Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis

Tefferi, Ayalew; Guglielmelli, Paola; Larson, Dirk R.; Finke, Christy; Wassie, Emnet A.; Pieri, Lisa; Gangat, Naseema; Fjerza, Rajmonda; Belachew, Alem A.; Lasho, Terra L.; Ketterling, Rhett P.; Hanson, Curtis A.; Rambaldi, Alessandro; Finazzi, Guido; Thiele, Jüergen; Barbui, Tiziano; Pardanani, Animesh; Vannucchi, Alessandro M.

doi:10.1182/blood-2014-05-579136

Cited by 600 publications

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“…In the particular study, among 826 Mayo Clinic patients with ET, PV or PMF, the respective median survivals were 20 years for ET, 14 years for PV and 6 years for PMF [35]; the corresponding values for patients younger than age 60 years were 33, 24, and 15 years. The study also showed that lifeexpectancy in ET was inferior to that of the sex-and age-matched US population.…”

Section: Advances In Prognosticationmentioning

confidence: 86%

“…Subsequent studies confirmed the presence of JAK2V617F in almost all patients with PV [28,29] and in 50-60% of those with ET [30][31][32][33] or PMF [34,35]. In 2006, a somatic MPLW515L exon 10 mutation (a G to T transition at nucleotide 1544 resulting in a tryptophan to leucine substitution at codon 515 of the transmembrane region) was described in JAK2V617F-negative PMF [24].…”

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confidence: 87%

“…Mature survival data in MPN was recently published by the Mayo Clinic-Italian collaborative group [35]. In the particular study, among 826 Mayo Clinic patients with ET, PV or PMF, the respective median survivals were 20 years for ET, 14 years for PV and 6 years for PMF [35]; the corresponding values for patients younger than age 60 years were 33, 24, and 15 years.…”

Section: Advances In Prognosticationmentioning

confidence: 99%

“…With rare exceptions [37,38], CALR and MPL mutations are absent in PV and their frequencies are 20-25% and 3-4%, respectively, in ET, and 20-25% and 6-7% in PMF [35]. In other words, 10-15% of patients with PMF or ET do not express any one of the three mutations and are referred to as being "triple-negative" [35]. Most recently, whole exome sequencing revealed the presence of somatic or germline MPL or JAK2 variants in 3 of 8 triple-negative patients with MPN and subsequent MPL/JAK2 entire codon sequencing among 62 ET and 49 PMF triple-negative cases revealed novel somatic or germline MPL variants in 5 of 62 cases and JAK2 variants in 5 of 57 cases [39].…”

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confidence: 98%

“…The most recent (December 2013) driver mutation to be described in MPN was CALR [22,23]. With rare exceptions [37,38], CALR and MPL mutations are absent in PV and their frequencies are 20-25% and 3-4%, respectively, in ET, and 20-25% and 6-7% in PMF [35]. In other words, 10-15% of patients with PMF or ET do not express any one of the three mutations and are referred to as being "triple-negative" [35].…”

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confidence: 99%

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Myeloproliferative neoplasms: A decade of discoveries and treatment advances

2015

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Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR‐ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK‐STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, “driver” mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN. Am. J. Hematol. 91:50–58, 2016. © 2015 Wiley Periodicals, Inc.

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Section: Advances In Prognosticationmentioning

confidence: 86%

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confidence: 87%

Section: Advances In Prognosticationmentioning

confidence: 99%

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confidence: 98%

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Myeloproliferative neoplasms: A decade of discoveries and treatment advances

2015

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Myeloproliferative Neoplasms

2015

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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.

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Age-Related Macular Degeneration in Patients With Chronic Myeloproliferative Neoplasms

et al. 2017

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IMPORTANCE It has been suggested that systemic inflammation increases the risk of age-related macular degeneration (AMD). Given that chronic immune modulation is present in patients with myeloproliferative neoplasms (MPNs), the risk of AMD in these patients may be increased.OBJECTIVE To compare the risk of AMD in patients with MPNs with the risk of AMD in matched controls from the general population. DESIGN, SETTING, AND PARTICIPANTSA nationwide population-based cohort study using Danish registers was conducted of all patients in Denmark who received a diagnosis between January 1, 1994, and December 31, 2013, of essential thrombocythemia, polycythemia vera, myelofibrosis, or unclassifiable MPNs. For each patient, 10 age-and sex-matched controls were included. All patients without prior AMD were followed up from the date of diagnosis (or corresponding entry date for the controls) until the first AMD diagnosis, death or emigration, or December 31, 2013, whichever occurred first. Data analysis was performed from April 1, 2015, to October 31, 2016. MAIN OUTCOMES AND MEASURESIncidence of AMD recorded in specialized hospital-based care. The rates and absolute risk of AMD were calculated. Using Cox proportional hazards regression models, smoking and risk-time adjusted hazard ratios (HRs) between patients and controls were calculated. In addition, HRs of neovascular AMD after 2006 were calculated since antivascular endothelial growth factor treatment was introduced nationwide at hospitals thereafter.RESULTS A total of 7958 patients with MPNs (4279 women [53.8%] and 3679 men [46.2%]; mean [SD] age at diagnosis, 66.4 [14.3] years) were included in the study. The rate of AMD per 1000 person-years at risk was 5.2 (95% CI, 4.6-5.9) for patients with MPNs (2628 with essential thrombocythemia, 3063 with polycythemia vera, 547 with myelofibrosis, and 1720 with unclassifiable MPNs) and 4.3 (95% CI, 4.1-4.4) for the 77 445 controls, while the 10-year risk of AMD was 2.4% (95% CI, 2.1%-2.8%) for patients with MPNs and 2.3% (95% CI, 2.2%-2.4%) for the controls. The risk of AMD was increased overall for patients with MPNs (adjusted HR, 1.3; 95% CI, 1.1-1.5), with adjusted HRs for the subtypes of 1.2 (95% CI, 1.0-1.6) for essential thrombocythemia, 1.4 (95% CI, 1.2-1.7) for polycythemia vera, 1.7 (95% CI, 0.8-4.0) for myelofibrosis, and 1.5 (95% CI, 1.1-2.1) for unclassifiable MPNs. In addition, patients with MPNs had a higher risk of neovascular AMD (adjusted HR, 1.4; 95% CI, 1.2-1.6). CONCLUSIONS AND RELEVANCEOur results suggest that patients with MPNs are at increased risk of AMD, supporting the possibility that systemic inflammation is involved in the pathogenesis of AMD.

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Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis

Abstract: Key Points Survival in ET is superior to that of PV, regardless of mutational status, but remains inferior to the sex- and age-matched US population. JAK2/CALR/MPL mutational status is prognostically informative in PMF, regarding overall and leukemia-free survival.

Cited by 600 publications

References 23 publications

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

Myeloproliferative Neoplasms

Age-Related Macular Degeneration in Patients With Chronic Myeloproliferative Neoplasms

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