Abstract
Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of hematologic malignancies, including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), as well as post-PV-MF and post-ET-MF. Progression to more symptomatic disease, such as overt MF or acute leukemia, represents one of the major causes of morbidity and mortality. There are clinically evident but also subclinical types of MPN progression. Clinically evident progression includes evolution from ET to PV, ET to post-ET-MF, PV to post-PV-MF, or pre-PMF to overt PMF, and transformation of any of these subtypes to myelodysplastic neoplasms or acute leukemia. Thrombosis, major hemorrhage, severe infections, or increasing symptom burden (e.g., pruritus, night sweats) may herald progression. Subclinical types of progression may include increases in the extent of bone marrow fibrosis, increases of driver gene mutational allele burden, and clonal evolution. The underlying causes of MPN progression are diverse and can be attributed to genetic alterations and chronic inflammation. Particularly, bystander mutations in genes encoding epigenetic regulators or splicing factors were associated with progression. Finally, comorbidities such as systemic inflammation, cardiovascular diseases, and organ fibrosis may augment the risk of progression. The aim of this review was to discuss types and mechanisms of MPN progression and how their knowledge might improve risk stratification and therapeutic intervention. In view of these aspects, we discuss the potential benefits of early diagnosis using molecular and functional imaging and exploitable therapeutic strategies that may prevent progression, but also highlight current challenges and methodological pitfalls.
Highlights
Classical Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPN) are a group of clonal myeloid stem cell disorders comprising essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF)
These observations suggest that individuals harboring the JAK2V617F mutation with very low allelic burden are at risk to develop MPN, it is uncertain in how many individuals progression to an overt MPN might eventually occur throughout their life
We suggest that (a) low-dose quantitative computed tomography (CT) [80] or (b) fibrosis-specific functional or molecular imaging [81,82] might aid in detection of progression from ET/PV to sMF and discrimination between the various early stages
Summary
Classical Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPN) are a group of clonal myeloid stem cell disorders comprising essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). These risk factors for MPN progression and their dynamic changes over time will determine the disease course of an individual patient This may be evident by the development of thrombosis or thromboembolism, major bleeding, severe infections which poorly respond to antibiotic therapy, or increasing symptom burden, such as painful splenomegaly, unintended weight loss, night sweats, fever, and pruritus. As the acquisition of chromosomal aberrations is a common feature during accelerated and blast phases [21], this might explain the relatively high risk of transformation in PMF (10–20% at 10 years), compared with ET and PV (1–2.3% at 10 years) [12,22,23] While it is not completely understood how one mutation, JAK2V617F, can lead to three different disease phenotypes, the presence of a higher allelic burden is associated with a PV [24] or pPV-MF phenotype. Clinical progression of an MPN could be quantified using the MPN-specific prognostic scoring systems, where advancement to a higher risk group in such a prognostic scoring system (further discussed in Section 4) could be considered an indicator of disease progression
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