What is the primary target for management in polycythemia vera, hematocrit (Hct) or hemoglobin (Hb) levels?

Hematocrit is the Primary Target for Management in Polycythemia Vera

The primary target for management in polycythemia vera is hematocrit (Hct), which must be maintained strictly below 45% through therapeutic phlebotomy, as this target has been definitively proven to reduce cardiovascular death and major thrombotic events. 1

Evidence Supporting Hematocrit as the Primary Target

The landmark CYTO-PV randomized controlled trial provides the strongest evidence for hematocrit-based management. This study randomized 365 patients with polycythemia vera to either intensive treatment (target hematocrit <45%) or less intensive treatment (target hematocrit 45-50%). 1 The results were striking:

• Patients maintaining hematocrit <45% had a 74% reduction in the composite endpoint of cardiovascular death and major thrombotic events (2.7% vs 9.8%, hazard ratio 3.91,95% CI 1.45-10.53, P=0.007). 1
• When including superficial vein thrombosis, the benefit remained significant (4.4% vs 10.9%, hazard ratio 2.69, P=0.02). 1

This evidence has been incorporated into all major guidelines:

• The National Comprehensive Cancer Network recommends phlebotomy to maintain hematocrit <45% for all patients with polycythemia vera, regardless of risk category. 2, 3
• The European Society for Medical Oncology recommends the same hematocrit target based on the CYTO-PV study. 3
• The Mayo Clinic Proceedings emphasizes that aggressive phlebotomy to maintain hematocrit <45% has improved median survival to >10 years compared to <4 years historically with inadequate phlebotomy. 2

Why Hematocrit Rather Than Hemoglobin?

Hematocrit is the preferred monitoring parameter because it directly reflects blood viscosity and thrombotic risk, and all major clinical trials establishing treatment targets have used hematocrit rather than hemoglobin. 2, 1

• The CYTO-PV trial, which established the <45% target, specifically measured and targeted hematocrit levels. 1
• Historical studies demonstrating progressive increase in vascular occlusive episodes used hematocrit thresholds (>44%). 2
• Suboptimal cerebral blood flow has been documented at hematocrit ranges of 46-52%, not hemoglobin ranges. 2

Practical Implementation Algorithm

For All Patients with Polycythemia Vera:

1. Target hematocrit strictly <45% through therapeutic phlebotomy 2, 3, 1

   • Remove 300-450 mL weekly or twice weekly during induction phase until target achieved 4
   • Continue maintenance phlebotomy with same volume per session, intervals determined by hematocrit monitoring 4

2. Consider lower targets for specific populations:

   • Women: Target approximately 42% due to physiological differences 2, 3
   • African Americans: Target approximately 42% due to physiological differences 2

3. Add low-dose aspirin (81-100 mg daily) for all patients without contraindications 2, 3, 5

   • This significantly reduces cardiovascular death, myocardial infarction, stroke, and venous thromboembolism 2, 3

For High-Risk Patients (Age ≥60 years OR prior thrombosis):

1. Add cytoreductive therapy in addition to phlebotomy and aspirin 2, 3
   • First-line: Hydroxyurea (Level II, A evidence) 2, 3
   • Alternative first-line: Interferon-α (particularly for patients <40 years, pregnant patients, or those with pruritus) 3
   • Second-line: Ruxolitinib for hydroxyurea resistance/intolerance 2, 5

Critical Pitfalls to Avoid

• Do not accept hematocrit targets of 45-50% - the CYTO-PV trial definitively showed increased thrombotic risk at these levels (hazard ratio 3.91). 3, 1
• Perform phlebotomy with careful fluid replacement to prevent hypotension or fluid overload, particularly in elderly patients with cardiovascular disease. 2, 3
• Do not use hemoglobin as the primary monitoring parameter - all guideline recommendations and clinical trial evidence are based on hematocrit targets. 2, 1

Real-World Performance Gap

Despite clear evidence, real-world data reveals suboptimal hematocrit control:

• Among high-risk patients treated with phlebotomy monotherapy, 54% sometimes or always had hematocrit levels >50%. 6
• Only 36-44% of low-risk patients achieved adequate hematocrit control (<45%) at 6-12 months. 7
• This suboptimal control likely contributes to the 16% overall rate of thrombotic events observed in real-world practice. 6

These data underscore the critical importance of aggressive, consistent hematocrit monitoring and phlebotomy to maintain the <45% target established by the CYTO-PV trial. 1, 6