OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press27410.17650/1818-8346-2018-13-1-29-44HEMATOLOGIC MALIGNANCIES: DIAGNOSIS, TREATMENT, SUPPORTIVE CAREГЕМОБЛАСТОЗЫ: ДИАГНОСТИКА, ЛЕЧЕНИЕ, СОПРОВОДИТЕЛЬНАЯ ТЕРАПИЯNEW APPROACHES TO THERAPY OF CLASSICAL PH-NEGATIVE MYELOPROLIFERATIVE DISEASES: THE EXPERIENCE OF EARLY THERAPY WITH CEPEGINTERFERON ALPHA-2BНОВЫЕ ПОДХОДЫ К ТЕРАПИИ КЛАССИЧЕСКИХ PH-НЕГАТИВНЫХ МИЕЛОПРОЛИФЕРАТИВНЫХ НОВООБРАЗОВАНИЙ: ОПЫТ РАННЕГО ПРИМЕНЕНИЯ ЦЕПЭГИНТЕРФЕРОНА АЛЬФ А-2Bhttps://orcid.org/0000-0001-9238-8476PolyakovA. S.ПоляковА. С.
Russian Federation

Department of Faculty Therapy

6а Akademika Lebedeva St., Saint Petersburg 194044

Поляков Алексей Сергеевич,  кафедра факультетской терапии

194044 Санкт-Петербург, ул. Академика Лебедева, 6а

doctorpolyakov@gmail.comNoskovY. A.НосковЯ. А.
Russian Federation

Department of Faculty Therapy

6а Akademika Lebedeva St., Saint Petersburg 194044

Кафедра факультетской терапии

194044 Санкт-Петербург, ул. Академика Лебедева, 6а

TyrenkoV. V.ТыренкоВ. В.
Russian Federation

Department of Faculty Therapy

6а Akademika Lebedeva St., Saint Petersburg 194044

Кафедра факультетской терапии

194044 Санкт-Петербург, ул. Академика Лебедева, 6а

LapshovaA. S.ЛапшоваА. С.
Russian Federation

Department of Faculty Therapy

6а Akademika Lebedeva St., Saint Petersburg 194044

Кафедра факультетской терапии

194044 Санкт-Петербург, ул. Академика Лебедева, 6а

KovalevA. V.КовалевА. В.
Russian Federation

Department of Faculty Therapy

6а Akademika Lebedeva St., Saint Petersburg 194044

Кафедра факультетской терапии

194044 Санкт-Петербург, ул. Академика Лебедева, 6а

S. M. Kirov Military Medical Academy, Ministry of Defense of the Russian FederationФГБВОУ ВО «Военно-медицинская академия имени С. М. Кирова» Минобороны России1105201813129441105201811052018https://oncohematology.abvpress.ru/ongm/article/view/274

Background. Even 100 years after the first attempts to introduce the chemotherapeutic approaches (in 1918) and despite the completely formed notions of myeloproliferative diseases as a group of malignant neoplasms, in the majority of patients with Ph-negative myeloproliferative neoplasms (MPN), a symptomatic, in fact, therapy approach – the impact on peripheral blood indices and nonspecific thromboprophylaxis – is allowed. The limitations of classical cytoreduction and current targeted therapy, as well as the conviction of most specialists in the impossibility of adequately containment of disease progression, continue to be the main factors that keep physicians from the early start of pathogenetic therapy.

Objective: to study the efficacy and safety of cepeginterferon alpha-2b (cePEG-IFN alpha-2b) in early (non-risk-adjusted) therapy of classical Ph-negative myeloproliferative neoplasms in initial use and after therapy with other pegylated interferons (PEG-IFN).

Materials and methods. Twenty seven patients with polycythemia vera or essential thrombocythemia, without considering risk, received cePEG-IFN alpha-2b: initially, or after 6 or 12 months of other pegylated interferon therapy, in a dosage of 200 μg per week, with a decrease to 100 μg per week if 2 degree hematological toxicity developed. Hematological and molecular responses were assessed. Follow-up – from 20 to 46 months.

Results. In all groups, a hematologic response comparable in depth and dynamics, as well as a molecular response as a steady decrease in the JAK2V617F allelic load, was achieved. There was no effect on the results of change to therapy with cePEG-IFN alpha-2b. CePEGIFN alpha-2b showed less dose-limiting toxicity for neutropenia and better pharmacoeconomic feasibility.

Discussion. New data about mechanisms of antiproliferative effects of interferon alfa preparations are given. The pharmacological advantages of cePEG-IFN alpha-2b are discussed: superiority in pharmacokinetic parameters, the presence of one position isomer purity of the drug substance, the convenience of self-application.

 Conclusion. Early administration of an effective pathogenic therapy is an independent preventive measure to prevent the MPN progression and complications development. The use of cePEG-IFN alpha-2b may help to improve the care of MPN patients.

Введение. Даже спустя 100 лет после первых попыток внедрения в практику химиотерапевтических подходов (1918 г.) и несмотря на окончательно сформировавшиеся представления о миелопролиферативных заболеваниях как о группе злокачественных новообразований, в отношении большинства пациентов с Ph-негативными миелопролиферативными новообразованиями (МПН) допускается, по сути, симптоматический подход к терапии – воздействие на показатели периферической крови и неспецифическая тромбопрофилактика. Ограничения классической циторедукции и современной таргетной терапии, а также убежденность большинства специалистов в невозможности адекватного сдерживания прогрессирования заболевания остаются основными факторами, удерживающими врачей от раннего назначения патогенетической терапии.

 Цель исследования – изучение эффективности и безопасности цепэгинтерферона альфа-2b (цеПЭГ-ИФН α-2b) в ранней (не рискадаптированной) терапии классических Ph-негативных МПН при инициальном назначении и при переходе с терапии другими пегилированными интерферонами.

Материалы и методы. Пациентам (n = 27) с истинной полицитемией или эссенциальной тромбоцитемией без учета риска назначен цеПЭГ-ИФН α-2b: инициально или после 6 либо 12 мес терапии другими пегилированными интерферонами в дозе 200 мкг в неделю со снижением до 100 мкг в неделю при развитии гематологической токсичности II степени. Оценивали гематологический и молекулярный ответ. Время наблюдения – от 20 до 46 мес.

 Результаты. Во всех группах достигнут сопоставимый по глубине и динамике гематологический ответ со стойкой нормализацией показателей, а также молекулярный ответ в виде устойчивого снижения уровня аллельной нагрузки JAK2V617F. Влияние на результаты фактора переключения на терапию цеПЭГ-ИФН α-2b отсутствовало. ЦеПЭГ-ИФН α-2b показал меньшую дозолимитирующую токсичность по нейтропении и лучшую фармакоэкономическую целесообразность.

Обсуждение. Новые данные о механизмах антипролиферативного действия препаратов интерферона α позволяют говорить о фармакологических преимуществах цеПЭГ-ИФН α-2b по фармакокинетическим показателям; отмечены наличие одного позиционного изомера, чистота лекарственной субстанции, удобство самостоятельного применения.

 Заключение. Раннее назначение эффективной патогенетической терапии является самостоятельной превентивной мерой в профилактике развития осложнений МПН. Внедрение цеПЭГ-ИФН α-2b может способствовать совершенствованию помощи пациентам с МПН.

: myeloproliferative neoplasmsMPNpolycythemia veraessential thrombocythemiamyelofibrosispegylated interferon alphacepeginterferon alpha-2b: миелопролиферативные новообразованияистинная полицитемияэссенциальная тромбоцитемиямиелофиброзпегилированный интерферон αцепэгинтерферон альфа-2bDameshek W. Some speculations on the myeloproliferative syndromes. Blood 1951;6(4):372–5.Goldman J. M. Chronic myeloid leukemia: reversing the chronic phase. J Clin Oncol 2010;28(3):363–5. DOI: 10.1200/JCO.2009.26.5587. PMID: 20008612.Polyakov A. S., Tyrenko V. V., Noskov Y. A. Clinical and laboratory features of different types of interferon therapy classic Ph-negative myeloproliferative neoplasms. Geny i kletki = Genes and cells 2016;11(3): 153–61 (In Russ.).Поляков А. С., Тыренко В. В., Носков Я. А. Клинико-лабораторные особенности различных видов интерферонотерапии классических Ph-негативных миелопролиферативных неоплазий. Гены и клетки 2016;11(3):153–61.Larsen T. S., Pallisgaard N., Møller M. B., Hasselbalch H. C. The JAK2 V617F allele burden in essential thrombocythemia, polycythemia vera and primary myelofibrosis – impact on disease phenotype. Eur J Haematol 2007;79(6):508–15. DOI: 10.1111/j.1600-0609.2007.00960.x. PMID: 17961178.Baxter E. J., Scott L. M., Campbell P. J. 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. PMID: 15781101.Campbell P. J., Green A. R. The myeloproliferative disorders. N Engl J Med 2006;355(23):2452–66. DOI: 10.1056/NEJMra063728.PMID: 17151367.Campbell P. J., Green A. R. The myeloproliferative disorders. N Engl J Med 2006;355(23):2452–66. DOI: 10.1056/NEJMra063728. PMID: 17151367.Cazzola M., Kralovics R. From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms. Blood 2014;123(24):3714–9. DOI: 10.1182/blood-2014‑03‑530865. PMID: 24786775.James C., Ugo V., Le Couédic J. P. et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434(7037): 1144–8. DOI: 10.1038/nature03546. PMID: 15793561.Klampfl T., Gisslinger H., Harutyunyan A. S. et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013;369(25):2379–90. DOI: 10.1056/NEJMoa1311347. PMID: 24325356.Kralovics R., Passamonti F., Buser A. S. 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. PMID: 15858187.Levine R. L., Pardanani A., Tefferi A., Gilliland D. G. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 2007;7(9):673–83. DOI: 10.1038/nrc2210. PMID: 17721432.Levine R. L., 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. PMID: 15837627.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. PMID: 24478400.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.Hanahan D., Weinberg R. A. Hallmarks of cancer: the next generation. Cell 2011;144(5):646–74. DOI: 10.1016/j.cell.2011.02.013 PMID: 21376230.Hanahan D., Weinberg R. A The hallmarks of cancer. Cell 2000;100(1):57–70. PMID: 10647931.Frederiksen H., Farkas D. K., Christiansen C. F. et al. Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population-based cohort study. Blood 2011;118(25):6515–20. DOI: 10.1182/blood-2011‑04‑348755. PMID: 22039256.Singdong R., Siriboonpiputtana T., Chareonsirisuthigul T. et al. Characterization and Prognosis Significance of JAK2 (V617F), MPL, and CALR Mutations in Philadelphia-Negative Myeloproliferative Neoplasms. Asian Pac J Cancer Prev 2016;17(10):4647–53. DOI: 10.22034/APJCP.2016.17.10.4647. PMID: 27892678.Passamonti F., Rumi E., Pietra D. et al. A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia 2010;24(9):1574–9. DOI: 10.1038/leu.2010.148. PMID: 20631743.Bjørn M. E., Hasselbalch H. C. The role of reactive oxygen species in myelofibrosis and related neoplasms. Mediators Inflamm 2015;2015:648090. DOI: 10.1155/2015/648090. PMID: 26538833.Hasselbalch H. C., Bjørn M. E. MPNs as inflammatory diseases: the evidence, consequences, and perspectives. Mediators Inflamm 2015;2015:102476. DOI: 10.1155/2015/102476. PMID: 26604428.Hasselbalch H. C., Thomassen M., Riley C. H. et al. Whole blood transcriptional profiling reveals deregulation of oxidative and antioxidative defence genes in myelofibrosis and related neoplasms. Potential implications of downregulation of Nrf2 for genomic instability and disease progression. PLoS One 2014;9(11):e112786. DOI: 10.1371/journal.pone.0112786. PMID: 25397683.Hasselbalch H. C. A role of NF-E2 in chronic inflammation and clonal evolution in essential thrombocythemia, polycythemia vera and myelofibrosis. Leuk Res 2014;38(2):263–6.DOI: 10.1016/j.leukres2013.07.002. PMID: 23932394.Hasselbalch H. C. Chronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development. Leuk Res 2013;37(2):214–20. DOI: 10.1016/j.leukres.2012.10.020. PMID: 23174192.Hasselbalch H. C. Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer. Blood 2012;119(14):3219–25. DOI: 10.1182/blood-2011‑11‑394775. PMID: 22318201.Hasselbalch H. C. The role of cytokines in the initiation and progression of myelofibrosis. Cytokine Growth Factor Rev 2013;24(2):133–45. DOI: 10.1016/j.cytogfr.2013.01.004. PMID: 23415024.Hermouet S., Vilaine M. The JAK2 46/1 haplotype: a marker of inappropriate myelomonocytic response to cytokine stimulation, leading to increased risk of inflammation, myeloid neoplasm, and impaired defense against infection? Haematologica 2011;96(11):1575–9. DOI: 10.3324/haematol.2011.055392. PMID: 22058280.Kristinsson S. Y., Landgren O., Samuelsson J. et al. Autoimmunity and the risk of myeloproliferative neoplasms. Haematologica 2010;95(7):1216–20. DOI: 10.3324/haematol.2009.020412. PMID: 20053870.Marty C., Lacout C., Droin N. et al. A role for reactive oxygen species in JAK2 V617F myeloproliferative neoplasm progression. Leukemia 2013;27(11):2187– 95. DOI: 10.1038/leu.2013.102. PMID: 23558526.Skov V., Larsen T. S., Thomassen M. et al. Molecular profiling of peripheral blood cells from patients with polycythemia vera and related neoplasms: identification of deregulated genes of significance for inflammation and immune surveillance. Leuk Res 2012;36(11):1387–92. DOI: 10.1016/j.leukres.2012.07.009. PMID: 22877729.Skov V., Larsen T. S., Thomassen M. et al. Whole-blood transcriptional profiling of interferon-inducible genes identifies highly upregulated IFI27 in primary myelofibrosis. Eur J Haematol 2011;87(1):54–60. DOI: 10.1111/j.1600-0609.2011.01618.x. PMID: 21447007.Skov V., Thomassen M., Riley C. H. et al. Gene expression profiling with principal component analysis depicts the biological continuum from essential thrombocythemia over polycythemia vera to myelofibrosis. Exp Hematol 2012;40(9):771–80. DOI: 10.1016/j.exphem.2012.05.011. PMID: 22659388.Feenstra J. M., Rumi E., Pietra D. et al. Whole exome sequencing reveals clonal evolution of myeloproliferative neoplasms to acute myeloid leukemia. ASH abstr. Blood 2015;126(23):1626.Barosi G., Rosti V., Bonetti E. et al. Evidence that prefibrotic myelofibrosis is aligned along a clinical and biological continuum featuring primary myelofibrosis. PLoS One 2012;7(4):e35631. DOI: 10.1371/journal.pone.0035631. PMID: 22536419.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. PMID: 25189724.Hasselbalch H. C. Myelofibrosis with myeloid metaplasia: the advanced phase of an untreated disseminated hematological cancer. Leuk Res 2009;33(1):11–8. DOI: 10.1016/j.leukres.2008.06.002. PMID: 18632152.Tefferi A. The history of myeloproliferative disorders: before and after Dameshek. Leukemia 2008;22(1):3–13. DOI: 10.1038/sj.leu.2404946. PMID: 17882283.Berlin N. I. Prologue: polycythemia vera. The closing of the Wasserman-Polycythemia Vera Study Group era. Semin Hematol 1997;34(1):1–5. PMID: 9025156.Abdulkadyrov K. M., Shuvaеv V. A., Martynkevich I. S. Myeloproliferative neoplasms. Moscow: Litterra, 2016, 190 p. (In Russ.).Абдулкадыров К. М., Шуваев В. А., Мартынкевич И. С. Миелопролиферативные новообразования. М.: Литтерра, 2016. 190 с.Barosi G., Tefferi A., Besses G. et al. Clinical end points for drug treatment trials in BCR-ABL1-negativ classic myeloproliferative neoplasms: consensus statements from European LeukemiaNET (ELN) and Internation Working Group – Myeloproliferative Neoplasms Research and Treatment (IWG-MRT). Leukemia 2015;29(1):6–20. DOI: 10.1038/leu.2014.250. PMID: 25151955.Carlson R. W. The NCCN 22nd Annual Conference: Discussing Treatment Disparities, the Doctor – Patient Relationship, the Latest NCCN Guidelines Updates, and More. J Natl Compr Canc Netw 2017;15(5S):653–4. PMID: 28515239.Tefferi A., Vannucchi A., Barbui T. Polycythemia vera treatment algorithm 2018. Blood Cancer J 2018;8(1):3. DOI: 10.1038/s41408‑017‑0042‑7. PMID: 29321547.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. PMID: 24881037.Wolfe L. Ruxolitinib in Myelofibrosis and Polycythemia Vera. J Adv Pract Oncol 2016;7(4):436–44. PMID: 29226001.Mesa R. A., Vannucchi A. M., Mead A. et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol 2017;4(5):225–36. DOI: 10.1016/S2352-3026(17)30027-3. PMID: 28336242.Polyakov A. S., Tyrenko V. V., Noskov Y. A. Hemostasis disorders in myeloproliferative neoplasms. Tromby, krovotochivost i bolezni sosudov = Thrombi, bleeding and vascular disorders 2017;15(2):46–7. (In Russ.).Поляков А. С., Тыренко В. В., Носков Я. А. Нарушения гемостаза при миелопролиферативных новообразованиях. Тромбы, кровоточивость и болезни сосудов 2017;15(2):46–47.Barbui T., De Stefano V. Management of venous thromboembolism in myeloproliferative neoplasms. Curr Opin Hematol 2017;24(2):108–14. DOI: 10.1097/MOH.0000000000000312. PMID: 27875375.Tyrenko V. V., Polyakov A. S., Noskov Y. A., Kovalev A. V. Improving the antitumor immunotherapy of myeloproliferative neoplasms among veteran athletes. Uchenye zapiski universiteta imeni P. F. Lesgafta = Scientific notes of the P. F. Lesgaft University 2016;6(136):158–62 (In Russ.).Тыренко В. В., Поляков А. С., Носков Я. А., Ковалев А. В. Совершенствование противоопухолевой иммунотерапии миелопролиферативных неоплазий у спортсменов-ветеранов старшего возраста. Ученые записки университета имени П. Ф. Лесгафта 2016;6(136):158–62.Noskov Y. A. Clinical and laboratory features of myeloproliferative disorders during different types of interferon therapy. Dissertation. St. Petersburg, 2016. (In Russ.).Носков Я. А. Клинико-лабораторные особенности течения миелопролиферативных неоплазий на фоне различных видов интерферонотерапии: дис. … канд. мед. наук. СПб., 2016. 136 с.Polyakov A. S., Noskov Y. A., Petrova O. R., Golubtsov O. Yu. Perspective interferon therapy of Ph-negative myeloproliferative neoplasms: cepeginterferon alfa-2b (Algeron®). Botkinskie chteniya (conference), 2017, St. Petersburg. P. 213–215 (In Russ)..Поляков А. С., Носков Я. А., Петрова О. Р., Голубцов О. Ю. Перспективная интерферонотерапия Ph-негативных миелопролиферативных новообразований: цепэгинтерферон α-2b (Альгерон®). Боткинские чтения. Санкт-Петербург, 2017. С. 213–215.Le Bousse-Kerdilès M. C. Primary myelofibrosis and the “bad seeds in bad soil” concept. Fibrogenesis Tissue Repair 2012;5(Suppl 1):S20. DOI: 10.1186/1755‑1536‑5-S1-S20. PMID: 23259918.Christensen A. S., Møller J. B., Hasselbalch H. C. Chronic kidney disease in patients with the Philadelphia-negative chronic myeloproliferative neoplasms. Leuk Res 2014;38(4):490–5. DOI: 10.1016/j.leukres.2014.01.014. PMID: 24630365.Farmer S., Horváth-Puhó E., Vestergaard H. et al. Chronic myeloproliferative neoplasms and risk of osteoporotic fractures; a nationwide population-based cohort study. Br J Haematol 2013;163(5):603–10. DOI: 10.1111/bjh.12581. PMID: 24111669.Hasselbalch H. C. Perspectives on the impact of JAK-inhibitor therapy upon inflammation-mediated comorbidities in myelofibrosis and related neoplasms. Expert Rev Hematol 2014;7(2):203–16. DOI: 10.1586/17474086.2013.876356. PMID: 24524202.Silver R. T. A new treatment for polycythemia vera: recombinant interferon alfa. Blood 1990;76(4):664–5. PMID: 2383649.Gisslinger H., Zagrijtschuk O., BuxhoferAusch V. et al. Ropeginterferon alfa-2b, a novel IFN a -2b, induces high response rates with low toxicity in patients with polycythemia vera. Blood 2015;126(15):1762–70. DOI: 10.1182/blood-2015‑04‑637280. PMID: 26261238.Gowin K., Thapaliy P., Samuelson J. et al. Experience with pegylated interferon α-2a in advanced myeloproliferative neoplasms in an international cohort of 118 patients. Haematologica 2012;97(10):1570–3. DOI: 10.3324/haematol.2011.061390. PMID: 22419578.Kiladjian J. J., 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(8):3065–72. DOI: 10.1182/blood-2008‑03‑143537. PMID: 18650451.Quintás-Cardama A., Abdel-Wahab O., Manshouri T. et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood 2013;122(6):893–901. DOI: 10.1182/blood-2012‑07‑442012. PMID: 23782935.Quintás-Cardama A., Kantarjian H., Manshouri T. et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol 2009;27(32):5418–24. DOI: 10.1200/JCO.2009.23.6075. PMID: 19826111.Stauffer Larsen T., Iversen K. F., Hansen E. et al. Long term molecular responses in a cohort of Danish patients with essential thrombocythemia, polycythemia vera and myelofibrosis treated with recombinant interferon alpha. Leuk Res 2013;37(9):1041–5. DOI: 10.1016/j.leukres.2013.06.012. PMID: 23827351.Utke Rank C., Weis Bjerrum O., Larsen T. S. et al. Minimal residual disease after long-term interferon-alpha2 treatment: a report on hematological, molecular and histomorphological response patterns in 10 patients with essential thrombocythemia and polycythemia vera. Leuk Lymphoma 2015, Jun 18:1–7. [Epub ahead of print]. DOI: 10.3109/10428194.2015.1049171. PMID: 25956046.The state register of the maximum selling prices for medications included in the list of vital and essential medicines(as of 01.02.2018). Available from: https://grls.rosminzdrav.ru/pricelims.aspx. (In Russ.).Государственный реестр предельных отпускных цен производителей на лекарственные препараты, включенные в перечень жизненно необходимых и важнейших лекарственных препаратов (по состоянию на 01.02.2018). Доступно по: https://grls.rosminzdrav.ru/pricelims.aspx.Hasselbalch H. C. A new era for IFN-α in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms. Expert Rev Hematol 2011;4(6):637–55. DOI: 10.1586/EHM.11.63. PMID: 22077528.Kiladjian J. J., Giraudier S., Cassinat B. Interferon-alpha for the therapy of myeloproliferative neoplasms: targeting the malignant clone. Leukemia 2016;30(4):776–81. DOI: 10.1038/leu.2015.326. PMID: 26601783.Silver R. T., Kiladjian J. J., Hasselbalch H. C. Interferon and the treatment of polycythemia vera, essential thrombocythemia and myelofibrosis. Expert Rev Hematol 2013;6(1):49–58. DOI: 10.1586/ehm12.69. PMID: 23373780.Birgegard G. Advances and challenges in the management of essential thrombocythemia. Ther Adv Hematol 2015;6(3):142–56. DOI: 10.1177/2040620715580068. PMID: 26137205.Latagliata R., Spadea A., Cedrone M. et al. Symptomatic mucocutaneous toxicity of hydroxyurea in Philadelphia chromosome-negative myeloproliferative neoplasms: the Mister Hyde face of a safe drug. Cancer 2012;118(2):404–9. DOI: 10.1002/cncr.26194. PMID: 21692060.Massa M., Campanelli R., Fois G. et al. Reduced frequency of CD4+CD25+ +CD127low/– FOXp3+ regulatory T-cells in patients with primary myelofibrosis. ASH abstract. Blood 2015;126(23):2809.Parampalli Yajnanarayana S., Stübig T., Cornez I. et al. JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms. Br J Haematol 2015;169(6):824–33. DOI: 10.1111/bjh.13373. PMID: 25824483.Spivak J. L., Hasselbalch H. Hydroxycarbamide: a user’s guide for chronic myeloproliferative disorders. Expert Rev Anticancer Ther 2011;11(3):403–14. DOI: 10.1586/era.11.10. PMID: 21417854.Bailey A. D., Gray L. T., Pavelitz T. et al. The conserved Cockayne syndrome BpiggyBac fusion protein (CSB-PGBD3) affects DNA repair and induces both interferon-like and innate antiviral responses in CSB-null cells. DNA Repair(Amst) 2012;11(5):488–501. DOI: 10.1016/j.dnarep.2012.02.004. PMID: 22483866.Yamane A., Nakamura T., Suzuki H. et al. Interferon-alpha 2b-induced thrombocytopenia is caused by inhibition of platelet production but not proliferation and endomitosis in human megakaryocytes. Blood 2008;112(3):542–50. DOI: 10.1182/blood-2007‑12‑125906. PMID: 18523149.Shivdasani R. A., Fujuwara Y., McDevitt M.A., Orkin S. H. A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO J 1997;16(13):3965–74. DOI: 10.1093/emboj/16.13.3965. PMID: 9233806.Muntean A. G., Pang L., Poncz M. et al. Cyclin D–Cdk4 is regulated by GATA-1 and required for megakaryocyte growth and polyploidization. Blood 2007;109(12):5199–207. DOI: 10.1182/blood-2006‑11‑059378. PMID: 17317855.Igarashi K., Kataoka K., Itoh K. et al. Regulation of transcription by dimerization of erythroid factor NF-E2 p45 with small Maf proteins. Nature 1994;367(6463):568–72. DOI: 10.1038/367568a0. PMID: 8107826.Shivdasani R. A., Rosenblatt M. F., Zucker-Franklin D. et al. Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Cell 1995;81(5):695–704. PMID: 7774011.Hasselbalch H. C., Kiladjian J. J., Silver R. T. Interferon alfa in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms. J Clin Oncol 2011;29(18):e564–5. DOI: 10.1200/JCO.2011.35.6238. PMID: 21576637.Them N. C., Bagienski K., Berg T. et al. Molecular responses and chromosomal aberrations in patients with polycythemia vera treated with peg-proline-interferon alpha-2b. Am J Hematol 2015;90(4): 288–94. DOI: 10.1002/ajh.23928. PMID: 25545244.Verger E., Cassinat B., Dosquet C. et al. Clinical and molecular response to interferon-alfa therapy in essential thrombocythemia patients with CALR mutations. Blood 2015;126(24):2585–92. DOI: 10.1182/blood-2015‑07‑659060. PMID: 26486786.Duek A., Lundberg P., Shimizu T. et al. Loss of Stat1 decreases megakaryopoiesis and favors erythropoiesis in a JAK2V617F-drivenmouse model of MPNs. Blood 2014;123(25):3943–50. DOI: 10.1182/blood-2013‑07‑514208. PMID: 24820309.Au-Yeung N., Mandhana R., Horvath C. M. Transcriptional regulation by STAT1 and STAT2 in the interferon JAK-STAT pathway. JAKSTAT 2013;2(3):e23931. DOI: 10.4161/jkst.23931. PMID: 24069549.Platanias L. C., Uddin S., Bruno E. et al. CrkL and CrkII participate in the generation of the growth inhibitory effects of interferons on primary hematopoietic progenitors. Exp Hematol 1999;27(8):1315–21. PMID: 10428508.Härtlova A., Erttmann S. F., Raffi F. A. et al. DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity. Immunity 2015;42(2):332–43. DOI: 10.1016/j.immuni.2015.01.012. PMID: 25692705.Scheller M., Foerster J., Heyworth C. M. et al. Altered development and cytokine responses of myeloid progenitors in the absence of transcription factor, interferon consensus sequence binding protein. Blood 1999;94(11):3764–71. PMID: 10572090.Eklund E. A., Kakar R. Recruitment of CBP by PU. 1, IRF1 and ICSBP is necessary for gp91phox and p67phox expression. Immunol 1999;163(11): 6095–105. PMID: 10570299.Eklund E. A., Jalava A., Kakar R. PU.1, interferon regulatory factor 1, and interferon consensus sequence binding protein cooperate to increase gp91phox expression. J Biol 1998;273(22):13957–65. PMID: 9593745.Kurotaki D., Osato N., Nishiyama A. et al. Essential role of the IRF8-KLF4 transcription factor cascade in murine monocyte differentiation. Blood 2013;121(10):1839–49. DOI: 10.1182/blood-2012‑06‑437863. PMID: 23319570Rehli M., Poltorak A., Schwarzfischer L. et al. PU.1 and interferon consensus sequence-binding protein regulate the myeloid expression of the human Tolllike receptor 4 gene. J Biol Chem 2000;275(13):9773–81. PMID: 10734131.Huang W., Saberwal G., Horvath E. et al. Leukemia associated, constitutively active mutants of SHP2 protein tyrosine phosphatase inhibit NF1-transcriptional activation by the interferon consensus sequence binding protein. Mol Cell Biol 2006;26(17):6311–32. DOI: 10.1128/MCB.00036-06. PMID: 16914719.Kakar R., Kautz B., Eklund E. A. JAK2 is necessary and sufficient for interferoninduced transcription of the gene encoding gp91PHOX. J Leukoc Biol 2005;77(1):120–7. DOI: 10.1189/jlb.0704429. PMID: 15496449.Konieczna I., Horvath E., Wang H. et al. Constitutive activation of SHP2 cooperates with ICSBP-deficiency to accelerate progression to acute myeloid leukemia. J Clin Invest 2008;118(3):853–67. DOI: 10.1172/JCI33742. PMID: 18246201.Hu L., Huang W., Hjort E. E. et al. The Interferon Consensus Sequence Binding Protein(Icsbp/Irf8) Is Required for Termination of Emergency Granulopoiesis. J Biol Chem 2016;291(8):4107–20. DOI: 10.1074/jbc.M115.681361. PMID: 26683374.Carobbio A., Finazzi G., Antonioli E. et al. JAK2V617F allele burden and thrombosis: a direct comparison in essential thrombocythemia and polycythemia vera. Exp Hematol 2009;37(9):1016–21. DOI: 10.1016/j.exphem.2009.06.006. PMID: 19559071.Vannucchi A. M., Antonioli E., Guglielmelli P. et al. Prospective identification of high-risk polycythemia vera patients based on JAK2 (V617F) allele burden. Leukemia 2007;21(9):1952–9. DOI: 10.1038/sj.leu.2404854. PMID: 17625606.Silver R. T., Vandris K., Wang Y. L. et al. JAK2(V617F) allele burden in polycythemia vera correlates with grade of myelofibrosis, but is not substantially affected by therapy. Leuk Res 2011;35(2):177–82. DOI: 10.1016/j.leukres.2010.06.017. PMID: 20650526.Antonioli E., Guglielmelli P., Poli G. et al. Influence of JAK2V617F allele burden on phenotype in essential thrombocythemia. Haematologica 2008;93(1):41–8. DOI: 10.3324/haematol.11653 PMID: 18166784.Kiladjian J. J., Mesa R. A., Hoffman R. The renaissance of interferon therapy for the treatment of myeloid malignancies. Blood 2011;117(18):4706–15. DOI: 10.1182/blood-2010‑08‑258772. PMID: 21389325.Hasselbalch H. C., Larsen T. S., Riley C. H. et al. Interferon-alpha in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms. Status and perspectives. Curr Drug Targets 2011;12(3):392–419. PMID: 21143149.Hasselbalch H. C., Silver R. T. Interferon in polycythemia vera and related neoplasms. Can it become the treatment of choice without a randomized trial? Expert Rev Hematol 2015;8(4):439–45. DOI: 10.1586/17474086.2015.1045409. PMID: 25996953.Pizzi M., Silver R. T., Barel A., Orazi A. Recombinant interferon-α in myelofibrosis reduces bone marrow fibrosis, improves its morphology and is associated with clinical response. Mod Pathol 2015;28(10):1315–23. DOI: 10.1038/modpathol.2015.93. PMID: 26271725.Silver R. T., Vandris K., Goldman J. J. Recombinant interferon-α may retard progression of early primary myelofibrosis: a preliminary report. Blood 2011;117(24):6669–72. DOI: 10.1182/blood-2010‑11‑320069. PMID: 21518929.Silver R. T., Vandris K., Goldman J. J. Recombinant interferon-α may retard progression of early primary myelofibrosis: a preliminary report. Blood 2011;117(24):6669–72. DOI: 10.1182/blood-2010‑11‑320069. PMID: 21518929.Silver R. T. Long-term effects of the treatment of polycythemia vera with recombinant interferon-α. Cancer 2006;107(3):451–8. DOI: 10.1002/cncr.22026. PMID: 16804923.Saberwal G., Horvath E., Hu L. et al. The interferon consensus sequence binding protein (ICSBP/IRF8) activates transcription of the FANCF gene during myeloid differentiation. J Biol Chem 2009;284(48):33242–54. DOI: 10.1074/jbc.M109.010231. PMID: 19801548.Bailey A. D., Gray L. T., Pavelitz T. et al. The conserved Cockayne syndrome BpiggyBac fusion protein (CSB-PGBD3) affects DNA repair and induces both interferon-like and innate antiviral responses in CSB-null cells. DNA Repair (Amst) 2012;11(5):488–501. DOI: 10.1016/j.dnarep.2012.02.004. PMID: 22483866.Huang B. T., Zeng Q. C., Zhao W. H. et al. Interferon α-2b gains high sustained response therapy for advanced essential thrombocythemia and polycythemia vera with JAK2V617F positive mutation. Leuk Res 2014;38(10):1177–83. DOI: 10.1016/j.leukres.2014.06.019. PMID: 25069759.