What is the role of hydroxyurea in managing polycythemia vera?

Hydroxyurea in Polycythemia Vera

Role and Positioning

Hydroxyurea is the recommended first-line cytoreductive agent for high-risk polycythemia vera patients (age ≥60 years or history of thrombosis), with strong evidence supporting its efficacy in reducing thrombotic complications when combined with phlebotomy and low-dose aspirin. 1, 2

When to Initiate Hydroxyurea

Cytoreductive therapy with hydroxyurea should be started in the following situations:

• High-risk patients: Age ≥60 years and/or any history of thrombosis 1, 2
• Poor phlebotomy tolerance or requirement for frequent phlebotomy 1, 3
• Symptomatic or progressive splenomegaly 2, 3
• Severe disease-related symptoms 2
• Extreme thrombocytosis (platelet count >1,500 × 10⁹/L) 1, 2
• Progressive leukocytosis 2, 3

Low-risk patients (age <60 years without thrombosis history) typically require only phlebotomy and aspirin, without cytoreductive therapy. 2

Dosing and Treatment Goals

Starting dose: 500 mg twice daily orally (or 2 g/day, with 2.5 g/day if body weight >80 kg) 1, 2

Target response criteria:

• Hematocrit <45% maintained without phlebotomy 2
• Platelet count ≤400 × 10⁹/L 2
• WBC count ≤10 × 10⁹/L 2
• Time to response: approximately 3-5 days 1

Efficacy Data

Real-world evidence demonstrates that hydroxyurea effectively controls disease parameters:

• Thrombosis rates: 1.9% persons/year at age 60, increasing to 3.6% at age 70 and 6.8% at age 80 4
• Leukemic transformation: 0.4% persons/year 4
• Myelofibrosis transformation: 5.0% at 5 years, 33.7% at 10 years 4

A randomized phase 3 trial showed hydroxyurea achieved 37% complete response at 12 months, with more frequent histopathologic responses compared to interferon-α, though both agents were equally effective in preventing thrombotic events. 5

Defining Treatment Failure

Hydroxyurea resistance or intolerance is defined by the European LeukemiaNet criteria as: 1, 2

• Need for phlebotomy to maintain hematocrit <45% after 3 months of at least 2 g/day
• Uncontrolled myeloproliferation (platelet count >400 × 10⁹/L and WBC >10 × 10⁹/L) after 3 months of at least 2 g/day
• Failure to reduce massive splenomegaly by ≥50% or failure to relieve splenomegaly-related symptoms
• Cytopenia (ANC <1.0 × 10⁹/L or platelets <100 × 10⁹/L or hemoglobin <10 g/dL) at any dose
• Unacceptable mucocutaneous manifestations or other adverse effects at any dose

Approximately 15-24% of patients develop resistance or intolerance to hydroxyurea. 6, 7

Real-World Treatment Patterns and Challenges

Analysis from the REVEAL study of 1,381 patients showed significant gaps in optimal hydroxyurea management: 8

• Only 6.4% received the recommended ≥2 g/day dosing
• 57.1% had hematocrit values >45% on at least one occasion despite treatment
• 33.1% continued requiring phlebotomies
• 27.4% had uncontrolled myeloproliferation
• 18.6% discontinued hydroxyurea, most commonly due to adverse events/intolerance (37.1%) or lack of efficacy (35.5%)

This emphasizes the critical need for active dose titration rather than accepting suboptimal control. 8

Age-Specific Considerations and Cautions

Use hydroxyurea with caution in young patients (<40 years) due to potential leukemogenic risk with prolonged exposure. 1, 2 In this population, interferon-α is strongly preferred as it is non-leukemogenic and can reduce JAK2V617F allelic burden. 1, 2

For older patients (>40 years), hydroxyurea remains the first-line choice with Level II, A evidence. 1, 2

Busulfan may be considered only in very elderly patients (>70 years) as an alternative. 1, 2

Common Adverse Effects

Frequent adverse effects include: 1

• Anemia, neutropenia
• Oral and skin ulcers
• Hyperpigmentation and nail changes
• Leg ulcers (less common)
• Nausea, diarrhea, fever
• Elevated liver function tests

Second-Line Options After Hydroxyurea Failure

When hydroxyurea fails, the European LeukemiaNet guidelines recommend: 1

Ruxolitinib (strong recommendation): FDA-approved for hydroxyurea-resistant/intolerant PV, demonstrating superior hematocrit control, splenomegaly reduction, and symptom improvement in the RESPONSE trial. 1 Real-world data shows 68.2% of patients achieve hematocrit control with 92.3% maintaining hematocrit <45% at 24 months. 7

Recombinant interferon-α (appropriate alternative): Should be preferred in young patients requiring long-term treatment due to its non-leukemogenic profile and ability to reduce JAK2V617F burden. 1, 6

The choice between these agents should be based on patient age and drug availability, with interferon-α preferred for younger patients. 1

Special Populations

Pregnancy: Interferon-α is the cytoreductive agent of choice, not hydroxyurea, due to theoretical teratogenicity concerns. 1, 2

Women of childbearing age: Interferon-α is preferred over hydroxyurea. 1, 2

Intractable pruritus: Consider interferon-α as it can be particularly effective for this symptom. 1, 2

Critical Pitfalls to Avoid

• Do not accept suboptimal dosing: Many patients receive inadequate doses (<2 g/day); active titration is essential 8
• Do not accept hematocrit 45-50%: The CYTO-PV trial definitively showed increased thrombotic risk at these levels; maintain strict <45% target 2
• Do not use chlorambucil or ³²P in younger patients: These carry significantly increased leukemia risk 1, 2
• Do not continue hydroxyurea indefinitely if criteria for resistance/intolerance are met: Patients who fail hydroxyurea have increased risk of death and transformation 6

Monitoring Strategy

Monitor the following every 3-6 months in stable patients: 2

• Hematocrit levels (maintain strict <45% target)
• Complete blood count
• New thrombotic or bleeding events
• Signs/symptoms of disease progression
• Symptom burden assessment