What is the next step for a patient on hydroxyurea (hydroxycarbamide) with persistently elevated platelet counts?

Management of Persistently Elevated Platelet Counts on Hydroxyurea

If platelet counts remain elevated after 3 months on hydroxyurea at ≥2 g/day (or ≥2.5 g/day if body weight >80 kg), this meets European LeukemiaNet criteria for hydroxyurea resistance, and you should switch to second-line therapy with either ruxolitinib or interferon-alpha rather than escalating the hydroxyurea dose further. 1, 2

Step 1: Confirm Hydroxyurea Resistance

First, verify that the patient meets formal criteria for hydroxyurea resistance or intolerance:

For Essential Thrombocythemia:

• Platelet count >600 × 10⁹/L after 3 months of at least 2 g/day hydroxyurea (2.5 g/day if body weight >80 kg) 1, 2
• This is the primary criterion indicating treatment failure 1

For Polycythemia Vera:

• Uncontrolled myeloproliferation defined as platelet count >400 × 10⁹/L AND white blood cell count >10 × 10⁹/L after 3 months of at least 2 g/day hydroxyurea 1
• Or need for continued phlebotomy to maintain hematocrit <45% despite adequate hydroxyurea dosing 1

For Primary Myelofibrosis:

• Uncontrolled myeloproliferation (platelet count >400 × 10⁹/L AND white blood cell count >10 × 10⁹/L) after 3 months of at least 2 g/day hydroxyurea 1

Step 2: Check for Intolerance Criteria

Before declaring resistance, ensure the patient hasn't developed intolerance that prevents adequate dosing:

• Absolute neutrophil count <1.0 × 10⁹/L at any dose 1, 2
• Platelet count <100 × 10⁹/L (for PV) or <50 × 10⁹/L (for PMF) at the lowest effective dose 1
• Hemoglobin <10 g/dL at any dose 1, 2
• Leg ulcers or mucocutaneous toxicity (rash, oral ulcers) at any dose 1, 2
• Hydroxyurea-related fever 1

If intolerance is present, this also mandates switching to alternative therapy 1, 2.

Step 3: Do Not Exceed Maximum Recommended Doses

The maximum dose of hydroxyurea is 2 g/day (or 2.5 g/day in patients >80 kg) for myeloproliferative neoplasms. 2 Further dose escalation beyond these thresholds is not recommended and increases toxicity risk without improving efficacy 2.

Step 4: Initiate Second-Line Therapy

For High-Risk Essential Thrombocythemia or Polycythemia Vera:

• Ruxolitinib (JAK1/2 inhibitor) is a guideline-recommended second-line option 2
• Interferon-alpha is an alternative second-line agent, particularly preferred in younger patients (<40 years) due to lower leukemogenic risk 2, 3

For Primary Myelofibrosis:

• Ruxolitinib is the preferred second-line therapy 2
• Interferon-alpha may be considered in selected cases 2

Historical Alternative (Less Commonly Used):

• Anagrelide has been used as an adjunctive therapy specifically for thrombocytosis in CML and essential thrombocythemia when traditional drugs fail to control platelet counts 4, 3
• However, anagrelide is generally considered after hydroxyurea failure and is more commonly used in essential thrombocythemia than other myeloproliferative neoplasms 3

Critical Monitoring During Transition

• Continue monitoring complete blood counts weekly during the transition period 1
• Assess for thrombotic or hemorrhagic complications, as uncontrolled thrombocytosis increases risk 5, 3
• In essential thrombocythemia, maintaining platelet count <600 × 10⁹/L significantly reduces thrombotic events (24% vs 3.6% in one randomized trial) 5

Common Pitfalls to Avoid

• Do not continue escalating hydroxyurea beyond 2-2.5 g/day hoping for better response—this only increases toxicity without benefit 2
• Do not delay switching therapy if formal resistance criteria are met after 3 months, as prolonged uncontrolled disease increases thrombotic risk 1, 5
• Do not overlook intolerance criteria (cytopenias, mucocutaneous toxicity) that may be limiting effective dosing 1, 2