What is the management of Myeloproliferative Neoplasms (MPN) with hydroxyurea?

Management of Myeloproliferative Neoplasms (MPN) with Hydroxyurea

Hydroxyurea is the first-line cytoreductive therapy for high-risk patients with polycythemia vera (PV) and essential thrombocythemia (ET), targeting platelet counts below 400 × 10⁹/L and reducing thrombotic complications. 1, 2

Risk Stratification and Indications for Hydroxyurea

High-risk patients requiring cytoreductive therapy include:

• Age ≥60 years 1, 3
• History of thrombosis or major hemorrhagic complications 1, 3
• Platelet count >1,500 × 10⁹/L (bleeding risk) 1, 2
• Progressive splenomegaly or uncontrolled disease-related symptoms 1
• Poorly tolerated phlebotomy regimen in PV 1

Low-risk patients (age <60 years, no thrombosis history) should receive aspirin and phlebotomy only, without cytoreductive therapy unless they develop complications. 3

Dosing and Administration

Initial dosing:

• Standard dose: 2 g/day for at least 3 months 1
• Patients >80 kg: 2.5 g/day 1, 2
• Base dosing on actual or ideal weight, whichever is less 4

Renal impairment adjustments:

• Creatinine clearance <60 mL/min or ESRD: reduce dose by 50% (7.5 mg/kg once daily) 4
• Administer after hemodialysis on dialysis days 4

Administration:

• Swallow capsules whole; do NOT open, break, or chew 4
• Prophylactic folic acid is recommended 4

Monitoring Response

Target therapeutic goals:

• Platelet count <400 × 10⁹/L 1, 2, 3
• WBC count <10 × 10⁹/L 1, 2
• Hematocrit <45% without phlebotomy (for PV) 1, 3
• Resolution of disease-related symptoms 2

Monitoring schedule:

• Blood counts at least weekly initially 4
• Every 4-8 weeks once stabilized 2
• No routine bone marrow monitoring needed for clinical follow-up 1, 2
• Bone marrow examination only indicated when assessing transformation to myelofibrosis or acute leukemia 2

Resistance and Intolerance Criteria

For Essential Thrombocythemia, resistance/intolerance is defined as:

• 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
• Leg ulcers or unacceptable mucocutaneous manifestations at any dose 1, 2
• Hydroxyurea-related fever 1

For Polycythemia Vera, resistance/intolerance is defined as:

• 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 1
• Failure to reduce massive splenomegaly by >50% after 3 months 1
• ANC <1.0 × 10⁹/L OR platelet count <100 × 10⁹/L OR hemoglobin <10 g/dL at lowest effective dose 1, 5
• Leg ulcers or unacceptable nonhematologic toxicities (mucocutaneous manifestations, GI symptoms, pneumonitis, fever) 1

Second-Line Therapy Options

When hydroxyurea fails or is not tolerated:

• For PV: Interferon-alpha is the preferred second-line agent due to non-leukemogenic properties 1, 2
• For ET: Anagrelide is the recommended second-line therapy 2
• For both: Ruxolitinib may be considered for resistant/intolerant cases 2
• Pipobroman, busulfan, and ³²P are reserved for elderly patients with short life expectancy 1

Critical Safety Considerations

Use with extreme caution in young patients (<40 years) due to long-term leukemogenic risk; interferon-alpha should be strongly considered instead. 1, 2, 3

Major toxicities requiring monitoring:

• Myelosuppression: Monitor blood counts weekly initially; dose reduce or discontinue if severe 4
• Secondary malignancies: Hydroxyurea is a human carcinogen; secondary leukemia and skin cancer reported with long-term use 4
• Cutaneous vasculitic toxicities: Including leg ulcers and gangrene; discontinue if these occur 4
• Pulmonary toxicity: Interstitial lung disease, pneumonitis, pulmonary fibrosis (including fatal cases); discontinue and treat with corticosteroids 4
• Macrocytosis: Self-limiting but may mask pernicious anemia; prophylactic folic acid recommended 4

Avoid live vaccines during hydroxyurea therapy due to immunosuppression. 4

Pregnancy: Hydroxyurea is teratogenic; use effective contraception (females: 6 months after therapy; males: 1 year after therapy). 4

Drug interactions: Pancreatitis, hepatotoxicity, and peripheral neuropathy reported with antiretroviral drugs (didanosine, stavudine). 4

Adjunctive Management

All MPN patients should receive:

• Low-dose aspirin (81-100 mg/day) unless contraindicated by major bleeding 1, 3
• Aggressive cardiovascular risk factor management 1, 3
• Smoking cessation counseling 1

Common pitfall: The European LeukemiaNet guidelines emphasize that approximately 5% of MPN patients develop clinically significant hydroxyurea-related toxicities, which are often underestimated and underdiagnosed in clinical practice. 6, 7 Vigilant monitoring for cutaneous adverse events is essential, as these may necessitate therapy change despite adequate disease control.