What risk‑stratification scales are used for JAK2‑positive myeloproliferative disorders (polycythemia vera, essential thrombocythemia, primary myelofibrosis) and how do they guide treatment?

Risk Stratification Scales for JAK2-Positive Myeloproliferative Disorders

Disease-specific prognostic scoring systems must be employed for each JAK2-positive myeloproliferative neoplasm subtype—polycythemia vera, essential thrombocythemia, and primary myelofibrosis—because each disease has distinct clinical outcomes, risk factors, and therapeutic implications that require tailored risk stratification. 1

Polycythemia Vera (PV) Risk Stratification

PV uses a two-tier risk stratification system based solely on age and thrombosis history to guide cytoreductive therapy decisions. 1, 2

Risk Categories

• High-risk: Age ≥60 years OR prior thrombosis history 1, 2, 3
• Low-risk: Age <60 years AND no prior thrombosis history 1, 2, 3

Treatment Implications by Risk Category

• High-risk patients require: Phlebotomy to maintain hematocrit <45%, low-dose aspirin (80-100 mg daily), AND cytoreductive therapy with hydroxyurea or interferon-α 1, 2
• Low-risk patients receive: Phlebotomy and low-dose aspirin only, with observation for disease progression 1, 2

Emerging Risk Factors

• Elevated leukocyte count is emerging as an additional thrombosis risk factor, though an intermediate-risk category incorporating leukocytosis has not yet been formally validated 1, 4

Essential Thrombocythemia (ET) Risk Stratification

ET employs the IPSET-thrombosis scoring system, which incorporates age, prior thrombosis, cardiovascular risk factors, and JAK2V617F mutation status to define four distinct risk categories. 1, 5

IPSET-Thrombosis Scoring Points

• Age ≥60 years: 1 point 1
• Prior thrombosis: 2 points 1
• JAK2V617F mutation: 2 points 1
• Cardiovascular risk factors (smoking, diabetes, hypertension, hypercholesterolemia): 1 point 1

Risk Categories Based on Total Score

• Very low risk (0 points): Age ≤60 years, no thrombosis history, JAK2 wild-type 1, 2, 3
• Low risk (1 point): Same as very low but JAK2 mutation present 1, 2, 3
• Intermediate risk (2 points): Age >60 years, no thrombosis history, JAK2 wild-type 1, 2, 3
• High risk (≥3 points): Thrombosis history present OR age >60 years with JAK2 mutation 1, 2, 3

Treatment Implications by Risk Category

• Very low-risk: May not require therapy; observation alone 2, 3
• Low-risk: Low-dose aspirin therapy (once-daily or twice-daily) 2, 3, 5
• Intermediate-risk: Cytoreductive therapy is optional, not mandatory 2, 3
• High-risk: Cytoreductive therapy with hydroxyurea or pegylated interferon-α PLUS low-dose aspirin 1, 2, 5

Additional Prognostic Considerations

• JAK2V617F mutation is associated with higher thrombosis risk but does not affect overall survival in ET 2, 3, 5
• MPL and CALR-1 mutations are associated with increased risk of myelofibrosis transformation 5
• Spliceosome mutations correlate with inferior overall and myelofibrosis-free survival 5

Primary Myelofibrosis (PMF) Risk Stratification

PMF requires different scoring systems depending on timing: IPSS at diagnosis, and DIPSS or DIPSS-Plus during follow-up to reflect disease evolution. 1

International Prognostic Scoring System (IPSS) - At Diagnosis

The IPSS incorporates five adverse factors: 1

• Age >65 years
• Constitutional symptoms (fever, night sweats, weight loss)
• Hemoglobin <10 g/dL
• White blood cell count >25 × 10⁹/L
• Peripheral blood blasts ≥1%

Dynamic IPSS (DIPSS) and DIPSS-Plus - During Follow-Up

• DIPSS-Plus adds three independent risk factors to DIPSS: 1
  • Unfavorable cytogenetics
  • Red-cell transfusion dependence
  • Platelet count <100 × 10⁹/L

Molecular Risk Stratification - Critical for Prognosis

• CALR-positive/ASXL1-negative: Longest median survival (≈10 years) 1
• CALR-negative/ASXL1-positive: Shortest median survival (≈2 years) 1
• ASXL1 mutation testing is mandatory for all intermediate-1 risk patients because the mutation independently worsens prognosis and may shift management toward allogeneic stem-cell transplantation 1

Transplant Evaluation Criteria

• Patients with expected median survival <5 years should be evaluated for allogeneic hematopoietic stem-cell transplantation (the only curative option): 1
  • Intermediate-2 or high-risk by DIPSS-Plus
  • Transfusion-dependent
  • Unfavorable cytogenetics

Critical Pitfalls to Avoid

• Do not apply a single unified MPN scoring system across all JAK2-positive disorders—each disease requires its own validated risk stratification tool 1
• Do not omit bone marrow biopsy in the diagnostic work-up of suspected MPNs, except in PV patients whose hemoglobin exceeds 18.5 g/dL (males) or 16.5 g/dL (females) 1
• Do not skip driver-mutation screening (JAK2V617F, CALR, MPL) in any suspected Philadelphia-negative MPN; the recommended sequence is JAK2V617F first, followed by CALR and MPL in ET/MF, or JAK2 exon 12 testing in JAK2V617F-negative PV 1
• Iron-deficiency anemia can mask polycythemia vera by lowering hemoglobin while red-cell mass remains elevated; therefore, assess iron studies and mean corpuscular volume when PV is suspected 1
• Do not initiate JAK-inhibitor therapy in asymptomatic low-risk myelofibrosis patients, as these agents are palliative and have not demonstrated disease-modifying benefits 1
• In ET, it is most important to exclude the possibility of prefibrotic myelofibrosis through careful bone marrow morphology assessment, as this distinction fundamentally alters prognosis and management 2, 3, 5