Прогностическое значение мутации ASXL1 при первичном миелофиброзе. Обзор литературы и описание клинического случая

Меликян А.Л., Суборцева И.Н., Гилязитдинова Е.А. и др. Прогностическое значение мутации ASXL1 при первичном миелофиброзе. Обзор литературы и описание клинического случая. Терапевтический архив. 2020; 92 (7): 95–99.
DOI: 10.26442/00403660.2020.07.000788

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Melikyan A.L., Subortseva I.N., Gilyazitdinova E.A., et al. The prognostic value of ASXL1 mutation in primary myelofibrosis. Literature review and clinical case description. Therapeutic Archive. 2020; 92 (7): 95–99. DOI: 10.26442/00403660.2020.07.000788

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Аннотация

Первичный миелофиброз (ПМФ) представляет собой миелопролиферативное новообразование, которое возникает de novo, характеризуется клональной пролиферацией стволовых клеток, аномальной экспрессией цитокинов, фиброзом костного мозга, гепатоспленомегалией – как следствие экстрамедуллярного гемопоэза, симптомами опухолевой интоксикации, кахексией, лейкоэритробластозом в периферической крови, лейкемической прогрессией и невысокой выживаемостью. ПМФ является хроническим неизлечимым заболеванием. Цели терапии: предупреждение прогрессии, увеличение общей выживаемости, улучшение качества жизни. Выбор лечебной тактики ограничен. Трансплантация аллогенных гемопоэтических стволовых клеток (алло-ТГСК) – единственный метод, дающий шанс на излечение. В настоящее время активно изучается роль мутаций ряда генов в раннем выявлении кандидатов для алло-ТГСК. В статье представлено описание клинического случая выявления мутации гена ASXL1 у больного префиброзным ПМФ. Диагноз установлен на основании критериев Всемирной организации здравоохранения 2016 г. При обследовании выявлена мутация ASXL1. Проводится терапия интерфероном альфа, в результате которой достигнута клинико-гематологическая ремиссия. Несмотря на выявленную мутацию, пациент не является кандидатом для алло-ТГСК. Учитывая неблагоприятное прогностическое значение мутации ASXL1, пациент подлежит активному динамическому наблюдению и агрессивной терапевтической тактике при появлении признаков прогрессирования заболевания.

Ключевые слова: первичный миелофиброз, миелопролиферативные заболевания, мутации в гене ASXL1, аллогенная трансплантация гемопоэтических стволовых клеток.

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Primary myelofibrosis is a myeloproliferative neoplasm that occurs de novo, characterized by clonal proliferation of stem cells, abnormal expression of cytokines, bone marrow fibrosis, hepatosplenomegaly – as a result of extramedullary hematopoiesis, symptoms of tumor intoxication, cachexemia, peripheral blood leukoerythroblastosis, leukemic progression and low survival. Primary myelofibrosis is a chronic incurable disease. The aims of therapy: preventing progression, increasing overall survival, improving quality of life. The choice of therapeutic tactics is limited. Allogenic hematopoietic stem cell transplantation is the only method that gives a chance for a cure. The role of mutations in a number of genes in the early identification of candidates for allogeneic hematopoietic stem cell transplantation is being actively studied. The article describes the clinical case of the detection of ASXL1 gene mutations in a patient with prefibrous primary myelofibrosis. The diagnosis was established on the basis of WHO criteria 2016. The examination revealed a mutation of ASXL1. Interferon alfa therapy is carried out, against the background of which clinico-hematological remission has been achieved. Despite the identified mutation, the patient is not a candidate for allogeneic hematopoietic stem cell transplantation. Given the unfavorable prognostic value of the ASXL1 mutation, the patient is subject to active dynamic observation and aggressive therapeutic tactics when signs of disease progression appear.

Keywords: primary myelofibrosis, myeloproliferative neoplasms, ASXL1 mutations, allogeneic stem cell transplantation.

Список литературы

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1. Melikyan AL, Turkina AG, Kovrigina AM, et al. Clinical recommendations for the diagnosis and therapy of Ph-negative myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, primary myelofibrosis) (edition 2016). Hematology and transfusiology. 2017;62(1):25-60 (In Russ.) doi: 10.25837/HAT.2019.51.88.001
2. Melikyan AL, Subortseva IN, Galstyan GM. Protocol of differentiated syndromic treatment of patients with primary myelofibrosis. In: Abramova AV, Abdullaev AO, Azimova MKh, et al. Diagnostic algorithms and protocols for the treatment of the blood system diseases. Moscow, 2018; p. 777-802 (In Russ.)
3. Nangalia J, Massie C, Baxter E, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391-405. doi: 10.1056/NEJMoa1312542
4. Klampfl T, Gisslinger H, Harutyunyan A, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-90. doi: 10.1056/NEJMoa1311347
5. 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
6. Guglielmelli P, Lasho T, Rotunno G, et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia. 2014;28(9):1804-10. doi: 10.1038/leu.2014.76
7. Vannucchi A, Lasho T, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27(9):1861-9. doi: 10.1038/leu.2013.119
8. Melikyan AL, Subortseva IN. Molecular pathogenesis of myeloproliferative diseases. Materials of the 19th congress of the European Hematology Association (2014, Milano). Klinicheskaya onkogematologiya. Fundamental'nye issledovaniya i klinicheskaya praktika. 2014;7(4):598-607 (In Russ.)
9. Melikyan AL, Subortseva IN. Biology of myeloproliferative disease. Clinical oncohematology. Basic research and clinical practice. 2016;9(3):314-25 (In Russ.) doi: 10.21320/2500-2139-2016-9-3-314-325
10. Abdel-Wahab O, Adli M, LaFave L, et al. ASXLl 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
11. Inoue D, Fujino T, Sheridan P, et al. A novel ASXLl-OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies. Leukemia. 2018;32(6):1327-37. doi: 10.1038/s41375-018-0083-3
12. Yang H, Kurtenbach S, Guo Y, et al. Gain of function of ASXLl truncating protein in the pathogenesis of myeloid malignancies. Blood. 2018;131(3):328-41. doi: 10.1182/blood-2017-06-789669
13. Tefferi A, Nicolosi M, Mudireddy M, et al. Driver mutations and prognosis in primary myelofibrosis: Mayo-Careggi MPN alliance study of 1,095 patients. Am
J Hematol. 2018;93(3):348-55. doi: 10.1002/ajh.24978
14. Tefferi A, Lasho T, Finke C, et al. Prognostic significance of ASXLl mutation types and allele burden in myelofibrosis. Leukemia. 2018;32(3):837-9. doi: 10.1038/leu.2017.318
15. Tefferi A, Guglielmelli P, Lasho TL, et al. CALR and ASXLI 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
16. Spiegel J, McNamara C, Kennedy J, et al. lmpact of genomic alterations on outcomes in myelofibrosis patients undergoing JAKl/2 inhibitor therapy. Blood Adv. 2017;1(20):1729-38. doi: 10.1182/bloodadvances.2017009530
17. Newberry K, Patel K, Masarova L, et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood. 2017;130(9):1125-31. doi: 10.1182/blood-2017-05-783225
18. Kröger N, Panagiota V, Badbaran A, et al. Impact of molecular genetics on outcome in myelofibrosis patients after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2017;23(7):1095-01. doi: 10.1016/j.bbmt.2017.03.034
19. Arber D, 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
20. Guglielmelli P, Pacilli A, Rotunno G, et al; AGIMM Group. Presentation and outcome of patients with 2016 WHO diagnosis of prefibrotic and overt primary myelofibrosis. Blood. 2017;129(24):3227-36. doi: 10.1182/blood-2017-01-761999
21. 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
22. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWGMRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115(9):1703-8. doi: 10.1182/blood-2009-09-245837
23. 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. Leukemia. 2017;31(12):2726-31. doi: 10.1038/leu.2017.169
24. Guglielmelli P, Lasho T, Rotunno G, et al. MIPSS70: mutationenhanced International Prognostic Score System for transplantationage patients with primaty myelofibrosis. J Clin Oneal. 2018;36(4):310-8. doi: 10.1200/JCO.2017.76.4886
25. Tefferi A, Guglielmelli P, Nicolosi M, et al. GIPSS: genetically inspired prognostic scoring system for p1imary myelofibrosis. Leukemia. 2018;32(7):1631-42. doi: 10.1038/s41375-018-0107-z
26. Hobbs GS, Rozelle S, Mullally A. The development and use of Janus Kinase 2 inhibitors for the treatment of myeloproliferative neoplasms. Hematol Oneal Clin North Am. 2017;31(4):613-26. doi: 10.1016/j.hoc.2017.04.002
27. Verstovsek S, Mesa R, Gotlib J, et al. A double-blind, placebocontrolled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi: 10.1056/NEJMoa1110557
28. Harrison C, Kiladjian J, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-98. doi: 10.1056/NEJMoa1110556
29. Vannucchi A, Kiladjian J, 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
30. Deininger M, Radich J, Burn T, et al. The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis. Blood. 2015;126(13):1551-4. doi: 10.1182/blood-2015-03-635235
31. Guglielmelli P, Rotunno G, Bogani C, et al; COMFORT-II Investigators. Ruxolitinib is an effective treatment for CALR-positive patients with myelofibrosis. Br
J Haematol. 2016;173(6):938-40. doi: 10.1111/bjh.13644
32. Vannucchi A, Verstovsek S, Guglielmelli P, et al. Ruxolitinib reduces JAK2 p.V617F allele burden in patients with polycythernia vera enrolled in the RESPONSE study. Ann Hematol. 2017;96(7):1113-20. doi: 10.1007/s00277-017-2994-x
33. Patel K, Newberry K, Luthra R, et al. Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib. Blood. 2015;126(6):790-7. doi: 10.1182/blood-2015-03-633404
34. Harrison C, Vannucchi A, Kiladjian J, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis [published correction appears in Leukemia. 2017;31:775]. Leukemia. 2016;30(8):1701-7. doi: 10.1038/leu.2016.148
35. Guglielmelli P, Biamonte F, Rotunno G, et al; COMFORT-II Investigators; Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative (AGIMM) Investigators. Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-IT study. Blood. 2014;123(14):2157-60. doi: 10.1182/blood-2013-11-536557
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Авторы

А.Л. Меликян, И.Н. Суборцева, Е.А. Гилязитдинова, Т.И. Колошейнова, Е.К. Егорова, Е.И. Пустовая, А.Б. Судариков, А.О. Абдуллаев, Л.А. Горгидзе, Д.И. Чеботарев

ФГБУ «Национальный медицинский исследовательский центр гематологии» Минздрава России, Москва, Россия

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A.L. Melikyan, I.N. Subortseva, E.A. Gilyazitdinova, T.I. Koloshejnova, E.K. Egorova, E.I. Pustovaya, A.B. Sudarikov, A.O. Abdullaev, L.A. Gorgidze, D.I. Chebotarev

National Research Center for Hematology, Moscow, Russia

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