эссенциальная тромбоцитемия

Биология миелопролиферативных новообразований

МИЕЛОИДНЫЕ ОПУХОЛИ , , , , , , ,

А.Л. Меликян, И.Н. Суборцева

ФГБУ «Гематологический научный центр» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167

Для переписки: Ирина Николаевна Суборцева, канд. мед. наук, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167; тел.: +7(495)612-44-71; e-mail: soubortseva@yandex.ru

Для цитирования: Меликян А.Л., Суборцева И.Н. Биология миелопролиферативных новообразований. Клиническая онкогематология. 2016;9(3):314-25.

DOI: 10.21320/2500-2139-2016-9-3-314-325

РЕФЕРАТ

Хронические миелопролиферативные заболевания (ВОЗ, 2001), или миелопролиферативные новообразования/опухоли (МПН) (ВОЗ, 2008), являются клональными заболеваниями, характеризуются пролиферацией одной или более клеточной линии миелопоэза в костном мозге с признаками сохраняющейся терминальной дифференцировки и, как правило, сопровождаются изменениями показателей крови. В группу классических Ph-негативных МПН отнесены истинная полицитемия, эссенциальная тромбоцитемия, первичный миелофиброз и МПН неклассифицируемое. Приобретенные соматические мутации, лежащие в основе патогенеза Ph-негативных МПН, представлены мутациями генов JAK2 (V617F, экзон 12), MPL, CALR. Мутации перечисленных генов наблюдаются примерно у 90 % больных. Однако данные молекулярные события не являются уникальными в патогенезе заболеваний. Мутации других генов (ТЕТ2, ASXL1, CBL, IDH1/IDH2, IKZF1, DNMT3A, SOCS, EZH2, TP53, RUNX1 и HMGA2) принимают участие в формировании фенотипа заболевания. В настоящем обзоре описываются современные представления о молекулярной биологии МПН.

Ключевые слова: хронические миелопролиферативные заболевания, миелопролиферативные новообразования, истинная полицитемия, эссенциальная тромбоцитемия, первичный миелофиброз, ген JAK2, ген CALR, ген MPL.

Получено: 11 апреля 2016 г.

Принято в печать: 11 апреля 2016 г.

Читать статью в PDFpdficon

ЛИТЕРАТУРА

  1. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011;29(6):761–70. doi: 10.1200/jco.2010.31.8436.
  2. Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer. 2009;115(17):3842–7. doi: 10.1002/cncr.24440.
  3. Barosi G. Essential thrombocythemia vs. early/prefibrotic myelofibrosis: why does it matter. Best Pract Res Clin Haematol. 2014;27(2):129–40. doi: 10.1016/j.beha.2014.07.004.
  4. Vannucchi AM. Management of myelofibrosis. Am Soc Hematol Educ Program. 2011;2011(1):222–30. doi:10.1182/asheducation-2011.1.222.
  5. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895–901. doi: 10.1182/blood-2008-07-170449.
  6. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29(4):392–7. doi: 10.1200/jco.2010.32.2446.
  7. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115(9):1703–8. doi: 10.1182/blood-2009-09-245837.
  8. Tefferi A. How I treat myelofibrosis. Blood. 2011;117(13):3494–504. doi: 10.1182/blood-2010-11-315614.
  9. Tefferi A, Guglielmelli P, Lasho TL, et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia. 2014;28(7):1494–500. doi: 10.1038/leu.2014.57.
  10. Agarwal MB, Malhotra H, Chakrabarti P, et al. Myeloproliferative neoplasms working group consensus recommendations for diagnosis and management of primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Indian J Med Paediatr Oncol. 2015;36(1):3–16. doi: 10.4103/0971-5851.151770.
  11. Campregher PV, Santos FP, Perini GF, Hamerschlak N. Molecular biology of Philadelphia-negative myeloproliferative neoplasms. Rev Bras Hematol Hemoter. 2012;34(2):150–5. doi: 10.5581/1516-8484.20120035.
  12. Ghoreschi K, Laurence A, O’Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009;228(1):273–87. doi: 10.1111/j.1600-065X.2008.00754.x.
  13. Liu KD, Gaffen SL, Goldsmith MA. JAK/STAT signaling by cytokine receptors. Curr Opin Immunol. 1998;10(3):271–8. doi: 10.1016/s0952-7915(98)80165-9.
  14. Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia. 2010;24(6):1128–38. doi: 10.1038/leu.2010.69.
  15. Riedy MC, Dutra AS, Blake TB, et al. Genomic sequence, organization, and chromosomal localization of human JAK3. Genomics. 1996;37(1):57–61. doi: 10.1006/geno.1996.0520.
  16. Saharinen P, Silvennoinen O. The pseudokinase domain is required for suppression of basal activity of Jak2 and Jak3 tyrosine kinases and for cytokine-inducible activation of signal transduction. J Biol Chem. 2002;277(49):47954–63. doi: 10.1074/jbc.M205156200.
  17. Benekli M, Baer MR, Baumann H, Wetzler M. Signal transducer and activator of transcription proteins in leukemias. Blood. 2003;101(8):2940–54. doi: 10.1182/blood-2002-04-1204.
  18. Vainchenker W, Delhommeau F, Constantinescu SN, Bernard OA. New mutations and pathogenesis of myeloproliferative neoplasms. Blood. 2011;118(7):1723–35. doi: 10.1182/blood-2011-02-292102.
  19. Lacout C, Pisani DF, Tulliez M, et al. JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis. Blood. 2006;108(5):1652–660. doi: 10.1182/blood-2006-02-002030.
  20. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144–8. doi: 10.1038/nature03546.
  21. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779–90. doi: 10.1056/NEJMoa051113.
  22. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7(4):387–97. doi: 10.1016/j.ccr.2005.03.023.
  23. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. The Lancet. 2005;365(9464):1054–61. doi: 10.1016/S0140-6736(05)71142-9.
  24. Butcher CM, Hahn U, To LB, et al. Two novel JAK2 exon 12 mutations in JAK2V617F-negative polycythaemia vera patients. Leukemia. 2008;22(4):870–3. doi: 10.1038/sj.leu.2404971.
  25. Jelinek J, Oki Y, Gharibyan V, et al. JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocyticleukemia. Blood. 2005;106(10):3370–3. doi: 10.1182/blood-2005-05-1800.
  26. Pich A, Riera L, Sismondi F, et al. JAK2V617F activating mutation is associated with the myeloproliferative type of chronic myelomonocytic leukaemia. J Clin Pathol. 2009;62(9):798–801. doi: 10.1136/jcp.2009.065904.
  27. Johan MF, Goodeve AC, Bowen DT, et al. JAK2 V617F Mutation is uncommon in chronic myelomonocytic leukaemia. Br J Haematol. 2005;130(6):968. doi: 10.1111/j.1365-2141.2005.05719.x.
  28. Renneville A, Quesnel B, Charpentier A, et al. High occurrence of JAK2 V617 mutation in refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Leukemia. 2006;20(11):2067–70. doi: 10.1038/sj.leu.2404405.
  29. Verstovsek S, Silver RT, Cross NC, Tefferi A. JAK2V617F mutational frequency in polycythemia vera: 100%, > 90%, less? Leukemia. 2006;20(11):2067. doi:10.1038/sj.leu.2404379.
  30. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;110(3):840–6. doi: 10.1182/blood-2006-12-064287.
  31. Barosi G, Bergamaschi G, Marchetti M, et al. JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. Blood. 2007;110(12):4030–6. doi: 10.1182/blood-2007-07-099184.
  32. Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27(9):1861–9. doi: 10.1038/leu.2013.119.
  33. Lussana F, Caberlon S, Pagani C, et al. Association of V617F Jak2 mutation with the risk of thrombosis among patients with essential thrombocythaemia or idiopathic myelofibrosis: a systematic review. Thromb Res. 2009;124(4):409–17. doi: 10.1016/j.thromres.2009.02.004.
  34. Wang M, He N, Tian T, et al. Mutation analysis of JAK2V617F, FLT3-ITD, NPM1, and DNMT3A in Chinese patients with myeloproliferative neoplasms. BioMed Res Int. 2014;2014:485645. doi: 10.1155/2014/485645.
  35. Passamonti F, Thiele J, Girodon F, 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(6):1197–201. doi: 10.1182/blood-2012-01-403279.
  36. Barbui T, Carobbio A, Rambaldi A, Finazzi G. Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: is leukocytosis a causative factor? Blood. 2009;114(4):759–63. doi: 10.1182/blood-2009-02-206797.
  37. Barbui T, Finazzi G, Carobbio A, et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood. 2012;120(26):5128–33. doi: 10.1182/blood-2012-07-444067.
  38. Tefferi A, Pardanani A. Myeloproliferative neoplasms – a contemporary review. JAMA Oncol. 2015;1(1):97–105. doi: 10.1001/jamaoncol.2015.89.
  39. Nussenzveig RH, Swierczek SI, Jelinek J, et al. Polycythemia vera is not initiated by JAK2V617F mutation. Exp Hematol. 2007;35(1):32–8. doi: 10.1016/j.exphem.2006.11.012.
  40. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356(5):459–68. doi: 10.1056/NEJMoa065202.
  41. Williams DM, Kim AH, Rogers O, et al. Phenotypic variations and new mutations in JAK2 V617F-negative polycythemia vera, erythrocytosis, and idiopathic myelofibrosis. Exp Hematol. 2007;35(11):1641–6. doi: 10.1016/j.exphem.2007.08.010.
  42. Passamonti F, Elena C, Schnittger S, et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood. 2011;117(10):2813–6. doi: 10.1182/blood-2010-11-316810.
  43. Campbell PJ, Griesshammer M, Dohner K, et al. V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis. Blood. 2006;107(5):2098–100. doi: 10.1182/blood-2005-08-3395.
  44. Martinez-Aviles L, Besses C, Alvarez-Larran A, et al. JAK2 exon 12 mutations in polycythemia vera or idiopathic erythrocytosis. Haematologica. 2007;92(12):1717–8. doi: 10.3324/haematol.12011.
  45. Sangkhae V, Etheridge SL, Kaushansky K, Hitchcock IS. The thrombopoietin receptor, MPL, is critical for development of a JAK2V617F-induced myeloproliferative neoplasm. Blood. 2014;124(26):3956–63. doi: 10.1182/blood-2014-07-587238.
  46. Chou FS, Mulloy JC. The thrombopoietin/MPL pathway in hematopoiesis and leukemogenesis. J Cell Biochem. 2011;112(6):1491-8. doi: 10.1002/jcb.23089.
  47. Abe M, Suzuki K, Inagaki O, et al. A novel MPL point mutation resulting in thrombopoietin-independent activation. Leukemia. 2002;16(8):1500–6. doi: 10.1038/sj.leu.2402554.
  48. Ding J, Komatsu H, Wakita A, et al. Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. Blood. 2004;103(11):4198–200. doi: 10.1182/blood-2003-10-3471.
  49. Moliterno AR, Williams DM, Gutierrez-Alamillo LI, et al. Mpl Baltimore: A thrombopoietin receptor polymorphism associated with thrombocytosis. Proc Natl Acad Sci USA. 2004;101(31):11444–7. doi: 10.1073/pnas.0404241101.
  50. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3(7):e270. doi: 10.1371/journal.pmed.0030270.
  51. Staerk J, Lacout C, Sato T, et al. An amphipathic motif at the transmembrane-cytoplasmic junction prevents autonomous activation of the thrombopoietin receptor. Blood. 2006;107(5):1864–71. doi: 10.1182/blood-2005-06-2600.
  52. Boyd EM, Bench AJ, Goday-Fernandez A, et al. Clinical utility of routine MPL exon 10 analysis in the diagnosis of essential thrombocythaemia and primary myelofibrosis. Br J Haematol. 2010;149(2):250–7. doi: 10.1111/j.1365-2141.2010.08083.x.
  53. Lambert MP, Jiang J, Batra V, et al. A novel mutation in MPL (Y252H) results in increased thrombopoietin sensitivity in essential thrombocythemia. Am J Hematol. 2012;87(5):532–4. doi: 10.1002/ajh.23138.
  54. Hussein K, Bock O, Theophile K, et al. MPLW515L mutation in acute megakaryoblastic leukaemia. Leukemia. 2009;23(5):852–5. doi: 10.1038/leu.2008.371.
  55. Beer PA, Campbell PJ, Scott LM, et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood. 2008;112(1):141–9. doi: 10.1182/blood-2008-01-131664.
  56. Akpinar TS, Hancer VS, Nalcaci M, Diz-Kucukkaya R. MPL W515L/K Mutations in chronic myeloproliferative neoplasms. Turk J Haematol. 2013;30(1):8–12. doi: 10.4274/tjh.65807.
  57. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia. Blood. 2008;112(3):844–7. doi: 10.1182/blood-2008-01-135897.
  58. Teofili L, Giona F, Torti L, et al. Hereditary thrombocytosis caused by MPLSer505Asn is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis. Haematologica. 2010;95(1):65–70. doi: 10.3324/haematol.2009.007542.
  59. Sun C, Zhang S, Li J. Calreticulin gene mutations in myeloproliferative neoplasms without Janus kinase 2 mutations. Leuk Lymphoma. 2015;56(6):1593–8. doi: 10.3109/10428194.2014.953153.
  60. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379–90. doi: 10.1056/NEJMoa1311347.
  61. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391–405. doi: 10.1056/NEJMoa1312542.
  62. Shirane S, Araki M, Morishita S, et al. JAK2, CALR, and MPL mutation spectrum in Japanese myeloproliferative neoplasms patients. Haematologica. 2015;100(2):46–8. doi: 10.3324/haematol.2014.115113.
  63. Lundberg P, Karow A, Nienhold R, et al. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood. 2014;123(14):2220–8. doi: 10.1182/blood-2013-11-537167.
  64. Lavi N. Calreticulin mutations in myeloproliferative neoplasms. Rambam Maimonides Med J. 2014;5(4):e0035. doi: 10.5041/RMMJ.10169.
  65. Rumi E, Harutyunyan AS, Pietra D, et al. CALR exon 9 mutations are somatically acquired events in familial cases of essential thrombocythemia or primary myelofibrosis. Blood. 2014;123(15):2416–9. doi: 10.1182/blood-2014-01-550434.
  66. Haslam K, Langabeer SE. Incidence of CALR mutations in patients with splanchnic vein thrombosis. Br J Haematol. 2015;168(3):459–60. doi: 10.1111/bjh.13121.
  67. Turon F, Cervantes F, Colomer D, et al. Role of calreticulin mutations in the aetiological diagnosis of splanchnic vein thrombosis. J Hepatol. 2015;62(1):72–4. doi: 10.1016/j.jhep.2014.08.032.
  68. Tefferi A, Wassie EA, Lasho TL, et al. Calreticulin mutations and long-term survival in essential thrombocythemia. Leukemia. 2014;28(12):2300–3. doi: 10.1038/leu.2014.148.
  69. Tefferi A, Lasho TL, Finke CM, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014;28(7):1472–7. doi: 10.1038/leu.2014.3.
  70. Tefferi A, Lasho TL, Finke C, et al. Type 1 vs type 2 calreticulin mutations in primary myelofibrosis: differences in phenotype and prognostic impact. Leukemia. 2014;28(7):1568–70. doi: 10.1038/leu.2014.83.
  71. Shide K, Kameda T, Shimoda H, et al. TET2 is essential for survival and hematopoietic stem cell homeostasis. Leukemia. 2012;26(10):2216–23. doi: 10.1038/leu.2012.94.
  72. Ito S, D’Alessio AC, Taranova OV, et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010;466(7310):1129–33. doi: 10.1038/nature09303.
  73. Paulsson K, Haferlach C, Fonatsch C, et al. The idic(X)(q13) in myeloid malignancies: breakpoint clustering in segmental duplications and association with TET2 mutations. Hum Mol Genet. 2010;19(8):1507–14. doi: 10.1093/hmg/ddq024.
  74. Tefferi A, Pardanani A, Lim KH, et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia. 2009;23(5):905–11. doi: 10.1038/leu.2009.47.
  75. Martinez-Aviles L, Besses C, Alvarez-Larran A, et al. TET2, ASXL1, IDH1, IDH2, and c-CBL genes in JAK2- and MPL-negative myeloproliferative neoplasms. Ann Hematol. 2012;91(4):533–41. doi: 10.1007/s00277-011-1330-0.
  76. Patriarca A, Colaizzo D, Tiscia G, et al. TET2 mutations in Ph-negative myeloproliferative neoplasms: identification of three novel mutations and relationship with clinical and laboratory findings. BioMed Res Int. 2013;2013:929840. doi: 10.1155/2013/929840.
  77. Schaub FX, Looser R, Li S, et al. Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms. Blood. 2010;115(10):2003–7. doi: 10.1182/blood-2009-09-245381.
  78. Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360(22):2289–301. doi: 10.1056/NEJMoa0810069.
  79. Beer PA, Delhommeau F, LeCouedic JP, et al. Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood. 2010;115(14):2891–900. doi: 10.1182/blood-2009-08-236596.
  80. Ortmann CA, Kent DG, Nangalia J, et al. Effect of mutation order on myeloproliferative neoplasms. N Engl J Med. 2015;372(7):601–12. doi: 10.1056/NEJMoa1412098.
  81. Gelsi-Boyer V, Trouplin V, Adelaide J, et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol. 2009;145(6):788–800. doi: 10.1111/j.1365-2141.2009.07697.x.
  82. Carbuccia N, Murati A, Trouplin V, et al. Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia. 2009;23(11):2183–6. doi: 10.1038/leu.2009.141.
  83. Carbuccia N, Trouplin V, Gelsi-Boyer V, et al. Mutual exclusion of ASXL1 and NPM1 mutations in a series of acute myeloid leukemias. Leukemia. 2010;24(2):469–73. doi: 10.1038/leu.2009.218.
  84. Abdel-Wahab O, Adli M, LaFave LM, et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell. 2012;22(2):180–93. doi: 10.1016/j.ccr.2012.06.032.
  85. Brecqueville M, Rey J, Bertucci F, et al. Mutation analysis of ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 in myeloproliferative neoplasms. Genes Chromos Cancer. 2012;51(8):743–55. doi: 10.1002/gcc.21960.
  86. Katoh M. Functional and cancer genomics of ASXL family members. Br J Cancer. 2013;109(2):299–306. doi: 10.1038/bjc.2013.281.
  87. Cervantes F. How I treat myelofibrosis. Blood. 2014;124(17):2635–42. doi: 10.1182/blood-2014-07-575373.
  88. Ernst T, Chase AJ, Score J, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet. 2010;42(8):722–6. doi: 10.1038/ng.621.
  89. Simon JA, Lange CA. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res. 2008;647(1–2):21–9. doi: 10.1016/j.mrfmmm.2008.07.010.
  90. Im AP, Sehgal AR, Carroll MP, et al. DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies. Leukemia. 2014;28(9):1774–83. doi: 10.1038/leu.2014.124.
  91. Walter MJ, Ding L, Shen D, et al. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia. 2011;25(7):1153–8. doi: 10.1038/leu.2011.44.
  92. Yamashita Y, Yuan J, Suetake I, et al. Array-based genomic resequencing of human leukemia. Oncogene. 2010;29(25):3723–31. doi: 10.1038/onc.2010.117.
  93. Abdel-Wahab O, Pardanani A, Rampal R, et al. DNMT3A mutational analysis in primary myelofibrosis, chronic myelomonocytic leukemia and advanced phases of myeloproliferative neoplasms. Leukemia. 2011;25(7):1219–20. doi: 10.1038/leu.2011.82.
  94. Brecqueville M, Cervera N, Gelsi-Boyer V, et al. Rare mutations in DNMT3A in myeloproliferative neoplasms and myelodysplastic syndromes. Blood Cancer J. 2011;1(5):e18. doi: 10.1038/bcj.2011.15.
  95. Rudd CE. Lnk adaptor: novel negative regulator of B cell lymphopoiesis. Sci STKE. 2001;2001(85):pe1. doi: 10.1126/stke.2001.85.pe1.
  96. Gery S, Cao Q, Gueller S, et al. Lnk inhibits myeloproliferative disorder-associated JAK2 mutant, JAK2V617F. J Leuk Biol. 2009;85(6):957–65. doi: 10.1189/jlb.0908575.
  97. Soriano G, Heaney M. Polycythemia vera and essential thrombocythemia: new developments in biology with therapeutic implications. Curr Opin Hematol. 2013;20(2):169–75. doi: 10.1097/MOH.0b013e32835d82fe.
  98. Oh ST, Simonds EF, Jones C, et al. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood. 2010;116(6):988–92. doi: 10.1182/blood-2010-02-270108.
  99. Lasho TL, Pardanani A, Tefferi A. LNK mutations in JAK2 mutation-negative erythrocytosis. N Engl J Med. 2010;363(12):1189–90. doi: 10.1056/NEJMc1006966.
  100. Rathinam C, Thien CB, Flavell RA, Langdon WY. Myeloid leukemia development in c-Cbl RING finger mutant mice is dependent on FLT3 signaling. Cancer Cell. 2010;18(4):341–52. doi: 10.1016/j.ccr.2010.09.008.
  101. Loh ML, Sakai DS, Flotho C, et al. Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood. 2009;114(9):1859–63. doi: 10.1182/blood-2009-01-198416.
  102. Sanada M, Suzuki T, Shih LY, et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature. 2009;460(7257):904–8. doi: 10.1038/nature08240.
  103. Zhang MY, Fung TK, Chen FY, Chim CS. Methylation profiling of SOCS1, SOCS2, SOCS3, CISH and SHP1 in Philadelphia-negative myeloproliferative neoplasm. J Cell Mol Med. 2013;17(10):1282–90. doi: 10.1111/jcmm.12103.
  104. Fourouclas N, Li J, Gilby DC, et al. Methylation of the suppressor of cytokine signaling 3 gene (SOCS3) in myeloproliferative disorders. Haematologica. 2008;93(11):1635–44. doi: 10.3324/haematol.13043.
  105. Kastner P, Chan S. Role of Ikaros in T-cell acute lymphoblastic leukemia. World J Biol Chem. 2011;2(6):108–14. doi: 10.4331/wjbc.v2.i6.108.
  106. Jager R, Kralovics R. Molecular pathogenesis of Philadelphia chromosome negative chronic myeloproliferative neoplasms. Curr Cancer Drug Targets. 2011;11(1):20–30. doi: 10.2174/156800911793743628.
  107. Ikeda K, Ogawa K, Takeishi Y. The role of HMGA2 in the proliferation and expansion of a hematopoietic cell in myeloproliferative neoplasms. Fukushima J Med Sci. 2012;58(2):91–100. doi: 10.5387/fms.58.91.
  108. Harada-Shirado K, Ikeda K, Ogawa K, et al. Dysregulation of the MIRLET7/HMGA2 axis with methylation of the CDKN2A promoter in myeloproliferative neoplasms. Br J Haematol. 2015;168(3):338–49. doi: 10.1111/bjh.13129.
  109. Raza S, Viswanatha D, Frederick L, et al. TP53 mutations and polymorphisms in primary myelofibrosis. Am J Hematol. 2012;87(2):204–6. doi: 10.1002/ajh.22216.
  110. Lu M, Hoffman R. p5 as a target in myeloproliferative neoplasms. Oncotarget. 2012;3(10):1052–3. doi: 10.18632/oncotarget.719.
  111. Gurney AL, Wong SC, Henzel WJ, de Sauvage FJ. Distinct regions of c-Mpl cytoplasmic domain are coupled to the JAK-STAT signal transduction pathway and Shc phosphorylation. Proc Natl Acad Sci USA. 1995;92(12):5292–6. doi: 10.1073/pnas.92.12.5292
  112. Tefferi A, Thiele J, Vannucchi AM, Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia. 2014;28(7):1407–13. doi: 10.1038/leu.2014.35.
  113. Broseus J, Park JH, Carillo S, et al. Presence of calreticulin mutations in JAK2-negative polycythemia vera. Blood. 2014;124(26):3964–6. doi: 10.1182/blood-2014-06-583161.
  114. Hasan S, Lacout C, Marty C, et al. JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNa. Blood. 2013;122(8):1464–77. doi: 10.1182/blood-2013-04-498956.
  115. Pardanani A, Lasho T, Finke C, et al. LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations. Leukemia. 2010;24(10):1713–8. doi: 10.1038/leu.2010.163.

Современные подходы к диагностике и лечению эссенциальной тромбоцитемии: обзор литературы и собственные данные

РЕДКИЕ ГЕМАТОЛОГИЧЕСКИЕ ЗАБОЛЕВАНИЯ И СИНДРОМЫ , , ,

Абдулкадыров К.М., Шуваев В.А., Мартынкевич И.С.

ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», ул. 2-я Советская, д. 16, Санкт-Петербург, Российская Федерация, 191024

Для переписки: Василий Анатольевич Шуваев, канд. мед. наук, ул. 2-я Советская, д. 16, Санкт-Петербург, Российская Федерация, 191024; тел.: +7(921)636-54-72; e-mail: shuvaev77@mail.ru

Для цитирования: Абдулкадыров К.М., Шуваев В.А., Мартынкевич И.С. Современные подходы к диагностике и лечению эссенциальной тромбоцитемии: обзор литературы и собственные данные. Клиническая онкогематология. 2015;8(3):235–47.

РЕФЕРАТ

Цель. Обзор литературы с освещением вопросов эпидемиологии, терминологии, этиологии, механизмов становления и развития эссенциальной тромбоцитемии, а также представление собственных данных.

Методы. Описываются молекулярно-генетические основы патогенеза заболевания и клиническая картина его проявлений. Рассматриваются вопросы, касающиеся диагностических критериев, дифференциальной диагностики и классификации эссенциальной тромбоцитемии. Приведены результаты молекулярно-генетических и цитогенетических исследований, основные причины развития тромботических осложнений, методы их профилактики и лечения. Широко освещаются методы лечения, мониторинг и оценка эффективности терапии заболевания. Представлен анализ собственного опыта диагностики и лечения 218 взрослых пациентов с эссенциальной тромбоцитемией. Женщин было 161, мужчин — 57, соотношение по полу 2,8:1, медиана возраста составила 57,2 года (диапазон 18,3–89,3 года). Хромосомные аберрации выявлены у 7 (9,3 %) из 65 обследованных цитогенетически пациентов. Мутация JAK2V617F обнаружена у 79 (58,1 %) из 136 больных, а гена MPL — у 1 (2,3 %) из 44.

Результаты. Общая 10-летняя выживаемость 218 больных эссенциальной тромбоцитемией составила 83,9 %. Прогрессирование в фазу вторичного посттромбоцитемического миелофиброза зарегистрировано у 13 (6 %) пациентов. Лечение осуществлялось гидроксимочевиной (n = 132), интерферонами-a (n = 37), анагрелидом (n = 10), ацетилсалициловой кислотой (n = 54). Летальность за весь период наблюдения в течение 10 лет составила 16,1 % (n = 35).

Заключение. Своевременная и ранняя диагностика эссенциальной тромбоцитемии, определение тактики терапии с учетом риска тромбоэмболических осложнений и последующее динамическое наблюдение за больными с контролем уровня тромбоцитов служат залогом сохранения продолжительности и качества жизни пациентов.

Ключевые слова: эссенциальная тромбоцитемия, мутация в гене Янус-киназы 2 (JAK2), риск тромботических осложнений, алгоритм диагностики и лечения.

Получено: 14 января 2015 г.

Принято в печать: 26 мая 2015 г.

Читать статью в PDFpdficon

ЛИТЕРАТУРА

  1. Izaguirre-Avila R, Penia-Diaz A, De la Barinagarrementeria-Aldatz F, et al. Effect of Clopidogrel on Platelet Aggregation and Plasma Concentration of Fibrinogen in Subjects with Cerebral or Coronary Atherosclerotic Disease. Clin Applied Thromb Hemost. 2002;8(2):169–77. doi: 10.1177/107602960200800214.
  2. Абдулкадыров К.М. Клиническая гематология: справочник. СПб.: Питер Принт, 2006. 447 с.
    [Abdulkadyrov KM. Klinicheskaya gematologiya: spravochnik. (Clinical hematology: textbook.) Saint Petersburg: Piter Print Publ.; 2006. 447 p. (In Russ)]
  3. Воробьев А.И. Руководство по гематологии. М.: Ньюдиамед, 2003. Ч. 3. С. 9–15.
    [Vorob’ev AI. Rukovodstvo po gematoligii. (Guidelines in Hematology.) Moscow: NewDiamed Publ.; 2003. Vol. 3. pp. 9–15. (In Russ)]
  4. Абдулкадыров К.М., Шуваев В.А. Эссенциальная тромбоцитемия: современные представления о диагностике и лечении. СПб., 2014. 49 с.
    [Abdulkadyrov KM, Shuvaev VA. Essentialnaya trombocytemia: sovremennye predstavleniya o diagnostike i lechenii. (Essential thrombocythemia: modern concepts about diagnostics and treatment.) Saint Petersburg; 2014. 49 p. (In Russ)]
  5. Epstein E, Goedel A. Hammorhagische thrombocythamie bei vascularer schrumpfmilz. Virchow Arch. (Pathol. Anat.) 1934;292(2):233–48. doi: 10.1007/bf01891529.
  6. Dameshek W. Editorial: Some Speculations on the Myeloproliferative Syndromes. Blood. 1951;6(4):372–5.
  7. Mesa RA, Silverstein MN, Jacobsen SJ, et al. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: An Olmsted county study, 1976–1995. Am J Hematol. 1999;61(1):10–5. doi: 10.1002/(sici)1096-8652(199905)61:1<10::aid-ajh3>3.0.co;2-i.
  8. Tefferi A, Solberg LA Jr, Silverstein MN. A clinical update in polycythemia vera and essential thrombocythemia. Am J Med. 2000;109(2):141–9. doi: 10.1016/s0002-9343(00)00449-6.
  9. Shuvaev VA, Abdulkadyrova AS, Martynkevich IS, et al. Essential thrombocythemia – population analysis, a single center 10-years’ experience. ELN Inform Letter. October 2013:21.
  10. Beer PA, Erber WN, Campbell PJ, et al. How I treat essential thrombocythemia. Blood. 2011;117(5):1472–82. doi: 10.1182/blood-2010-08-270033.
  11. Levine RL, Heaney M. New advances in the pathogenesis and therapy of essential thrombocythemia. Hematology Am Soc Hematol Educ Program. 2008(1):76–82. 10.1182/asheducation-2008.1.76.
  12. Vannucchi AM, Guglielmelli P. Molecular pathophysiology of Philadelphia-negative myeloproliferative disorders: beyond JAK2 and MPL mutations. Haematologica. 2008;93(7):972–6. doi: 10.3324/haematol.13266.
  13. Tefferi A. Polycythemia vera and essential thrombocythemia: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol. 2013;88(6):507–16. doi: 10.1002/ajh.23417.
  14. Barosi G, Mesa R, Finazzi G, et al. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood. 2013;121(23):4778–81. doi: 10.1182/blood-2013-01-478891.
  15. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms. N Engl J Med. 2013;369(25):2379–90. doi: 10.1056/nejmoa1311347.
  16. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2. N Engl J Med. 2013;369(25):2391–405. doi: 10.1056/nejmoa1312542.
  17. Hofmann SR, Lam AQ, Frank S, et al. Jak3-Independent Trafficking of the Common g Chain Receptor Subunit: Chaperone Function of Jaks Revisited. Mol Cell Biol. 2004;24(11):5039–49. doi: 10.1128/mcb.24.11.5039-5049.2004.
  18. Kamakura S, Oishi K, Yoshimatsu T, et al. Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signalling. Nat Cell Biol. 2004;6(6):547–54. doi: 10.1038/ncb1138.
  19. Campbell PJ, Scott LM, Buck G, et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. The Lancet. 2005;366(9501):1945–53. doi: 10.1016/s0140-6736(05)67785-9.
  20. Levine RL, Heaney M. New Advances in the Pathogenesis and Therapy of Essential Thrombocythemia. ASH Educ Program Book. 2008:76–82. doi: 10.1182/asheducation-2008.1.76.
  21. Tefferi A, Thiele J, Vannucchi AM, Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia. 2014;28(7):1407–13. doi: 10.1038/leu.2014.35.
  22. Abe M, Suzuki K, Inagaki O, et al. A novel MPL point mutation resulting in thrombopoietin-independent activation. Leukemia. 2002;16(8):1500–6. doi: 10.1038/sj.leu.2402554.
  23. Rotunno G, Mannarelli C, Guglielmelli P, et al. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood. 2013;123(10):1552–5. doi: 10.1182/blood-2013-11-538983.
  24. Rumi E, Pietra D, Ferretti V, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood. 2013;123(10):1544–51. doi: 10.1182/blood-2013-11-539098.
  25. Kiladjian J-J, Rain J-D, Bernard J-F, et al. Long-Term Incidence of Hematological Evolution in Three French Prospective Studies of Hydroxyurea and Pipobroman in Polycythemia Vera and Essential Thrombocythemia. Semin Thromb Hemost. 2006;32(4):417–21. doi: 10.1055/s-2006-942762.
  26. Nielsen I, Hasselbalch HC. Acute leukemia and myelodysplasia in patients with a Philadelphia chromosome negative chronic myeloproliferative disorder treated with hydroxyurea alone or with hydroxyurea after busulphan. Am J Hematol. 2003;74(1):26–31. doi: 10.1002/ajh.10375.
  27. Passamonti F, Rumi E, Arcaini L, et al. Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients. Haematologica. 2008;93(11):1645–51. doi: 10.3324/haematol.13346.
  28. Passamonti F, Rumi E, Pungolino E, et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med. 2004;117(10):755–61. doi: 10.1016/j.amjmed.2004.06.032.
  29. Alvarez-Larran A, Cervantes F, Bellosillo B, et al. Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Leukemia. 2007;21(6):1218–23. doi: 10.1038/sj.leu.2404967.
  30. Campbell PJ, MacLean C, Beer PA, et al. Correlation of blood counts with vascular complications in essential thrombocythemia: analysis of the prospective PT1 cohort. Blood. 2012;120(7):1409–11. doi: 10.1182/blood-2012-04-424911.
  31. Ruggeri M, Tosetto A, Frezzato M, et al. The Rate of Progression to Polycythemia Vera or Essential Thrombocythemia in Patients with Erythrocytosis or Thrombocytosis. Ann Intern Med. 2003;139(6):470–5. doi: 10.7326/0003-4819-139-6-200309160-00009.
  32. Murphy S, Peterson P, Iland H, Laszlo J. Experience of the Polycythemia Vera Study Group with essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment. Semin Hematol. 1997;34(1):29–39.
  33. Panani AD. Cytogenetic Findings in Untreated Patients with Essential Thrombocythemia. In Vivo. 2006;20(3):381–4.
  34. Thiele J, Kvasnicka HM, Facchetti F, et al. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005;90(8):1128–32.
  35. Tefferi A, Thiele J, Orazi A, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood. 2007;110(4):1092–7. doi: 10.1182/blood-2007-04-083501.
  36. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2007;22(1):14–22. doi: 10.1038/sj.leu.2404955.
  37. Barbui T, Finazzi G, Carobbio A, et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization – essential thrombocythemia (IPSET-thrombosis). Blood. 2012;120(26):5128–33. doi: 10.1182/blood-2012-07-444067.
  38. Jensen MK, De Nully B, Hasselbach OJ, et al. Incidence, clinical features and outcome of essential thrombocythaemia in a well defined geographical area. Eur J Haematol. 2000;65(2):132–9. doi: 10.1034/j.1600-0609.2000.90236.x.
  39. Michiels JJ, Van Genderen P, Lindemans JJ, et al. Erythromelalgic, Thrombotic and Hemorrhagic Manifestations in 50 Cases of Thrombocythemia. Leuk Lymphoma. 1996;22(s1):47–56. doi: 10.3109/10428199609074360.
  40. Alvarez-Larran, A, Cervantes F, Pereira A, et al. Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia. Blood. 2010;116(8):1205–10. doi: 10.1182/blood-2010-01-263319.
  41. Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for Patients with Essential Thrombocythemia and a High Risk of Thrombosis. N Engl J Med. 1995;332(17):1132–7. doi: 10.1056/nejm199504273321704.
  42. Gisslinger H, Holowiecki J, Penka M, et al. Final Results of the ANAHYDRET-Study: Non-Inferiority of Anagrelide Compared to Hydroxyurea in Newly Diagnosed WHO-Essential Thrombocythemia Patients. Blood (ASH Annual Meeting Abstracts). 2008;112:661.
  43. Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea Compared with Anagrelide in High-Risk Essential Thrombocythemia. N Engl J Med. 2005;353(1):33–45. doi: 10.1056/nejmoa043800.
  44. Fruchtman SM, Mack K, Kaplan ME, et al. From efficacy to safety: a Polycythemia Vera Study group report on hydroxyurea in patients with polycythemia vera. Semin Hematol. 1997;34(1):17–23.
  45. Kiladjian JJ, Chomienne C, Fenaux P. Interferon-[alpha] therapy in bcr-abl-negative myeloproliferative neoplasms. Leukemia. 2008;22(11):1990–8. doi: 10.1038/leu.2008.280.
  46. Lengfelder E, Griesshammer M, Hehlmann R. Interferon-alpha in the Treatment of Essential Thrombocythemia. Leuk Lymphoma. 1996;22(Suppl 1):135–42. doi: 10.3109/10428199609074371.
  47. Quintas-Cardama A, Kantarjian H, Manshouri T, et al. Pegylated Interferon Alfa-2a Yields High Rates of Hematologic and Molecular Response in Patients With Advanced Essential Thrombocythemia and Polycythemia Vera. J Clin Oncol. 2009;27(32):5418–24. doi: 10.1200/jco.2009.23.6075.
  48. Quintas-Cardama A, Abdel-Wahab O, Manshouri T, et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon a-2a. Blood. 2013;122(6):893–901. doi: 10.1182/blood-2012-07-442012.
  49. Cassinat B, Verger E, Kiladjian J-J. Interferon Alfa Therapy in CALR-Mutated Essential Thrombocythemia. N Engl J Med. 2014;371(2):188–9. doi: 10.1056/nejmc1401255.
  50. Sacchi S, Tabilio A, Leoni P, et al. Interferon alpha-2b in the long-term treatment of essential thrombocythemia. Ann Hematol. 1991;63(4):206–9. doi: 10.1007/bf01703444.
  51. Langer C, Lengfelder E, Thiele J, et al. Pegylated interferon for the treatment of high risk essential thrombocythemia: results of a phase II study. Haematologica. 2005;90(10):1333–8.
  52. Mascarenhas J, Mesa R, Prchal J, et al. Optimal therapy for polycythemia vera and essential thrombocythemia can only be determined by the completion of randomized clinical trials. Haematologica. 2014;99(6):945–9. doi: 10.3324/haematol.2014.106013.
  53. Alvarado Y, Cortes J, Verstovsek S, et al. Pilot study of pegylated interferon-alpha 2b in patients with essential thrombocythemia. Cancer Chemother Pharmacol. 2003;51(1):81–6. doi: 10.1007/s00280-002-0533-4.
  54. Quintas-Cardama A, Verstovsek S. Spleen deflation and beyond: The pros and cons of Janus kinase 2 inhibitor therapy for patients with myeloproliferative neoplasms. Cancer. 2012;118(4):870–7. doi: 10.1002/cncr.26359.
  55. Santos FP.S, Verstovsek S. JAK2 Inhibitors: Are They the Solution? Clin Lymph Myel Leuk. 2011;11(Suppl 1):S28–S36. doi: 10.1016/j.clml.2011.02.007.
  56. Tibes R, Mesa RA. Myeloproliferative neoplasms 5 years after discovery of JAK2V617F: what is the impact of JAK2 inhibitor therapy? Leuk Lymphoma. 2011;52(7):1178–87. doi: 10.3109/10428194.2011.566952.
  57. Verstovsek S, Passamonti F, Rambaldi A, et al. Durable Responses with the JAK1/JAK2 Inhibitor, INCB018424, In Patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) Refractory or Intolerant to Hydroxyurea (HU). Blood (ASH Annual Meeting Abstracts). 2010;116(21):313.
  58. Moliterno AR, Roboz GJ, Carroll M, et al. An Open-Label Study of CEP-701 in Patients with JAK2 V617F-Positive Polycythemia Vera and Essential Thrombocytosis. Blood (ASH Annual Meeting Abstracts). 2008;112(11):99.
  59. Baerlocher GM, Leibundgut EO, Ayran C, et al. Imetelstat Rapidly Induces and Maintains Substantial Hematologic and Molecular Responses in Patients with Essential Thrombocythemia (ET) Who Are Refractory or Intolerant to Prior Therapy: Preliminary Phase II Results. Blood (ASH Annual Meeting Abstracts). 2012;120(21):179.
  60. Barosi G, Birgegard G, Finazzi G, et al. Response criteria for essential thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus conference. Blood. 2009;113(20):4829–33. doi: 10.1182/blood-2008-09-176818.
  61. Schmitt-Graeff A. Standardization of Bone Marrow Biopsy Reporting in Ph-CMPD. LeukemiaNet. 2013; WP9.6:1.
  62. Wolanskyj AP, Schwager SM, McClure RF, et al. Essential Thrombocythemia Beyond the First Decade: Life Expectancy, Long-term Complication Rates, and Prognostic Factors. Mayo Clin Proceed. 2006;81(2):159–66. doi: 10.4065/81.2.159.
  63. Cervantes F, Alvarez-Larran A, Talarn C, et al. Myelofibrosis with myeloid metaplasia following essential thrombocythaemia: actuarial probability, presenting characteristics and evolution in a series of 195 patients. Br J Haematol. 2002;118(3):786–90. doi: 10.1046/j.1365-2141.2002.03688.x.
  64. Verstovsek S, Mesa RA, Gotlib J, et al. Consistent Benefit of Ruxolitinib Over Placebo in Spleen Volume Reduction and Symptom Improvement Across Subgroups and Overall Survival Advantage: Results From COMFORT-I. Blood (ASH Annual Meeting Abstracts). 2011;118(21):278.
  65. Harrison CN, Kiladijan JJ, Al-Ali HK, et al. Results of a randomized study of the JAK inhibitor INC424 compared with best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF). J Clin Oncol (ASCO Meeting Abstracts). 2011;29:LBA6501.
  66. Struve S, Finazzi G, Doehner K, et al. Pregnancies in Patients with Philadelphia Negative Chronic Myeloproliferative Disorders: Interim Report of the European LeukemiaNet Data Base. Blood (ASH Annual Meeting Abstracts). 2008;112(11):2806.
  67. Passamonti F, Randi ML, Rumi E, et al. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation. Blood. 2007;110(2):485–9. doi: 10.1182/blood-2007-01-071068.
  68. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-Negative Classical Myeloproliferative Neoplasms: Critical Concepts and Management Recommendations From European LeukemiaNet. J Clin Oncol. 2011;29(6):761–70. doi: 10.1200/jco.2010.31.8436.
  69. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. The Lancet. 2007;369(9575):1791–8. doi: 10.1016/s0140-6736(07)60712-0.
  70. Bangerter M, Guthner C, Beneke H, et al. Pregnancy in essential thrombocythaemia: treatment and outcome of 17 pregnancies. Eur J Haematol. 2000;65(3):165–9. doi: 10.1034/j.1600-0609.2000.90214.x.
  71. Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood. 2005;106(2):401–7. doi: 10.1182/blood-2005-02-0626.
  72. Hunt BJ, Gattens M, Khamashta M, et al. Thromboprophylaxis with unmonitored intermediate-dose low molecular weight heparin in pregnancies with a previous arterial or venous thrombotic event. Blood Coagul Fibrinol 2003;14(8):735–9. doi: 10.1097/00001721-200312000-00007.
  73. Gris J-C, Mercier E, Quere I, et al. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood. 2004;103(10):3695–9. doi: 10.1182/blood-2003-12-4250.
  74. Liebelt EL, Balk SJ, Faber W, et al. NTP-CERHR Expert Panel Report on the reproductive and developmental toxicity of hydroxyurea. Birth Defects Research Part B. Devel Reprod Toxicol. 2007;80(4):259–366. doi: 10.1002/bdrb.20123.
  75. Fenaux P, Simon M, Caulier MT, et al. Clinical course of essential thrombocythemia in 147 cases. Cancer. 1990;66(3):549–56. doi: 10.1002/1097-0142(19900801)66:3<549::aid-cncr2820660324>3.0.co;2-6.