White Blood Cell Count May Help Refine Risk Assessment in Polycythemia Vera

For decades, risk stratification in polycythemia vera (PV) has rested on two variables: age and history of thrombosis. Patients younger than 60 years with no prior clot are classified as low risk, with cytoreductive therapy reserved for those who cross into the high-risk category. A growing body of evidence suggests that an elevated white blood cell (WBC) count may independently predict thrombotic events, including among patients with otherwise low-risk PV.

In a virtual Case-Based Roundtable event for oncologists in the San Diego, California, area, Casey L. O'Connell, MD, FACP, professor of medicine in the Jane Anne Nohl Division of Hematology at the Keck School of Medicine of the University of Southern California, reviewed risk-stratification and treatment data for PV using a case of newly diagnosed low-risk disease to consider how leukocytosis may factor into patient management.

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CASE SUMMARY

• 42-year-old woman
• Asymptomatic at diagnosis
• Regular physical activity
• Body mass index: 23.4 kg/m²
• No significant prior medical history
• Abnormal bloodwork at annual physical
• Hematocrit: 52%
• Hemoglobin: 17.2 g/dL
• WBC: 9.8 × 10⁹/L
• Platelets: 450 × 10⁹/L
• Erythropoietin: 3 mU/mL (low)
• JAK2 V617F: Positive
• Low-risk category
• Age <60 years
• No prior thrombosis

Initial Management

• Phlebotomy (target hematocrit <45%)
• Aspirin 81 mg/day
• Cardiovascular risk factor management
• Monitor for progression

8-year routine follow-up visit

• Hematocrit 45%
• Left lower leg deep vein thrombosis
• Increased fatigue
• Active treatment: anticoagulation

EVENT RECAP

European LeukemiaNet criteria classify PV patients as low risk if they are younger than 60 years with no prior thrombotic event. O'Connell noted that a newer model, MIPSS-PV, an overall survival prognostic model, also assigns points for a leukocyte count of 15 × 10⁹/L or higher and for adverse mutations such as SRSF2, with median overall survival ranging from 24 years in the lowest-risk group to 3.2 years in the highest.¹

The panel's initial recommendation for the case patient, phlebotomy to a hematocrit target below 45% plus low-dose aspirin, reflects the randomized ECLAP trial, in which aspirin reduced thrombotic events compared with placebo (RR, 0.40; 95% CI, 0.18-0.91; P = .02),² and the CYTO-PV trial, in which patients kept below a hematocrit of 45% had significantly fewer cardiovascular deaths and major thrombotic events than those allowed to reach 45% to 50% (HR, 3.91; 95% CI, 1.45-10.53; P = .007).³

It was a secondary finding from that same CYTO-PV analysis, O'Connell told the group, that reframed how she thinks about the disease: patients with a WBC count of 11 × 10⁹/L or higher had a significantly higher risk of major thrombotic events, even after accounting for hematocrit.⁴

The REVEAL study corroborated the signal at larger scale; a WBC count above 11 × 10⁹/L was again associated with thrombosis, whereas a sustained platelet count above 400 × 10⁹/L was not, and among patients who met low-risk criteria by age and thrombosis history alone, WBC was the only blood-count variable significantly associated with a thrombotic event.⁵

"These data did sort of change my thinking on the disease, because I used to tell patients it doesn't matter [because] we're not treating you for the white count," O'Connell said. "Now I've definitely revised my thoughts on that."

No randomized trial has yet shown that pharmacologically normalizing WBC count itself reduces thrombotic risk, O'Connell noted. She pointed to the Low-PV trial, which randomly assigned low-risk patients to ropeginterferon alfa-2b (Besremi) or standard care, as one option for patients whose counts warrant a closer look. In the trial, ropeginterferon achieved hematocrit control more consistently than standard care and produced a mean 23.1% reduction in JAK2 V617F variant allele frequency at 24 months, versus an increase with standard care, although 16% of ropeginterferon-treated patients discontinued treatment because of adverse events.⁶

That ambiguity surfaced in how event participants described their own patients. One oncologist recounted a 59-year-old man with familial hypercholesterolemia who could not tolerate hydroxyurea (Hydrea) and, after an insurance delay, was switched to ropeginterferon and regained hematocrit control, prompting the physician to describe the case as sitting at the border of the low-risk category despite meeting the formal definition.

The case ultimately illustrated the limits of that binary. Eight years after diagnosis, the patient returned with a left lower extremity deep vein thrombosis and worsening fatigue despite a hematocrit of 45%, prompting anticoagulation and a shift to high-risk management under NCCN guidelines, which recommend cytoreductive therapy with hydroxyurea or ropeginterferon alfa-2b as preferred initial regimens; ruxolitinib is a preferred option for patients with inadequate or lost response, particularly those with hydroxyurea resistance or intolerance.⁷

Whether an elevated WBC count should itself trigger earlier cytoreductive therapy in ostensibly low-risk PV, rather than simply flagging patients for closer monitoring, remains an open question that further research would be required to definitively resolve.

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REFERENCES

1. Tefferi A, Guglielmelli P, Lasho TL, et al. Mutation-enhanced international prognostic systems for essential thrombocythaemia and polycythaemia vera. Br J Haematol. 2020;189(2):291-302. doi:10.1111/bjh.16380

2. Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004;350(2):114-124. doi:10.1056/NEJMoa035572

3. Marchioli R, Finazzi G, Specchia G, et al; CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22-33. doi:10.1056/NEJMoa1208500

4. Barbui T, Carobbio A, Ghirardi A, et al. White blood cell counts and thrombosis in polycythemia vera: a subanalysis of the CYTO-PV study. Blood. 2015;126(4):560-561. doi:10.1182/blood-2015-04-638502

5. Gerds AT, Mesa R, Burke JM, et al. Association between elevated white blood cell counts and thrombotic events in polycythemia vera: analysis from REVEAL. Blood. 2024;143(16):1646-1655. doi:10.1182/blood.2023020232

6. Barbui T, Vannucchi AM, De Stefano V, et al. Ropeginterferon versus standard therapy for low-risk patients with polycythemia vera. NEJM Evid. 2023;2(6):EVIDoa2200335. doi:10.1056/EVIDoa2200335

7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Myeloproliferative Neoplasms. Version 2.2025. Accessed August 21, 2026.