OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press21110.17650/1818-8346-2016-11-4-8-17HEMATOLOGIC MALIGNANCIES: DIAGNOSIS, TREATMENT, SUPPORTIVE CAREГЕМОБЛАСТОЗЫ: ДИАГНОСТИКА, ЛЕЧЕНИЕ, СОПРОВОДИТЕЛЬНАЯ ТЕРАПИЯMYELODYSPLASTIC/MYELOPROLIFERATIVE DISEASESМИЕЛОДИСПЛАСТИЧЕСКИЕ/МИЕЛОПРОЛИФЕРАТИВНЫЕ ЗАБОЛЕВАНИЯSubortsevaI. N.СуборцеваИ. Н.
Russian Federation

4a Novyy Zykovskiy Passage, Moscow 125167, Russia

125167 Москва, Новый Зыковский проезд, 4а

MelikyanA. I.МеликянА. Л.
Russian Federation

4a Novyy Zykovskiy Passage, Moscow 125167, Russia

125167 Москва, Новый Зыковский проезд, 4а

anoblood@mail.ruHematological Research CenterГематологический научный центр0312201611481703012017030120172016https://oncohematology.abvpress.ru/ongm/article/view/211

Chronic myeloid malignancies that have characteristics of both the myelodysplastic and myeloproliferative disorders allocated to myelodysplastic/myeloproliferative diseases (MDS/MPD) group in 2008 World Health Organization classification. This group includes chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia, refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T) and unclassified MDS/MPD. Except RARS-T diseases in this group have similar molecular characteristics and clinical manifestations, which require the study of biology, specific molecular markers, morphological features and a clearer definition of nosology. This review provides information on international guidelines for the diagnosis and treatment of MDS/MPD.

В классификации Всемирной организации здравоохранения 2008 г. хронические миелоидные злокачественные заболевания (неоплазии, опухоли), которые имеют характеристики как миелодиспластических, так и миелопролиферативных заболеваний, отнесены в группу «миелодиспластические/миелопролиферативные заболевания (неоплазии)» (МДС/МПЗ). Она объединяет хронический миеломоноцитарный лейкоз, ювенильный миеломоноцитарный лейкоз, атипичный хронический миелоидный лейкоз, рефрактерную анемию с кольцевыми сидеробластами и тромбоцитозом (РАКСТ) и МДС/МПЗ неклассифицированные. За исключением РАКСТ, между заболеваниями данной группы существует сходство молекулярных характеристик и клинических проявлений, что диктует необходимость изучения биологии, выявления конкретных молекулярных маркеров, морфологических особенностей и более четкого определения нозологической формы. В данном обзоре приводятся международные рекомендации по диагностике и лечению МДС/МПЗ.

myeloproliferative diseaseschronic myelomonocytic leukemiajuvenile myelomonocytic leukemiaatypical chronic myeloid leukemiarefractory anemia with ringed sideroblastsмиелопролиферативные заболеванияхронический миеломоноцитарный лейкозювенильный миеломоноцитарный лейкозатипичный хронический миелоидный лейкозрефрактерная анемия с кольцевыми сидеробластами и тромбоцитозомГрант Президента РФ для государственной поддержки молодых российских ученых1. Меликян А.Л., Туркина А.Г., Абдулкадыров К.М. и др. Клинические рекомендации по диагностике и терапии Ph-негативных миелопролиферативных заболеваний (истинная полицитемия, эссенциальная тромбоцитемия, первичный миелофиброз). Гематология и трансфузиология 2014;59(4):31–56. [Melikyan A.L., Turkina A.G., Abdulkadyrov K.M. et al. Clinical guidelines for the diagnosis and treatment of Ph-negative myeloproliferative disorders (polycythemia vera, essential thrombocythemia, primary myelofibrosis). Gematologiya i transfuziologiya = Hematology and Transfusiology 2014;59(4):31–56. (In Russ.)].Меликян А.Л., Туркина А.Г., Абдулкадыров К.М. и др. Клинические рекомендации по диагностике и терапии Ph-негативных миелопролиферативных заболеваний (истинная полицитемия, эссенциальная тромбоцитемия, первичный миелофиброз). Гематология и трансфузиология 2014;59(4):31–56. [Melikyan A.L., Turkina A.G., Abdulkadyrov K.M. et al. Clinical guidelines for the diagnosis and treatment of Ph-negative myeloproliferative disorders (polycythemia vera, essential thrombocythemia, primary myelofibrosis). Gematologiya i transfuziologiya = Hematology and Transfusiology 2014;59(4):31–56. (In Russ.)].2. Swerdlow S.H., Campo E., Harris N.L. et al. World Health Organization Classification of tumors of haematopoietic and lymphoid tissue. 4th edn. Lyon: IARC Press, 2008. Pp. 32–7.Swerdlow S.H., Campo E., Harris N.L. et al. World Health Organization Classification of tumors of haematopoietic and lymphoid tissue. 4th edn. Lyon: IARC Press, 2008. Pp. 32–7.3. Orazi A., Germing U. The myelodysplastic/ myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 2008;22(7):1308–19. DOI: 10.1038/leu.2008.119. PMID: 18480833.Orazi A., Germing U. The myelodysplastic/ myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 2008;22(7):1308–19. DOI: 10.1038/leu.2008.119. PMID: 18480833.4. Hebeda K.M., Fend F. Changed concepts and definitions of myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and myelodysplastic/ myeloproliferative neoplasms (MDS/MPN) in the updated 2008 WHO classification. J Hematop 2009;2(4):205–10.Hebeda K.M., Fend F. Changed concepts and definitions of myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and myelodysplastic/ myeloproliferative neoplasms (MDS/MPN) in the updated 2008 WHO classification. J Hematop 2009;2(4):205–10.DOI: 10.1007/s12308-009-0048-6. PMID: 20309429.5. Tiu R.V., Gondek L.P., O’Keefe C.L. et al. Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood 2011;117(17): 4552–60. DOI: 10.1182/blood-2010-07-295857. PMID: 21285439.Tiu R.V., Gondek L.P., O’Keefe C.L. et al. Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood 2011;117(17): 4552–60. DOI: 10.1182/blood-2010-07-295857. PMID: 21285439.6. Delhommeau F., Pisani D.F., James C. et al. Oncogenic mechanisms in myeloproliferative disorders. Cell Mol Life Sci 2006;63(24):2939–53. DOI: 10.1007/s00018-006-6272-7. PMID: 17131059.Delhommeau F., Pisani D.F., James C. et al. Oncogenic mechanisms in myeloproliferative disorders. Cell Mol Life Sci 2006;63(24):2939–53. DOI: 10.1007/s00018-006-6272-7. PMID: 17131059.7. Steensma D.P., Dewald G.W., Lasho T.L. et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and the myelodysplastic syndrome. Blood 2005;106(4):1207–9. DOI: 10.1182/blood-2005-03-1183. PMID: 15860661.Steensma D.P., Dewald G.W., Lasho T.L. et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and the myelodysplastic syndrome. Blood 2005;106(4):1207–9. DOI: 10.1182/blood-2005-03-1183. PMID: 15860661.8. Cools J., DeAngelo D. J., Gotlib J. et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes is a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348(13):1201–14. DOI: 10.1056/NEJMoa025217. PMID: 12660384.Cools J., DeAngelo D. J., Gotlib J. et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes is a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348(13):1201–14. DOI: 10.1056/NEJMoa025217. PMID: 12660384.9. Chase A., Bryant C., Score J., Cross N.C. Ponatinib as targeted therapy for FGR1 fusions associated with the 8p11 myeloproliferative syndrome. Haematologica 2003;98(1):103–6. DOI: 10.3324/haematol.2012.066407. PMID: 22875613.Chase A., Bryant C., Score J., Cross N.C. Ponatinib as targeted therapy for FGR1 fusions associated with the 8p11 myeloproliferative syndrome. Haematologica 2003;98(1):103–6. DOI: 10.3324/haematol.2012.066407. PMID: 22875613.10. Lierman E., Selleslag D., Smits S. et al. Ruxolitinib inhibits transforming JAK2 fusion proteins in vitro and induces complete remission in t(8;9)(p22;p24)/PCM1-JAK2-positive chronic eosinophilic leukemia. Blood 2012;120(7):1529–31. DOI: 10.1182/blood-2012-06-433821. PMID: 22899477.Lierman E., Selleslag D., Smits S. et al. Ruxolitinib inhibits transforming JAK2 fusion proteins in vitro and induces complete remission in t(8;9)(p22;p24)/PCM1-JAK2-positive chronic eosinophilic leukemia. Blood 2012;120(7):1529–31. DOI: 10.1182/blood-2012-06-433821. PMID: 22899477.11. Kohlmann A., Grossmann V., Haferlach T. Integration of next-generation sequencing into clinical practice: are we there yet? Semin Oncol 2012;39(1):26–36. DOI: 10.1053/j.seminoncol.2011.11.008. PMID: 22289489.Kohlmann A., Grossmann V., Haferlach T. Integration of next-generation sequencing into clinical practice: are we there yet? Semin Oncol 2012;39(1):26–36. DOI: 10.1053/j.seminoncol.2011.11.008. PMID: 22289489.12. Yoshida K., Sanada M., Shiraishi Y. et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011;478(7367):64–9. DOI: 10.1038/nature10496. PMID: 21909114.Yoshida K., Sanada M., Shiraishi Y. et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011;478(7367):64–9. DOI: 10.1038/nature10496. PMID: 21909114.13. Меликян А.Л., Суборцева И.Н. Биология миелопролиферативных заболеваний. Клиническая онкогематология 2016;9(3):314–25. [Melikyan A.L., Subortseva I.N. Biology of myeloproliferative malignancies. Klinicheskaya onkogematologiya = Clinical Oncohematology 2016;9(3):314–25. (In Russ.)]. DOI: 10.21320/2500-2139-2016-9-3-314-325.Меликян А.Л., Суборцева И.Н. Биология миелопролиферативных заболеваний. Клиническая онкогематология 2016;9(3):314–25. [Melikyan A.L., Subortseva I.N. Biology of myeloproliferative malignancies. Klinicheskaya onkogematologiya = Clinical Oncohematology 2016;9(3):314–25. (In Russ.)]. DOI: 10.21320/2500-2139-2016-9-3-314-325.14. Flotho C., Steinemann D., Mullighan C.G. et al. Genome-wide single nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11. Oncogene 2007;26(39):5816–21. DOI: 10.1038/sj.onc.1210361. PMID: 17353900.Flotho C., Steinemann D., Mullighan C.G. et al. Genome-wide single nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11. Oncogene 2007;26(39):5816–21. DOI: 10.1038/sj.onc.1210361. PMID: 17353900.15. Wang J., Liu Y., Li Z. et al. Endogenous oncogenic Nras mutation promotes aberrant GM-CSF signaling in granulocytic/monocytic precursors in a murine model of chronic myelomonocytic leukemia. Blood 2010;116(26):5991–6002. DOI: 10.1182/blood-2010-04-281527. PMID: 20921338.Wang J., Liu Y., Li Z. et al. Endogenous oncogenic Nras mutation promotes aberrant GM-CSF signaling in granulocytic/monocytic precursors in a murine model of chronic myelomonocytic leukemia. Blood 2010;116(26):5991–6002. DOI: 10.1182/blood-2010-04-281527. PMID: 20921338.16. Sattler M., Durstin M.A., Frank D.A. et al. The thrombopoietin receptor c-MPL activates JAK2 and TYK2 tyrosine kinases. Exp Hematol 1995;23(9):1040–8. PMID: 7543416.Sattler M., Durstin M.A., Frank D.A. et al. The thrombopoietin receptor c-MPL activates JAK2 and TYK2 tyrosine kinases. Exp Hematol 1995;23(9):1040–8. PMID: 7543416.17. Klinakis A., Lobry C., Abdel-Wahab O. et al. A novel tumor-suppressor function for Notch pathway in myeloid leukemia. Nature 2011;473(7346):230–3. DOI: 10.1038/nature09999. PMID: 21562564.Klinakis A., Lobry C., Abdel-Wahab O. et al. A novel tumor-suppressor function for Notch pathway in myeloid leukemia. Nature 2011;473(7346):230–3. DOI: 10.1038/nature09999. PMID: 21562564.18. Shih A.H., Abdel-Wahab O., Patel J.P., Levine R.L. The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer 2012;12(9):599–612. DOI: 10.1038/nrc3343. PMID: 22898539.Shih A.H., Abdel-Wahab O., Patel J.P., Levine R.L. The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer 2012;12(9):599–612. DOI: 10.1038/nrc3343. PMID: 22898539.19. Makishima H., Visconte V., Sakaguchi H. et al. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 2012;119(14):3203–10. DOI: 10.1182/blood-2011-12-399774. PMID: 22323480.Makishima H., Visconte V., Sakaguchi H. et al. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 2012;119(14):3203–10. DOI: 10.1182/blood-2011-12-399774. PMID: 22323480.20. Abdel-Wahab O., Mullally A., Hedvat C. et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 2009;114(1):144–7. DOI: 10.1182/blood-2009-03-210039. PMID: 19420352.Abdel-Wahab O., Mullally A., Hedvat C. et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 2009;114(1):144–7. DOI: 10.1182/blood-2009-03-210039. PMID: 19420352.21. Pandit S., Zhou Y., Shiue L. et al. Genome-wide analysis reveals SR protein cooperation and competition in regulated splicing. Mol Cell 2013;50(2):223–35. DOI: 10.1016/j.molcel.2013.03.001. PMID: 23562324.Pandit S., Zhou Y., Shiue L. et al. Genome-wide analysis reveals SR protein cooperation and competition in regulated splicing. Mol Cell 2013;50(2):223–35. DOI: 10.1016/j.molcel.2013.03.001. PMID: 23562324.22. Kar S.A., Jankowska A., Makishima H. et al. Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia. Haematologica 2013;98(1):107–13. DOI: 10.3324/haematol.2012.064048. PMID: 22773603.Kar S.A., Jankowska A., Makishima H. et al. Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia. Haematologica 2013;98(1):107–13. DOI: 10.3324/haematol.2012.064048. PMID: 22773603.23. Visconte V., Makishima H., Jankowska A. et al. SF3B1, a splicing factor is frequently mutated in refractory anemia with ringed sideroblasts. Leukemia 2012;26(3):542–5. DOI: 10.1038/leu.2011.232. PMID: 21886174.Visconte V., Makishima H., Jankowska A. et al. SF3B1, a splicing factor is frequently mutated in refractory anemia with ringed sideroblasts. Leukemia 2012;26(3):542–5. DOI: 10.1038/leu.2011.232. PMID: 21886174.24. Hirabayashi S., Flotho C., Moetter J. et al. Spliceosomal gene aberrations are rare, coexist with oncogenic mutations, and are unlikely to exert a driver effect in childhood MDS and JMML. Blood 2012;119(11):e96–9. DOI: 10.1182/blood-2011-12-395087. PMID: 22238327.Hirabayashi S., Flotho C., Moetter J. et al. Spliceosomal gene aberrations are rare, coexist with oncogenic mutations, and are unlikely to exert a driver effect in childhood MDS and JMML. Blood 2012;119(11):e96–9. DOI: 10.1182/blood-2011-12-395087. PMID: 22238327.25. Piazza R., Valletta S., Winkelmann N. et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet 2013;45(1):18–24. DOI: 10.1038/ng.2495. PMID: 23222956.Piazza R., Valletta S., Winkelmann N. et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet 2013;45(1):18–24. DOI: 10.1038/ng.2495. PMID: 23222956.26. Nangalia J., Massie C.E., Baxter E.J. et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013;369(25):2391–405. DOI: 10.1056/NEJMoa1312542. PMID: 24325359.Nangalia J., Massie C.E., Baxter E.J. et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013;369(25):2391–405. DOI: 10.1056/NEJMoa1312542. PMID: 24325359.27. Меликян А.Л., Суборцева И.Н. Материалы 56-го конгресса Американского гематологического общества (декабрь 2014 г., Сан-Франциско). Клиническая онкогематология. Фундаментальные исследования и клиническая практика 2015;8(2):201–32. [Melikyan A.L., Subortseva I.N. Proceedings of the 56th Congress of the American Society of Hematology (December 2014, San Francisco). Klinicheskaya onkogematologiya. Fundamental’nye issledovaniya i klinicheskaya praktika = Clinical Oncohematology. Basic Research and Clinical Practice 2015;8(2):201–32. (In Russ.)].Меликян А.Л., Суборцева И.Н. Материалы 56-го конгресса Американского гематологического общества (декабрь 2014 г., Сан-Франциско). Клиническая онкогематология. Фундаментальные исследования и клиническая практика 2015;8(2):201–32. [Melikyan A.L., Subortseva I.N. Proceedings of the 56th Congress of the American Society of Hematology (December 2014, San Francisco). Klinicheskaya onkogematologiya. Fundamental’nye issledovaniya i klinicheskaya praktika = Clinical Oncohematology. Basic Research and Clinical Practice 2015;8(2):201–32. (In Russ.)].28. Emanuel P.D. Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. Leukemia 2008;22(7):1335–42. DOI: 10.1038/leu.2008.162. PMID: 18548091.Emanuel P.D. Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. Leukemia 2008;22(7):1335–42. DOI: 10.1038/leu.2008.162. PMID: 18548091.29. Rollison D.E., Howlader N., Smith M.T. et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001–2004, using data from the NAACCR and SEER programs. Blood 2008;112(1):45–52. DOI: 10.1182/blood-2008-01-134858. PMID: 18443215.Rollison D.E., Howlader N., Smith M.T. et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001–2004, using data from the NAACCR and SEER programs. Blood 2008;112(1):45–52. DOI: 10.1182/blood-2008-01-134858. PMID: 18443215.30. Patnaik M.M., Parikh S.A., Hanson C.A., Tefferi A. Chronic myelomonocytic leukaemia: a concise clinical and pathophysiological review. Br J Haematol 2014; 165(3):273–86. DOI: 10.1111/bjh.12756. PMID: 24467717.Patnaik M.M., Parikh S.A., Hanson C.A., Tefferi A. Chronic myelomonocytic leukaemia: a concise clinical and pathophysiological review. Br J Haematol 2014; 165(3):273–86. DOI: 10.1111/bjh.12756. PMID: 24467717.31. Boiocchi L., Espinal-Witter R., Geyer J.T. et al. Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease. Mod Pathol 2013;26(2):204–12. DOI: 10.1038/modpathol.2012. PMID: 23018876.Boiocchi L., Espinal-Witter R., Geyer J.T. et al. Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease. Mod Pathol 2013;26(2):204–12. DOI: 10.1038/modpathol.2012. PMID: 23018876.32. Itzykson R., Kosmider O., Renneville A. et al. Clonal architecture of chronic myelomonocytic leukemias. Blood 2013;121(12):2186–98. DOI: 10.1182/blood-2012-06-440347. PMID: 23319568.Itzykson R., Kosmider O., Renneville A. et al. Clonal architecture of chronic myelomonocytic leukemias. Blood 2013;121(12):2186–98. DOI: 10.1182/blood-2012-06-440347. PMID: 23319568.33. Itzykson R., Kosmider O., Renneville A. et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol 2013;31(19):2428–36. DOI: 10.1200/JCO.2012.47.3314. PMID: 23690417.Itzykson R., Kosmider O., Renneville A. et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol 2013;31(19):2428–36. DOI: 10.1200/JCO.2012.47.3314. PMID: 23690417.34. Schuler E., Schroeder M., Neukirchen J. et al. Refined medullary blast and white blood cell count based classification of chronic myelomonocytic leukemias. Leuk Res 2014;38(12):1413–9. DOI: 10.1016/j.leukres.2014.09.003. PMID: 25444076.Schuler E., Schroeder M., Neukirchen J. et al. Refined medullary blast and white blood cell count based classification of chronic myelomonocytic leukemias. Leuk Res 2014;38(12):1413–9. DOI: 10.1016/j.leukres.2014.09.003. PMID: 25444076.35. Padron E., Painter J.A., Kunigal S. et al. GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia. Blood 2013;121(25):5068–77. DOI: 10.1182/blood-2012-10-460170. PMID: 23632888.Padron E., Painter J.A., Kunigal S. et al. GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia. Blood 2013;121(25):5068–77. DOI: 10.1182/blood-2012-10-460170. PMID: 23632888.36. Itzykson R., Solary E. An evolutionary perspective on chronic myelomonocytic leukemia. Leukemia 2013;27(7):1441–50. DOI: 10.1038/leu.2013.100. PMID: 23558522.Itzykson R., Solary E. An evolutionary perspective on chronic myelomonocytic leukemia. Leukemia 2013;27(7):1441–50. DOI: 10.1038/leu.2013.100. PMID: 23558522.37. Vardiman J.W., Thiele J., Arber D.A. et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009;114(5):937–51. DOI: 10.1182/blood-2009-03-209262. PMID: 19357394.Vardiman J.W., Thiele J., Arber D.A. et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009;114(5):937–51. DOI: 10.1182/blood-2009-03-209262. PMID: 19357394.38. Onida F., Kantarjian H.M., Smith T.L. et al. Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood 2002;99(3):840–9. DOI: 10.1182/blood.V99.3.840. PMID: 11806985.Onida F., Kantarjian H.M., Smith T.L. et al. Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood 2002;99(3):840–9. DOI: 10.1182/blood.V99.3.840. PMID: 11806985.39. Worsley A., Oscier D.G., Stevens J. et al. Prognostic features of chronic myelomonocytic leukaemia: a modified Bournemouth score gives the best prediction of survival. Br J Haematol 1988;68(1):17–21. PMID: 3422815.Worsley A., Oscier D.G., Stevens J. et al. Prognostic features of chronic myelomonocytic leukaemia: a modified Bournemouth score gives the best prediction of survival. Br J Haematol 1988;68(1):17–21. PMID: 3422815.40. Gonzalez-Medina I., Bueno J., Torrequebrada A. et al. Two groups of chronic myelomonocyticleukaemia: myelodysplastic and myeloproliferative. Prognostic implications in a series of a single center. Leuk Res 2002;26(9):821–4. DOI: 10.1016/S0145-2126(02)00021-8. PMID: 12127557.Gonzalez-Medina I., Bueno J., Torrequebrada A. et al. Two groups of chronic myelomonocyticleukaemia: myelodysplastic and myeloproliferative. Prognostic implications in a series of a single center. Leuk Res 2002;26(9):821–4. DOI: 10.1016/S0145-2126(02)00021-8. PMID: 12127557.41. Germing U., Kundgen A., Gattermann N. Risk assessment in chronic myelomonocytic leukemia (CMML). Leuk Lymphoma 2004;45(7):1311–8. DOI: 10.1080/1042819042000207271. PMID: 15359628.Germing U., Kundgen A., Gattermann N. Risk assessment in chronic myelomonocytic leukemia (CMML). Leuk Lymphoma 2004;45(7):1311–8. DOI: 10.1080/1042819042000207271. PMID: 15359628.42. Such E., Cervera J., Costa D. et al. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica 2011;96(3):375–83. DOI: 10.3324/haematol.2010.030957. PMID: 21109693.Such E., Cervera J., Costa D. et al. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica 2011;96(3):375–83. DOI: 10.3324/haematol.2010.030957. PMID: 21109693.43. Kantarjian H., O’Brien S., Ravandi F. et al. Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System. Cancer 2008;113(6):1351–61. DOI: 10.1002/cncr.23697. PMID: 18618511.Kantarjian H., O’Brien S., Ravandi F. et al. Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System. Cancer 2008;113(6):1351–61. DOI: 10.1002/cncr.23697. PMID: 18618511.44. Such E., Germing U., Malcovati L. et al. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood 2013;121(15):3005–15. DOI: 10.1182/blood-2012-08-452938. PMID: 23372164.Such E., Germing U., Malcovati L. et al. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood 2013;121(15):3005–15. DOI: 10.1182/blood-2012-08-452938. PMID: 23372164.45. Laborde R.R., Patnaik M.M., Lasho T.L. et al. SETBP1 mutations in 415 patients with primary myelofibrosis or chronic myelomonocytic leukemia: independent prognostic impact in CMML. Leukemia 2013;27(10):2100–2. DOI: 10.1038/leu.2013.97. PMID: 23558523.Laborde R.R., Patnaik M.M., Lasho T.L. et al. SETBP1 mutations in 415 patients with primary myelofibrosis or chronic myelomonocytic leukemia: independent prognostic impact in CMML. Leukemia 2013;27(10):2100–2. DOI: 10.1038/leu.2013.97. PMID: 23558523.46. Park S., Labopin M., Yakoub-Agha I. et al. Allogeneic stem cell transplantation for chronic myelomonocytic leukemia: a report from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Eur J Haematol 2013;90(5):355–64. DOI: 10.1111/ejh.12073. PMID: 23320648.Park S., Labopin M., Yakoub-Agha I. et al. Allogeneic stem cell transplantation for chronic myelomonocytic leukemia: a report from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Eur J Haematol 2013;90(5):355–64. DOI: 10.1111/ejh.12073. PMID: 23320648.47. Eissa H., Gooley T.A., Sorror M.L. et al. Allogeneic hematopoietic cell transplantation for chronic myelomonocytic leukemia: relapse-free survival is determined by karyotype and co-morbidities. Biol Blood Marrow Transplant 2011;17(6):908–15. DOI: 10.1016/j.bbmt.2010.09.018. PMID: 20932924.Eissa H., Gooley T.A., Sorror M.L. et al. Allogeneic hematopoietic cell transplantation for chronic myelomonocytic leukemia: relapse-free survival is determined by karyotype and co-morbidities. Biol Blood Marrow Transplant 2011;17(6):908–15. DOI: 10.1016/j.bbmt.2010.09.018. PMID: 20932924.48. Gonsalves W., Gangat N., Gupta V. et al. The role of induction chemotherapy and allogeneic stem cell transplantation in patients with chronic myelomonocytic leukemia who have undergone leukemia transformation. Biol Blood Marrow Transplant 2014;20: S151–64; abstr 216.Gonsalves W., Gangat N., Gupta V. et al. The role of induction chemotherapy and allogeneic stem cell transplantation in patients with chronic myelomonocytic leukemia who have undergone leukemia transformation. Biol Blood Marrow Transplant 2014;20: S151–64; abstr 216.49. Wong E., Seymour J., Kenealy M. et al. Treatment of chronic myelomonocytic leukemia with azacitidine. Leuk Lymphoma 2013;54(4):878–80. DOI: 10.3109/10428194.2012.730615. PMID: 22988826.Wong E., Seymour J., Kenealy M. et al. Treatment of chronic myelomonocytic leukemia with azacitidine. Leuk Lymphoma 2013;54(4):878–80. DOI: 10.3109/10428194.2012.730615. PMID: 22988826.50. Ades L., Sekeres M.A., Wolfromm A. et al. Predictive factors of response and survival among chronic myelomonocytic leukemia patients treated with azacitidine. Leuk Res 2013;37(6):609–13. DOI: 10.1016/j.leukres.2013.01.004. PMID: 23415110.Ades L., Sekeres M.A., Wolfromm A. et al. Predictive factors of response and survival among chronic myelomonocytic leukemia patients treated with azacitidine. Leuk Res 2013;37(6):609–13. DOI: 10.1016/j.leukres.2013.01.004. PMID: 23415110.51. Fend F., Horn T., Koch I. et al. Atypical chronic myeloid leukemia as defined in the WHO classification is a JAK2 V617F negative neoplasm. Leuk Res 2008;32(12):1931–5. DOI: 10.1016/j.leukres.2008.04.024. PMID: 18555525.Fend F., Horn T., Koch I. et al. Atypical chronic myeloid leukemia as defined in the WHO classification is a JAK2 V617F negative neoplasm. Leuk Res 2008;32(12):1931–5. DOI: 10.1016/j.leukres.2008.04.024. PMID: 18555525.52. Hernandez J.M., del Canizo M.C., Cuneo A. et al. Clinical, hematological, cytogenetic characteristics of atypical chronic myeloid leukemia. Ann Oncol 2000;11(4):441–4. PMID: 10847463.Hernandez J.M., del Canizo M.C., Cuneo A. et al. Clinical, hematological, cytogenetic characteristics of atypical chronic myeloid leukemia. Ann Oncol 2000;11(4):441–4. PMID: 10847463.53. Wang S.A., Hasserjian R.P., Fox P.S. et al. Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms. Blood 2014;123(17):2645–51. DOI: 10.1182/blood-2014-02-553800. PMID: 24627528.Wang S.A., Hasserjian R.P., Fox P.S. et al. Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms. Blood 2014;123(17):2645–51. DOI: 10.1182/blood-2014-02-553800. PMID: 24627528.54. Trimarchi T., Ntziachristos P., Aifantis I. A new player SETs in myeloid malignancy. Nat Genet 2013;45(8):846–7. DOI: 10.1038/ng.2709. PMID: 23892662.Trimarchi T., Ntziachristos P., Aifantis I. A new player SETs in myeloid malignancy. Nat Genet 2013;45(8):846–7. DOI: 10.1038/ng.2709. PMID: 23892662.55. Bellesso M., Santucci R., Dias D.F. et al. Atypical chronic myeloid leukemia with t(9;22)(p24,11.2), a BCR-JAK2 fusion gene. Rev Bras Hematol Hemoter 2013;35(3):218–9. DOI: 10.5581/1516-8484.20130044. PMID: 23904814.Bellesso M., Santucci R., Dias D.F. et al. Atypical chronic myeloid leukemia with t(9;22)(p24,11.2), a BCR-JAK2 fusion gene. Rev Bras Hematol Hemoter 2013;35(3):218–9. DOI: 10.5581/1516-8484.20130044. PMID: 23904814.56. Murayama H., Matsushita H., Ando K. Atypical chronic myeloid leukemia harboring NUP98-HOXA9. Int J Hematol 2013;98(2): 143–4. DOI: 10.1007/s12185-013-1381-1. PMID: 23754767.Murayama H., Matsushita H., Ando K. Atypical chronic myeloid leukemia harboring NUP98-HOXA9. Int J Hematol 2013;98(2): 143–4. DOI: 10.1007/s12185-013-1381-1. PMID: 23754767.57. Gambacorti-Passerini C., Donadoni C., Parmiani A. et al. Recurrent ETNK1 mutations in aytipcal chronic myeloid leukemia. Blood 2015;125(3):499–503. DOI: 10.1182/blood-2014-06-579466. PMID: 25343957.Gambacorti-Passerini C., Donadoni C., Parmiani A. et al. Recurrent ETNK1 mutations in aytipcal chronic myeloid leukemia. Blood 2015;125(3):499–503. DOI: 10.1182/blood-2014-06-579466. PMID: 25343957.58. Gotlib J., Maxson J.E., George T.I., Tyner J.W. The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment. Blood 2013;122(10):1707–11. DOI: 10.1182/blood-2013-05-500959. PMID: 23896413.Gotlib J., Maxson J.E., George T.I., Tyner J.W. The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment. Blood 2013;122(10):1707–11. DOI: 10.1182/blood-2013-05-500959. PMID: 23896413.59. Maxson J.E., Gotlib J., Pollea D.A. et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med 2013;368(19):1781–90. DOI: 10.1056/NEJMoa1214514. PMID: 23656643.Maxson J.E., Gotlib J., Pollea D.A. et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med 2013;368(19):1781–90. DOI: 10.1056/NEJMoa1214514. PMID: 23656643.60. Plo I., Zhang Y., Le Couédic J.P. et al. An activating mutation in the CSF3R gene induces a hereditary chronic neutrophilia. J Exp Med 2009;206(8):1701–7. DOI: 10.1084/jem.20090693. PMID: 19620628.Plo I., Zhang Y., Le Couédic J.P. et al. An activating mutation in the CSF3R gene induces a hereditary chronic neutrophilia. J Exp Med 2009;206(8):1701–7. DOI: 10.1084/jem.20090693. PMID: 19620628.61. Tefferi A., Thiele J., Vannucchi A.M., Barbui T. An overview of 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. PMID: 24441292.Tefferi A., Thiele J., Vannucchi A.M., Barbui T. An overview of 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. PMID: 24441292.62. Passmore S.J., Chessells J.M., Kempski H. et al. Paediatric myelodysplasticPassmore S.J., Chessells J.M., Kempski H. et al. Paediatric myelodysplastic62. Passmore S.J., Chessells J.M., Kempski H. et al. Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival. Br J Haematol 2003;121(5):758–67. DOI: 10.1046/j.1365-2141.2003.04361.x. PMID: 12780790.Passmore S.J., Chessells J.M., Kempski H. et al. Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival. Br J Haematol 2003;121(5):758–67. DOI: 10.1046/j.1365-2141.2003.04361.x. PMID: 12780790.63. Bader-Meunier B., Tchernia G., Mielot F. et al. Occurrence of myeloproliferative disorder in patients with Noonan syndrome. J Pediatr 1997;130(6):885–9. DOI: 10.1016/S0022-3476(97)70273-7. PMID: 9202609.Bader-Meunier B., Tchernia G., Mielot F. et al. Occurrence of myeloproliferative disorder in patients with Noonan syndrome. J Pediatr 1997;130(6):885–9. DOI: 10.1016/S0022-3476(97)70273-7. PMID: 9202609.64. Matsuda K., Shimada A., Yoshida N. et al. Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations. Blood 2007;109(12):5477–80. DOI: 10.1182/blood-2006-09-046649. Br J Haematol 2010;151(5):460–8. DOI: 10.1111/j.1365-2141.2010.08393.x. PMID: 20955399.Matsuda K., Shimada A., Yoshida N. et al. Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations. Blood 2007;109(12):5477–80. DOI: 10.1182/blood-2006-09-046649. Br J Haematol 2010;151(5):460–8. DOI: 10.1111/j.1365-2141.2010.08393.x. PMID: 20955399.67. Emanuel P.D., Bates L.J., Castleberry R.P. et al. Selective hypersensitivity to granulocytemacrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. Blood 1991;77(5):925–9. PMID: 1704804.Emanuel P.D., Bates L.J., Castleberry R.P. et al. Selective hypersensitivity to granulocytemacrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. Blood 1991;77(5):925–9. PMID: 1704804.68. Woods W.G., Barnard D.R., Alonzo T.A. et al. Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: a report from the Children’s Cancer Group. J Clin Oncol 2002;20(2): 434–40. DOI: 10.1200/jco.2002.20.2.434. PMID: 11786571.Woods W.G., Barnard D.R., Alonzo T.A. et al. Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: a report from the Children’s Cancer Group. J Clin Oncol 2002;20(2): 434–40. DOI: 10.1200/jco.2002.20.2.434. PMID: 11786571.69. Bunda S., Kang M.W., Sybingco S.S. et al. 69. Bunda S., Kang M. W., Sybingco S. S. et al. Inhibition of SRC corrects GM-SCF hypersensitivity that underlies juvenile myelomonocytic leukemia. Cancer Res 2013;73(8):2540–50. DOI: 10.1158/0008-5472.CAN-12-3425. PMID: 23400592.Bunda S., Kang M.W., Sybingco S.S. et al. 69. Bunda S., Kang M. W., Sybingco S. S. et al. Inhibition of SRC corrects GM-SCF hypersensitivity that underlies juvenile myelomonocytic leukemia. Cancer Res 2013;73(8):2540–50. DOI: 10.1158/0008-5472.CAN-12-3425. PMID: 23400592.70. Kongи G., Wunderlich M., Yang D. et al. Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm. J Clin Invest 2014;124(6): 2762–73. DOI: 10.1172/JCI74182. PMID: 24812670.Kongи G., Wunderlich M., Yang D. et al. Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm. J Clin Invest 2014;124(6): 2762–73. DOI: 10.1172/JCI74182. PMID: 24812670.71. Furlan I., Balz C., Flotho C. et al. Intriguing response to azacitidine in a patient with myelomonocytic leukemia and monosomy 7. Blood 2009;113(12): 2867–8. DOI: 10.1182/blood-2008-12-195693. PMID: 19299654.Furlan I., Balz C., Flotho C. et al. Intriguing response to azacitidine in a patient with myelomonocytic leukemia and monosomy 7. Blood 2009;113(12): 2867–8. DOI: 10.1182/blood-2008-12-195693. PMID: 19299654.72. Wardrop D., Steensma D.P. Is refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T) a necessary or useful diagnostic category? Br J Haemаtol 2008;144(6):809–17. DOI: 10.1111/j.1365-2141.2008.07526.x. PMID: 19120370.Wardrop D., Steensma D.P. Is refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T) a necessary or useful diagnostic category? Br J Haemаtol 2008;144(6):809–17. DOI: 10.1111/j.1365-2141.2008.07526.x. PMID: 19120370.73. Szpurka H., Tiu R., Murugesan G. et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myloproliferative condition characterized by JAK2 V617F PMID: 17332249.Szpurka H., Tiu R., Murugesan G. et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myloproliferative condition characterized by JAK2 V617F PMID: 17332249.65. Makishima H., Yoshida K., Nguyen N. et al. Somatic SETBP1 mutations in myeloid malignancies. Nat Genet 2013;45(8):942–6. DOI: 10.1038/ng.2696. PMID: 23832012.Makishima H., Yoshida K., Nguyen N. et al. Somatic SETBP1 mutations in myeloid malignancies. Nat Genet 2013;45(8):942–6. DOI: 10.1038/ng.2696. PMID: 23832012.66. Perez B., Kosmider O., Cassinat B. et al. Genetic typing of CBL, ASXL1, RUNX1, TET2 and JAK2 in juvenile myelomonocytic leukaemia reveals a genetic profile distinct from chronic myelomonocytic leukaemia. Inhibition of SRC corrects GM-SCF hypersensitivity that underlies juvenile myelomonocytic leukemia. Cancer Res 2013;73(8):2540–50. DOI: 10.1158/0008-5472.CAN-12-3425. PMID: 23400592.Perez B., Kosmider O., Cassinat B. et al. Genetic typing of CBL, ASXL1, RUNX1, TET2 and JAK2 in juvenile myelomonocytic leukaemia reveals a genetic profile distinct from chronic myelomonocytic leukaemia. Inhibition of SRC corrects GM-SCF hypersensitivity that underlies juvenile myelomonocytic leukemia. Cancer Res 2013;73(8):2540–50. DOI: 10.1158/0008-5472.CAN-12-3425. PMID: 23400592.70. Kong G., Wunderlich M., Yang D. et al. Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm. J Clin Invest 2014;124(6):2762–73. DOI: 10.1172/JCI74182. PMID: 24812670. mutation. Blood 2006;108(7):2173–81. DOI: 10.1182/blood-2006-02-005751. PMID: 16741247.Kong G., Wunderlich M., Yang D. et al. Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm. J Clin Invest 2014;124(6):2762–73. DOI: 10.1172/JCI74182. PMID: 24812670. mutation. Blood 2006;108(7):2173–81. DOI: 10.1182/blood-2006-02-005751. PMID: 16741247.74. DiNardo C.D., Daver N., Jain N. et al. Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U): natural history and clinical outcome by treatment strategy. Leukemia 2014;28(4):958–61. DOI: 10.1038/leu.2014.8. PMID: 24492324.DiNardo C.D., Daver N., Jain N. et al. Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U): natural history and clinical outcome by treatment strategy. Leukemia 2014;28(4):958–61. DOI: 10.1038/leu.2014.8. PMID: 24492324.