discussed in detail separately. (See "Sickle cell disease: Obstetric considerations", section on 'Hydroxyurea'.)

Possible effects on fertility are discussed below. (See 'Fertility' below.)

Fertility — One of the consistently noted barriers to hydroxyurea therapy has been a concern about possible effects on fertility, especially since SCD may already confer a reduction in sexual functioning, sperm counts, or other reproductive factors [113,114]. A 2024 systematic review and meta-analysis of the impact of hydroxyurea on fertility concluded that exposure to hydroxyurea irreversibly reduces both sperm number in males and decreases markers of ovarian reserve in females in a statistically significant manner [115].

●Males – There has been concern based on data from animal models that suggest a further reduction in spermatogenesis with hydroxyurea. However, preliminary data from two pilot studies provide some reassurance that fertility is unlikely to be permanently impaired by the drug.

•In one study, sperm parameters were compared in 15 adolescents and young adults with SCD who were treated with hydroxyurea during childhood (median duration, 4 years) and 23 controls who had not received hydroxyurea [116]. Most had more than one sample analyzed. There were abnormalities of sperm number and quality in both groups, but sperm parameters were not adversely affected in the individuals treated with hydroxyurea.

•In another study, 30 boys with SCD who were undergoing hematopoietic stem cell transplantation had harvesting of testicular tissue for fertility preservation; 17 had been treated with hydroxyurea (for a median of 36 months) and 13 had not, allowing a comparison between groups [117]. On histological examination of resected testicular tissue, spermatogonial tissue was similar between groups. However, compared with controls without SCD, all of the children with SCD had a reduced spermatogonial stem cell pool, indicating that SCD contributes to spermatogonial depletion.

It is possible that earlier cohort studies that observed reduced sperm counts and low sperm quality may have reflected changes due to SCD rather than hydroxyurea, although they do not eliminate a possible role for hydroxyurea in reduced male fertility [118,119]. If an effect on fertility exists, it is not known whether the effect is reversible with cessation of hydroxyurea.

●Females – There are few data on the impact of hydroxyurea therapy on female fertility in SCD [114]. One cross-sectional cohort study of females with SCD showed that those on hydroxyurea had equivalent numbers of primordial follicles and only a marginally lower number of growing follicles, suggesting that hydroxyurea does not reduce ovarian reserve [120].

A study from 2020 found an association between hydroxyurea and decreased ovarian reserve, using anti-müllerian hormone (AMH) as a marker [121]. In a multivariable analysis, hydroxyurea use was associated with decreased AMH levels. Further research in this area is needed so that individuals can be accurately counseled about this possible risk and be offered measures for fertility preservation when appropriate. (See "Female infertility: Evaluation", section on 'Anti-müllerian hormone'.)

Cumulatively, these results indicate the importance of discussing the potential impact of hydroxyurea on future fertility before initiating treatment.

No evidence for carcinogenicity — A theoretical concern with long-term hydroxyurea is whether the drug is a carcinogen in individuals with SCD. This concern is mostly based on reports of increased incidence of malignancy in individuals receiving hydroxyurea for myeloproliferative neoplasms (MPNs), for whom the baseline risk of hematologic malignancy is increased. Even for these MPNs, it is not clear whether hydroxyurea is a mild leukemogen or whether it merely unmasks the risk of leukemia by allowing patients to live longer.

There is no evidence from the published literature or our clinical experience that suggests individuals with SCD receiving hydroxyurea have an increased risk of malignancy compared with individuals with SCD who are not receiving hydroxyurea.

●Reports from 2003 and 2010 described long-term outcomes in 233 adults who participated in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) trial, which evaluated the role of hydroxyurea in reducing painful episodes [49,50]. Nine years after the trial started, three patients had developed a malignancy, including one each of breast, cervix, and uterus cancer. At least one of the three patients had a preexisting condition predisposing to increased cancer risk. There were no additional cancers described after an additional 17.5 years of follow-up, with an overall rate of malignancy of 0.1 per 100 patient-years.

●A 2004 report described outcomes in 122 children treated with hydroxyurea for up to eight years [122]. There were no malignancies or myelodysplasia, and in vitro testing for increased DNA mutations using VDJ rearrangements in 26 of the children showed no evidence of mutagenesis.

●A 2011 report tested in vitro parameters of chromosome stability in 50 children with SCD who had received hydroxyurea for up to 12 years compared with 28 children who had not received hydroxyurea [123]. Compared with controls, the children who had received hydroxyurea had less chromosome damage and similar chromosome repair.

●A study from 2023 found that hydroxyurea was not mutagenic [124].

Additional long-term studies are needed, as people with SCD have an increased risk of hematologic malignancies without exposure to hydroxyurea [125].

While it is possible that these studies failed to detect a very small increase in carcinogenicity, this risk, if present, must be weighed against the clinically significant benefits of hydroxyurea in reducing complications and prolonging survival. (See 'Evidence for efficacy' above.)

SPECIAL SCENARIOS

Lack of hematologic response — Lack of hematologic response (hemoglobin F [Hb F] increasing by less than twofold, mean corpuscular volume [MCV] ≤100 fL, or MCV increased by <10 fL) is sometimes seen and is usually attributed to reduced medication adherence.

Often, nonadherence to medication is the reason for lack of a hematologic response; however, lack of response should not automatically be used as a surrogate for nonadherence because some individuals who take hydroxyurea as directed do not have a hematologic response.

When efficacy is carefully tracked and compliance is assumed to be 100 percent, it appears that approximately 5 to 10 percent of children and 25 to 30 percent of adults have true lack of efficacy from hydroxyurea [5]. The reason is not completely understood but may be due to factors that control Hb F production. (See 'Mechanism of action' above.)

For an individual who does not have the expected response, the following is appropriate:

●Review administration – Proper daily use of hydroxyurea should be reviewed and barriers to proper use addressed. (See 'Eliminating barriers to appropriate therapy' above.)

●Optimize adherence – Adherence should be reviewed and optimized as best as possible before significant dose escalation to reduce the risk of excessive myelosuppression at higher doses. Ideally this includes review of pharmacy dispensing records.

●Allow six months of therapy – If the individual has only been taking the medication for a short time, we continue therapy for six months after the maximum tolerated dose (MTD) has been reached. (See 'Monitoring, response assessment, dose titration' above.)

●Focus on clinical benefit – If the patient has clinical benefit from treatment despite lack of the expected hematologic changes, we continue the medication as long as there are no apparent adverse effects.

●Consider adding an ESA – An erythropoiesis stimulating agent (ESA) can be added to hydroxyurea, typically at doses similar to those used for cancer or inflammatory causes of anemia. This approach was suggested in the American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease [126]. Individuals with kidney disease and older individuals have increased endogenous erythropoietin but not to the markedly elevated levels typically seen in young people with SCD.

●Address nutrient deficiencies – Iron, vitamin B12, or folate deficiency may limit response to hydroxyurea. If the patient's clinical or laboratory picture suggests these possibilities, assess and supplement as needed. Ferritin may be in the normal range or even elevated in people with SCD with absent bone marrow stores, due to chronic inflammation [127]. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Iron requirements and iron deficiency in adolescents" and "Diagnosis of iron deficiency and iron deficiency anemia in adults" and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency" and "Anemia of chronic disease/anemia of inflammation".)

●Stop for true lack of benefit – If the patient is taking the drug as directed and not experiencing any clinical benefit (no reduction in pain episodes or other vaso-occlusive complications) and/or is not having the expected hematologic changes, we may discontinue the medication, as the risks of continuing therapy, albeit small, may no longer be justified.

For these patients, other options include other disease-modifying medications, chronic transfusions, investigative agents, and hematopoietic cell transplantation. These approaches are not mutually exclusive. The choice among them is individualized according to the needs of the individual. The risks and benefits of these therapies are discussed in separate topic reviews. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease" and "Red blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications" and "Investigational pharmacologic therapies for sickle cell disease" and "Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy".)

Severe myelosuppression — Some individuals treated with hydroxyurea may have more severe myelosuppression than expected. Typically, the drug is held and restarted at a lower dose, and a maximum tolerated dose can eventually be determined. (See 'Monitoring, response assessment, dose titration' above.)

Rarely, an individual may be unable to tolerate hydroxyurea even at reduced doses (eg, with severe kidney dysfunction). For these patients, options for treatment include chronic transfusion therapy, investigational agents, hematopoietic cell transplantation, and supportive/symptomatic care. The choice among these is individualized. Risks and benefits are discussed separately. (See "Red blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications" and "Investigational pharmacologic therapies for sickle cell disease" and "Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy".)

Transition from chronic transfusions to hydroxyurea — Selected individuals can be transitioned from chronic transfusions to hydroxyurea therapy, as shown in the table (table 2). This subject is discussed in detail separately. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Chronic transfusion followed by transition to hydroxyurea'.)

Pregnancy and breastfeeding — Decisions about hydroxyurea during attempted conception, pregnancy, and breastfeeding are discussed in detail separately. (See "Sickle cell disease: Obstetric considerations", section on 'Hydroxyurea'.)

Hospitalization — Patients receiving hydroxyurea should continue the drug during an acute hospitalization unless there is significant myelosuppression or severe acute kidney injury, both of which would warrant discontinuation and possibly restarting at a lower dose. (See "Sickle cell disease: Overview of management during hospital admission", section on 'Continue hydroxyrea and other oral medications' and 'Initial dosing' above.)

Hydroxyurea generally can be continued during hospitalization for a febrile illness or an uncomplicated infection. It is prudent to temporarily hold hydroxyurea during severe infectious illnesses with worsening cytopenias or worsening clinical status in order to avoid severe myelosuppression.

We do not hold hydroxyurea therapy before surgery because the major concern postoperatively is acute chest syndrome (ACS), and hydroxyurea decreases this risk. ACS is potentially life-threatening, and its risk reduction outweighs a risk of poor wound healing from myelosuppression.

Hydroxyurea is also continued for individuals who are admitted for complications that require transfusions, as the effect of transfusions is likely to be transient.

For those who are transitioned to chronic (regular) transfusion therapy, hydroxyurea may be discontinued, since the complication that necessitated transfusion occurred despite hydroxyurea. Restarting the hydroxyurea at a future time may be appropriate; this decision is individualized. However, some individuals receiving chronic transfusions may continue hydroxyurea, as it may reduce the number of transfusions needed [128].

For those who are unable to take anything by mouth, hydroxyurea must be held, as there is no parenteral formulation. The medication should be restarted as soon as reasonably possible, using the nasogastric route when necessary.

If a patient with SCD who is not receiving hydroxyurea is hospitalized and a decision is made to start the medication, this is typically done on an outpatient basis (after discharge) to allow for full discussion of the risks and benefits and establishment of a mutually agreed upon surveillance schedule.

Resource-limited settings — (See "Sickle cell disease in sub-Saharan Africa".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Sickle cell disease (The Basics)" and "Patient education: When your child has sickle cell disease (The Basics)")

PATIENT PERSPECTIVE TOPIC

Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY AND RECOMMENDATIONS

●Mechanism of action – Hydroxyurea reduces vaso-occlusive events such as pain and acute chest syndrome (ACS) in people with sickle cell disease (SCD). The most important mechanism is an increase in fetal hemoglobin (Hb F), which reduces sickle hemoglobin (Hb S) polymerization, sickling, and vaso-occlusion. (See 'Mechanism of action' above.)

●Indications – Hydroxyurea is effective in improving survival and reducing complications of SCD (table 1). Our approach to deciding whether to use hydroxyurea is shown in the algorithm (algorithm 1). (See 'Indications and evidence for efficacy' above.)

•Hb SS or sickle beta⁰ thalassemia

-Infants, children, and adolescents – For infants ≥9 months, children, and adolescents with Hb SS or sickle beta⁰ thalassemia, we recommend hydroxyurea (Grade 1B). A randomized trial and several observational studies demonstrated reductions in vaso-occlusive complications (dactylitis, painful episodes, acute chest syndrome). Hydroxyurea may be appropriate in infants between six and nine months who are symptomatic. (See 'Infants and young children' above and 'Older children, adolescents, and adults' above.)

-Adults – For adults with homozygous Hb SS or sickle beta⁰ thalassemia, we continue (or offer) hydroxyurea; these individuals are almost always symptomatic. Exceptions include rare individuals who are not symptomatic and those trying to conceive or pregnant; for the latter, the timing of starting and discontinuing hydroxyurea is individualized. (See 'Older children, adolescents, and adults' above and "Sickle cell disease: Obstetric considerations", section on 'Hydroxyurea'.)

•Other genotypes – For individuals with Hb SC disease, sickle beta⁺ thalassemia, or other genotypes associated with milder disease, use of hydroxyurea is individualized based on disease severity. For rare individuals with Hb SC disease and symptomatic disease (defined as two or more vaso-occlusive events per year [eg, vaso-occlusive pain, dactylitis, acute chest syndrome, priapism]), we suggest hydroxyurea (Grade 2B). Hydroxyurea is generally not used for those with milder disease.

●Baseline testing – Testing prior to initiating hydroxyurea includes complete blood count (CBC) with differential, platelet count, reticulocyte count, Hb F percentage, tests of kidney and liver function, and pregnancy test for females of childbearing potential. (See 'Baseline testing' above.)

●Dosing – We generally start infants and children at 20 mg/kg daily and adults at 15 to 20 mg/kg daily; the daily dose may be rounded to the nearest 2.5 mg/kg. For creatinine clearance <60 mL/minute, reduce the dose by one-half. The dose is typically titrated by 5 mg/kg/day every eight weeks to maximum tolerated dose (MTD) using hematologic parameters (table 2). Compounding support is needed to create a liquid formulation. Treatment is continued indefinitely if effective. (See 'Initial dosing' above and 'Monitoring, response assessment, dose titration' above.)

Dosing and monitoring in sub-Saharan Africa are discussed separately. (See "Sickle cell disease in sub-Saharan Africa".)

●Adverse effects – Hydroxyurea is relatively nontoxic. Myelosuppression is the predictable, dose-limiting toxicity (table 3). Skin, hair, and nail changes and gastrointestinal upset may occur. Some serum creatinine assays and continuous glucose monitor readings may be altered. Reduced sperm number and quality may occur without hydroxyurea, and preliminary data suggest hydroxyurea does not worsen these parameters. Concerns about possible carcinogenesis have largely been refuted. (See 'Adverse effects' above.)

●Lack of response – Evaluate for modifiable causes of lack of response; if there is no hematologic response, therapy may be discontinued and/or other therapies used. (See 'Lack of hematologic response' above.)

●Alternatives and additions to hydroxyurea – Separate topics discuss:

•Other aspects of SCD management – (See "Overview of preventive/outpatient care in sickle cell disease" and "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

•Other medical therapies – (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease" and "Investigational pharmacologic therapies for sickle cell disease".)

•Chronic transfusions – (See "Red blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications".)

•Hematopoietic stem cell transplantation and gene therapy – (See "Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy".)

ACKNOWLEDGMENTS — 

UpToDate gratefully acknowledges Stanley L Schrier, MD, who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges extensive contributions of Donald H Mahoney, Jr, MD, to earlier versions of this topic review.