myeloproliferative neoplasms

National Clinical Guidelines on Diagnosis and Treatment of Ph-Negative Myeloproliferative Neoplasms (Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis) (Edition 2020)

AUTOIMMUNE THROMBOCYTOPENIA , , , , , ,

AL Melikyan1, AM Kovrigina1, IN Subortseva1, VA Shuvaev2, EV Morozova3, EG Lomaia4, BV Afanasyev3, TA Ageeva5, VV Baikov3, OYu Vinogradova6, SV Gritsaev2, AYu Zaritskey4, TI Ionova7, KD Kaplanov6, IS Martynkevich2, TA Mitina8, ES Polushkina9, TI Pospelova5, MA Sokolova1, AB Sudarikov1, AG Turkina1, YuV Shatokhin10, RG Shmakov9, VG Savchenko1

1 National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

2 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

3 RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

4 VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

5 Novosibirsk State Medical University, 52 Krasnyi pr-t, Novosibirsk, Russian Federation, 630091

6 Moscow Municipal Center for Hematology, SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

7 NI Pirogov Clinic for High Medical Technology, Saint Petersburg State University, 7/9 Universitetskaya emb., Saint Petersburg, Russian Federation, 199034

8 NF Vladimirskii Moscow Regional Research Clinical Institute, 61/2 Shchepkina str., Moscow, Russian Federation, 129110

9 VI Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 4 Akademika Oparina str., Moscow, Russian Federation, 117997

10 ФГБОУ ВО «Ростовский государственный медицинский университет» Минздрава России, Нахичеванский пер., д. 29, Ростов-на-Дону, Российская Федерация, 344022

For correspondence: Anait Levonovna Melikyan, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: anoblood@ mail.ru

For citation: Melikyan AL, Kovrigina AM, Subortseva IN, et al. National Clinical Guidelines on Diagnosis and Treatment of Ph-Negative Myeloproliferative Neoplasms (Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis) (Edition 2020). Clinical oncohematology. 2021;14(2):262–98. (In Russ).

DOI: 10.21320/2500-2139-2021-14-2-262-298

ABSTRACT

The development of National clinical guidelines on diagnosis and treatment of Ph-negative myeloproliferative neoplasms comes in response to the need to standardize the approach to diagnosis and treatment. The availability of clinical guidelines can facilitate the choice of adequate treatment strategy, provides practicing physicians with exhaustive and up-to-date information on advantages and shortcomings of different treatment methods as well as lets health professionals better assess expected extents of treatment required by patients. In 2013 a working group was formed to develop and formulate clinical guidelines on the treatment of myeloproliferative neoplasms. These guidelines were first published in 2014, afterwards they were revised and republished. The dynamic development of current hematology presupposes constant updating of knowledge and implementation of new diagnosis and treatment methods in clinical practice. In this context clinical guidelines present a dynamic document to be continuously amended, expanded, and updated in accordance with scientific findings and new requirements of specialists who deal directly with this category of patients. The present edition is an upgraded version of clinical guidelines with updated information on the unification of constitutional symptoms assessment using MPN-SAF TSS questionnaire (MPN10), on applying prognostic scales in primary myelofibrosis, assessing therapy efficacy in myeloproliferative neoplasms, revising indications for prescription, on dose correction, and discontinuation of targeted drugs (ruxolitinib). The guidelines are intended for oncologists, hematologists, healthcare executives, and medical students.

Keywords: myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, primary myelofibrosis, JAK2V617F, CALR, MPL, prognosis, hydroxyurea, interferon-α, ruxolitinib, anagrelide.

Received: November 12, 2020

Accepted: February 23, 2021

Read in PDF

Статистика Plumx английский

 

Current View on Diagnosis and Treatment of Classical Ph-Negative Myeloproliferative Neoplasms

AUTOIMMUNE THROMBOCYTOPENIA , , , , ,

AL Melikyan1, IN Subortseva1, VA Shuvaev2,3, EG Lomaia4, EV Morozova5, LA Kuzmina1, OYu Vinogradova6,7,8, AYu Zaritskey4

1 National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

2 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

3 VV Veresaev Municipal Clinical Hospital, 10 Lobnenskaya str., Moscow, Russian Federation, 127644

4 VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

5 RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

6 SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

7 Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela str., Moscow, Russian Federation, 117997

8 NI Pirogov Russian National Research Medical University, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

For correspondence: Anait Levonovna Melikyan, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: anoblood@mail.ru

For citation: Melikyan AL, Subortseva IN, Shuvaev VA, et al. Current View on Diagnosis and Treatment of Classical Ph-Negative Myeloproliferative Neoplasms. Clinical oncohematology. 2021;14(1):129–37. (In Russ).

DOI: 10.21320/2500-2139-2021-14-1-129-137

ABSTRACT

Classical Ph-negative myeloproliferative neoplasms (MPN) constitute a group of diseases including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Over the past decade, the approaches to understanding of MPN pathogenesis and therapy have considerably changed. At the same time, etiological factors and pathophysiological mechanisms of disease progress are being thoroughly studied. The improvement of diagnosis methods and new approaches to therapy can reduce complications and mortality risks. The review outlines the current diagnosis methods, such as the molecular genetic one, and provides prognostic scores. Different methods of conservative therapy are assessed. Special attention is paid to quality of life measurement and targeted treatment of patients.

Keywords: myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, primary myelofibrosis, JAK2V617F, CALR, MPL, prognosis, constitutional symptoms, MPN10, ruxolitinib.

Received: September 1, 2020

Accepted: December 10, 2020

Read in PDF

Статистика Plumx английский

REFERENCES

  1. 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;59:31–56.
    [Melikyan AL, Turkina AG, Abdulkadyrov KM, et al. Clinical guidelines on diagnosis and therapy of Ph-negative myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, primary myelofibrosis). Gematologiya i transfuziologiya. 2014;59:31–56. (In Russ)]
  2. Меликян А.Л., Ковригина А.М., Суборцева И.Н. и др. Национальные клинические рекомендации по диагностике и терапии Ph-негативных миелопролиферативных заболеваний (истинная полицитемия, эссенциальная тромбоцитемия, первичный миелофиброз) (редакция 2018 г.) Гематология и трансфузиология. 2018;63(3):275–315.
    [Melikyan AL, Kovrigina AM, Subortseva IN, et al. National clinical guidelines on diagnosis and therapy of Ph-negative myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, primary myelofibrosis) (edition 2018). Gematologiya i transfuziologiya. 2018;63(3):275–315. (In Russ)]
  3. Абрамова А.В., Абдуллаев А.О., Азимова М.Х. и др. Алгоритмы диагностики и протоколы лечения заболеваний системы крови. В 2 томах. М.: Практика, 2018. Том 2.
    [Abramova AV, Abdullaev AO, Azimova MKh, et al. Algoritmy diagnostiki i protokoly lecheniya zabolevanii sistemy krovi. V 2 tomakh. (Diagnostic algorithms and treatment protocols in hematological diseases. 2 volumes.) Moscow: Praktika Publ.; 2018. 2. (In Russ)]
  4. Меликян А.Л., Суборцева И.Н., Галстян Г.М. Протокол дифференцированного посиндромного лечения больных первичным миелофиброзом. В кн.: Алгоритмы диагностики и протоколы лечения заболеваний системы крови. По ред. А.В. Абрамовой, А.О. Абдуллаева и др. В 2 томах. М.: Практика, 2018. Том 2. С. 777–802.
    [Melikyan AL, Subortseva IN, Galstyan GM. Protocol of differentiated syndromic treatment of patients with primary myelofibrosis. In: Abramova AV, Abdullaev AO, et al., eds. Algoritmy diagnostiki i protokoly lecheniya zabolevanii sistemy krovi. V 2 tomakh. (Diagnostic algorithms and treatment protocols in hematological diseases. 2 volumes.) Moscow: Praktika Publ.; 2018. Vol. 2. pр. 777–802. (In Russ)]
  5. Geyer H, Scherber R, Kosiorek H, et al. Symptomatic Profiles of Patients With Polycythemia Vera: Implications of Inadequately Controlled Disease. J Clin Oncol. 2016. 34(2):151–9. doi: 10.1200/JCO.2015.62.9337.
  6. Ионова Т.И., Анчукова Л.В., Виноградова О.Ю. и др. Качество жизни и спектр симптомов у больных миелофиброзом на фоне терапии: данные клинической практики. Гематология и трансфузиология. 2016;61(1):17–25. doi: 10.18821/0234-5730-2016-61-1-17-25.
    [Ionova TI, Anchukova LV, Vinogradova OYu, et al. Quality of life and symptom profile in patients with myelofibrosis undergoing treatment: Data of clinical practice. Gematologiya i transfuziologiya. 2016;61(1):17–25. doi: 10.18821/0234-5730-2016-61-1-17-25. (In Russ)]
  7. Xiao Z, Chang C-S, Morozova E, et al. Impact of myeloproliferative neoplasms (MPNS) and perceptions of treatment goals amongst physicians and patients in 6 countries: an expansion of the MPN landmark survey. 2019;3(s1):294–5. doi: 10.1097/01.hs9.0000561008.75001.e7.
  8. 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. 2009;113(13):2895–901. doi: 10.1182/blood-2008-07-170449.
  9. Passamonti F, Cervantes F, Vannucchi AM, et al. Dynamic International Prognostic Scoring System (DIPSS) predicts progression to acute myeloid leukemia in primary myelofibrosis. 2010;116(15):2857–8. doi: 10.1182/blood-2010-06-293415.
  10. 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.
  11. Vannucchi AM, Guglielmelli P, Rotunno G, et al. Mutation-Enhanced International Prognostic Scoring System (MIPSS) for primary myelofibrosis: an AGIMM & IWG-MRT project. 2014;124(21):405. doi: 10.1182/blood.v124.21.405.405.
  12. Guglielmelli P, Lasho TL, Rotunno G, et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for transplantation-age patients with primary myelofibrosis. J Clin Oncol. 2018;36(4):310–8. doi: 10.1200/JCO.2017.76.4886.
  13. Passamonti F, Giorgino T, Mora B, et al. A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis. 2017;31(12):2726–31. doi: 10.1038/leu.2017.169.
  14. Robin M, de Wreede LC, Wolschke C, et al. Long-term outcome after allogeneic hematopoietic cell transplantation for myelofibrosis. 2019;104(9):1782–8. doi: 10.3324/haematol.2018.205211.
  15. Барабанщикова М.В., Морозова Е.В., Байков В.В. и др. Аллогенная трансплантация гемопоэтических стволовых клеток при миелофиброзе. Клиническая онкогематология. 2016;9(3):279–86. doi: 10.21320/2500-2139-2016-9-3-279-286.
    [Barabanshchikova MV, Morozova EV, Baykov VV, et al. Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis. Clinical oncohematology. 2016;9(3):279–86. doi: 10.21320/2500-2139-2016-9-3-279-286. (In Russ)]
  16. Виноградова О.Ю., Шуваев В.А., Мартынкевич И.С. и др. Таргетная терапия миелофиброза. Клиническая онкогематология. 2017;10(4):471–8. doi: 10.21320/2500-2139-2017-10-4-471-478.
    [Vinogradova OYu, Shuvaev VA, Martynkevich IS, et al. Targeted Therapy of Myelofibrosis. Clinical oncohematology. 2017;10(4):471–8. doi: 10.21320/2500-2139-2017-10-4-471-478. (In Russ)]
  17. Руксолитиниб (инструкция по медицинскому применению). Доступно по: https://www.vidal.ru/drugs/molecule/2304. Ссылка активна на 22.10.2020.
    [Ruxolitinib (package insert). Available from: https://www.vidal.ru/drugs/molecule/2304. (accessed 22.10.2020) (In Russ)]
  18. Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European Leukemia Net (ELN) consensus report. 2013;122(8):1395–8. doi: 10.1182/blood-2013-03-488098.
  19. Ломаиа Е.Г., Сиордия Н.Т., Сендерова О.М. и др. Ранний ответ и отдаленные результаты терапии миелофиброза руксолитинибом: многоцентровое ретроспективное исследование в 10 центрах Российской Федерации. Клиническая онкогематология. 2020;13(3):335–45. doi: 10.21320/2500-2139-2020-13-3-335-345.
    [Lomaia EG, Siordiya NT, Senderova OM, et al. Early Response and Long-Term Outcomes of Ruxolitinib Therapy in Myelofibrosis: Multicenter Retrospective Study in 10 Centers of the Russian Federation. Clinical oncohematology. 2020;13(3):335–45. doi: 10.21320/2500-2139-2020-13-3-335-345. (In Russ)]
  20. Lomaia E, Siordiya N, Dimov G, et al. Early spleen response is a good prognostic factor of ruxolinib outcome in patients with myelofibrosis. 2019;3(S1):989. doi: 10.1097/01.hs9.0000567308.09016.52.

Ph-Negative Myeloproliferative Neoplasms: Diagnosis and Treatment Challenges in Russia (the Case of Saint Petersburg)

AUTOIMMUNE THROMBOCYTOPENIA , ,

MO Ivanova, EV Morozova, MV Barabanshchikova, BV Afanasyev

IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Mariya Olegovna Ivanova, MD, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; e-mail: marilexo@yandex.ru

For citation: Ivanova MO, Morozova EV, Barabanshchikova MV, Afanasyev BV. Ph-Negative Myeloproliferative Neoplasms: Diagnosis and Treatment Challenges in Russia (the Case of Saint Petersburg). Clinical oncohematology. 2021;14(1):45–52. (In Russ).

DOI: 10.21320/2500-2139-2021-14-1-45-52

ABSTRACT

Ph-negative myeloproliferative neoplasms (MPN) are rare oncohematological diseases characterized by long duration and indolence. World epidemiological data on these diseases considerably vary depending on geographical area and time frame of the study. The breakthrough in the understanding of MPN pathogenesis, observed in the early 2000s, enabled to elaborate approaches to differential diagnosis and treatment of Ph-negative MPNs as well as to improve their prognosis. Although these approaches are specified in the Russian clinical guidelines, physicians still face challenges in their implementation in practice. The present review provides a detailed description and analysis of literature data on epidemiology, pathogenesis, and principles of Ph-negative MPN diagnosis and treatment. It also describes the situation in Saint Petersburg as an example of existing challenges in management of patients with Ph-negative MPNs in Russia and offers potential solutions.

Keywords: myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, primary myelofibrosis.

Received: August 13, 2020

Accepted: November 29, 2020

Read in PDF

Статистика Plumx английский

REFERENCES

  1. Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med. 2006;355(23):2452–66. doi: 10.1056/NEJMra063728.
  2. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405. doi: 10.1182/blood-2016-03-643544.
  3. Adamson JW, Fialkow PJ, Murphy S, et al. Polycythemia Vera: Stem-Cell and Probable Clonal Origin of the Disease. N Engl J Med. 1976;295(17):913–6. doi: 10.1056/NEJM197610212951702.
  4. Titmarsh GJ, Duncombe AS, Mcmullin MF, et al. How common are myeloproliferative neoplasms? A systematic review and meta-analysis. Am J Hematol. 2014;89(6):581–7. doi: 10.1002/ajh.23690.
  5. Deadmond MA, Smith-Gagen JA. Changing incidence of myeloproliferative neoplasms: trends and subgroup risk profiles in the USA, 1973–2011. J Cancer Res Clin Oncol. 2015;141(12):2131–8. doi: 10.1007/s00432-015-1983-5.
  6. Moulard O, Mehta J, Fryzek J, et al. Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol. 2014;92(4):289–97. doi: 10.1111/ejh.12256.
  7. Byun JM, Kim YJ, Youk T, et al. Real world epidemiology of myeloproliferative neoplasms: a population based study in Korea 2004–2013. Ann Hematol. 2017;96(3):373–81. doi: 10.1007/s00277-016-2902-9.
  8. Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma. 2014;55(3):595–600. doi: 10.3109/10428194.2013.813500.
  9. Shuvaev V, Martynkevich I, Abdulkadyrova A, et al. Ph-Negative Chronic Myeloproliferative Neoplasms – Population Analysis, a Single Center 10-years’ Experience. Blood. 2014;124(21):5556. doi: 10.1182/blood.v124.21.5556.5556.
  10. Федеральный закон от 21 ноября 2011 г. № 323-ФЗ «Об основах охраны здоровья граждан в Российской Федерации» [электронный документ]. Доступно по: https://minzdrav.gov.ru/documents/7025-federalnyy-zakon-323-fz-ot-21-noyabrya-2011-g. Ссылка активна на10.2020.
    [Federal Law of November 21, 2011 No. 323-FZ “On the fundamentals of public health protection in the Russian Federation”. [Internet] Available from: https://minzdrav.gov.ru/documents/7025-federalnyy-zakon-323-fz-ot-21-noyabrya-2011-g. (accessed 21.10.2020) (In Russ)]
  11. Schischlik F, Kralovics R. Mutations in myeloproliferative neoplasms–their significance and clinical use. Expert Rev Hematol. 2017;10(11):961–73. doi: 10.1080/17474086.2017.1380515.
  12. 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.
  13. 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.
  14. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054–61. doi: 10.1016/s0140-6736(05)71142-9.
  15. 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.
  16. Scott LM. The JAK2 exon 12 mutations: A comprehensive review. Am J Hematol. 2011;86(8):668–76. doi: 10.1002/ajh.22063.
  17. 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):1140–51. doi: 10.1371/journal.pmed.0030270.
  18. Pardanani AD, Levine RL, Lasho T, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: A study of 1182 patients. Blood. 2006;108(10):3472–6. doi: 10.1182/blood-2006-04-018879.
  19. 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.
  20. 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.
  21. Harrison CN, Vannucchi AM. Closing the gap: Genetic landscape of MPN. Blood. 2016;127(3):276–8. doi: 10.1182/blood-2015-10-674101.
  22. Barbui T, Thiele J, Gisslinger H, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018;8(2):15. doi: 10.1038/s41408-018-0054-y.
  23. Меликян А.Л., Ковригина А.М., Суборцева И.Н. и др. Ph-негативные миелопролиферативные заболевания. Клинические рекомендации. 2018 г. [электронный документ]. Доступно по: http://cr.rosminzdrav.ru/#!/recomend/96. Ссылка активна на 21.10.2020.
    [Melikyan AL, Kovrigina AM, Subortseva IN, et al. Ph-negative myeloproliferative neoplasms. Clinical guidelines. 2018. [Internet] Available from: http://cr.rosminzdrav.ru/#!/recomend/96. (accessed 21.10.2020) (In Russ)]
  24. Tefferi A. Primary myelofibrosis: 2019 update on diagnosis, risk-stratification and management. Am J Hematol. 2018;93(12):1551–60. doi: 10.1002/ajh.25230.
  25. 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.
  26. Vannucchi AM, Guglielmelli P, Rotunno G, et al. Mutation-Enhanced International Prognostic Scoring System (MIPSS) for Primary Myelofibrosis: An AGIMM & IWG-MRT Project. Blood. 2014;124(21):405. doi: 10.1182/blood.v124.21.405.405.
  27. Barbui T, Tefferi A, Vannucchi AM, et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet HHS Public Access. Leukemia. 2018;32(5):1057–69. doi: 10.1038/s41375-018-0077-1.
  28. NCCN Clinical Practice Guidelines in Oncology. Myeloproliferative Neoplasms. Version 2.2017. Available from: https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf (accessed 11.2020).
  29. Vannucchi AM, Barbui T, Cervantes F, et al. Philadelphia Chromosome-Negative Chronic Myeloproliferative neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):v85–v99. doi: 10.1093/annonc/mdv203.
  30. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera. N Engl J Med. 2015;372(5):426–35. doi: 10.1056/NEJMoa1409002.
  31. Griesshammer M, Saydam G, Palandri F, et al. Ruxolitinib for the treatment of inadequately controlled polycythemia vera without splenomegaly: 80-week follow-up from the RESPONSE-2 trial. Ann Hematol. 2018;97(9):1591–600. doi: 10.1007/s00277-018-3365-y.
  32. Verstovsek S, Passamonti F, Rambaldi A, et al. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. 2014;120(4):513–20. doi: 10.1002/cncr.28441.
  33. Распоряжение Правительства Российской Федерации от 12 октября 2019 г. № 2406-р [электронный документ]. Доступно по: http://static.government.ru/media/files/K1fPEUszF2gmvwTkw74iPOASarj7KggI.pdf. Ссылка активна на 21.10.2020.
    [Russian Federation government resolution of October 12, 2019 No. 2406-r. [Internet] Available from: http://static.government.ru/media/files/K1fPEUszF2gmvwTkw74iPOASarj7KggI.pdf. (accessed 10.2020) (In Russ)]
  34. Постановление Правительства РФ от 26 апреля 2012 г. № 403 «О порядке ведения Федерального регистра лиц, страдающих жизнеугрожающими и хроническими прогрессирующими редкими (орфанными) заболеваниями, приводящими к сокращению продолжительности жизни граждан или их инвалидности, и его регионального сегмента» (с изменениями и дополнениями) [электронный документ]. Доступно по: http://base.garant.ru/70168888/. Ссылка активна на 21.10.2020.
    [Russian Federation government decree of April 26, 2012 No. 403 “On the rules for Federal Register of persons with life-threatening and chronic progressive rare (orphan) diseases leading to the reduction in life expectancy or disability, and its regional segment” (amended and revised.) [Internet] Available from: http://base.garant.ru/70168888/. (accessed 10.2020) (In Russ)]

Development and Validation Results of the Russian MPN10 Form for Symptom Assessment in Patients with Myeloproliferative Neoplasms Compliant with International Recommendations

AUTOIMMUNE THROMBOCYTOPENIA

TI Ionova1,2, OYu Vinogradova3,4,5, EV Efremova6, AE Kersilova6, TP Nikitina1,2, MM Pankrashkina3, NM Porfir’eva2, A-PA Poshivai6, MS Fominykh6,7, DI Shikhbabaeva3, VA Shuvaev6

1 NI Pirogov Clinic for High Medical Technology, Saint Petersburg State University, 7-9 Universitetskaya nab., Saint Petersburg, Russian Federation, 199034

2 Multinational Research Center for Quality of Life, 1 Artilleriiskaya str., Saint Petersburg, Russian Federation, 191014

3 SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

4 Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela str., Moscow, Russian Federation, 117997

5 NI Pirogov Russian National Research Medical University, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

6 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

7 Saint Petersburg State University, 7-9 Universitetskaya nab., Saint Petersburg, Russian Federation, 199034

For correspondence: Tat’yana Pavlovna Nikitina, MD, PhD, 1 Artilleriiskaya str., Saint Petersburg, Russian Federation, 191014; Tel.: +7(962)710-17-12; e-mail: qolife@mail.ru

For citation: Ionova TI, Vinogradova OYu, Efremova EV, et al. Development and Validation Results of the Russian MPN10 Form for Symptom Assessment in Patients with Myeloproliferative Neoplasms Compliant with International Recommendations. Clinical oncohematology. 2020;13(2):176–84 (In Russ).

DOI: 10.21320/2500-2139-2020-13-2-176-184

ABSTRACT

Aim. To develop a Russian version of MPN10 form for patients with myeloproliferative neoplasms (MPN) compliant with international recommendations.

Materials & Methods. The trial included 57 patients treated in 2019 at the Moscow Municipal Center for Hematology of the SP Botkin Clinical Hospital (n = 30) and the Russian Research Institute of Hematology and Transfusiology (n = 27). Among them there were 36 myelofibrosis, 9 polycythemia vera, and 12 essential thrombocythemia patients. Mean age of the patients was 54.6 years (standard deviation 15.9 years; age range 20–79 years). The male/female ratio was 23/34 (40.4 %/59.6 %). Underlying disease duration was from 1 month to 33 years (mean duration 7 years; standard deviation 8.6 years).

Results. A stable structure and a high inner consistency of the form as well as its reproducibility as a tool were demonstrated. The trial also confirmed its convergent and discriminant validity and satisfactory sensitivity to changes in a patient’s status.

Conclusion. The Russian MPN10 version can be used for symptom assessment in MPN patients in clinical practice and scientific research.

Keywords: symptom assessment form, myeloproliferative neoplasms, psychometric properties of the form, validation.

Received: January 15, 2020

Accepted: March 29, 2020

Read in PDF

REFERENCES

  1. Меликян А.Л., Ковригина А.М., Суборцева И.Н. и др. Национальные клинические рекомендации по диагностике и терапии Ph-негативных миелопролиферативных заболеваний (истинная полицитемия, эссенциальная тромбоцитемия, первичный миелофиброз) (редакция 2018 г.). Гематология и трансфузиология. 2018;63(3):275–315. doi: 10.25837/HAT.2019.51.88.001.

    [Melikyan AL, Kovrigina AM, Subortseva IN, et al. National сlinical recommendations for diagnosis and therapy of Ph-negative myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, primary myelofibrosis) (edition 2018). Russian Journal of Hematology and Transfusiology. 2018;63(3):275–315. doi: 10.25837/HAT.2019.51.88.001. (In Russ)]

  2. Arber DA, Orazi А, Hasserjian R., et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405. doi: 10.1182/blood-2016-03-643544.

  3. Меликян А.Л., Суборцева И.Н. Материалы 57-го конгресса Американского гематологического общества (декабрь 2015 г., Орландо). Клиническая онкогематология. 2016;9(2):218–28.

    [Melikyan AL, Subortseva IN. Materials of the 57th Annual Meeting of the American Society of Hematology (December, 2015; Orlando). Clinical oncohematology. 2016;9(2):218–28. (In Russ)]

  4. Passamonti F, Merli M, Caramazza D, et al. Clinical Predictors of Outcome in MPN. Hematol Oncol Clin N Am. 2012;26(5):1101–16. doi: 10.1016/j.hoc.2012.07.009.

  5. Reilly JT, McMullin MF, Beer PA, et al. Guideline for the diagnosis and management of myelofibrosis. Br J Haematol. 2012;158(4):453–71. doi: 10.1111/j.1365-2141.2012.09179.x.

  6. Patient-reported outcomes in hematology. EHA SWG “Quality of life and Symptoms”. Forum Service Editore. Genoa; 2012. 206 p.

  7. Scherber R, Dueck AC, Johansson P, et al. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): international prospective validation and reliability trial in 402 patients. Blood. 2011;118(2):401–8. doi: 10.1182/blood-2011-01-328955.

  8. Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative Neoplasm (MPN) Symptom Assessment Form Total Symptom Score: Prospective International Assessment of an Abbreviated Symptom Burden Scoring System Among Patients With MPNs. J Сlin Oncol. 2012;30(33):4098–103. doi: 10.1200/jco.2012.42.3863.

  9. NCCN Clinical Practice Guidelines in Oncology. Myeloproliferative Neoplasms. Version 2.2019 — October 29, 2018. Available from: http://www.gaca.org.cn/uploadfolder/files/201903/ny27_930697.pdf (accessed 28.03.2020).

  10. 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.

  11. Bullinger M, Power MJ, Aaronson NK, et al. Creating and evaluating cross-cultural instruments. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. Philadelphia: Lippincott-Raven; 1996. pp. 659–68.

  12. Aaronson N, Alonso J, Burnam A, et al. Assessing health status and quality of life instruments: attributes and review. Qual Life Res. 2002;11(3):193–205.

  13. Beaton DE, Bombardier C, Guillemin F, et al. Guidelines for the process of cross-cultural adaptation of self-report measures. Spine. 2000;25(24):3186–91. doi: 10.1097/00007632-200012150-00014.

  14. Cull A, Sprangers M, Bjordal K, et al. Translation Procedure. EORTC Monograph. Brussels; 1998. 26

  15. Ионова Т.И. Принципы языковой и культурной адаптации опросников оценки качества жизни. Вестник Межнационального центра исследования качества жизни. 2018;31–32:12–7.

    [Ionova Principles of linguistic and cultural adaptation of life quality assessment forms. Vestnik Mezhnatsional’nogo tsentra issledovaniya kachestva zhizni. 2018;31–32:12–7. (In Russ)]

  16. Ионова Т.И., Виноградова О.Ю., Ефремова Е.В. и др. Языковая и культурная адаптация русской версии инструмента для оценки симптомов у пациентов с миелопролиферативными новообразованиями — МПН10. Вестник Межнационального центра исследования качества жизни. 2019;33–34:19–30.

    [Ionova TI, Vinogradova OYu, Efremova EV, et al. Linguistic and cultural adaptation of the Russian version of the instrument for symptom assessment in patients with myeloproliferative neoplasms — MPN10. Vestnik Mezhnatsional’nogo tsentra issledovaniya kachestva zhizni. 2019;33–34:19–30. (In Russ)]

  17. Guidelines for Best Practice in Cross-Cultural Surveys. Available from: https://ccsg.isr.umich.edu/images/PDFs/CCSG_Full_Guidelines_2016_Version.pdf (accessed 28.03.2020).

Biology of Myeloproliferative Malignancies

MYELOID TUMORS , , , , , , ,

AL Melikyan, IN Subortseva

Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Irina Nikolaevna Subortseva, PhD, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-44-71; e-mail: soubortseva@yandex.ru

For citation: Melikyan AL, Subortseva IN. Biology of Myeloproliferative Malignancies. Clinical oncohematology. 2016;9(3):326-35 (In Russ).

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

ABSTRACT

Chronic myeloproliferative diseases (WHO, 2001), or myeloproliferative neoplasms/malignancies (MPN) (WHO, 2008), are clonal diseases characterized by proliferation of one or more myelopoietic cell line in the bone marrow with signs of unimpaired terminal differentiation and is normally associated with changes in peripheral blood characteristics. The group of classical Ph-negative MPNs consists of polycythemia vera, essential thrombocythemia, primary myelofibrosis and unclassified MPNs. Acquired somatic mutations contributing to the pathogenesis of Ph-negative MPNs include JAK2 (V617F, exon 12), MPL, CALR gene mutations found in about 90 % of patients. However, these molecular events are not unique in the pathogenesis of the diseases. Mutations of other genes (ТЕТ2, ASXL1, CBL, IDH1/IDH2, IKZF1, DNMT3A, SOCS, EZH2, TP53, RUNX1, and HMGA2) are involved in formation of the disease phenotype. This review describes current concepts concerning the molecular biology of MPNs.

Keywords: chronic myeloproliferative diseases, myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, primary myelofibrosis, genes JAK2, CALR, and MPL.

Received: April 11, 2016

Accepted: April 11, 2016

Read in PDF (RUS)pdficon

REFERENCES

  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.

Polycythemia Vera: Literature Review and Own Data

MYELOID TUMORS , ,

I.N. Subortseva, T.I. Kolosheinova, E.I. Pustovaya, E.K. Egorova, A.M. Kovrigina, Yu.V. Pliskunova, T.V. Makarik, A.O. Abdullaev, A.L. Melikyan

Hematology Research Center under the Ministry of Health of the Russian Federation, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Irina Nikolaevna Subortseva, PhD, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-44-72; e-mail: soubortseva@yandex.ru

For citation: Subortseva IN, Kolosheinova TI, Pustovaya EI, et al. Polycythemia Vera: Literature Review and Own Data. Clinical oncohematology. 2015;8(4):397–412 (In Russ).

DOI: 10.21320/2500-2139-2015-8-4-397-412

ABSTRACT

Background & Aims. Polycythemia vera (PV) refers to a group of classic Ph-negative myeloproliferative neoplasms characterized by panmyelosis, pancytosis, high risk of thrombotic and hemorrhagic complications, poor quality of life due to symptoms of tumor proliferation. Low-dose acetylsalicylic acid and phlebotomy/erythrocytapheresis are recommended for patients at low risk of complications, while the cytoreductive therapy (hydroxyurea or interferon alpha) is recommended for patients at high risk of thrombotic and hemorrhagic complications. At present, much attention is paid to the problems of diagnosis and treatment PV.

Methods. The article presents a brief description of the condition, a review of modern methods of treatment, results of observation over 100 PV patients who have been treated in the outpatient department of the Hematology Research Center. The observation period ranged from 6 to 262 months (median follow-up is 14 months).

Results. Patients’ age ranged from 23 to 80 years (median 56 years); 67 % of them were women, and 33 % were men. PV was diagnosed according to 2008 WHO guidelines. JAK2V617F mutation was detected in 100 % of cases. Splenomegaly was found in 70 % of patients. Plethoric symptoms (such as facial and hand hyperemia, and scleral injection) were found in 65 % of patients. All patients complained of headaches and dizziness, and 25 % of patients complained of itching. All patients received symptomatic therapy, antiaggregants, medications improving microcirculation, or antihypoxants. Patients were treated according to clinical guidelines: 49 % of them received hydroxyurea, 14 % IFN a-2b, 14 % a combination therapy (hydroxyurea and phlebotomy or IFN a-2b and phlebotomy), and 23 % of patients phlebotomy alone. Response to treatment was evaluated according to 2009 European LeukemiaNet criteria. Among all patients, the frequency of complete remission was 48 %, the partial response rate was 41 %, and no effect was achieved in 11 % of patients regardless they received therapy or not. The therapy was changed, if the treatment had proved to be ineffective, or in case of intolerance or complications. Complete remission was not achieved after switching treatment from one method to another.

Conclusion. Treatment of PV is mainly symptomatic. The effectiveness of first line therapy (complete remission) ranged from 14.5 to 71 %. It is necessary to conduct clinical trials designed to evaluate the effectiveness and safety of new targeted therapies.

Keywords: myeloproliferative neoplasms, polycythemia vera, JAK2V617F, target therapy.

Received: June 30, 2015

Accepted: November 5, 2015

Read in PDF (RUS)pdficon

REFERENCES

  1. Stuart BJ, Viera AJ. Polycythemia vera. Am Fam Physician. 2004;69:2139–44.
  2. Hensley B, Geyer H, Mesa R. Polycythemia vera: current pharmacotherapy and future directions. Expert Opin. Pharmacother. 2013;14:609–17. doi: 10.1517/14656566.2013.779671.
  3. Vannucchi AM. Insights into the pathogenesis and management of thrombosis in polycythemia vera and essential thrombocythemia. Intern Emerg Med. 2010;5:177–84. doi: 10.1007/s11739-009-0319-3.
  4. Mehta J, Wang H, Iqbal SU, et al. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma. 2014;55:595–600. doi: 10.3109/10428194.2013.813500.
  5. Moulard O, Mehta J, Fryzek J, et al. Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol. 2014;92:289–97. doi: 10.1111/ejh.12256.
  6. 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;117:755–61. doi: 10.1016/j.amjmed.2004.06.032.
  7. Tibes R, Mesa RA. Emerging drugs for polycythemia vera. Expert Opin Emerg Drugs. 2013;18:393–404. doi: 10.1517/14728214.2013.832754.
  8. Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013;27:1874–81. doi: 10.1038/leu.2013.163.
  9. Bandaranayake RM, Ungureanu D, Shan Y, et al. Crystal structures of the JAK2 pseudo kinase domain and the pathogenic mutant V617F. Nat Struct Mol Biol. 2012;19(8):754–9. doi: 10.1038/nsmb.2348.
  10. Brooks AJ, Dai W, O’Mara ML, et al. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science. 2014;344(6185). doi:10.1126/science.1249783.
  11. Pradhan A, Lambert QT, Griner LN, et al. Activation of American Society of Hematology JAK2-V617F by components of heterodimeric cytokine receptors. J Biol Chem. 2010;285(22):16651–63. doi: 10.1074/jbc.m109.071191.
  12. Chen E, Mullally A. How does JAK2V617F contribute to the pathogenesis of myeloproliferative neoplasms? Hematol Am Soc Hematol Educ Program. 2015;2014:268–76. doi: 10.1182/asheducation-2014.1.268.
  13. 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.
  14. 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.
  15. Ma W, Kantarjian H, Zhang X, et al. Mutation profile of JAK2 transcripts in patients with chronic myeloproliferative neoplasias. J. Mol. Diagn. 2009;11(1):49–53. doi: 10.2353/jmoldx.2009.080114.
  16. Milosevic JD, Kralovics R. Genetic and epigenetic alterations of myeloproliferative disorders. Int J Hematol. 2013;97(2):183–97. doi:10.1007/s12185-012-1235-2.
  17. Tong W, Zhang J, Lodish HF. LNK inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways. Blood. 2005;105(12):4604–12. doi: 10.1182/blood-2004-10-4093.
  18. Gery S, Cao Q, Gueller S, et al. LNK inhibits myeloproliferative disorder-associated JAK2 mutant, JAK2V617F. J. Leukoc. Biol. 2009;85(6):957–65. doi: 10.1189/jlb.0908575.
  19. Gery S, Gueller S, Chumakova K, et al. Adaptor protein LNK negatively regulates the mutant MPL, MPLW515L associated with myeloproliferative disorders. Blood. 2007;110(9):3360–4. doi: 10.1182/blood-2007-05-089326.
  20. 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.
  21. 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.
  22. Moran-Crusio K, Reavie L, Shih A, et al. TET2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell. 2011;20(1):11–24. doi: 10.1016/j.ccr.2011.06.001.
  23. Swierczek SI, Yoon D, Bellanne-Chantelot C, et al. Extent of hematopoietic involvement by TET2 mutations in JAK2V617F polycythemia vera. Haematologica. 2011;96(5):775–8. doi: 10.3324/haematol.2010.029678.
  24. Li Z, Cai X, Cai CL, et al. Deletion of TET2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood. 2011;118(17):4509–18. doi: 10.1182/blood-2010-12-325241.
  25. Busque L, Patel JP, Figueroa ME, et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Genet. 2012;44(11):1179–81. doi: 10.1038/ng.2413.
  26. Pardanani A, Lasho TL, Finke CM, et al. IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms. Leukemia. 2010;24(6):1146–51. doi: 10.1038/leu.2010.77.
  27. Tefferi A, Lasho TL, Abdel-Wahab O, et al. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis. Leukemia. 2010;24(7):1302–9. doi: 10.1038/leu.2010.113.
  28. Tefferi A, Jimma T, Sulai NH, et al. IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F. Leukemia. 2012;26(3):475–80. doi: 10.1038/leu.2011.253.
  29. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363(25):2424–33. doi: 10.1056/nejmoa1005143.
  30. Stegelmann F, Bullinger L, Schlenk RF, et al. DNMT3A mutations in myeloproliferative neoplasms. Leukemia. 2011;25(7):1217–9. doi: 10.1038/leu.2011.77.
  31. 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.
  32. 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.
  33. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379–90. doi: 10.1056/nejmoa1311347.
  34. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369:2391–405. doi: 10.1056/nejmoa1312542.
  35. Girodon F, Broseus J, Park-Alexandre JH, et al. Presence of Calreticulin Mutations in JAK2-Negative Polycythemia Vera. Blood. 2014;124: Abstract 1819.
  36. Spivak JL, Considine M, Williams DM, et al. Two Clinical Phenotypes in Polycythemia Vera. N Engl J Med. 2014;371:808–17. doi: 10.1056/NEJMoa1403141.
  37. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–51. doi: 10.1182/blood-2009-03-209262.
  38. McMullin MF, Reilly JT, Campbell P, et al. Amendment to the guideline for diagnosis and investigation of polycythaemia/erythrocytosis. Br J Haematol. 2007;138:821–2. doi: 10.1111/j.1365-2141.2007.06741.x.
  39. Berk PD, Goldberg JD, Donovan PB, et al. Therapeutic recommendations in polycythemia vera based on polycythemia vera study group protocols. Semin. Hematol. 1986;23:132–43.
  40. Murphy S. Diagnostic criteria and prognosis in polycythemia vera and essential thrombocythemia. Semin Hematol. 1999;36:9–13.
  41. Barbui T, Thiele J, Vannucchi AM, et al. Rethinking the diagnostic criteria of polycythemia vera. Leukemia. 2014;28:1191–5. doi: 10.1038/leu.2013.380.
  42. Barbui T, Thiele J, Carobbio A, et al. Masked polycythemia vera diagnosed according to WHO and BCSH classification. Am J Hematol. 2014;89:199–202. doi: 10.1002/ajh.23617.
  43. Scherber R, Dueck AC, Johansson P, et al. The myeloproliferative neoplasm symptom assessment form (MPN-SAF): international prospective validation and reliability trial in 402 patients. Blood. 2011;118:401–8. doi: 10.1182/blood-2011-01-328955.
  44. Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs. J Clin Oncol. 2012;30:4098–103. doi: 10.1200/jco.2012.42.3863.
  45. Abelsson J, Andreasson B, Samuelsson J, et al. Patients with polycythemia vera have worst impairment of quality of life among patients with newly diagnosed myeloproliferative neoplasms. Leuk Lymphoma. 2013;54:2226–30. doi: 10.3109/10428194.2013.766732.
  46. Geyer HL, Emanuel RM, Dueck AC, et al. Distinct clustering of symptomatic burden amongst myeloproliferative neoplasm patients: retrospective assessment in 1470 patients. Blood. 2014;123(24):3803–10. doi: 10.1182/blood-2013-09-527903.
  47. Johansson P, Mesa R, Scherber R, et al. Association between quality of life and clinical parameters in patients with myeloproliferative neoplasms. Leuk Lymphoma. 2012;53:441–4. doi: 10.3109/10428194.2011.619608.
  48. Scherber R, Dueck AC, Kiladjian JJ, et al. (HU/IFNa/Aspirin) Conventional therapeutic options have limited impact on MPN symptoms: insights from a prospective analysis of the MPN-SAF. In: European Hematology Association, Amsterdam, Netherlands, June 14–17 2012. Abstract 366.
  49. Samuelsson J, Hasselbalch H, Bruserud O, et al. A phase II trial of pegylated interferon alpha-2b therapy for polycythemia vera and essential thrombocythemia: feasibility, clinical and biologic effects, and impact on quality of life. Cancer. 2006;106:2397–405. doi: 10.1002/cncr.21900.
  50. Tefferi A, Elliott M. Thrombosis in myeloproliferative disorders: prevalence, prognostic factors, and the role of leukocytes and JAK2V617F. Semin Thromb Hemost. 2007;33:313–20. doi: 10.1055/s-2007-976165.
  51. Chou YS, Gau JP, Yu YB, et al. Leukocytosis in polycythemia vera and splenomegaly in essential thrombocythemia are independent risk factors for hemorrhage. Eur J Haematol. 2013;90:228–36. doi: 10.1111/ejh.12064.
  52. Меликян А.Л., Суборцева И.Н., Суханова Г.А. Тромбогеморрагические осложнения у больных Ph-негативными миелопролиферативными заболеваниями. Кровь. 2014;2(18):21–5.
    [Melikyan AL, Subortseva IN, Sukhanova GA. Thrombohemorrhagic complications in patients with Ph-negative myeloproliferative diseases. Krov’. 2014;2(18):21–5. (In Russ)]
  53. Finazzi G, Caruso V, Marchioli R, et al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood. 2005;105:2664–70. doi: 10.1182/blood-2004-09-3426.
  54. Passamonti F, Brusamolino E, Lazzarino M, et al. Efficacy of pipobroman in the treatment of polycythemia vera: long-term results in 163 patients. Haematologica 2000;85:1011–8.
  55. Kanitakis J, Arbona-Vidal E, Faure M. Porokeratosis in patients with polycythemia rubra vera: a new side effect of hydroxyurea? J Eur Acad Dermatol Venereol. 2012;26:1040–1. doi: 10.1111/j.1468-3083.2011.04202.x.
  56. Marchioli R, Finazzi G, Landolfi R, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23:2224–32. doi: 10.1200/jco.2005.07.062.
  57. Kiladjian JJ, Chevret S, Dosquet C, et al. Treatment of polycythemia vera with hydroxyurea and pipobroman: final results of a randomized trial initiated in 1980. J Clin Oncol. 2011;29:3907–13. doi: 10.1200/jco.2011.36.0792.
  58. Tefferi A, Rumi E, Finazzi G, et al. Chronic myeloproliferative neoplasias survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013;27:1874–81. doi: 10.1038/leu.2013.163.
  59. Barbui T, Finazzi MC, Finazzi G. Front-line therapy in polycythemia vera and essential thrombocythemia. Blood. 2012;26:205–11. doi: 10.1016/j.blre.2012.06.002.
  60. Tefferi A. Polycythemia vera and essential thrombocythemia: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol. 2013;88:507–16. doi: 10.1002/ajh.23417.
  61. Finazzi G, Barbui T. Evidence and expertise in the management of polycythemia vera and essential thrombocythemia. Leukemia. 2008;22:1494–502. doi: 10.1038/leu.2008.177.
  62. Landolfi R, Di Gennaro L, Barbui T, et al. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood. 2007;109:2446–52. doi: 10.1182/blood-2006-08-042515.
  63. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F) allele burden. Leukemia. 2007;21:1952–9. doi: 10.1038/sj.leu.2404854.
  64. Tefferi A, Strand JJ, Lasho TL, et al. Bone marrow JAK2V617F allele burden and clinical correlates in polycythemia vera. Leukemia. 2007;21:2074–5. doi: 10.1038/sj.leu.2404724.
  65. Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004;350:114–24. doi: 10.1056/nejmoa035572.
  66. Mughal TI, Vaddi K, Sarlis NJ, et al. Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes. Int J Gen Med. 2014;7:89–101. doi: 10.2147/ijgm.s51800.
  67. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368:22–33. doi: 10.1056/nejmoa1208500.
  68. Braekkan SK, Mathiesen EB, Njolstad I, et al. Hematocrit and risk of venous thromboembolism in a general population. The Tromso study. Haematologica. 2010;95:270–5. doi: 10.3324/haematol.2009.008417.
  69. Gori T. Viscosity, platelet activation, and hematocrit: progress in understanding their relationship with clinical and subclinical vascular disease. Clin Hemorheol Microcirc. 2011;49:37–42. doi: 10.3233/CH-2011-1455.
  70. Marchioli R, Finazzi G, Specchia G, et al. The CYTO-PV: a large-scale trial testing the intensity of CYTO-reductive therapy to prevent cardiovascular events in patients with Polycythemia Vera. Thrombosis. 2011;2011:794240. doi: 10.1155/2011/794240.
  71. Sever M, Newberry KJ, Verstovsek S. Therapeutic options for patients with polycythemia vera and essential thrombocythemia refractory/resistant to hydroxyurea. Leuk Lymphoma. 2014;55:2685–90. doi: 10.3109/10428194.2014.893310.
  72. Alvarez-Larran A, Pereira A, Cervantes F, et al. Assessment and prognostic value of the European LeukemiaNet criteria for clinicohematologic response, resistance, and intolerance to hydroxyurea in polycythemia vera. Blood. 2012;119:1363–9. doi: 10.1182/blood-2011-10-387787.
  73. Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112:3065–72. doi: 10.1182/blood-2008-03-143537.
  74. Kiladjian JJ. Chomienne C, Fenaux P. Interferon-alpha therapy in bcr-abl-negative myeloproliferative neoplasms. Leukemia. 2008;22:1990–8. doi: 10.1038/leu.2008.280.
  75. Bjorkholm M, Derolf AR, Hultcrantz M, et al. Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms. J Clin Oncol. 2011;29:2410–5. doi: 10.1200/jco.2011.34.7542.
  76. Barosi G, Vannucchi AM, De Stefano V, et al. Identifying and addressing unmet clinical needs in Ph-neg classical myeloproliferative neoplasms: a consensus-based SIE, SIES, GITMO position paper. Leuk Res. 2014;38:155–60. doi: 10.1016/j.leukres.2013.09.008.
  77. Bleeker JS, Hogan WJ. Thrombocytosis: diagnostic evaluation, thrombotic risk stratification, and risk-based management strategies. Thrombosis. 2011;2011:536062. doi: 10.1155/2011/536062.
  78. Barosi G, Birgegard G, Finazzi G, et al. A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and primary myelofibrosis: results of a European LeukemiaNet (ELN) consensus process. Br J Haematol. 2010;148:961–3. doi: 10.1111/j.1365-2141.2009.08019.x.
  79. Barosi G, Mesa R, Finazzi G, et al. Revised response criteria for polycythemia vera and essential thrombocythemia: a ELN and IWG-MRT consensus project. Blood. 2013;121:4778–81. doi: 10.1182/blood-2013-01-478891.
  80. Hexner EO, Serdikoff C, Jan M, et al. Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood. 2008;111:5663–71. doi: 10.1182/blood-2007-04-083402.
  81. Hexner E, Roboz G, Hoffman R, et al. Open-label study of oral CEP-701 (lestaurtinib) in patients with polycythaemia vera or essential thrombocythaemia with JAK2-V617F mutation. Br J Haematol. 2014;164:83–93. doi: 10.1111/bjh.12607.
  82. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799–807. doi: 10.1056/nejmoa1110557.
  83. Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013;122:4047–53. doi: 10.1182/blood-2013-02-485888.
  84. Quintas-Cardama A, Kantarjian H, Cortes J, et al. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov. 2011;10:127–40. doi: 10.1038/nrd3264.
  85. Verstovsek S, Passamonti F, Rambaldi A, et al. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. Cancer. 2014;120:513–20. doi: 10.1002/cncr.28441.
  86. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372:426–35. doi: 10.1056/nejmoa1409002.
  87. Passamonti F, Saydam G, Lim L, et al. RESPONSE 2: a phase 3b study evaluating the efficacy and safety of ruxolitinib in patients with hydroxyurea-resistant/intolerant polycythemia vera vs best available therapy. J Clin Oncol. 2014;32: Abstract TPS7128.
  88. Mesa R, Vannucchi AM, Yacoub A, et al. The Efficacy and Safety of Continued Hydroxyurea Therapy Versus Switching to Ruxolitinib in Patients with Polycythemia Vera: A Randomized, Double-Blind, Double-Dummy, Symptom Study (RELIEF). ASH Education Book. 2014;124(21):3168.
  89. Pardanani A, Gotlib J, Gupta V, et al. Phase I/II study of CYT387, a JAK1/JAK2 inhibitor for the treatment of myelofibrosis. Blood. 2012;120: Abstract 178.
  90. Verstovsek S, Mesa RA, Salama ME, et al. Phase I study of LY2784544, a JAK2 selective inhibitor, in patients with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). Blood. 2013;122: Abstract 665.
  91. Vigushin DM, Coombes RC. Targeted histone deacetylase inhibition for cancer therapy. Curr Cancer Drug Targets. 2004;4:205–18. doi: 10.2174/1568009043481560.
  92. Rambaldi A, Dellacasa CM, Finazzi G, et al. A pilot study of the histone-deacetylase inhibitor givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms. Br J Haematol. 2010;150:446–55. doi: 10.1111/j.1365-2141.2010.08266.x.
  93. Andersen C, Mortensen N, Vestergaard H, et al. A phase II study of vorinostat (MK-0683) in patients with primary myelofibrosis (PMF) and post-polycythemia vera myelofibrosis (PPV-MF). Haematologica. 2013;98: Abstract P279.
  94. 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;27:5418–24. doi: 10.1200/jco.2009.23.6075.
  95. Mascarenhas J, Mesa R, Prchal J, Hoffman R. 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.
  96. Harrison CN, Garcia NC. Management of MPN beyond JAK2. ASH Education Book. 2014;2014(1):348–54. doi:10.1182/asheducation-2014.1.348.