Medscape Continuing Medical Education online

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint providership of Medscape, LLC and the American Society of Hematology.

Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.

Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at http://www.medscape.org/journal/blood; and (4) view/print certificate. For CME questions, see page 4004.

Disclosures

The authors, Associate Editor David Garcia, and CME questions author Laurie Barclay, freelance writer and reviewer, Medscape, LLC, declare no competing financial interests.

Learning objectives
  1. Describe indications for use of hydroxyurea in adults with sickle cell anemia.

  2. Describe indications for use of hydroxyurea in children with sickle cell anemia.

  3. Describe indications for use of hydroxyurea in patients with HbSβ+-thalassemia.

Release date: December 18, 2014; Expiration date: December 18, 2015

Case presentation

What is the evidence to start hydroxyurea in the following cases?

Case 1: A 29-year-old man with HbSS was hospitalized for 2 weeks with acute chest syndrome, during which time he underwent red blood cell exchange transfusion. He is now 1 month post–hospital discharge with infrequent pain, which responds to nonsteroidal anti-inflammatory drugs.

Case 2: A 5-year-old girl with HbSS is being seen for a routine follow-up visit. She has never had acute chest syndrome or other sickle cell–related complications. She currently has minimal pain and has not had any emergency room visits over the past year.

Case 3: A 22-year-old woman with HbSβ+-thalassemia has frequent painful episodes and was hospitalized for the fourth time in the last 14 months.

Introduction

Patients with sickle cell disease (SCD; defined as homozygous hemoglobin [Hb] S and compound heterozygotes, eg, HbSC) have hemolytic anemia and vaso-occlusion that result in pain, organ injury, and premature mortality. No specific therapy was available for these patients until the 1970s, when 2 studies recognized that patients with increased red blood cell fetal hemoglobin (HbF) levels had fewer adverse clinical events.1,2  In 1984, pharmacologic induction of HbF by hydroxyurea was documented in 2 adults with sickle cell anemia (SCA; defined in this review as HbSS or Sβ0-thalassemia).3  Subsequent prospective studies verified the efficacy and tolerability of hydroxyurea,4,5  leading to a placebo-controlled, randomized controlled trial (RCT) that demonstrated the efficacy of hydroxyurea in reducing painful vaso-occlusive crises (VOC) and acute chest syndrome (ACS) in adults with SCA.6  The US Food and Drug Administration approved hydroxyurea in 1998 for the treatment of adults with SCA with recurrent moderate to severe painful crises. In 2007, the European Medicines Agency authorized hydroxyurea for recurrent VOC and ACS in pediatric and adult patients with sickle cell syndromes.7  In 2008, the Agency for Healthcare Research and Quality (AHRQ) published a comprehensive systematic review and a National Institutes of Health Consensus Development Conference was held on hydroxyurea treatment of SCD.8,9  Our current objective is to analyze the current literature and provide evidence-based recommendations for hydroxyurea therapy in SCD.

Methods

Data sources and searches

The 2008 AHRQ review conducted a search of MEDLINE, EMBASE, TOXLine, and CINAHL through June 2007. In the current study, we performed a MEDLINE and EMBASE search involving hydroxyurea treatment of humans with SCD from January 2007 through December 2013. The search included MeSH terms sickle cell, hydroxyurea, and hydroxycarbamide (see Figure 1 for our search strategy). We reviewed the references of systematic reviews and pertinent articles to identify additional studies.

Figure 1

Study flow diagram.

Figure 1

Study flow diagram.

Study selection, data extraction, and quality assessment

Study selection was done independently in duplicate by 2 investigators. Titles and abstracts of citations identified were reviewed for inclusion. Eligibility criteria were adapted from the AHRQ review.8  Articles were included if they were peer reviewed, involved patients with SCD, and provided data about the efficacy and/or effectiveness of hydroxyurea on 1 or more clinically relevant measurable outcomes or described hydroxyurea toxicity in humans with SCD. RCTs published prior to 2007 were included if secondary analyses from the RCTs fulfilled eligibility criteria. We excluded non–English-language articles, review articles, case series, and studies with fewer than 20 patients unless the article was primarily reporting on toxicity. We included toxicity cases if the hydroxyurea dose and duration of treatment could be used to assess for causality. Although the AHRQ review examined barriers to hydroxyurea use, we decided a priori to not address this issue.

We based our data extraction forms on those used in the AHRQ review. Data extraction was done independently and in duplicate by 2 investigators for 4 studies to achieve calibration. These results were compared to achieve consensus, and the data for the remaining studies were extracted independently by a single investigator and reviewed by a second investigator for accuracy. Discrepancies were resolved by discussion or review by a third investigator.

Two investigators independently assessed study quality using the Jadad score for randomized studies10  and the Newcastle-Ottawa scale for nonrandomized studies.11,12  Toxicity reports were assessed using a tool based on 5 questions/criteria developed by the Cochrane Collaboration.13 

Detailed data extraction results and assessment of quality are available (supplemental Tables 1-13, available on the Blood Web site). Quality of evidence and recommendations were graded based on Grading of Recommendations Assessment Development and Evaluation tool.14  Disagreements were resolved by discussion or by mediation by a third investigator.

Results

A total of 48 studies were included (Figure 1): 5 RCTs, 11 secondary analyses presenting data from these RCTs, 27 observational studies, and 5 articles that addressed hydroxyurea toxicity (supplemental Tables 1, 4, 7, and 13). All but one RCT15  and its secondary analyses16-20  enrolled patients who had previous sickle cell–related symptoms or complications. Thirty studies enrolled children, 13 enrolled adults, and 5 enrolled both.

Hydroxyurea administration

When specified, all studies initiated orally administered hydroxyurea at doses between 10 and 20 mg/kg per day. Thirteen studies6,21-32  indicated a goal to increase to maximum tolerated dose (limited by mild myelosuppression), 5 studies increased until clinical or laboratory improvement was observed,33-37  and 5 studies used fixed dosing at 10 or 20 mg/kg per day.15,38-41  When stated, all studies used a maximum dose of 30 to 35 mg/kg per day.

Clinical outcomes

In 19 primary studies reporting hematologic data, hydroxyurea therapy was consistently associated with overall increases in HbF.6,15,22,24-26,28,30,32,34-43  Both children and adults with SCA benefited from reductions in the frequency of VOC in 11 studies,6,15,24,30,34-36,38-40,43  ACS in 7 studies,6,15,24,28,34,36,38  and transfusions in 8 studies.6,15,24,36,38-40,43 

In children, hydroxyurea was associated with decreased hospitalizations compared with placebo in 2 studies.15,39  In adults and children, decreased rates of hospitalization were reported for patients receiving hydroxyurea compared with prior to hydroxyurea use in 7 studies.28,30,35,36,38,43,44  In 2 observational studies, a reduction in frequency of VOC and in one study in ACS was observed in patients with HbSβ+-thalassemia30,36  (Tables 1 and 2).

Table 1

RCTs

Study/authors/locationInclusion criteriaInterventionAge mean/median (range)NFollow-up periodOutcomes for hydroxyurea treatment vs no hydroxyurea
MSH*/Charache et al, 1995/North America SCA; age >18 y; ≥3 crises/y HU vs placebo; HU: 15 mg/kg per day escalated to MTD 30 y (18-59) 299 (HU: 152) 21 mo (mean); 134/299 with 2 y 1°: decreased VOC (P < .001); 2°: decreased ACS (P < .001), decreased transfusions (P = .001) 
BABY HUG/Wang et al, 2011/United States SCA; 9-18 mo; no requirement for clinical severity HU vs placebo; HU: fixed at 20 mg/kg per day 13.6 mo (HU); 13.5 mo (placebo) 193 (HU: 96) 24 mo 1°: no difference in splenic function (P = .21) or renal function (P = .84); 2°: decreased VOC (P = .002), ACS (P = .02), dactylitis (P < .0001) 
CHAMPS/Wang et al, 2011/United States HbSC ; age ≥5 y; 1 VOC in previous y 4 groups: HU+placebo, Mg+placebo, HU+Mg, placebo+placebo; HU: fixed at 20 mg/kg per day 13.6 y (5-53) 44 (HU: 22) 36 patients: 8 wk; 22 patients: 44 wk Early trial termination due to poor accrual; 1°: no difference in hyperdense red cells; 2°: no difference in frequency of VOC (HU: increased HbF, week 8: P < .05 and week 24: P < .001) 
Jain et al, 2012/India SCA; >3 VOC/y; requiring hospitalization or transfusion >3/y HU vs placebo; HU: fixed at 10 mg/kg per day 12.7 ± 4.4 y (HU); 11.7 ± 4.1 y (placebo) (5-18) 60 (HU: 30) 18 mo 1°: decreased VOC (P < .001); 2°: decreased transfusions (P < .001); decreased hospitalizations (P < .001) 
SWiTCH/Ware et al, 2012/United States SCA HU/phlebotomy vs txn/chelation (noninferiority trial design); HU: 20 mg/kg per day escalated to MTD 13y (5-18) 133 (HU: 67) 24 mo (mean) Study closed at first interim analysis; 1°: equivalent liver iron content at interim analysis for both arms; rate of stroke with HU arm within noninferiority margin 
Study/authors/locationInclusion criteriaInterventionAge mean/median (range)NFollow-up periodOutcomes for hydroxyurea treatment vs no hydroxyurea
MSH*/Charache et al, 1995/North America SCA; age >18 y; ≥3 crises/y HU vs placebo; HU: 15 mg/kg per day escalated to MTD 30 y (18-59) 299 (HU: 152) 21 mo (mean); 134/299 with 2 y 1°: decreased VOC (P < .001); 2°: decreased ACS (P < .001), decreased transfusions (P = .001) 
BABY HUG/Wang et al, 2011/United States SCA; 9-18 mo; no requirement for clinical severity HU vs placebo; HU: fixed at 20 mg/kg per day 13.6 mo (HU); 13.5 mo (placebo) 193 (HU: 96) 24 mo 1°: no difference in splenic function (P = .21) or renal function (P = .84); 2°: decreased VOC (P = .002), ACS (P = .02), dactylitis (P < .0001) 
CHAMPS/Wang et al, 2011/United States HbSC ; age ≥5 y; 1 VOC in previous y 4 groups: HU+placebo, Mg+placebo, HU+Mg, placebo+placebo; HU: fixed at 20 mg/kg per day 13.6 y (5-53) 44 (HU: 22) 36 patients: 8 wk; 22 patients: 44 wk Early trial termination due to poor accrual; 1°: no difference in hyperdense red cells; 2°: no difference in frequency of VOC (HU: increased HbF, week 8: P < .05 and week 24: P < .001) 
Jain et al, 2012/India SCA; >3 VOC/y; requiring hospitalization or transfusion >3/y HU vs placebo; HU: fixed at 10 mg/kg per day 12.7 ± 4.4 y (HU); 11.7 ± 4.1 y (placebo) (5-18) 60 (HU: 30) 18 mo 1°: decreased VOC (P < .001); 2°: decreased transfusions (P < .001); decreased hospitalizations (P < .001) 
SWiTCH/Ware et al, 2012/United States SCA HU/phlebotomy vs txn/chelation (noninferiority trial design); HU: 20 mg/kg per day escalated to MTD 13y (5-18) 133 (HU: 67) 24 mo (mean) Study closed at first interim analysis; 1°: equivalent liver iron content at interim analysis for both arms; rate of stroke with HU arm within noninferiority margin 

1°, primary outcomes; 2°, secondary outcomes; BABY HUG, Pediatric Hydroxyurea in Sickle Cell Anemia; CHAMPS, Hydroxyurea and Magnesium Pidolate to Treat People with Hemoglobin Sickle Cell Disease; HU, hydroxyurea; Mg, magnesium pidolate; MTD, maximum tolerated dose; txn, transfusion.

*

Secondary analyses of MSH included in the current review.

Table 2

Observational studies evaluating frequency of acute clinical events in SCD*

Authors/locationPatient population/study designGenotype/inclusion criteriaNFollow-up period mean/median (range)Clinical outcomes HU vs no HUComments
VOCACSTransfusionStrokeHospital use
Ali et al, 2011/Jamaica Children/retrospective 42 SCA, 1 HbSC; neuroimaging documentation of stroke or dx of clinical stroke 43 (HU: 10) HU: 4.6 y; no HU:4.2 y    HU: (2/ 100 p-y); no HU or txn: (29/100 p-y) (HR 9.4, P = .03)  Chronic transfusion program was not available 
Gilmore et al, 2011/United Kingdom Children and adults/retrospective 61 SCA, 1 HbSD; majority-recurrent VOC; VOC with ACS 62 (HU: 62) 3 y (1-9) ↓; P = .02 at 2 y ↓; P = .0007 at 7 y ↓; P = .002 at 7 y  Inpatient annual days; ↓; P < .001 at 7 y Registry data 
Italia et al, 2008/India Children and adults/prospective 54 HbSS, 23 HbSβthal; Arab-Indian haplotype; 5+ VOC/y, 1 CVA in life, 2+ ACS/life, or (AVN of femur + any of the above 77 (HU: 77) 2 y ↓ ↓ ↓ ↓ ↓ High baseline HbF level; reduction in clinical events score stratified according to initial severity (P < .0001) 
Lobo et al, 2013/Brazil Children/retrospective SCD; indications for HU: recurrent VOC; >1 ACS; Hb <6 g/dL, CVA 1760 (HU: 267 [SCA: 243; HbSB+thal: 10; HbSC: 10; HbSD: 4]) 7 y (3-17) HU: 2 y (0.1-6.5)  HU:1 no HU: 17  HU: 0; no HU: 4 ↓50% P < .001 ↓ mortality; 1 in HU group; 37 in no-HU group 
ED visits ↓35% P < .001 
Nzouakou et al, 2010/France Adults and adolescents/retrospective SCA; ≥3 VOC hospitalizations/y; recurrent ACS; recurrent priapism; switch from txn program 123 (HU: 123) 4.9 y (0.44-13.5) ↓; P < .0001  15/31 pts stopped txn  ↓ (data on 64 pts); P < .0001  
Patel et al, 2012/India Children and adults/prospective SCA: Asian haplotype; VOC >3 or txn >2 in previous y 118 (HU: 118) 2 y 87.2% with ↓ 50% or more  19/20 pts txn free   High baseline HbF level 
Rigano et al, 2013/Italy Adults/retrospective HbSβ0thal:34; HbSβ+thal:67; 2-3 VOC previous y; hx of ACS 104 (HU: 104) 11 y ↓; P < .0001   6.7% overt stroke ↓; P < .0001 30% with new/progressed SCI 
Sharef et al, 2013/Oman Children/retrospective, prospective SCD (not specified); >3 VOC hospitalizations/y or 1 episode of ACS 142 (HU: 142) 4 y (1.5-10)  ↓   ↓; P < .001  
Singh et al, 2010/India Adults/prospective SCA; ≥3VOC hospitalizations/y, ACS, stroke or Hb <7 g/dL 24 (HU: 24) 1 y ↓; P = .008    ↓; P = .03 High baseline HbF level 
Steinberg et al, 2010 (MSH)/North America Adults/prospective SCA; MSH RCT cohort; analysis by HU use, not original trial assignment 129/299 of original cohort deceased Up to 17 y, 7 mo    NS  HU for at least 5 y compared with <5 y had ↓ mortality 
Voskaridou et al, 2010 (LaSHS)/Greece Adults/prospective HbSS: 34, HbSβ0thal: 131, HbSβ+thal: 165; ≥3 VOC/previous y; jaundice; or complications (CVA or ACS in past 5 y) 330 (HU:131 [SCA:87; SB+thal:44]) HU: 8 y (0.1-17); no HU: 5 y (0.1-18) ↓; P < .001 ↓; P = .016 ↓; P < .001 HU: 5; no HU: 10 ↓; P < .001 10 y survival: 86% for HU; 65% for non-HU; P = .001 
Authors/locationPatient population/study designGenotype/inclusion criteriaNFollow-up period mean/median (range)Clinical outcomes HU vs no HUComments
VOCACSTransfusionStrokeHospital use
Ali et al, 2011/Jamaica Children/retrospective 42 SCA, 1 HbSC; neuroimaging documentation of stroke or dx of clinical stroke 43 (HU: 10) HU: 4.6 y; no HU:4.2 y    HU: (2/ 100 p-y); no HU or txn: (29/100 p-y) (HR 9.4, P = .03)  Chronic transfusion program was not available 
Gilmore et al, 2011/United Kingdom Children and adults/retrospective 61 SCA, 1 HbSD; majority-recurrent VOC; VOC with ACS 62 (HU: 62) 3 y (1-9) ↓; P = .02 at 2 y ↓; P = .0007 at 7 y ↓; P = .002 at 7 y  Inpatient annual days; ↓; P < .001 at 7 y Registry data 
Italia et al, 2008/India Children and adults/prospective 54 HbSS, 23 HbSβthal; Arab-Indian haplotype; 5+ VOC/y, 1 CVA in life, 2+ ACS/life, or (AVN of femur + any of the above 77 (HU: 77) 2 y ↓ ↓ ↓ ↓ ↓ High baseline HbF level; reduction in clinical events score stratified according to initial severity (P < .0001) 
Lobo et al, 2013/Brazil Children/retrospective SCD; indications for HU: recurrent VOC; >1 ACS; Hb <6 g/dL, CVA 1760 (HU: 267 [SCA: 243; HbSB+thal: 10; HbSC: 10; HbSD: 4]) 7 y (3-17) HU: 2 y (0.1-6.5)  HU:1 no HU: 17  HU: 0; no HU: 4 ↓50% P < .001 ↓ mortality; 1 in HU group; 37 in no-HU group 
ED visits ↓35% P < .001 
Nzouakou et al, 2010/France Adults and adolescents/retrospective SCA; ≥3 VOC hospitalizations/y; recurrent ACS; recurrent priapism; switch from txn program 123 (HU: 123) 4.9 y (0.44-13.5) ↓; P < .0001  15/31 pts stopped txn  ↓ (data on 64 pts); P < .0001  
Patel et al, 2012/India Children and adults/prospective SCA: Asian haplotype; VOC >3 or txn >2 in previous y 118 (HU: 118) 2 y 87.2% with ↓ 50% or more  19/20 pts txn free   High baseline HbF level 
Rigano et al, 2013/Italy Adults/retrospective HbSβ0thal:34; HbSβ+thal:67; 2-3 VOC previous y; hx of ACS 104 (HU: 104) 11 y ↓; P < .0001   6.7% overt stroke ↓; P < .0001 30% with new/progressed SCI 
Sharef et al, 2013/Oman Children/retrospective, prospective SCD (not specified); >3 VOC hospitalizations/y or 1 episode of ACS 142 (HU: 142) 4 y (1.5-10)  ↓   ↓; P < .001  
Singh et al, 2010/India Adults/prospective SCA; ≥3VOC hospitalizations/y, ACS, stroke or Hb <7 g/dL 24 (HU: 24) 1 y ↓; P = .008    ↓; P = .03 High baseline HbF level 
Steinberg et al, 2010 (MSH)/North America Adults/prospective SCA; MSH RCT cohort; analysis by HU use, not original trial assignment 129/299 of original cohort deceased Up to 17 y, 7 mo    NS  HU for at least 5 y compared with <5 y had ↓ mortality 
Voskaridou et al, 2010 (LaSHS)/Greece Adults/prospective HbSS: 34, HbSβ0thal: 131, HbSβ+thal: 165; ≥3 VOC/previous y; jaundice; or complications (CVA or ACS in past 5 y) 330 (HU:131 [SCA:87; SB+thal:44]) HU: 8 y (0.1-17); no HU: 5 y (0.1-18) ↓; P < .001 ↓; P = .016 ↓; P < .001 HU: 5; no HU: 10 ↓; P < .001 10 y survival: 86% for HU; 65% for non-HU; P = .001 

↓, decreased; AVN, avascular necrosis; CVA, stroke; dx, diagnosis; HbSβ0thal, HbSβ0-thalassemia; HbSβ+thal, HbSβ+-thalassemia; HU, hydroxyurea; hx, history; LaSHS, Laikon Study of Hydroxyurea in Sickle Cell Syndromes; NS, not significant; p-y, patient-years; pts, patients; SCI, silent cerebral infarction; txn, transfusion.

*

Outcomes evaluated in single studies included cognitive function,62  physical fitness,37  perioperative,27  quality of life,63  retionopathy,23  and tricuspid regurgitant velocity.42 

Pre/post comparisons in single group studies.

Evidence for primary stroke prevention was limited to observational data. Three studies found decreased stroke rates in those administered hydroxyurea compared with no treatment (Table 2).28,36,38  Children receiving hydroxyurea had reduced transcranial Doppler (TCD) velocities.20,32  More definitive information was available on the prevention of recurrent stroke. Hydroxyurea was not equivalent to transfusion in the Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial based on a composite end point (Table 1).31  In a cohort of children with SCA, hydroxyurea decreased the rate of recurrent stroke compared with no therapy (Table 2).21  In adults with HbSβ0- and HbSβ+-thalassemia, new ischemic neurologic events occurred on hydroxyurea despite effectively reducing VOC and hospitalizations (Table 2).30 

Hydroxyurea compared with placebo did not prevent early evidence of renal or splenic dysfunction in toddlers aged 9 to 18 months (Table 1),15  but observational studies in children aged 9 months to 20 years noted significant improvement in splenic uptake, glomerular filtration rate, renal hypertrophy, ability to concentrate urine, microalbuminuria, and retinopathy.16,22,23,26,33 

Toxicity

Leukopenia, neutropenia, and thrombocytopenia were the most frequently reported side effects of hydroxyurea.6,15,20,22,28,34,36,38-40,43,45,46  These effects were generally mild and reversible with discontinuation or a decrease in hydroxyurea dose. Other side effects reported include skin and nail changes,6,24,36,39-41,43,45  leg ulcers,36,43,45  and gastrointestinal disturbances6,20,41,46 ; however, the evidence for hydroxyurea being the causative agent of these side effects is not definitive (supplemental Tables 3, 6, and 9).

Concerns about somatic and/or germ line genotoxicity underlie the potential serious late effects of hydroxyurea. Decreased sperm counts, which did not normalize after hydroxyurea cessation, were noted in one study without a comparator group.47  After 17 years of follow-up, 94 pregnancies were reported by female and male subjects enrolled in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) regardless of their HU exposure.48  Of female subjects with known HU exposure at conception or during gestation and by male subjects with known exposure at the time of conception, 16 pregnancy outcomes were reported with 8 live births (6 term and 2 premature deliveries), 5 elective abortions, and 3 spontaneous abortions. Of the live births, no birth defects were described consistent with findings in 3 other studies reporting pregnancy outcomes24,36,47  (supplemental Table 9).

Five malignancies were reported in 951 patients taking hydroxyurea (0.5%) and 1 malignancy among 1736 patients not taking hydroxyurea (0.06%).24,28,34,36,43,49  Three case reports were published after 2007 describing a hematologic malignancy presenting 4 to 15 years after starting hydroxyurea in patients with SCD.50-52  Ex vivo studies of mononuclear cells taken from patients on hydroxyurea did not demonstrate increased genomic instability that might contribute to teratogenesis or leukemogenesis.18,29 

Mortality

Hydroxyurea treatment was associated with decreased mortality in symptomatic patients with SCA compared with patients receiving shorter-term hydroxyurea or no hydroxyurea (Table 2).49  Decreased mortality was also seen in 2 other cohort studies among pediatric28  and adult36  patients with SCA receiving hydroxyurea, which was not statistically significant for patients with HbSβ+-thalassemia in adults.

Recommendations

  1. In adults with SCA who have ≥3 moderate to severe pain episodes in a 12-month period, we recommend hydroxyurea therapy (grade 1A).

  2. In adults with SCA who have a history of ACS or symptomatic anemia, we recommend hydroxyurea therapy (grade 1B).

  3. In children with SCA who have ≥3 moderate to severe pain episodes in a 12-month period, we recommend hydroxyurea therapy (grade 1B).

  4. In children with SCA who have a history of ACS or symptomatic anemia, we recommend hydroxyurea therapy (grade 1B).

  5. For infants and children age 9 months or older with SCA who are asymptomatic or have infrequent pain episodes, we recommend hydroxyurea therapy (grade 1B). We acknowledge the improvements in outcome are based on secondary outcomes from a RCT, which may or may not hold value for an individual patient.

  6. In patients with SCA who have a history of stroke and a contraindication to chronic transfusions, we suggest hydroxyurea therapy as compared with no therapy (grade 2B).

  7. In adults with HbSβ+-thalassemia with ≥3 moderate to severe pain episodes in a 12-month period or a history of ACS, we suggest hydroxyurea therapy (grade 2C).

  8. In patients with HbSC and children with HbSβ+-thalassemia, there is insufficient evidence to provide recommendations on hydroxyurea therapy.

Discussion

A systematic review of published literature from 2007 to 2013 was performed to update the evidence review sponsored by the AHRQ.8  The current literature provides a substantive increase in data on children and long-term outcomes for adults with SCD receiving hydroxyurea. Our recommendations are based on the evidence derived from both this current and the AHRQ systematic reviews.

To date, only 5 RCTs have addressed the efficacy of hydroxyurea in patients with SCA.6,15,31,39,53  Thus, evidence gathered using other study designs substantially informs our recommendations. With the exception of the SWiTCH trial, these other RCTs described a benefit for patients receiving hydroxyurea compared with the standard of care.31  The MSH study reported reduced frequency of VOC, ACS, and transfusions.6  A Belgian RCT with a crossover design found fewer VOC, hospitalizations, and hospital days in children receiving hydroxyurea.53  Although BABY HUG did not demonstrate prevention or improvement of splenic or renal dysfunction with hydroxyurea, differences were seen in secondary end points with significant decreases in pain and dactylitis as well as moderate decreases in ACS, hospitalization rates, and transfusion.15  A small RCT from India reported a significant decrease in the number of VOC, transfusion requirements, and hospitalizations with hydroxyurea compared with placebo despite high baseline HbF levels and low-dose therapy.39  Findings from nonrandomized studies are consistent with those from RCTs in SCA, confirming decreased frequency of VOC, ACS, transfusion, and hospitalizations as well as overall safety of hydroxyurea in both children and adults. Furthermore, the long-term observational studies support the sustainability of effectiveness. Mortality is difficult to assess in the RCTs due to the limited follow-up period. However, results from 3 prospective observational studies with substantial sample size for trials in SCA (2 in adults, 1 in children) indicate a survival advantage for patients receiving hydroxyurea.28,36,49 

The strength of the evidence and serious consequences of frequent VOC or ACS provide the basis for our strong recommendations for hydroxyurea use in treating adults and children with SCA for these indications. There are no phase 3 RCTs enrolling patients with genotypes other than HbSS and HbSβ0-thalassemia. Evidence from cohort studies of patients from Greece and Italy with HbSβ+-thalassemia extend the findings for SCA to this population; however, the recommendation to use hydroxyurea is weak based on a relatively small sample size compared with data on SCA.30,36  Furthermore, in the Greek cohort, the majority of patients had the IVSI-110 mutation, which is associated with more severe disease than those of African ancestry with HbSβ+-thalassemia.36  The recommendation to use hydroxyurea treatment in asymptomatic children with SCA is based on secondary outcomes of BABY HUG and safety data from previously reported and currently cited studies.8,15  In those children and adults who have experienced prior stroke or children at risk of initial stroke based on elevated TCD velocity, chronic blood transfusion is the standard of care to prevent recurrence or initial stroke.54  Findings from the SWiTCH trial add support to this recommendation. The upcoming TCD with Transfusions Changing to Hydroxyurea (TWiTCH) study is a National Heart Lung and Blood Institute (NHLBI)-sponsored, phase 3, multicenter trial that will compare monthly transfusions, the current established treatment, to daily hydroxyurea to reduce the risk of primary stroke in children with SCA and abnormal TCD velocities.55  However, in circumstances where transfusion is not available or is contraindicated, lower-quality evidence suggests use of hydroxyurea rather than no therapy.21,25  For patients with HbSC, the paucity of clinical data despite encouraging laboratory findings with hydroxyurea, does not allow us to make a recommendation for or against treatment in any clinical scenario.41 

Two sets of clinical guidelines published in 2014 address the use of hydroxyurea in SCD.56,57  Our recommendations for hydroxyurea therapy are generally aligned with those presented in the NHLBI-sponsored Evidence-Based Management of Sickle Cell Disease Expert Panel Report.56  The American Thoracic Society guidelines on the management of pulmonary hypertension in SCD recommend hydroxyurea for patients identified as being at increased risk for mortality.57  The risk assessment includes elevated tricuspid regurgitation jet velocity, elevated brain natriuretic peptide, or documented pulmonary hypertension. We found no direct evidence for the efficacy of hydroxyurea for these particular indications.

Hydroxyurea is currently the only US Food and Drug Administration–approved medication to modify the disease course in SCD. Studies reviewed herein provide increasing support of efficacy, effectiveness, and safety in both children and adults, yet indicate serious underuse for indications with the strongest evidence.8,9,58,59  Although data on toxicity associated with hydroxyurea therapy in SCD from our review are derived from case reports or series and clinical studies where toxicities were not systematically assessed, findings are consistent with the assessment in the AHRQ review.8  To highlight an example, the consideration of malignancy associated with hydroxyurea has been identified as a potential barrier to its use.60,61  The identification of 3 additional case reports of hematologic malignancies given the substantial increase in patient-years of exposure based on inclusion of more recent studies and ex vivo investigations does not provide adequate evidence of this increased risk. The decision to start hydroxyurea can be effectively based on patient and family preferences after discussing benefits and risks in the context of assuring a clear understanding of the significant burden of disease and early mortality associated with SCD.

Cases revisited

In cases 1 and 2 we recommend and in case 3 we suggest hydroxyurea therapy.

The online version of this article contains a data supplement.

Acknowledgments

The authors thank George Buchanan, Joylene John-Sowah, Craig Kitchens, Abdullah Kutlar, Merry Jennifer Markham, Anita Rajasekhar, Lisa Richardson, Barbara Yawn, and Marc Zumberg for reviewing the manuscript and providing recommendations. R.L. was a panel member on the NHLBI-sponsored Evidence-Based Management of Sickle Cell Disease Expert Panel Report.

Authorship

Contribution: T.E.W. reviewed the articles, developed outcome tables, performed data extraction and quality assessments, analyzed the data, and wrote the manuscript; A.M.B. performed the article search, reviewed the articles, developed outcome tables, performed data extraction and quality assessments, analyzed the data, and wrote the manuscript; W.L. designed the study, performed the article search, developed outcome tables, analyzed the data, and wrote the manuscript; and R.L. conceived the study, developed outcome tables, performed data extraction and quality assessments, analyzed the data, and wrote the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Richard Lottenberg, Division of Hematology/Oncology, Department of Medicine, University of Florida, Box 100278, Gainesville, FL 32610-0278; e-mail: lottenr@medicine.ufl.edu.

References

References
1
Platt
 
OS
Thorington
 
BD
Brambilla
 
DJ
, et al. 
Pain in sickle cell disease. Rates and risk factors.
N Engl J Med
1991
, vol. 
325
 
1
(pg. 
11
-
16
)
2
Powars
 
DR
Weiss
 
JN
Chan
 
LS
Schroeder
 
WA
Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia?
Blood
1984
, vol. 
63
 
4
(pg. 
921
-
926
)
3
Platt
 
OS
Orkin
 
SH
Dover
 
G
Beardsley
 
GP
Miller
 
B
Nathan
 
DG
Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia.
J Clin Invest
1984
, vol. 
74
 
2
(pg. 
652
-
656
)
4
Charache
 
S
Dover
 
GJ
Moore
 
RD
, et al. 
Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia.
Blood
1992
, vol. 
79
 
10
(pg. 
2555
-
2565
)
5
Rodgers
 
GP
Dover
 
GJ
Noguchi
 
CT
Schechter
 
AN
Nienhuis
 
AW
Hematologic responses of patients with sickle cell disease to treatment with hydroxyurea.
N Engl J Med
1990
, vol. 
322
 
15
(pg. 
1037
-
1045
)
6
Charache
 
S
Terrin
 
ML
Moore
 
RD
, et al. 
Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia
Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia.
N Engl J Med
1995
, vol. 
332
 
20
(pg. 
1317
-
1322
)
7
European Medicines Agency Pre-authorisation Evaluation of Medicines for Human Use
 
8
Segal
 
JB
Strouse
 
JJ
Beach
 
MC
, et al. 
Hydroxyurea for the treatment of sickle cell disease.
Evid Rep Technol Assess (Full Rep)
2008
165
(pg. 
1
-
95
)
9
Brawley
 
OW
Cornelius
 
LJ
Edwards
 
LR
, et al. 
National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease.
Ann Intern Med
2008
, vol. 
148
 
12
(pg. 
932
-
938
)
10
Jadad
 
AR
Moore
 
RA
Carroll
 
D
, et al. 
Assessing the quality of reports of randomized clinical trials: is blinding necessary?
Control Clin Trials
1996
, vol. 
17
 
1
(pg. 
1
-
12
)
11
Wells
 
GS
 
B; O'Connell, D.; et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of non randomized studies in meta-analysis. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed July 23, 2014
12
Stang
 
A
Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.
Eur J Epidemiol
2010
, vol. 
25
 
9
(pg. 
603
-
605
)
13
Higgins
 
JPT
 
Green, S. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0, Part 14.6.3. http://handbook.cochrane.org/. Accessed July 23, 2014
14
Guyatt
 
GH
Oxman
 
AD
Vist
 
GE
, et al. 
GRADE Working Group
GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
BMJ
2008
, vol. 
336
 
7650
(pg. 
924
-
926
)
15
Wang
 
WC
Ware
 
RE
Miller
 
ST
, et al. 
BABY HUG investigators
Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG).
Lancet
2011
, vol. 
377
 
9778
(pg. 
1663
-
1672
)
16
Alvarez
 
O
Miller
 
ST
Wang
 
WC
, et al. 
BABY HUG Investigators
Effect of hydroxyurea treatment on renal function parameters: results from the multi-center placebo-controlled BABY HUG clinical trial for infants with sickle cell anemia.
Pediatr Blood Cancer
2012
, vol. 
59
 
4
(pg. 
668
-
674
)
17
Lebensburger
 
J
Johnson
 
SM
Askenazi
 
DJ
Rozario
 
NL
Howard
 
TH
Hilliard
 
LM
Protective role of hemoglobin and fetal hemoglobin in early kidney disease for children with sickle cell anemia.
Am J Hematol
2011
, vol. 
86
 
5
(pg. 
430
-
432
)
18
McGann
 
PT
Flanagan
 
JM
Howard
 
TA
, et al. 
BABY HUG Investigators
Genotoxicity associated with hydroxyurea exposure in infants with sickle cell anemia: results from the BABY-HUG Phase III Clinical Trial.
Pediatr Blood Cancer
2012
, vol. 
59
 
2
(pg. 
254
-
257
)
19
Wang
 
WC
Oyeku
 
SO
Luo
 
Z
, et al. 
BABY HUG Investigators
Hydroxyurea is associated with lower costs of care of young children with sickle cell anemia.
Pediatrics
2013
, vol. 
132
 
4
(pg. 
677
-
683
)
20
Thornburg
 
CD
Files
 
BA
Luo
 
Z
, et al. 
BABY HUG Investigators
Impact of hydroxyurea on clinical events in the BABY HUG trial.
Blood
2012
, vol. 
120
 
22
(pg. 
4304
-
4310, quiz 4448
)
21
Ali
 
SB
Moosang
 
M
King
 
L
Knight-Madden
 
J
Reid
 
M
Stroke recurrence in children with sickle cell disease treated with hydroxyurea following first clinical stroke.
Am J Hematol
2011
, vol. 
86
 
10
(pg. 
846
-
850
)
22
Aygun
 
B
Mortier
 
NA
Smeltzer
 
MP
Shulkin
 
BL
Hankins
 
JS
Ware
 
RE
Hydroxyurea treatment decreases glomerular hyperfiltration in children with sickle cell anemia.
Am J Hematol
2013
, vol. 
88
 
2
(pg. 
116
-
119
)
23
Estepp
 
JH
Smeltzer
 
MP
Wang
 
WC
Hoehn
 
ME
Hankins
 
JS
Aygun
 
B
Protection from sickle cell retinopathy is associated with elevated HbF levels and hydroxycarbamide use in children.
Br J Haematol
2013
, vol. 
161
 
3
(pg. 
402
-
405
)
24
Gilmore
 
A
Cho
 
G
Howard
 
J
, et al. 
North West London Haemoglobinopathy Registry Group
Feasibility and benefit of hydroxycarbamide as a long-term treatment for sickle cell disease patients: results from the North West London Sickle Cell Disease Registry.
Am J Hematol
2011
, vol. 
86
 
11
(pg. 
958
-
961
)
25
Greenway
 
A
Ware
 
RE
Thornburg
 
CD
Long-term results using hydroxyurea/phlebotomy for reducing secondary stroke risk in children with sickle cell anemia and iron overload.
Am J Hematol
2011
, vol. 
86
 
4
(pg. 
357
-
361
)
26
Hankins
 
JS
Helton
 
KJ
McCarville
 
MB
Li
 
CS
Wang
 
WC
Ware
 
RE
Preservation of spleen and brain function in children with sickle cell anemia treated with hydroxyurea.
Pediatr Blood Cancer
2008
, vol. 
50
 
2
(pg. 
293
-
297
)
27
Hayashi
 
M
Calatroni
 
A
Herzberg
 
B
Ross
 
AK
Rice
 
HE
Thornburg
 
C
Impact of hydroxyurea on perioperative management and outcomes in children with sickle cell anemia.
J Pediatr Hematol Oncol
2011
, vol. 
33
 
7
(pg. 
487
-
490
)
28
Lobo
 
CL
Pinto
 
JF
Nascimento
 
EM
Moura
 
PG
Cardoso
 
GP
Hankins
 
JS
The effect of hydroxcarbamide therapy on survival of children with sickle cell disease.
Br J Haematol
2013
, vol. 
161
 
6
(pg. 
852
-
860
)
29
McGann
 
PT
Howard
 
TA
Flanagan
 
JM
Lahti
 
JM
Ware
 
RE
Chromosome damage and repair in children with sickle cell anaemia and long-term hydroxycarbamide exposure.
Br J Haematol
2011
, vol. 
154
 
1
(pg. 
134
-
140
)
30
Rigano
 
P
Pecoraro
 
A
Calvaruso
 
G
Steinberg
 
MH
Iannello
 
S
Maggio
 
A
Cerebrovascular events in sickle cell-beta thalassemia treated with hydroxyurea: a single center prospective survey in adult Italians.
Am J Hematol
2013
, vol. 
88
 
11
(pg. 
E261
-
E264
)
31
Ware
 
RE
Helms
 
RW
SWiTCH Investigators
Stroke With Transfusions Changing to Hydroxyurea (SWiTCH).
Blood
2012
, vol. 
119
 
17
(pg. 
3925
-
3932
)
32
Zimmerman
 
SA
Schultz
 
WH
Burgett
 
S
Mortier
 
NA
Ware
 
RE
Hydroxyurea therapy lowers transcranial Doppler flow velocities in children with sickle cell anemia.
Blood
2007
, vol. 
110
 
3
(pg. 
1043
-
1047
)
33
McKie
 
KT
Hanevold
 
CD
Hernandez
 
C
Waller
 
JL
Ortiz
 
L
McKie
 
KM
Prevalence, prevention, and treatment of microalbuminuria and proteinuria in children with sickle cell disease.
J Pediatr Hematol Oncol
2007
, vol. 
29
 
3
(pg. 
140
-
144
)
34
Sharef
 
SW
Al-Hajri
 
M
Beshlawi
 
I
, et al. 
Optimizing Hydroxyurea use in children with sickle cell disease: low dose regimen is effective.
Eur J Haematol
2013
, vol. 
90
 
6
(pg. 
519
-
524
)
35
Singh
 
H
Dulhani
 
N
Kumar
 
BN
Singh
 
P
Tiwari
 
P
Effective control of sickle cell disease with hydroxyurea therapy.
Indian J Pharmacol
2010
, vol. 
42
 
1
(pg. 
32
-
35
)
36
Voskaridou
 
E
Christoulas
 
D
Bilalis
 
A
, et al. 
The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS).
Blood
2010
, vol. 
115
 
12
(pg. 
2354
-
2363
)
37
Wali
 
YA
Moheeb
 
H
Effect of hydroxyurea on physical fitness indices in children with sickle cell anemia.
Pediatr Hematol Oncol
2011
, vol. 
28
 
1
(pg. 
43
-
50
)
38
Italia
 
K
Jain
 
D
Gattani
 
S
, et al. 
Hydroxyurea in sickle cell disease—a study of clinico-pharmacological efficacy in the Indian haplotype.
Blood Cells Mol Dis
2009
, vol. 
42
 
1
(pg. 
25
-
31
)
39
Jain
 
DL
Sarathi
 
V
Desai
 
S
Bhatnagar
 
M
Lodha
 
A
Low fixed-dose hydroxyurea in severely affected Indian children with sickle cell disease.
Hemoglobin
2012
, vol. 
36
 
4
(pg. 
323
-
332
)
40
Patel
 
DK
Mashon
 
RS
Patel
 
S
Das
 
BS
Purohit
 
P
Bishwal
 
SC
Low dose hydroxyurea is effective in reducing the incidence of painful crisis and frequency of blood transfusion in sickle cell anemia patients from eastern India.
Hemoglobin
2012
, vol. 
36
 
5
(pg. 
409
-
420
)
41
Wang
 
W
Brugnara
 
C
Snyder
 
C
, et al. 
The effects of hydroxycarbamide and magnesium on haemoglobin SC disease: results of the multi-centre CHAMPS trial.
Br J Haematol
2011
, vol. 
152
 
6
(pg. 
771
-
776
)
42
Gordeuk
 
VR
Campbell
 
A
Rana
 
S
, et al. 
Relationship of erythropoietin, fetal hemoglobin, and hydroxyurea treatment to tricuspid regurgitation velocity in children with sickle cell disease.
Blood
2009
, vol. 
114
 
21
(pg. 
4639
-
4644
)
43
Nzouakou
 
R
Bachir
 
D
Lavaud
 
A
, et al. 
Clinical follow-up of hydroxyurea-treated adults with sickle cell disease.
Acta Haematol
2011
, vol. 
125
 
3
(pg. 
145
-
152
)
44
Stallworth
 
JR
Jerrell
 
JM
Tripathi
 
A
Cost-effectiveness of hydroxyurea in reducing the frequency of pain episodes and hospitalization in pediatric sickle cell disease.
Am J Hematol
2010
, vol. 
85
 
10
(pg. 
795
-
797
)
45
Tripathi
 
A
Jerrell
 
JM
Stallworth
 
JR
Clinical complications in severe pediatric sickle cell disease and the impact of hydroxyurea.
Pediatr Blood Cancer
2011
, vol. 
56
 
1
(pg. 
90
-
94
)
46
Alvarez
 
O
Yovetich
 
NA
Scott
 
JP
, et al. 
Investigators of the Stroke With Transfusions Changing to Hydroxyurea Clinical Trial (SWiTCH)
Pain and other non-neurological adverse events in children with sickle cell anemia and previous stroke who received hydroxyurea and phlebotomy or chronic transfusions and chelation: results from the SWiTCH clinical trial.
Am J Hematol
2013
, vol. 
88
 
11
(pg. 
932
-
938
)
47
Berthaut
 
I
Guignedoux
 
G
Kirsch-Noir
 
F
, et al. 
Influence of sickle cell disease and treatment with hydroxyurea on sperm parameters and fertility of human males.
Haematologica
2008
, vol. 
93
 
7
(pg. 
988
-
993
)
48
Ballas
 
SK
McCarthy
 
WF
Guo
 
N
, et al. 
Multicenter Study of Hydroxyurea in Sickle Cell Anemia
Exposure to hydroxyurea and pregnancy outcomes in patients with sickle cell anemia.
J Natl Med Assoc
2009
, vol. 
101
 
10
(pg. 
1046
-
1051
)
49
Steinberg
 
MH
McCarthy
 
WF
Castro
 
O
, et al. 
Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia and MSH Patients’ Follow-Up
The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up.
Am J Hematol
2010
, vol. 
85
 
6
(pg. 
403
-
408
)
50
Baz
 
W
Najfeld
 
V
Yotsuya
 
M
Talwar
 
J
Terjanian
 
T
Forte
 
F
Development of myelodysplastic syndrome and acute myeloid leukemia 15 years after hydroxyurea use in a patient with sickle cell anemia.
Clin Med Insights Oncol
2012
, vol. 
6
 (pg. 
149
-
152
)
51
Couronné
 
L
Schneider
 
P
de Montalembert
 
M
Dumesnil
 
C
Lahary
 
A
Vannier
 
JP
Hodgkin lymphoma in a sickle cell anaemia child treated with hydroxyurea.
Ann Hematol
2009
, vol. 
88
 
6
(pg. 
597
-
598
)
52
Taylor
 
JG
Darbari
 
DS
Maric
 
I
McIver
 
Z
Arthur
 
DC
Therapy-related acute myelogenous leukemia in a hydroxyurea-treated patient with sickle cell anemia.
Ann Intern Med
2011
, vol. 
155
 
10
(pg. 
722
-
724
)
53
Ferster
 
A
Vermylen
 
C
Cornu
 
G
, et al. 
Hydroxyurea for treatment of severe sickle cell anemia: a pediatric clinical trial.
Blood
1996
, vol. 
88
 
6
(pg. 
1960
-
1964
)
54
DeBaun
 
MR
 
Secondary prevention of overt strokes in sickle cell disease: therapeutic strategies and efficacy. Hematology Am Soc Hematol Educ Program. 2011;2011:427-433
55
Aygun
 
B
Wruck
 
LM
Schultz
 
WH
, et al. 
TCD With Transfusions Changing to Hydroxyurea (TWiTCH) Trial Investigators
Chronic transfusion practices for prevention of primary stroke in children with sickle cell anemia and abnormal TCD velocities.
Am J Hematol
2012
, vol. 
87
 
4
(pg. 
428
-
430
)
56
National Institutes of Health. Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014. Available at: http://www.nhlbi.nih.gov/health-pro/guidelines/sickle-cell-disease-guidelines/. Accessed September 17, 2014
57
Klings
 
ES
Machado
 
RF
Barst
 
RJ
, et al. 
American Thoracic Society Ad Hoc Committee on Pulmonary Hypertension of Sickle Cell Disease
An official American Thoracic Society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease.
Am J Respir Crit Care Med
2014
, vol. 
189
 
6
(pg. 
727
-
740
)
58
Candrilli
 
SD
O’Brien
 
SH
Ware
 
RE
Nahata
 
MC
Seiber
 
EE
Balkrishnan
 
R
Hydroxyurea adherence and associated outcomes among Medicaid enrollees with sickle cell disease.
Am J Hematol
2011
, vol. 
86
 
3
(pg. 
273
-
277
)
59
Lanzkron
 
S
Haywood
 
C
Fagan
 
PJ
Rand
 
CS
Examining the effectiveness of hydroxyurea in people with sickle cell disease.
J Health Care Poor Underserved
2010
, vol. 
21
 
1
(pg. 
277
-
286
)
60
Lanzkron
 
S
Haywood
 
C
Hassell
 
KL
Rand
 
C
Provider barriers to hydroxyurea use in adults with sickle cell disease: a survey of the Sickle Cell Disease Adult Provider Network.
J Natl Med Assoc
2008
, vol. 
100
 
8
(pg. 
968
-
973
)
61
Zumberg
 
MS
Reddy
 
S
Boyette
 
RL
Schwartz
 
RJ
Konrad
 
TR
Lottenberg
 
R
Hydroxyurea therapy for sickle cell disease in community-based practices: a survey of Florida and North Carolina hematologists/oncologists.
Am J Hematol
2005
, vol. 
79
 
2
(pg. 
107
-
113
)
62
Puffer
 
E
Schatz
 
J
Roberts
 
CW
The association of oral hydroxyurea therapy with improved cognitive functioning in sickle cell disease.
Child Neuropsychol
2007
, vol. 
13
 
2
(pg. 
142
-
154
)
63
Thornburg
 
CD
Calatroni
 
A
Panepinto
 
JA
Differences in health-related quality of life in children with sickle cell disease receiving hydroxyurea.
J Pediatr Hematol Oncol
2011
, vol. 
33
 
4
(pg. 
251
-
254
)