What are the initial management approaches for patients diagnosed with myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and primary myelofibrosis?

Diagnosis and Management of Myeloproliferative Neoplasms

Initial Diagnostic Workup

All patients with suspected MPNs require a comprehensive diagnostic evaluation including CBC with differential, peripheral blood smear examination, bone marrow aspirate and biopsy with reticulin staining, molecular testing for driver mutations (JAK2 V617F, CALR, MPL), and BCR-ABL1 testing to exclude chronic myeloid leukemia. 1

Essential Laboratory and Molecular Testing

• Complete blood count with differential to identify cytopenias or cytoses 1
• Peripheral blood smear examination for morphologic abnormalities 1
• Bone marrow aspirate and biopsy with trichrome and reticulin staining to assess cellularity, megakaryocyte morphology, and fibrosis grade 1
• Bone marrow cytogenetics (karyotype ± FISH) for prognostic stratification 1
• Molecular testing sequence: First test for JAK2 V617F mutation; if negative, test for CALR and MPL mutations (for ET and MF patients) and JAK2 Exon 12 mutations (for PV patients) 1
• BCR-ABL1 testing via FISH or RT-PCR to definitively exclude chronic myeloid leukemia 1
• Serum erythropoietin level (typically suppressed in PV) 1
• Comprehensive metabolic panel including uric acid, LDH, and liver function tests 1

Additional Baseline Assessments

• Symptom burden assessment using the MPN Symptom Assessment Form (MPN-SAF) at baseline 1
• Coagulation testing in selected patients to evaluate for acquired von Willebrand disease, particularly those with elevated platelet counts, splenomegaly, or unexplained bleeding 1
• HLA typing if allogeneic hematopoietic cell transplant is being considered 1
• Documentation of transfusion and medication history 1

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Risk Stratification

Polycythemia Vera and Essential Thrombocythemia

Patients with PV or ET are classified as high-risk if they are older than 60 years or have a history of previous thrombosis. 1

• Age >60 years defines high-risk status 1
• Prior thrombotic event defines high-risk status regardless of age 1
• Leukocytosis and JAK2 V617F mutation presence are emerging risk factors for thrombosis 2

Primary Myelofibrosis

Risk stratification in PMF should utilize the International Prognostic Scoring System (IPSS) for newly diagnosed patients and Dynamic IPSS (DIPSS-Plus) for patients during disease course, incorporating cytogenetics and transfusion status. 1

IPSS/DIPSS-Plus Risk Categories:

• Low risk: IPSS score = 0 1
• Intermediate-1 (INT-1): IPSS = 1, DIPSS-Plus = 1, or DIPSS = 1-2 1
• Intermediate-2 (INT-2): IPSS = 2, DIPSS-Plus = 2-3, or DIPSS = 3-4 1
• High risk: IPSS ≥3, DIPSS-Plus = 4-6, or DIPSS = 5-6 1

Key Prognostic Factors in PMF:

• Advanced age (>60 years) 2
• Anemia 2
• Leukocytosis (WBC >25 × 10⁹/L) 2
• Presence of circulating blast cells (≥1%) 2
• Constitutional symptoms 2
• Adverse cytogenetics 1
• High-risk mutations (ASXL1, EZH2, IDH1/IDH2, SRSF2) 1

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Management of Polycythemia Vera

High-Risk PV

High-risk PV patients require phlebotomy to maintain hematocrit <45%, low-dose aspirin 81-100 mg daily, and cytoreductive therapy with either hydroxyurea or interferon-alpha. 1, 3

First-Line Cytoreductive Therapy:

• Hydroxyurea is the standard first-line cytoreductive agent at any age 1
• Interferon-alpha is an acceptable first-line alternative, particularly in younger patients or those with vasculitic complications 1, 3

Second-Line Therapy:

• Ruxolitinib is recommended for patients who are intolerant of or have inadequate response to hydroxyurea 1
• Interferon-alpha (recombinant interferon alpha, pegylated interferon alpha-2a, or pegylated interferon alpha-2b) is an alternative second-line option 1

Essential Supportive Care:

• Phlebotomy to maintain hematocrit <45% 1, 3
• Low-dose aspirin 81-100 mg daily for thrombosis prevention 1, 3

Low-Risk PV

• Phlebotomy alone to maintain hematocrit <45% 1
• Low-dose aspirin 81-100 mg daily unless contraindicated 1
• Observation with monitoring every 3-6 months 1

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Management of Essential Thrombocythemia

High-Risk ET

High-risk ET patients require cytoreductive therapy with hydroxyurea as first-line treatment at any age, combined with low-dose aspirin unless contraindicated. 1

First-Line Cytoreductive Therapy:

• Hydroxyurea is the standard first-line agent 1
• Target platelet count normalization or near-normalization 4

Second-Line Therapy:

• Interferon-alpha for patients intolerant of or with inadequate response to hydroxyurea 1, 3
• Anagrelide may be considered as an alternative 3

Antiplatelet Therapy:

• Low-dose aspirin 81-100 mg daily unless contraindicated by bleeding risk 1, 3

Low-Risk ET

• Observation with monitoring 1
• Low-dose aspirin may be considered based on cardiovascular risk factors 1

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Management of Primary Myelofibrosis

Low-Risk MF

Asymptomatic low-risk MF patients should be observed with monitoring every 3-6 months for signs of disease progression. 1

• Observation is appropriate for asymptomatic patients 1
• Clinical trial enrollment should be considered 1
• For symptomatic patients, treatment options include ruxolitinib or interferons 1

Intermediate-1 Risk MF

INT-1 risk MF patients require individualized management based on symptom burden, with ruxolitinib recommended for those with symptomatic splenomegaly. 1

• Observation for asymptomatic patients with monitoring every 3-6 months 1
• Ruxolitinib for symptomatic splenomegaly 1
• Allogeneic HCT should be considered for patients with low platelet counts and complex cytogenetics 1

Intermediate-2 and High-Risk MF

All INT-2 and high-risk MF patients should be evaluated for allogeneic hematopoietic cell transplantation, which is the only curative therapy and is recommended for transplant-eligible patients with expected median survival <5 years. 1

Transplant-Eligible Patients:

• Allogeneic HCT is the treatment of choice for INT-2 and high-risk disease 1
• Transplant should be performed in controlled settings 1
• Consider transplant for INT-1 patients with refractory transfusion-dependent anemia, peripheral blood blasts >2%, adverse cytogenetics, or high-risk mutations 1

Non-Transplant Candidates:

For symptomatic patients with platelets >50,000/μL:

• Ruxolitinib is first-line therapy for MF-associated splenomegaly 1
• Fedratinib is FDA-approved for intermediate-2 or high-risk primary or secondary myelofibrosis 5
• Clinical trial enrollment should be strongly considered 1

For patients with platelets ≤50,000/μL:

• Clinical trials are preferred 1
• Consider investigational agents such as pacritinib or momelotinib 1

Management of MF-Associated Anemia

Anemia in PMF should be treated with corticosteroids, androgens, erythropoiesis-stimulating agents, or immunomodulators as first-line options. 1

• Corticosteroids (e.g., prednisone) 1
• Androgens (e.g., danazol) 1
• Erythropoiesis-stimulating agents 1
• Immunomodulators (e.g., thalidomide, lenalidomide) 1

Management of MF-Associated Splenomegaly

Hydroxyurea is the first-line treatment for PMF-associated splenomegaly. 1

Indications for Splenectomy:

• Symptomatic portal hypertension 1
• Drug-refractory painful splenomegaly 1
• Frequent RBC transfusion requirements 1

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Monitoring and Response Assessment

PV and ET Monitoring

Response in PV and ET should be monitored using ELN clinicohematologic criteria with assessment every 3-6 months. 1

• Monitor for signs of disease progression including new thrombosis, major bleeding, progressive splenomegaly, progressive leukocytosis, or worsening constitutional symptoms 3
• Perform bone marrow aspirate and biopsy if there are signs of progression to myelofibrosis 3
• Reassess symptom burden regularly using MPN-SAF 1, 3

MF Monitoring

• Symptom assessment using MPN-SAF TSS-10 items 1
• Monitor for disease progression every 3-6 months 1
• Reassess risk stratification during disease course using DIPSS-Plus 1

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Special Considerations

Perioperative Management

MPN patients undergoing surgery require careful perioperative thromboprophylaxis with LMWH due to substantial thrombotic risk (arterial events in ~3.8% of surgical cases). 4

• Ensure platelet count control before elective surgery, particularly if counts exceed 1,000/mm³ 4
• Discontinue aspirin one week prior to surgery and restart 24 hours postoperatively once bleeding risk is acceptable 4
• Consider extended prophylaxis with LMWH for high venous thromboembolism risk procedures 4

Vasculitic Complications

High-risk PV and ET patients with vasculitic complications should transition to interferon-alpha as the cytoreductive agent while maintaining phlebotomy (hematocrit <45%) and aspirin therapy. 3

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Common Pitfalls and Caveats

• Do not overlook BCR-ABL1 testing: Failure to exclude chronic myeloid leukemia can lead to inappropriate management 1
• Do not delay molecular testing: Testing for CALR and MPL mutations is essential when JAK2 is negative, as these mutations have diagnostic and prognostic implications 1
• Do not underestimate thrombotic risk: Even with optimal management, vascular occlusion occurs in 7.7% and major hemorrhage in 7.3% of MPN surgical patients 4
• Do not miss prefibrotic myelofibrosis: Careful bone marrow morphology assessment is required to distinguish ET from prefibrotic PMF, as prognosis differs significantly 1, 6
• Do not delay transplant evaluation: All INT-2 and high-risk MF patients should be evaluated for allogeneic HCT early, as this is the only curative option 1
• Referral to specialized centers: Strongly recommended for all patients diagnosed with MF, PV, or ET given the complexity of management 1