What is the best course of treatment for a patient with a history of erythrocytosis (increased red blood cell count) for a year who now presents with new onset leukocytosis (elevated white blood cell count)?

Evaluation and Management of New-Onset Leukocytosis in a Patient with Chronic Erythrocytosis

This patient likely has polycythemia vera (PV) that is now progressing or requiring cytoreductive therapy, and you should initiate hydroxyurea as first-line treatment while maintaining phlebotomy and aspirin therapy. 1, 2, 3

Initial Diagnostic Workup

Confirm the diagnosis of PV and assess for disease progression:

• Obtain JAK2 V617F mutation testing if not previously done, as it is present in >95% of PV patients and confirms the diagnosis 3, 4
• Perform bone marrow aspirate and biopsy with morphologic examination, cytogenetics, and molecular testing to evaluate for disease progression or transformation 2, 1
• Check comprehensive metabolic panel including LDH and uric acid to assess for metabolic complications 2
• Measure platelet count to determine if thrombocytosis is also developing, which would further support PV progression 3, 5
• Assess spleen size clinically and consider imaging if splenomegaly is suspected 1, 6

The development of progressive leukocytosis in a patient with established erythrocytosis is a potential indication for cytoreductive therapy and suggests evolution of the myeloproliferative process. 1

Risk Stratification

Classify the patient into risk categories:

• High-risk PV is defined as age >60 years OR history of thrombosis 1, 3, 5
• Low-risk PV is absence of both risk factors 3, 5
• Progressive leukocytosis itself is a potential indication for cytoreductive therapy regardless of traditional risk category 1
• Assess cardiovascular risk factors as they contribute to thrombotic risk 1, 2

Treatment Algorithm

All Patients with PV (Regardless of Risk Category):

Maintain phlebotomy to keep hematocrit <45%, as this significantly reduces thrombotic events 1, 2, 3, 5

Continue low-dose aspirin (81 mg once or twice daily) in the absence of contraindications, as it reduces the combined risk of nonfatal MI, stroke, PE, major venous thrombosis, or cardiovascular death 2, 3, 5

For Progressive Leukocytosis (Your Patient):

Initiate hydroxyurea as first-line cytoreductive therapy:

• Start at 15-20 mg/kg/day (typically 1000-1500 mg daily), adjusting based on blood counts 1, 7
• Hydroxyurea is the preferred first-line cytoreductive agent for both high-risk PV and progressive leukocytosis 1, 2, 3, 5
• For significant leukocytosis (WBC >30,000/μL) with symptoms of leukostasis, consider higher doses (2-4g per day) 8, 7

Second-line options if hydroxyurea fails or is not tolerated:

• Interferon-α (pegylated interferon alfa-2a or alfa-2b) is the preferred second-line agent 1, 2, 3, 5
• Busulfan is another second-line option with lower leukemogenic potential than older alkylating agents 1, 3, 5
• Ruxolitinib should be reserved ONLY for severe protracted pruritus or marked splenomegaly unresponsive to hydroxyurea and interferon 2, 3, 5

Monitoring and Follow-Up

Monitor response to therapy:

• Check CBC every 1-2 weeks initially when starting hydroxyurea, then every 4-6 weeks once stable 1
• Assess for symptoms using MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) every 3-6 months 1
• Monitor for signs of disease progression including new thrombosis, symptomatic splenomegaly, or cytopenias 1
• There is no evidence-based target WBC count, but normalization of blood counts is typically pursued in clinical practice 1

Repeat bone marrow evaluation as clinically indicated if there are signs of progression such as increasing symptoms, worsening cytopenias, or suspected transformation 1, 2

Critical Pitfalls to Avoid

Do not perform therapeutic phlebotomy for leukocytosis - phlebotomy is only for maintaining hematocrit <45% and does not address leukocytosis 1, 2

Avoid leukapheresis unless absolutely necessary due to risk of complications; it should only be considered for extreme leukocytosis with symptoms of leukostasis 8, 7

Do not use older alkylating agents like chlorambucil or radioactive phosphorus (32P) as they have significantly higher rates of leukemic transformation (10.6% and 8.3% respectively) compared to hydroxyurea (5.9%) 1

Screen for acquired von Willebrand disease before starting aspirin if extreme thrombocytosis (platelets >1000 × 10⁹/L) is present, as this increases bleeding risk 1, 9

Monitor for hydroxyurea resistance or intolerance, defined by development of cytopenia at the lowest effective dose, as this is an adverse prognostic factor associated with higher risk of death and AML transformation 1