Myeloproliferative Neoplasms Diagnosis and Management

Introduction to MPNs

JAK2 mutations, particularly JAK2V617F, are diagnostic hallmarks of Philadelphia-negative myeloproliferative neoplasms (MPNs), found in 95% of polycythemia vera cases and 50-60% of essential thrombocythemia and primary myelofibrosis cases 1

Polycythemia vera patients often experience aquagenic pruritus (itching after water exposure), headaches, dizziness, visual disturbances from hyperviscosity, erythromelalgia (burning pain in extremities), and fatigue and weakness 1, 2
Essential thrombocythemia patients may be asymptomatic at diagnosis or experience vasomotor symptoms (headaches, visual disturbances, erythromelalgia) and bleeding manifestations with extreme thrombocytosis (>1500 × 10⁹/L) 1
Primary myelofibrosis patients often present with constitutional symptoms: fatigue, night sweats, weight loss, early satiety from splenomegaly, bone pain, and progressive anemia symptoms 1, 3, 4

JAK2 mutation analysis is mandatory for all suspected MPNs, with JAK2V617F present in >90% of polycythemia vera cases and approximately 60% of essential thrombocythemia and primary myelofibrosis 1, 4, 5
If JAK2 is negative, testing for CALR mutations and MPL mutations is recommended 4, 5
Bone marrow examination is crucial for diagnosis, with distinct features for each MPN subtype, including hypercellularity, panmyelosis, and pleomorphic mature megakaryocytes in polycythemia vera, and megakaryocyte proliferation and atypia with fibrosis in primary myelofibrosis 4

All JAK2-positive MPN patients must be risk-stratified, with high-risk criteria including age >60 years and previous thrombosis for polycythemia vera and essential thrombocythemia, and the International Prognostic Scoring System (IPSS) for primary myelofibrosis 1
Treatment for polycythemia vera includes phlebotomy, low-dose aspirin, and cytoreductive therapy with hydroxyurea or interferon-alpha, while essential thrombocythemia treatment involves cytoreductive therapy with hydroxyurea and low-dose aspirin 1, 6
Primary myelofibrosis treatment includes JAK inhibitors (ruxolitinib) for symptomatic splenomegaly and splenectomy for patients who fail or cannot tolerate JAK inhibitors 3

Splanchnic vein thrombosis requires low molecular weight heparin followed by long-term oral anticoagulation and hydroxyurea to reduce platelet count 2
Intractable pruritus can be managed with cyproheptadine, interferon-alpha, or paroxetine 2
Pregnancy management involves phlebotomy, low-dose aspirin, and prophylactic-dose low molecular weight heparin postpartum for low-risk pregnancies, and low molecular weight heparin throughout pregnancy for high-risk pregnancies 2

All MPN patients require regular complete blood counts, monitoring for cytopenias, assessment of spleen size, and bone marrow examination before initiating cytoreductive therapy 1, 3, 6
Thrombocytopenia management on anticoagulation involves adjusting anticoagulation doses based on platelet count 6

The European LeukemiaNet guidelines recommend testing JAK2V617F first, then CALR and MPL in that sequential order for suspected Essential Thrombocythemia (ET) and myelofibrosis 7
Test for CALR mutations immediately as the next diagnostic step, since CALR mutations are found in approximately 20-25% of JAK2-negative ET and Primary Myelofibrosis (PMF) cases 7
Test for MPL mutations (particularly MPL W515L/K) if CALR is negative, as these account for an additional 3-5% of JAK2-negative MPN cases 7

Approximately 10-15% of ET and PMF cases are triple-negative (JAK2/CALR/MPL negative) but still represent true clonal MPN based on bone marrow histology and clinical features 7
In these cases, bone marrow biopsy becomes the definitive diagnostic test rather than an optional one, to evaluate for characteristic MPN histopathology 7
Consider expanded molecular panel including ASXL1, EZH2, IDH1/IDH2, SRSF2, TET2, and DNMT3A to identify additional clonal markers that support MPN diagnosis in triple-negative cases 7

Bone marrow histology can establish MPN diagnosis even in triple-negative cases when morphology is characteristic 7
Perform bone marrow biopsy with reticulin staining to evaluate for characteristic MPN histopathology, which remains diagnostic even without driver mutations 7