Myeloproliferative Neoplasms Beyond Polycythemia Vera
The myeloproliferative neoplasms (MPNs) include essential thrombocythemia, primary myelofibrosis, chronic myeloid leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, mastocytosis, and unclassifiable myeloproliferative neoplasms, according to the WHO classification system. 1
Philadelphia-Negative Classical MPNs
The three major Philadelphia-negative classical MPNs besides polycythemia vera are:
Essential Thrombocythemia (ET)
- Characterized by sustained platelet count ≥450 × 10⁹/L with proliferation mainly of the megakaryocytic lineage showing increased numbers of enlarged, mature megakaryocytes. 1
- Approximately 60% of ET patients harbor the JAK2V617F mutation, with additional patients carrying MPL or CALR mutations. 1, 2
- Diagnosis requires meeting all four major WHO criteria: sustained thrombocytosis, characteristic bone marrow findings, exclusion of other myeloid neoplasms, and demonstration of JAK2V617F or other clonal marker (or absence of reactive thrombocytosis). 1
- ET patients face thrombotic risk with arterial events in approximately 3.8% of surgical cases and variable bleeding risk with major hemorrhage complicating approximately 10.5% of surgeries. 3
Primary Myelofibrosis (PMF)
- Defined by megakaryocyte proliferation and atypia accompanied by reticulin and/or collagen fibrosis, or in its absence, a prefibrotic cellular-phase disease. 1
- Approximately 50-60% of PMF patients carry JAK2V617F, with others harboring MPL mutations (particularly MPLW515K/L) or CALR mutations. 1, 2
- Diagnosis requires all three major criteria (characteristic bone marrow findings, exclusion of other myeloid neoplasms, demonstration of clonal marker) plus two of four minor criteria: leukoerythroblastosis, elevated lactate dehydrogenase, anemia, or splenomegaly. 1
- PMF has the worst prognosis among classical MPNs, with median survival expected to be less than 5 years in transplantation-eligible high-risk patients. 1
Philadelphia-Positive MPN
Chronic Myeloid Leukemia (CML)
- Distinguished by the presence of the BCR-ABL1 fusion gene resulting from the Philadelphia chromosome t(9;22)(q34;q11.2). 1, 2
- The Philadelphia chromosome was discovered by Nowell and Hungerford in 1960 and represents the defining feature separating CML from other MPNs. 2
- Classic CML features include basophilia, marked leukocytosis, neutrophil left-shift with myelocyte bulge, and "dwarf" megakaryocytes. 4
Less Common MPN Subtypes
Chronic Neutrophilic Leukemia
Chronic Eosinophilic Leukemia, Not Otherwise Specified
- Defined by persistent eosinophilia with clonal markers, excluding cases with PDGFRA, PDGFRB, or FGFR1 rearrangements which are classified separately. 1
- The FIP1L1-PDGFRA fusion can be detected by RT-PCR or FISH in some myeloid neoplasms with eosinophilia. 1, 5
Mastocytosis
- Characterized by abnormal accumulation of mast cells, frequently harboring KIT(D816V) mutations. 1, 5
Myeloproliferative Neoplasm, Unclassifiable
- Reserved for cases that meet general MPN criteria but cannot be classified into specific subtypes. 1
Common Molecular Features
All MPNs share activating mutations of tyrosine kinases and associated signal transduction pathways (BCR-ABL, JAK2V617F, MPL, KIT, FIP1L1-PDGFRA) that drive abnormal proliferation. 5
- JAK2V617F is present in >90% of PV, ~60% of ET, and ~50% of PMF cases. 1, 2
- These mutations enable exclusion of reactive processes and contribute to MPN subtyping with varying specificity. 5
- Detection of these driver mutations has led to revisions in WHO diagnostic criteria and risk stratification. 2
Clinical Significance
The primary clinical concerns across all MPNs include thrombotic complications, hemorrhagic events, risk of progression to myelofibrosis or acute leukemia, and significant symptom burden affecting quality of life. 6, 7