Hydroxyurea Treatment for Young Adults with Sickle Cell Disease
Recommended Treatment Approach
Young adults with sickle cell disease should be treated with hydroxyurea as lifelong therapy, starting at 15-20 mg/kg/day orally once daily, with dose escalation to a maximum tolerated dose of 20-35 mg/kg/day, and continued indefinitely as mortality benefits only emerge after at least 5 years of continuous treatment. 1, 2
Initial Dosing and Titration
- Start hydroxyurea at 15-20 mg/kg/day as a single daily oral dose 1
- Titrate upward to achieve maximum tolerated dose (MTD) of 20-35 mg/kg/day based on hematologic response and tolerance 1
- Most patients reach MTD at 25-30 mg/kg/day, where they achieve key laboratory thresholds (Hb ≥9 g/dL and HbF ≥20%) without excessive myelosuppression 3
- Hydroxyurea is available as capsules, rapid-dissolving tablets, or liquid formulations 1, 4
Monitoring Requirements
- During initial dose titration: Monitor CBC with reticulocyte count every 2-4 weeks 4
- Once on stable dose: Monitor CBC with reticulocyte count every 1-3 months depending on duration of therapy and dose stability 4
- Target laboratory parameters: Hemoglobin ≥9 g/dL and HbF ≥20% 3
Managing Toxicity
- Myelosuppression is the primary dose-limiting toxicity but typically resolves within 2 weeks of temporary discontinuation 5, 1, 4
- If severe myelosuppression occurs (decrease in one or more cell lines), temporarily suspend hydroxyurea 1
- After resolution, resume therapy at a lower dose 5, 4
- Severe neutropenia (ANC <500/mm³) is rare and has not been complicated by infection in clinical trials 1
Special Considerations for Renal Impairment
- Reduce hydroxyurea dose by 50% in patients with creatinine clearance <60 mL/min 6
- Hydroxyurea exposure (AUC) is 64% higher in patients with CrCl <60 mL/min compared to normal renal function 6
- Also reduce dose by 50% in patients with ESRD following hemodialysis 6
Duration of Treatment: Critical for Mortality Benefit
- Hydroxyurea must be continued indefinitely as lifelong therapy 2
- Mortality benefits only emerge after prolonged treatment:
- Critical pitfall: Do not discontinue hydroxyurea after short-term use based on clinical improvement alone, as mortality benefit only becomes apparent with prolonged therapy 2
Expected Clinical Benefits
- Reduces vaso-occlusive pain crises, acute chest syndrome, hospitalizations, and transfusion requirements by approximately 50% 1
- Median annual crisis rate decreases from 4.5 to 2.5 crises per year 7
- Time to first crisis extends from 1.5 to 3.0 months 7
- Improves quality of life measures including social function and general health perception 5
Long-Term Safety Profile
- No increased risk of birth defects, infections, stroke, or neoplasia in long-term follow-up studies 5, 1, 4
- Three cases of cancer reported in the MSH trial cohort over 17 years, with one fatal 8
- No increases in stroke, myelodysplasia, or carcinogenicity detected in SCA patient cohorts with drug exposure reaching 15 years 3
Important Drug Interactions and Precautions
- Do not suspend hydroxyurea when initiating doxycycline or other antibiotics 1
- Avoid live vaccines in patients taking hydroxyurea 6
- In patients with HIV on antiretroviral drugs, monitor for pancreatitis, hepatotoxicity, and neuropathy 6
- Advise sun protection and monitor for secondary malignancies 6
Contraindications
- Previous hypersensitivity to hydroxyurea or any component of its formulation 6
- Markedly depressed bone marrow function 6