What are the dosing guidelines, monitoring parameters, and contraindications for hydroxyurea in sickle cell disease, polycythemia vera, and essential thrombocythemia?

Hydroxyurea: Dosing, Monitoring, and Contraindications

Hydroxyurea is first-line cytoreductive therapy for high-risk polycythemia vera and essential thrombocythemia, with standard dosing of 2 g/day (2.5 g/day if >80 kg) for at least 3 months, while in sickle cell disease, start at 10-15 mg/kg/day and escalate by 5 mg/kg every 4-6 weeks up to 25-35 mg/kg/day maximum, monitoring CBC every 2-4 weeks during titration. 1, 2

Disease-Specific Dosing Guidelines

Polycythemia Vera and Essential Thrombocythemia

Initial Dosing:

• Start hydroxyurea at 2 g/day (or 2.5 g/day in patients weighing >80 kg) 1
• Continue this dose for at least 3 months to assess response 1
• Hydroxyurea or interferon-alpha are both acceptable first-line options, though hydroxyurea should be used with caution in patients <40 years old 1

Target Goals:

• For polycythemia vera: hematocrit <45%, platelet count ≤400 × 10⁹/L, WBC count ≤10 × 10⁹/L 1
• For essential thrombocythemia: platelet count <600 × 10⁹/L 1

Sickle Cell Disease

Initial Dosing:

• Start at 10-15 mg/kg/day (lower than the traditional 15-20 mg/kg/day recommendation) 2, 3
• This lower starting dose is particularly appropriate in populations with ethnic neutropenia 3

Dose Escalation:

• Increase by 5 mg/kg every 4-6 weeks based on tolerance and response 2
• Maximum dose: 25-35 mg/kg/day 2, 4
• Most patients achieve therapeutic goals (Hb ≥9 g/dL, HbF ≥20%) at doses below the maximum 2

Important Note: Low-dose regimens (10-15.9 mg/kg/day) demonstrate equivalent efficacy to higher doses (16-26 mg/kg/day) for reducing vaso-occlusive crises while maintaining better safety profiles 3, 5

Monitoring Parameters

Hematologic Monitoring Schedule

During Dose Titration:

• CBC with reticulocyte count every 2-4 weeks 2, 6
• Weekly CBC until stable dose achieved 2, 6

After Stable Dose Established:

• CBC every 1-3 months for myeloproliferative neoplasms 2, 6
• CBC every 8-12 weeks for sickle cell disease 6

Additional Laboratory Tests:

• Renal function (BUN, creatinine) periodically 2, 6
• Hepatic enzymes periodically 2
• Serum uric acid (may rise with toxicity) 6

Physical Examination

• Biannual examination focusing on lymph nodes and skin cancer surveillance 2, 6
• Monitor for mucocutaneous toxicities including leg ulcers 2, 6

Response Assessment

• Assess response at 3 months to determine if resistance/intolerance criteria are met 1, 2

Mandatory Discontinuation Thresholds

Immediate discontinuation required if ANY of the following occur:

Hematologic Toxicity

• Absolute neutrophil count <1.0 × 10⁹/L 1, 6, 4
• Platelet count <100 × 10⁹/L (polycythemia vera) or <50 × 10⁹/L (myelofibrosis) 1, 6
• Hemoglobin <10 g/dL 1, 6, 4

Critical Pitfall: These cytopenias can develop at the lowest dose required for therapeutic response, defining hydroxyurea intolerance 1

Mucocutaneous Toxicity

• Leg ulcers or other unacceptable mucocutaneous manifestations 1, 2
• Oral or skin ulcers 2

Systemic Toxicity

• Drug-induced fever (>39°C/102°F) 1, 2
• Pneumonitis or interstitial lung disease 2, 4
• Severe gastrointestinal symptoms 1

Resistance/Intolerance Criteria

Polycythemia Vera (any ONE criterion defines resistance/intolerance):

1. Need for phlebotomy to maintain hematocrit <45% after 3 months of ≥2 g/day 1
2. Uncontrolled myeloproliferation (platelet count >400 × 10⁹/L AND WBC >10 × 10⁹/L) after 3 months of ≥2 g/day 1
3. Failure to reduce massive splenomegaly (>10 cm from costal margin) by >50% or relieve splenomegaly symptoms after 3 months of ≥2 g/day 1
4. Development of cytopenias at the lowest effective dose 1
5. Unacceptable nonhematologic toxicities at any dose 1

Essential Thrombocythemia (any ONE criterion):

1. Platelet count >600 × 10⁹/L after 3 months of ≥2 g/day (2.5 g/day if >80 kg) 1
2. Platelet count >400 × 10⁹/L with hemoglobin <10 g/dL at any dose 1
3. Platelet count >400 × 10⁹/L with ANC <1.0 × 10⁹/L at any dose 1
4. Mucocutaneous manifestations or fever at any dose 1

When resistance/intolerance occurs: Consider interferon-alpha or ruxolitinib as second-line therapy 1, 7

Contraindications

Absolute Contraindications

• Previous hypersensitivity to hydroxyurea or any formulation component 4
• Markedly depressed bone marrow function 4

Relative Contraindications and Precautions

Pregnancy and Lactation:

• Hydroxyurea causes fetal harm; advise effective contraception 4
• Advise women not to breastfeed 4

Age Considerations:

• Use with caution in patients <40 years old due to potential long-term leukemogenic risk 1
• Elderly patients (>70 years) may require lower doses and closer renal function monitoring 4

Renal Impairment:

• Reduce dose by 50% if creatinine clearance <60 mL/min 4

Drug Interactions:

• Avoid live vaccines in patients taking hydroxyurea 4
• Monitor closely for pancreatitis, hepatotoxicity, and neuropathy in HIV patients on antiretroviral drugs 4

Prior Radiation:

• Monitor for radiation recall (skin erythema) in patients with previous radiation exposure 4

Management of Toxicity

After Discontinuation for Cytopenias:

• Bone marrow suppression is typically reversible within approximately 2 weeks 6
• Once recovered (hemoglobin >10 g/dL and resolution of other cytopenias), may re-initiate at 25-50% lower dose 6

Hydration Requirements:

• Ensure adequate daily hydration (2.5-3 L) to minimize hyperuricemia 2
• Consider sodium bicarbonate to adjust urine pH to 6.4-6.8 for uric acid excretion 2

Special Considerations:

• Discontinue at least 72 hours before any planned CAR-T cell infusion 2
• If hemolysis suspected (not just marrow suppression), evaluate with LDH, haptoglobin, indirect bilirubin, and Coombs test 6

Post-Splenectomy Patients

Specific Indications:

• Hydroxyurea is first-line for managing severe thrombocytosis and leukocytosis post-splenectomy 7
• Initiate when platelet counts exceed 400-600 × 10⁹/L or when symptomatic complications arise 7
• Prophylactic cytoreduction before splenectomy with platelets maintained <400 × 10⁹/L prevents postoperative extreme thrombocytosis 7