Myeloproliferative Neoplasms

Introduction

Myeloproliferative neoplasms (MPNs) are characterized by the presence of genetic mutations, including JAK2, CALR, and MPL, which are used for diagnosis and prognosis 1, 2

The JAK2 gene mutation occurs in exon 14, resulting from a G to T substitution at nucleotide 1849, causing valine to be replaced by phenylalanine at position 617, and is present in >90-95% of Polycythemia Vera (PV) cases 3, 1
The 2016 WHO classification includes JAK2 mutations as major diagnostic criteria for PV, Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF) 4, 2
JAK2 exon 12 mutations are present in 2-4% of PV cases and are associated with isolated erythrocytosis, higher hemoglobin levels, and lower platelet and leukocyte counts at diagnosis, with a strength of evidence level of moderate 1
The following mutations are commonly used for diagnosis of MPNs:

JAK2 mutation testing helps distinguish between true polycythemia vs. secondary erythrocytosis, essential thrombocythemia vs. reactive thrombocytosis, and primary myelofibrosis vs. secondary myelofibrosis 2
Bone marrow examination typically shows hypercellularity with erythroid hyperplasia and atypical megakaryocytes, a key diagnostic feature 1
The National Comprehensive Cancer Network recommends testing for JAK2 V617F mutation first, and if negative, testing for JAK2 exon 12 mutations in patients suspected of having PV, with a high level of evidence supporting this approach 1

The American Society of Clinical Oncology recommends that treatment decisions for PV or ET be based on risk stratification (age >60 years and history of thrombosis), rather than JAK2 mutation status 5
Risk stratification is typically performed using the International Prognostic Scoring System (IPSS), Dynamic IPSS (DIPSS), or DIPSS-plus, to guide treatment decisions 4
The following treatment options are recommended based on risk stratification:

Risk Category	Treatment
High-risk	Cytoreductive therapy and antiplatelet agents
Low-risk	Phlebotomy and low-dose aspirin

Phlebotomy should be used to maintain hematocrit <45%, and low-dose aspirin (81-100 mg/day) should be administered 6, 5
Cytoreductive therapy with either hydroxyurea or interferon-alpha should be used, with alternative agents such as anagrelide considered if intolerant or resistant to hydroxyurea 6, 5
Ruxolitinib (JAK1/JAK2 inhibitor) is recommended as the first-line treatment for patients with intermediate-2 or high-risk myelofibrosis presenting with symptomatic splenomegaly and constitutional symptoms 1, 4
AlloSCT is currently the only potentially curative treatment for myelofibrosis, recommended for patients younger than 70 years with intermediate-2 or high-risk disease, and patients younger than 65 years with intermediate-1 risk disease who have poor-risk features 1, 4, 7

For patients with JAK2 mutation and splanchnic vein thrombosis (SVT), indefinite anticoagulation with vitamin K antagonists is recommended, and anti-proliferative therapy (interferon-alpha or hydroxyurea) should be added to normalize blood counts 8
For high-risk pregnancy, interferon-alpha should be considered if platelet count ≥1,500 × 10^9/L, and low molecular weight heparin should be used throughout pregnancy and 6 weeks postpartum 5
Cytopenias (thrombocytopenia and anemia) are common with JAK inhibitors and should be managed with dose adjustments rather than discontinuation when possible 1
Ruxolitinib discontinuation should be done gradually to avoid a shock-like syndrome due to re-emergence of suppressed inflammatory cytokines 1

Long-term outcomes appear similar between JAK2 V617F and exon 12 mutation carriers, with similar incidences of thrombosis, progression to myelofibrosis, leukemic transformation, and death 1
Monitoring JAK2, MPL, and CALR mutations is useful for assessing disease progression, as changes in mutant allele burden may indicate disease progression 10
Regular monitoring should include assessment of spleen size, blood counts, constitutional symptoms, and bone marrow morphology alongside molecular testing 5