Essential thrombocythemia: Biology, clinical features, thrombotic risk, therapeutic options and outcome
Article Sidebar
Main Article Content
Abstract
Essential Thrombocythemia (ET) is currently classified as a Philadelphia negative myeloproliferative neoplasm (MPN) together with polycythemia vera (PV) and primary myelofibrosis (PMF); the latter can be further divided in pre-fibrotic primary myelofibrosis (pre-PMF) and overt myelofibrosis, as listed in the revised 2016 World Health Organization classification of myeloid malignancies (WHO 2016). Overall, respect to the others MPNs, ET is characterized by favorable prognosis, lower life expectancy if compared to the control population, increased risk of thrombohemorrhagic complications along with possible evolution in myelofibrosis and leukemic transformation. In this review the authors will review current knowledge on biology, clinical aspects, prognosis and stratification of thrombotic risk, therapeutic options and outcome in ET patients.
Article Details
Copyright (c) 2019 Accurso V, et al.
This work is licensed under a Creative Commons Attribution 4.0 International License.
Daniel AA, Attilio Orazi, Robert Hasserjian, Thiele J, Borowitz MJ, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. BLOOD. 2016; 127: 20. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27069254
Ma X, Vanasse G, Cartmel B, Wang Y, Selinger HA. Prevalence of polycythemia vera and essential thrombocythemia. Am J Hematol. 2008; 83: 359-362. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18181200
Johansson P. Epidemiology of the myeloproliferative disorders polycythemia vera and essential thrombocythemia. Semin Thromb Hemost. 2006; 32: 171-173. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16673273
Cortelazzo S, Viero P, Finazzi G, D'Emilio A, Rodeghiero F, et al. Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. J Clin Oncol. 1990; 8: 556-562. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/2307991
Fenaux P, Simon M, Caulier MT, Lai JL, Goudemand J, et al. Clinical course of essential thrombocythemia in 147 cases. Cancer 1990; 66: 549-556. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/2364366
Tefferi A, Fonseca R, Pereira DL, Hoagland HC. A long-term retrospective study of young women with essential thrombocythemia. Mayo Clin Proc. 2001; 76: 22-28. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11155408
Tefferi A, Barbui T. Polycytemia vera and essential thrombocythemia: 2019 update on diagnosis, risk stratification and management. Am J Hematol. 2019; 94: 133-143. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30281843
Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005; 365: 1054-1061. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15781101
Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia M with myelofibrosis. Cancer Cell. 2005; 7: 387-397.
James C, Ugo V, Le Couedic J-P, Staerk J, Delhommeau F, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005; 434: 1144-1148. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15793561
Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, et al. A gain-offunctionmutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005; 352: 1779-1790. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15858187
Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, et al. Mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood. 2006; 108: 3472-3476. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16868251
Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006; 3: e270. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16834459
Cazzola M, Kralovics R. From Janus kinase 2 to calreticulin:the clinically relevant genomic landscape of myeloproliferative neoplasms. Blood. 2014, 123: 3714-3719. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24786775
Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013; 369: 2379-2392.
Marty C, Pecquet C, Nivarthi H, El-Khoury M1, Chachoua I, et al. Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with frequent progression to myelofibrosis. Blood. 2016; 127: 1317-1324. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26608331
Mansier O, Luque Paz D, Ianotto JC, Le Bris Y, Chauveau A, et al. Clinical and biological characterization of MPN patients harboring two driver mutations, a French intergroup of myeloproliferative neoplasms (FIM) study. Am J Hematol. 2018; 93: 84-86. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29266414
Campbell PJ, Scott LM, Buck G, Wheatley K, East CL, et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet. 2005; 366: 1945-1953. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16325696
Cheung B, Radia D, Pantelidis P, Yadegarfar G, Harrison C. The presence of the JAK2 mutation is associated with a higher haemoglobin and increased risk of thrombosis in essential thrombocythaemia. Br J Haematol. 2006; 132: 244-245. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16398659
Zhang S, Qiu H, Fischer BS. JAK2 V617F patients with essential thrombocythemia present with clinical features of polycythemia vera. Leuk Lymphoma. 2008; 49: 696-699. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18398736
Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, et al. CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood. 2014; 123: 1544-1551. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24366362
Rotunno G, Mannarelli C, Guglielmelli P, Pacilli A, Pancrazzi A, et al. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood. 2014; 123: 1552-1555. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24371211
Pietra D, Rumi E, Ferretti VV, Di Buduo CA, Milanesi C, et al. Differential clinical effects of different mutation subtypes in CALR mutant myeloproliferative neoplasms. Leukemia. 2016; 30: 431-438. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26449662
Cabagnols X, Favale F, Pasquier F, Messaoudi K, Defour JP, et al. Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients. Blood. 2016; 127: 333-342. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26450985
Milosevic Feenstra JD, Nivarthi H, Gisslinger H, Leroy E, Rumi E, et al. Sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms. Blood. 2016; 127: 325-332. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26423830
Yamamoto Y, Iba S, Abe A, et al. Elongation of MPL transmembrane domain is a novel activating-mutation in essential thrombocythemia. Blood. 2015; 126: 1628-1628.
Tefferi A. Novel mutations and their functional andclinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia. 2010; 24: 1128-1138. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20428194
Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013; 369: 2391-2405. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24325359
Tefferi A, Lasho TL, Finke C. Targeted next-generation sequencing in polycythemia vera and essential thrombocythemia. Blood. 2015; 126: 354-354.
Scherber R, Dueck AC, Johansson P, Barbui T, Barosi G, et al. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): International Prospective Validation and Reliability Trial in 402 patients. Blood. 2011; 118: 2. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21536863
Andriani A, Latagliata R, Anaclerico B, Spadea A, Rago A, et al. Spleen enlargement is a risk factor for thrombosis in essential thrombocythemia: Evaluation on 1,297 patients. American Journal of Hematology. 2016; 91: 3. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26748894
Dentali F, Ageno W, Rumi E, Casetti I, Poli D, et al. Cerebral venous thrombosis and myeloproliferative neoplasms: results from two large databases. Thromb Res. 2014; 134: 41-43. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24787989
Chait Y, Condat B, Cazals-Hatem D, Rufat P, Atmani S, et al. Relevance of the criteria commonly used to diagnose myeloproliferative disorder in patients with splanchnic vein thrombosis. Br J Haematol. 2005; 129: 553-560. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15877740
Rumi E, Cazzola M. How I treat essential thrombocythemia. Blood. 2016; 128: 2403-2414. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27561316
Dentali F, Squizzato A, Brivio L, Appio L, Campiotti L, et al. JAK2V617F mutation for the early diagnosis of Ph myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis. Blood. 2009; 113: 5617-5623. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19273837
Roques M, Park JH, Minello A, Bastie JN, Girodon F. Detection of the CALR mutation in the diagnosis of splanchnic vein thrombosis. Br J Haematol. 2015; 169: 601-603. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25413838
Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, et al. Philadelphia – Negative classical myeloproliferative neoplasms: critical concepts and management recomandation from European LeukemiaNet. J Clin Oncol. 2011; 29: 761-770. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21205761
Barbui T, Finazzi G, Carobbio A, et al. Development and validation an international Prognostic Score of thrombosis in World Health Organization essential thrombo cythemia. Blood. 2012; 120: 5128-5133. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23033268
Haider M, Gangat N, Lasho T, Abou Hussein AK, Elala YC, et al. Validation of the revised international prognostic score of thrombosis for essential thrombocythemia (IPSET-thrombosis) in 585 Mayo clinic patients. Am J Hematol. 2016; 91: 4. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26799697
Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2017 update, risk stratification, and management. Am J Hematol. 2017; 92: 94. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27991718
Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi E, et al. Incidence and risk factors for bleeding in 1104 patients with essential thrombocythemia or prefibrotic myelofibrosis diagnosed according to the 2008 WHO criteria. Leukemia. 2012; 26: 716-719. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21926959
Elliott MA, Tefferi A. Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br J Haematol. 2005; 128: 275-290. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15667529
Budde U, van Genderen PJ. Acquired von Willebrand disease in patients with high platelet counts. Semin Thromb Hemost. 1997; 23: 425-431. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/9387201
Federici AB, Rand JH, Bucciarelli P, Budde U, Van Genderen PJ, et al. Acquired von Willebrand syndrome: data from an international registry. Thromb Haemost. 2000; 84: 345-349. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10959711
Passamonti F, Rumi E, Arcaini L, Boveri E, Elena C, et al. Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients. Haematologica. 2008; 93: 1645-1651. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18790799
Gangat N, Wolanskyj AP, McClure RF, Li CY, Schwager S, et al. Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients. Leukemia. 2006; 21: 270-276. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17170720
Barbui T, Thiele J, Passamonti F, Rumi E, Boveri E, et al. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol. 2011; 29: 3179-3184. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21747083
Wolanskyj AP, Schwager SM, McClure RF, Larson DR, Tefferi A. Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors. Mayo Clin Proc. 2006; 81: 159-166. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16471068
Abdulkarim K, Ridell B, Johansson P, Kutti J, Safai-Kutti S, et al. The impact of peripheral blood values and bone marrowfindings on prognosis for patients with essential thrombocythemia and polycythemia vera. Eur J Haematol. 2011; 86: 148-155. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21059102
Pietra D, Rumi E, Ferretti VV, Di Buduo CA, Milanesi C, et al. Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms. Leukemia. 2016; 30: 431-438. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26449662
Barbui T, Tefferi A, Vannucchi AM, Passamonti F, Silver RT, et al, Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia. 2018; 32: 1057-1069. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29515238
Alvarez-Larran A, Pereira A, Guglielmelli P, Hernández-Boluda JC, Arellano-Rodrigo E, et al. Antiplatelet therapy versus observation in low-risk essential thrombocythemia with CALR mutation. Haematologica. 2016; 101: 926-931. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27175028
Barbui T, De Stefano V. Addressing and proposing solutions for unmet clinical needs in the managementof myeloproliferative neoplasm-as-associated thrombosis: A consensus-based position paper. Blood Cancer Journal. 2019; 9: 61.
Baerlocher GM, Oppliger Leibundgut E, Ottmann OG, Spitzer G, Odenike O, et al. Telomerase inhibitor imetelstat in patients with essential thrombocythemia. N Engl J Med. 2015; 373: 920-928. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26332546
Rambaldi A, Dellacasa CM, Finazzi G, Carobbio A, Ferrari ML, et al. A pilot study of the histonedeacetylase inhibitor givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms. Br J Haematol. 2010; 150: 446-455. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20560970
Andersen CL, McMullin MF, Ejerblad E, Zweegman S, Harrison C, et al. A phase II study of vorinostat (MK-0683) in patients with polycythaemia vera and essential thrombocythaemia. Br J Haematol. 2013; 162: 498-508. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23758082
Verstovsek S, Passamonti F, Rambaldi A, Barosi G5, Rumi E, et al. Ruxolitinib for essential thrombocythemia refractory to or intolerant of hydroxyurea: long-term phase 2 study results. Blood. 2017; 130: 1768-1771. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28827411
Mora B, Passamonti F. Developments in diagnosis and treatment of essential thrombocythemia. Expert Review of Hematology. 2019; 12: 159-171. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30793984
Wright CA, Tefferi A. A single institutional experience with 43 pregnancies in essential thrombocythemia. Eur J Haematol. 2001; 66: 152-159. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11350483
Lavi N, Brenner B, Avivi I. Management of pregnant women with myeloproliferative neoplasms. Thromb Res. 2013; 131: S11-S13. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23452731
Passamonti F, Randi ML, Rumi E, Pungolino E, Elena C, et al. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617VF) mutation. Blood. 2007; 110: 485-489. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17426257
Randi ML, Bertozzi I, Rumi E, Elena C, Finazzi G, et al. Pregnancy complications predict thrombotic events in young women with essential thrombocythemia. Am J Hematol. 2014; 89: 306-309. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24265194
Alimam S, Bewley S, Chappell LC, Knight M, Seed P, et al. Pregnancy outcomes in myeloproliferative neoplasms: UK prospective cohort study. Br J Haematol. 2016; 175: 31-36. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27612319
Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, et al. Philadelphia negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European leukemianet. J Clin Oncol. 2011; 29: 761-770. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21205761
Kreher S, Ochsenreither S, Trappe RU. Prophylaxis and management of venous thromboembolism in patients with myeloproliferative neoplasms: consensus statement of the Haemostasis Working Party of the German Society of Hematology and Oncology (DGHO),the Austrian Socie-ty of Hematology and Oncology (€OGHO) and Society of Thrombosis and Haemostasis Research (GTH eV). Ann Hematol. 2014; 93: 1953-1963.
Passamonti F, Rumi E, Pungolino E, Malabarba L, Bertazzoni P, et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med. 2004; 117: 755-761. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15541325
Passamonti F, Thiele J, Girodon F, Rumi E, Carobbio A, et al. A prognostic model to predict survival in 867 World Health Organization–defined essential thrombocythemia at diagnosis: a study by the International Working Group on Myelofibrosis Research and Treatment. Blood. 2012; 120: 1197-1201. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22740446
Napolitano M, Siragusa S. Comparison of clinical and laboratory data, including JAK-2 46/1 haplotipe, between patients With Idiopathic Erythrocytosis and Polycythemia Vera. EHA22 Abstract book PB 2039.
Hinds DA, Barnholt KE, Mesa RA, Kiefer AK, Do CB, et al. Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms. Blood. 2016; 128: 1121-1128. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27365426
Rumi E, Passamonti F, Pietra D, Della Porta MG, Arcaini L, et al. JAK2 (V617F) as an acquired somatic mutation and a secondary genetic event associated with disease progression in familial myeloproliferative disorders. Cancer. 2000; 107: 2206–2211. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16998940
Bellanne-Chantelot C, Chaumarel I, Labopin M, Labopin M, Bellanger F, et al. Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders. Blood. 2006; 108: 346-352.
Maffioli M, Mora B. Familial myeloproliferative neoplasms. A single institution: analysis of 22 families. EHA23 Abstract Book PS 1361.
Rumi E, Cazzola M. How we treat essential thrombocythemia. Blood. 2016; 128: 2403-2414. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27561316