Myeloproliferative Neoplasms

Abstract

Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) constitute the BCR-ABL1-negative myeloproliferative neoplasms and are characterized by mutually exclusive Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) mutations; respective frequencies of these mutations are approximately 95%, 0%, and 0% in PV, 60%, 20%, and 3% in ET, and 60%, 25%, and 7% in PMF. These mutations might be accompanied by other mutations that are less specific to myeloproliferative neoplasms but are prognostically relevant, such as additional sex combs-like 1 (ASXL1). Characteristic bone marrow morphology is required for World Health Organization-compliant diagnosis, especially in distinguishing ET from prefibrotic PMF and masked PV. Survival is the longest in ET, although still inferior to that of the age- and sex-matched control population; median survivals for patients younger than 60 years are approximately 33 years for ET, 24 for PV, and 15 for PMF. Major disease complications include thrombosis and leukemic or fibrotic transformation. In PV and ET, risk factors for survival include older age, leukocytosis, and thrombosis, whereas JAK2 mutation in ET is associated with increased risk of thrombosis. In PMF, type 1 or type 1-like CALR mutations are associated with superior and ASXL1 with inferior survival. Prevention of thrombosis in PV is secured by phlebotomy (hematocrit target <45%) and in both PV and ET by low-dose aspirin therapy; high-risk patients derive additional antithrombotic benefit from cytoreductive therapy with hydroxyurea as first-line and interferon-alfa and busulfan as second-line drugs of choice. Although the JAK inhibitor ruxolitinib was recently approved for use in hydroxyurea-resistant PV, its role in routine clinical practice remains debatable. In myelofibrosis, stem cell transplant is the current treatment of choice for genetically or clinically high-risk disease; for all other patients requiring treatment, participation in clinical trials may be preferred because currently available drugs, including JAK inhibitors, are palliative and not shown to be disease modifying.

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

“…Current drug therapy in PV, ET, or MF is neither curative nor capable of prolonging life or preventing disease progression [106]. Accordingly, treatment indications in PV and ET are primarily directed at prevention of thrombohemorrhagic complications and secondarily towards alleviation of symptoms and in PMF mostly at alleviation of symptoms with the possibility of cure limited to patients undergoing allogeneic stem cell transplant (ASCT) [107].…”

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

“…In routine practice, clonality is usually determined by the presence of an acquired mutation or cytogenetic abnormality, although additional clinical, laboratory and morphological information is important in the diagnosis of each specific subtype (5)(6)(7).…”

“…According to the available studies, the frequencies of these mutations are ~95, 0, and 0% in PV, 60, 3, and 20% in ET, and 60, 7, and 25% in PMF, respectively (6,(14)(15)(16)(17)(18). Although it is possible to identify one of these mutations in the majority of the BCR/ ABL-negative disorder patients, there are unidentified genetic defects in approximately 10-15% of cases, predominantly of ET and PMF and, furthermore, those mutations cannot fully explain the phenotypic heterogeneity of PN-MPNs nor the susceptibility of progression to myelofibrosis, acute myeloid leukaemia (AML) or myelodysplastic syndromes (MDS) (16).…”

Calreticulin variant stratified driver mutational status and prognosis in essential thrombocythemia

“…These so-called "driver" mutations [5] include Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) and are present in about 85% of patients with ET with respective frequencies of 58, 23, and 4% [6]; the remaining cases constituting 15% are wild-type for all three mutations and are operationally referred to as being "triple negative" [6,7]. More than 80% of CALR mutated ET patients harbor one of only two mutation variants: type 1, a 52-bp deletion (p.L367fs*46) and type 2, a 5-bp TTGTC insertion (p.K385fs*47) [7] with a frequency of 46 and 38%, respectively [8]; the rest of the CALR mutations are classified as type 1-like and type 2-like, based on their structural similarities to type 1 and type 2 CALR variants, respectively [9,10]. Specific driver mutations in ET have been associated with characteristic phenotypes [5][6][7][8][11][12][13] and the risk of thrombosis has been shown to be higher in patients with JAK2 or MPL mutations [12].…”