Treatment Duration for Hydroxyurea in Sickle Cell Disease
Hydroxyurea should be continued indefinitely as lifelong therapy in patients with sickle cell disease, as mortality benefits only emerge after at least 5 years of continuous treatment. 1
Critical Evidence on Duration and Mortality
The landmark Multicenter Study of Hydroxyurea (MSH) trial and its long-term extension studies provide the strongest evidence regarding treatment duration:
At 9 years of follow-up, patients who received hydroxyurea for at least 1 year had significantly reduced mortality compared to those who received it for less than 1 year or not at all (21% vs. 36.3% mortality; RR 0.58,95% CI 0.39-0.85). 1
At 17 years of follow-up, the mortality benefit was even more pronounced when patients received hydroxyurea for at least 5 years compared to those who received it for less than 5 years or not at all (30.4% vs. 51.1% mortality; RR 0.60,95% CI 0.44-0.81). 1
Crucially, there was no significant mortality difference when patients who received hydroxyurea for any duration were compared with those who never received it, demonstrating that prolonged therapy is necessary to achieve clinical benefit. 1
Rationale for Indefinite Treatment
Hydroxyurea is a disease-modifying therapy, not a curative treatment, and its benefits persist only while the medication is continued:
The American Thoracic Society guidelines explicitly state that "prolonged therapy may be necessary to achieve a clinical benefit" based on the MSH extension study findings. 1
Quality of life improvements (social function and general health perception) were sustained during ongoing treatment. 1
Long-term studies spanning up to 17 years demonstrated that hydroxyurea was not associated with increased incidence of birth defects, infection, stroke, or neoplasia, supporting the safety of indefinite use. 1
Pediatric Considerations
For children with sickle cell disease, the treatment approach supports early initiation and continuation:
The 2014 National Heart, Lung, and Blood Institute guidelines recommend offering hydroxyurea to every child with HbSS or Sβ0-thalassemia starting at 9 months of age, even without clinical symptoms. 1
The BABY HUG trial demonstrated that hydroxyurea has no unique adverse effects even if initiated in early infancy and continued for more than a decade. 1
Pediatric studies with treatment durations ranging from 6 to 50 months showed sustained clinical benefits throughout the treatment period. 2, 3
Long-Term Safety Profile
Extended treatment over years to decades has established an acceptable safety profile:
A 17-year single-center trial (LaSHS) involving 131 patients on hydroxyurea with median follow-up of 8 years demonstrated 86% 10-year survival probability versus 65% in non-treated patients. 4
Bone marrow suppression is the primary adverse effect but is reversible within 2 weeks of temporary discontinuation, with therapy resumed at lower doses. 1
Monitoring with CBC and reticulocyte count every 1-3 months once on stable dose is sufficient for long-term management. 1, 5
Critical Pitfall to Avoid
Do not discontinue hydroxyurea after short-term use (less than 5 years) based on clinical improvement alone, as the mortality benefit only becomes apparent with prolonged therapy. 1 The evidence clearly shows that patients need at least 5 years of continuous treatment to achieve significant mortality reduction, and benefits continue to accrue with longer duration of therapy. 1
Special Circumstances
In patients transitioning from chronic transfusion therapy to hydroxyurea (such as in the TWiTCH trial), the transition should occur after transfusion therapy for the longest possible interval, with transfusion continued during escalation to maximum tolerated dose of hydroxyurea. 1 However, once established on hydroxyurea, the same principle of indefinite continuation applies. 1