Материалы доступны только для специалистов сферы здравоохранения.
Чтобы посмотреть материал полностью
Авторизуйтесь
или зарегистрируйтесь.
Эффективность монотерапии иптакопаном при субоптимальном ответе на экулизумаб у пациентов с пароксизмальной ночной гемоглобинурией - Журнал Терапевтический архив №1 Поликлинические проблемы и организация медицинской помощи 2025
Эффективность монотерапии иптакопаном при субоптимальном ответе на экулизумаб у пациентов с пароксизмальной ночной гемоглобинурией
Климова О.У., Голубовская И.К., Кузнецов Ю.Н., Марченко М.В., Кулагин А.Д. Эффективность монотерапии иптакопаном при субоптимальном ответе на экулизумаб у пациентов с пароксизмальной ночной гемоглобинурией. Терапевтический архив. 2025;97(1):46–53. DOI: 10.26442/00403660.2025.01.203146
© ООО «КОНСИЛИУМ МЕДИКУМ», 2025 г.
© ООО «КОНСИЛИУМ МЕДИКУМ», 2025 г.
________________________________________________
Материалы доступны только для специалистов сферы здравоохранения.
Чтобы посмотреть материал полностью
Авторизуйтесь
или зарегистрируйтесь.
Аннотация
Цель. Оценить гематологический ответ в течение 4 нед монотерапии иптакопаном у больных с пароксизмальной ночной гемоглобинурией и субоптимальным ответом на длительную терапию экулизумабом.
Материалы и методы. В анализ включены 8 больных, медиана возраста 32 года, с сохранением анемии на длительной терапии экулизумабом. Оценивался гематологический ответ при переключении на пероральную монотерапию иптакопаном 200 мг 2 раза в сутки в течение 4 нед.
Результаты. Через 4 нед терапии иптакопаном повышение уровня гемоглобина более чем на 20 г/л достигнуто у 7/8 (88%), полный ответ – у 6/8 (75%). Медиана прироста уровня гемоглобина составила 32,5 г/л с исходной 85,5 г/л (74–100) до 121,5 г/л (80–141); p=0,00013. Независимость от трансфузий эритроцитов достигнута в 100% случаев. Достижение гематологического ответа на терапию иптакопаном сопровождалось снижением абсолютного числа ретикулоцитов, уровня билирубина и лактатдегидрогеназы, а также негативизацией анти-C3d прямого антиглобулинового теста.
Заключение. Пероральный ингибитор фактора В комплемента иптакопан является эффективной опцией лечения пароксизмальной ночной гемоглобинурии у пациентов с субоптимальным ответом на ингибитор комплемента С5 за счет более эффективного контроля экстраваскулярного С3-опосредованного гемолиза.
Ключевые слова: пароксизмальная ночная гемоглобинурия, ингибитор комплемента С5, субоптимальный ответ, ингибитор фактора B, иптакопан
Materials and methods. The analysis included 8 patients, median age 32 years, with persistent anemia on long-term therapy with eculizumab. The hematological response was assessed when switching to oral monotherapy with iptacopan 200 mg twice daily for 4 weeks.
Results. After 4 weeks of iptacopan therapy, an increase in hemoglobin levels by more than 20 g/l was achieved in 7/8 (88%), and a complete response in 6/8 (75%) patients. The median increase in hemoglobin levels was 32.5 g/l from the initial 85.5 g/l (74–100) to 121.5 g/l (80–141); p=0.00013. Independence from red blood cell transfusions was achieved in 100% of cases. Achieving a hematological response to iptacopan therapy was accompanied by a decrease in the level of absolute reticulocyte count, bilirubin and lactate dehydrogenase, as well as a negative result of the anti-C3d direct antiglobulin test.
Conclusion. The oral complement factor B inhibitor iptacopan is an effective treatment option for paroxysmal nocturnal hemoglobinuria in patients with a suboptimal response to complement inhibitor C5 due to more effective control of extravascular C3-mediated hemolysis.
Keywords: paroxysmal nocturnal hemoglobinuria, complement C5 inhibitor, suboptimal response, complement factor B inhibitor, iptacopan
Материалы и методы. В анализ включены 8 больных, медиана возраста 32 года, с сохранением анемии на длительной терапии экулизумабом. Оценивался гематологический ответ при переключении на пероральную монотерапию иптакопаном 200 мг 2 раза в сутки в течение 4 нед.
Результаты. Через 4 нед терапии иптакопаном повышение уровня гемоглобина более чем на 20 г/л достигнуто у 7/8 (88%), полный ответ – у 6/8 (75%). Медиана прироста уровня гемоглобина составила 32,5 г/л с исходной 85,5 г/л (74–100) до 121,5 г/л (80–141); p=0,00013. Независимость от трансфузий эритроцитов достигнута в 100% случаев. Достижение гематологического ответа на терапию иптакопаном сопровождалось снижением абсолютного числа ретикулоцитов, уровня билирубина и лактатдегидрогеназы, а также негативизацией анти-C3d прямого антиглобулинового теста.
Заключение. Пероральный ингибитор фактора В комплемента иптакопан является эффективной опцией лечения пароксизмальной ночной гемоглобинурии у пациентов с субоптимальным ответом на ингибитор комплемента С5 за счет более эффективного контроля экстраваскулярного С3-опосредованного гемолиза.
Ключевые слова: пароксизмальная ночная гемоглобинурия, ингибитор комплемента С5, субоптимальный ответ, ингибитор фактора B, иптакопан
________________________________________________
Materials and methods. The analysis included 8 patients, median age 32 years, with persistent anemia on long-term therapy with eculizumab. The hematological response was assessed when switching to oral monotherapy with iptacopan 200 mg twice daily for 4 weeks.
Results. After 4 weeks of iptacopan therapy, an increase in hemoglobin levels by more than 20 g/l was achieved in 7/8 (88%), and a complete response in 6/8 (75%) patients. The median increase in hemoglobin levels was 32.5 g/l from the initial 85.5 g/l (74–100) to 121.5 g/l (80–141); p=0.00013. Independence from red blood cell transfusions was achieved in 100% of cases. Achieving a hematological response to iptacopan therapy was accompanied by a decrease in the level of absolute reticulocyte count, bilirubin and lactate dehydrogenase, as well as a negative result of the anti-C3d direct antiglobulin test.
Conclusion. The oral complement factor B inhibitor iptacopan is an effective treatment option for paroxysmal nocturnal hemoglobinuria in patients with a suboptimal response to complement inhibitor C5 due to more effective control of extravascular C3-mediated hemolysis.
Keywords: paroxysmal nocturnal hemoglobinuria, complement C5 inhibitor, suboptimal response, complement factor B inhibitor, iptacopan
Полный текст
Список литературы
1. Hillmen P, Lewis SM, Bessler M, et al. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995;333:1253-8. DOI:10.1056/NEJM199511093331904
2. de Latour RP, Mary JY, Salanoubat C, et al.; French Society of Hematology; French Association of Young Hematologists. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood. 2008;112(8):3099-106. DOI:10.1182/blood-2008-01-133918
3. Bessler M, Mason PJ, Hillmen P, et al. Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene. EMBO J. 1994;13(1):110-7. DOI:10.1002/j.1460-2075.1994.tb06240.x
4. Hillmen P, Bessler M, Mason PJ, et al. Specific defect in N acetylglucosamine incorporation in the biosynthesis of the glycosylphosphatidylinositol anchor in cloned cell lines from patients with paroxysmal nocturnal hemoglobinuria. Proc Natl Acad Sci USA. 1993;90(11):5272-6. DOI:10.1073/pnas.90.11.5272
5. Nicholson-Weller A, March JP, Rosenfeld SI, Austen KF. Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria are deficient in the complement regulatory protein, decay accelerating factor. Proc Natl Acad Sci USA. 1983;80(16):5066-70. DOI:10.1073/pnas.80.16.5066
6. Hosokawa K, Nakao S. Somatic mutations and clonal expansions in paroxysmal nocturnal hemoglobinuria. Semin Hematol. 2022;59(3):143-9. DOI:10.1053/j.seminhematol.2022.08.004
7. Кулагин А.Д., Климова О.У., Добронравов А.В., и др. Клиническая манифестация и ошибки диагностики классической пароксизмальной ночной гемоглобинурии: анализ 150 наблюдений. Клиническая онкогематология. 2017;10(3):333-41 [Kulagin AD, Klimova OU, Dobronravov AV, et al. Clinical manifestation and diagnostic errors of classical paroxysmal nocturnal hemoglobinuria: analysis of 150 observations. Klinicheskaya onkogematologiya. 2017;10(3):333-41 (in Russian)]. DOI:10.21320/2500-2139-2017-10-3-333-34114
8. Кулагин А.Д., Климова О.У., Добронравов А.В., и др. Пароксизмальная ночная гемоглобинурия у детей и взрослых: сравнительный клинический профиль и долгосрочный прогноз. Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2018;17(3):11-21 [Kulagin AD, Klimova OU, Dobronravov AV, et al. Paroxysmal nocturnal hemoglobinuria in children and adults: a comparative clinical profile and long-term prognosis. Voprosy gematologii/onkologii i immunopatologii v pediatrii. 2018;17(3):11-21 (in Russian)]. DOI:10.24287/1726-1708-2018-17-3-11-2115
9. Пароксизмальная ночная гемоглобинурия. Клинические рекомендации (одобрены Минздравом России). Режим доступа: https://www.consultant.ru/document/cons_doc_LAW_489062/d30cb2687ade8f5cac6743fcab379c986113b3c7/ Ссылка активна на 16.12.2024 [Paroksizmal'naia nochnaia gemoglobinuriia. Klinicheskie rekomendatsii (odobreny Minzdravom Rossii). Available at: https://www.consultant.ru/document/cons_doc_LAW_489062/d30cb2687ade8f5cac6743fcab379c986113b3c7/Acce...: 16.12.2024 (in Russian)].
10. Hillmen P, Muus P, Dührsen U, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007;110(12):4123-8. DOI:10.1182/blood-2007-06-095646
11. Brodsky RA, Young NS, Antonioli E, et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008;111(4):1840-7. DOI:10.1182/blood-2007-06-094136
12. Kulasekararaj A, Brodsky R, Kulagin A, Jang JH. Biosimilars in rare diseases: a focus on paroxysmal nocturnal hemoglobinuria. Haematologica. 2023;108(5):1232-43. DOI:10.3324/haematol.2022.281562
13. Птушкин В.В., Кулагин А.Д., Лукина Е.А., и др. Результаты открытого многоцентрового клинического исследования Ib фазы по оценке безопасности, фармакокинетики и фармакодинамики первого биоаналога экулизумаба у нелеченых пациентов с пароксизмальной ночной гемоглобинурией в фазе индукции терапии. Терапевтический архив. 2020;92(7):77-84 [Ptushkin VV, Kulagin AD, Lukina EA, et al. Results of phase Ib open multicenter clinical trial of the safety, pharmacokinetics and pharmacodynamics of first biosimilar of eculizumab in untreated patients with paroxysmal nocturnal hemoglobinuria during induction of therapy. Terapevticheskii Arkhiv (Ter. Arkh.). 2020;92(7):77-84 (in Russian)]. DOI:10.26442/00403660.2020.07.000818
14. Kulagin AD, Ptushkin VV, Lukina EA, et al. Results of long-term therapy with a biosimilar of eculizumab in patients with paroxysmal nocturnal hemoglobinuria. Acta Haematol. 2024:1-9. DOI: 10.1159/000542294
15. Kulasekararaj AG, Griffin M, Langemeijer S, et al. Long-term safety and efficacy of ravulizumab in patients with paroxysmal nocturnal hemoglobinuria: 2-year results from two pivotal phase 3 studies. Eur J Haematol. 2022;109(3):205-14. DOI:10.1111/ejh.13783
16. Chonat S, Kulagin A, Maschan A, et al. Pharmacokinetics, pharmacodynamics, efficacy, and safety of ravulizumab in pediatric paroxysmal nocturnal hemoglobinuria. Blood Adv. 2024;8(11):2813-24. DOI:10.1182/bloodadvances.2023012267
17. Kulagin A, Klimova O, Rudakova T, et al. Benefits and limitations of long-term eculizumab treatment for paroxysmal nocturnal hemoglobinuria (PNH): Real-world data from large cohort study in Russia. Blood. 2018;132(Suppl. 1):2589. DOI:10.1182/blood-2018-99-120139
18. Debureaux PE, Kulasekararaj AG, Cacace F, et al. Categorizing hematological response to eculizumab in paroxysmal nocturnal hemoglobinuria: a multicenter real-life study. Bone Marrow Transplant. 2021;56(10):2600-2. DOI:10.1038/s41409-021-01372-0
19. Kelly RJ, Holt M, Vidler J, et al. Treatment outcomes of complement protein C5 inhibition in 509 UK patients with paroxysmal nocturnal hemoglobinuria. Blood. 2024;143(12):1157-66. DOI:10.1182/blood.2023021762
20. Notaro R, Sica M. C3-mediated extravascular hemolysis in PNH on eculizumab: Mechanism and clinical implications. Semin Hematol. 2018;55(3):130-5. DOI:10.1053/j.seminhematol.2018.05.014
21. Risitano AM, Marotta S, Ricci P, et al. Anti-complement Treatment for Paroxysmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper From the SAAWP of the EBMT. Front Immunol. 2019;10:1157. DOI:10.3389/fimmu.2019.01157
22. Hillmen P, Szer J, Weitz I, et al. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2021;384(11):1028-37. DOI:10.1056/NEJMoa2029073
23. Марченко М.В., Климова О.У., Аникина Е.В., и др. Ингибитор комплемента С3 у пациентов с пароксизмальной ночной гемоглобинурией при субоптимальном ответе на терапию ингибитором С5. Онкогематология. 2024;19(3):68-78 [Marchenko MV, Klimova OU, Anikina EV, et al. Complement C3 inhibitor in patients with paroxysmal nocturnal hemoglobinuria with suboptimal response to C5 inhibitor therapy. Oncohematology. 2024;19(3):68-78 (in Russian)]. DOI:10.17650/1818-8346-2024-19-3-68-78
24. Lee JW, Griffin M, Kim JS, et al. Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial. Lancet Haematol. 2023;10(12):e955-65. DOI:10.1016/S2352-3026(23)00315-0
25. Schubart A, Anderson K, Mainolfi N, et al. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc Natl Acad Sci USA. 2019;116(16):7926-31. DOI:10.1073/pnas.1820892116
26. Peffault de Latour R, Roeth A, Kulasekararaj AG, et al. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2024;390(11):994-1008. DOI:10.1056/NEJMoa2308695
27. Xu B, Kang B, Chen J, et al. Factor B inhibitor iptacopan for the treatment of paroxysmal nocturnal hemoglobinuria. Blood Rev. 2024;66:101210. DOI:10.1016/j.blre.2024.101210
28. Sipol AA, Babenko EV, Borisov VI, et al. An inter-laboratory comparison of PNH clone detection by high-sensitivity flow cytometry in a Russian cohort. Hematology. 2015;20(1):31-8. DOI:10.1179/1607845414Y.0000000162
29. Notaro R, Luzzatto L. Breakthrough Hemolysis in PNH with Proximal or Terminal Complement Inhibition. N Engl J Med. 2022;387(2):160-6. DOI:10.1056/NEJMra2201664
30. Латышев В.Д., Фидарова З.Т., Пономарев Р.В., и др. Оценка гематологического ответа на терапию ингибиторами С5-компонента комплемента у пациентов с пароксизмальной ночной гемоглобинурией. Онкогематология. 2024;19(1):83-91 [Latyshev VD, Fidarova ZT, Ponomarev RV, et al. Hematological response in patients with paroxysmal nocturnal hemoglobinuria treated with C5‑inhibitor. Onkogematolog iya = Oncohematology. 2024;19(1):83-91 (in Russian)]. DOI:10.17650/1818‑8346‑2024‑19‑1‑83‑91
31. Bodó I, Amine I, Boban A, et al. Complement Inhibition in Paroxysmal Nocturnal Hemoglobinuria (PNH): A Systematic Review and Expert Opinion from Central Europe on Special Patient Populations. Adv Ther. 2023;40(6):2752-72. DOI:10.1007/s12325-023-02510-4
2. de Latour RP, Mary JY, Salanoubat C, et al.; French Society of Hematology; French Association of Young Hematologists. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood. 2008;112(8):3099-106. DOI:10.1182/blood-2008-01-133918
3. Bessler M, Mason PJ, Hillmen P, et al. Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene. EMBO J. 1994;13(1):110-7. DOI:10.1002/j.1460-2075.1994.tb06240.x
4. Hillmen P, Bessler M, Mason PJ, et al. Specific defect in N acetylglucosamine incorporation in the biosynthesis of the glycosylphosphatidylinositol anchor in cloned cell lines from patients with paroxysmal nocturnal hemoglobinuria. Proc Natl Acad Sci USA. 1993;90(11):5272-6. DOI:10.1073/pnas.90.11.5272
5. Nicholson-Weller A, March JP, Rosenfeld SI, Austen KF. Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria are deficient in the complement regulatory protein, decay accelerating factor. Proc Natl Acad Sci USA. 1983;80(16):5066-70. DOI:10.1073/pnas.80.16.5066
6. Hosokawa K, Nakao S. Somatic mutations and clonal expansions in paroxysmal nocturnal hemoglobinuria. Semin Hematol. 2022;59(3):143-9. DOI:10.1053/j.seminhematol.2022.08.004
7. Kulagin AD, Klimova OU, Dobronravov AV, et al. Clinical manifestation and diagnostic errors of classical paroxysmal nocturnal hemoglobinuria: analysis of 150 observations. Klinicheskaya onkogematologiya. 2017;10(3):333-41 (in Russian). DOI:10.21320/2500-2139-2017-10-3-333-34114
8. Kulagin AD, Klimova OU, Dobronravov AV, et al. Paroxysmal nocturnal hemoglobinuria in children and adults: a comparative clinical profile and long-term prognosis. Voprosy gematologii/onkologii i immunopatologii v pediatrii. 2018;17(3):11-21 (in Russian). DOI:10.24287/1726-1708-2018-17-3-11-2115
9. Paroksizmal'naia nochnaia gemoglobinuriia. Klinicheskie rekomendatsii (odobreny Minzdravom Rossii). Available at: https://www.consultant.ru/document/cons_doc_LAW_489062/d30cb2687ade8f5cac6743fcab379c986113b3c7/Acce...: 16.12.2024 (in Russian).
10. Hillmen P, Muus P, Dührsen U, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007;110(12):4123-8. DOI:10.1182/blood-2007-06-095646
11. Brodsky RA, Young NS, Antonioli E, et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008;111(4):1840-7. DOI:10.1182/blood-2007-06-094136
12. Kulasekararaj A, Brodsky R, Kulagin A, Jang JH. Biosimilars in rare diseases: a focus on paroxysmal nocturnal hemoglobinuria. Haematologica. 2023;108(5):1232-43. DOI:10.3324/haematol.2022.281562
13. Ptushkin VV, Kulagin AD, Lukina EA, et al. Results of phase Ib open multicenter clinical trial of the safety, pharmacokinetics and pharmacodynamics of first biosimilar of eculizumab in untreated patients with paroxysmal nocturnal hemoglobinuria during induction of therapy. Terapevticheskii Arkhiv (Ter. Arkh.). 2020;92(7):77-84 (in Russian). DOI:10.26442/00403660.2020.07.000818
14. Kulagin AD, Ptushkin VV, Lukina EA, et al. Results of long-term therapy with a biosimilar of eculizumab in patients with paroxysmal nocturnal hemoglobinuria. Acta Haematol. 2024:1-9. DOI: 10.1159/000542294
15. Kulasekararaj AG, Griffin M, Langemeijer S, et al. Long-term safety and efficacy of ravulizumab in patients with paroxysmal nocturnal hemoglobinuria: 2-year results from two pivotal phase 3 studies. Eur J Haematol. 2022;109(3):205-14. DOI:10.1111/ejh.13783
16. Chonat S, Kulagin A, Maschan A, et al. Pharmacokinetics, pharmacodynamics, efficacy, and safety of ravulizumab in pediatric paroxysmal nocturnal hemoglobinuria. Blood Adv. 2024;8(11):2813-24. DOI:10.1182/bloodadvances.2023012267
17. Kulagin A, Klimova O, Rudakova T, et al. Benefits and limitations of long-term eculizumab treatment for paroxysmal nocturnal hemoglobinuria (PNH): Real-world data from large cohort study in Russia. Blood. 2018;132(Suppl. 1):2589. DOI:10.1182/blood-2018-99-120139
18. Debureaux PE, Kulasekararaj AG, Cacace F, et al. Categorizing hematological response to eculizumab in paroxysmal nocturnal hemoglobinuria: a multicenter real-life study. Bone Marrow Transplant. 2021;56(10):2600-2. DOI:10.1038/s41409-021-01372-0
19. Kelly RJ, Holt M, Vidler J, et al. Treatment outcomes of complement protein C5 inhibition in 509 UK patients with paroxysmal nocturnal hemoglobinuria. Blood. 2024;143(12):1157-66. DOI:10.1182/blood.2023021762
20. Notaro R, Sica M. C3-mediated extravascular hemolysis in PNH on eculizumab: Mechanism and clinical implications. Semin Hematol. 2018;55(3):130-5. DOI:10.1053/j.seminhematol.2018.05.014
21. Risitano AM, Marotta S, Ricci P, et al. Anti-complement Treatment for Paroxysmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper From the SAAWP of the EBMT. Front Immunol. 2019;10:1157. DOI:10.3389/fimmu.2019.01157
22. Hillmen P, Szer J, Weitz I, et al. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2021;384(11):1028-37. DOI:10.1056/NEJMoa2029073
23. Marchenko MV, Klimova OU, Anikina EV, et al. Complement C3 inhibitor in patients with paroxysmal nocturnal hemoglobinuria with suboptimal response to C5 inhibitor therapy. Oncohematology. 2024;19(3):68-78 (in Russian). DOI:10.17650/1818-8346-2024-19-3-68-78
24. Lee JW, Griffin M, Kim JS, et al. Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial. Lancet Haematol. 2023;10(12):e955-65. DOI:10.1016/S2352-3026(23)00315-0
25. Schubart A, Anderson K, Mainolfi N, et al. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc Natl Acad Sci USA. 2019;116(16):7926-31. DOI:10.1073/pnas.1820892116
26. Peffault de Latour R, Roeth A, Kulasekararaj AG, et al. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2024;390(11):994-1008. DOI:10.1056/NEJMoa2308695
27. Xu B, Kang B, Chen J, et al. Factor B inhibitor iptacopan for the treatment of paroxysmal nocturnal hemoglobinuria. Blood Rev. 2024;66:101210. DOI:10.1016/j.blre.2024.101210
28. Sipol AA, Babenko EV, Borisov VI, et al. An inter-laboratory comparison of PNH clone detection by high-sensitivity flow cytometry in a Russian cohort. Hematology. 2015;20(1):31-8. DOI:10.1179/1607845414Y.0000000162
29. Notaro R, Luzzatto L. Breakthrough Hemolysis in PNH with Proximal or Terminal Complement Inhibition. N Engl J Med. 2022;387(2):160-6. DOI:10.1056/NEJMra2201664
30. Latyshev VD, Fidarova ZT, Ponomarev RV, et al. Hematological response in patients with paroxysmal nocturnal hemoglobinuria treated with C5‑inhibitor. Onkogematolog iya = Oncohematology. 2024;19(1):83-91 (in Russian). DOI:10.17650/1818‑8346‑2024‑19‑1‑83‑91
31. Bodó I, Amine I, Boban A, et al. Complement Inhibition in Paroxysmal Nocturnal Hemoglobinuria (PNH): A Systematic Review and Expert Opinion from Central Europe on Special Patient Populations. Adv Ther. 2023;40(6):2752-72. DOI:10.1007/s12325-023-02510-4
2. de Latour RP, Mary JY, Salanoubat C, et al.; French Society of Hematology; French Association of Young Hematologists. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood. 2008;112(8):3099-106. DOI:10.1182/blood-2008-01-133918
3. Bessler M, Mason PJ, Hillmen P, et al. Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene. EMBO J. 1994;13(1):110-7. DOI:10.1002/j.1460-2075.1994.tb06240.x
4. Hillmen P, Bessler M, Mason PJ, et al. Specific defect in N acetylglucosamine incorporation in the biosynthesis of the glycosylphosphatidylinositol anchor in cloned cell lines from patients with paroxysmal nocturnal hemoglobinuria. Proc Natl Acad Sci USA. 1993;90(11):5272-6. DOI:10.1073/pnas.90.11.5272
5. Nicholson-Weller A, March JP, Rosenfeld SI, Austen KF. Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria are deficient in the complement regulatory protein, decay accelerating factor. Proc Natl Acad Sci USA. 1983;80(16):5066-70. DOI:10.1073/pnas.80.16.5066
6. Hosokawa K, Nakao S. Somatic mutations and clonal expansions in paroxysmal nocturnal hemoglobinuria. Semin Hematol. 2022;59(3):143-9. DOI:10.1053/j.seminhematol.2022.08.004
7. Кулагин А.Д., Климова О.У., Добронравов А.В., и др. Клиническая манифестация и ошибки диагностики классической пароксизмальной ночной гемоглобинурии: анализ 150 наблюдений. Клиническая онкогематология. 2017;10(3):333-41 [Kulagin AD, Klimova OU, Dobronravov AV, et al. Clinical manifestation and diagnostic errors of classical paroxysmal nocturnal hemoglobinuria: analysis of 150 observations. Klinicheskaya onkogematologiya. 2017;10(3):333-41 (in Russian)]. DOI:10.21320/2500-2139-2017-10-3-333-34114
8. Кулагин А.Д., Климова О.У., Добронравов А.В., и др. Пароксизмальная ночная гемоглобинурия у детей и взрослых: сравнительный клинический профиль и долгосрочный прогноз. Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2018;17(3):11-21 [Kulagin AD, Klimova OU, Dobronravov AV, et al. Paroxysmal nocturnal hemoglobinuria in children and adults: a comparative clinical profile and long-term prognosis. Voprosy gematologii/onkologii i immunopatologii v pediatrii. 2018;17(3):11-21 (in Russian)]. DOI:10.24287/1726-1708-2018-17-3-11-2115
9. Пароксизмальная ночная гемоглобинурия. Клинические рекомендации (одобрены Минздравом России). Режим доступа: https://www.consultant.ru/document/cons_doc_LAW_489062/d30cb2687ade8f5cac6743fcab379c986113b3c7/ Ссылка активна на 16.12.2024 [Paroksizmal'naia nochnaia gemoglobinuriia. Klinicheskie rekomendatsii (odobreny Minzdravom Rossii). Available at: https://www.consultant.ru/document/cons_doc_LAW_489062/d30cb2687ade8f5cac6743fcab379c986113b3c7/Acce...: 16.12.2024 (in Russian)].
10. Hillmen P, Muus P, Dührsen U, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007;110(12):4123-8. DOI:10.1182/blood-2007-06-095646
11. Brodsky RA, Young NS, Antonioli E, et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008;111(4):1840-7. DOI:10.1182/blood-2007-06-094136
12. Kulasekararaj A, Brodsky R, Kulagin A, Jang JH. Biosimilars in rare diseases: a focus on paroxysmal nocturnal hemoglobinuria. Haematologica. 2023;108(5):1232-43. DOI:10.3324/haematol.2022.281562
13. Птушкин В.В., Кулагин А.Д., Лукина Е.А., и др. Результаты открытого многоцентрового клинического исследования Ib фазы по оценке безопасности, фармакокинетики и фармакодинамики первого биоаналога экулизумаба у нелеченых пациентов с пароксизмальной ночной гемоглобинурией в фазе индукции терапии. Терапевтический архив. 2020;92(7):77-84 [Ptushkin VV, Kulagin AD, Lukina EA, et al. Results of phase Ib open multicenter clinical trial of the safety, pharmacokinetics and pharmacodynamics of first biosimilar of eculizumab in untreated patients with paroxysmal nocturnal hemoglobinuria during induction of therapy. Terapevticheskii Arkhiv (Ter. Arkh.). 2020;92(7):77-84 (in Russian)]. DOI:10.26442/00403660.2020.07.000818
14. Kulagin AD, Ptushkin VV, Lukina EA, et al. Results of long-term therapy with a biosimilar of eculizumab in patients with paroxysmal nocturnal hemoglobinuria. Acta Haematol. 2024:1-9. DOI: 10.1159/000542294
15. Kulasekararaj AG, Griffin M, Langemeijer S, et al. Long-term safety and efficacy of ravulizumab in patients with paroxysmal nocturnal hemoglobinuria: 2-year results from two pivotal phase 3 studies. Eur J Haematol. 2022;109(3):205-14. DOI:10.1111/ejh.13783
16. Chonat S, Kulagin A, Maschan A, et al. Pharmacokinetics, pharmacodynamics, efficacy, and safety of ravulizumab in pediatric paroxysmal nocturnal hemoglobinuria. Blood Adv. 2024;8(11):2813-24. DOI:10.1182/bloodadvances.2023012267
17. Kulagin A, Klimova O, Rudakova T, et al. Benefits and limitations of long-term eculizumab treatment for paroxysmal nocturnal hemoglobinuria (PNH): Real-world data from large cohort study in Russia. Blood. 2018;132(Suppl. 1):2589. DOI:10.1182/blood-2018-99-120139
18. Debureaux PE, Kulasekararaj AG, Cacace F, et al. Categorizing hematological response to eculizumab in paroxysmal nocturnal hemoglobinuria: a multicenter real-life study. Bone Marrow Transplant. 2021;56(10):2600-2. DOI:10.1038/s41409-021-01372-0
19. Kelly RJ, Holt M, Vidler J, et al. Treatment outcomes of complement protein C5 inhibition in 509 UK patients with paroxysmal nocturnal hemoglobinuria. Blood. 2024;143(12):1157-66. DOI:10.1182/blood.2023021762
20. Notaro R, Sica M. C3-mediated extravascular hemolysis in PNH on eculizumab: Mechanism and clinical implications. Semin Hematol. 2018;55(3):130-5. DOI:10.1053/j.seminhematol.2018.05.014
21. Risitano AM, Marotta S, Ricci P, et al. Anti-complement Treatment for Paroxysmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper From the SAAWP of the EBMT. Front Immunol. 2019;10:1157. DOI:10.3389/fimmu.2019.01157
22. Hillmen P, Szer J, Weitz I, et al. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2021;384(11):1028-37. DOI:10.1056/NEJMoa2029073
23. Марченко М.В., Климова О.У., Аникина Е.В., и др. Ингибитор комплемента С3 у пациентов с пароксизмальной ночной гемоглобинурией при субоптимальном ответе на терапию ингибитором С5. Онкогематология. 2024;19(3):68-78 [Marchenko MV, Klimova OU, Anikina EV, et al. Complement C3 inhibitor in patients with paroxysmal nocturnal hemoglobinuria with suboptimal response to C5 inhibitor therapy. Oncohematology. 2024;19(3):68-78 (in Russian)]. DOI:10.17650/1818-8346-2024-19-3-68-78
24. Lee JW, Griffin M, Kim JS, et al. Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial. Lancet Haematol. 2023;10(12):e955-65. DOI:10.1016/S2352-3026(23)00315-0
25. Schubart A, Anderson K, Mainolfi N, et al. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc Natl Acad Sci USA. 2019;116(16):7926-31. DOI:10.1073/pnas.1820892116
26. Peffault de Latour R, Roeth A, Kulasekararaj AG, et al. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2024;390(11):994-1008. DOI:10.1056/NEJMoa2308695
27. Xu B, Kang B, Chen J, et al. Factor B inhibitor iptacopan for the treatment of paroxysmal nocturnal hemoglobinuria. Blood Rev. 2024;66:101210. DOI:10.1016/j.blre.2024.101210
28. Sipol AA, Babenko EV, Borisov VI, et al. An inter-laboratory comparison of PNH clone detection by high-sensitivity flow cytometry in a Russian cohort. Hematology. 2015;20(1):31-8. DOI:10.1179/1607845414Y.0000000162
29. Notaro R, Luzzatto L. Breakthrough Hemolysis in PNH with Proximal or Terminal Complement Inhibition. N Engl J Med. 2022;387(2):160-6. DOI:10.1056/NEJMra2201664
30. Латышев В.Д., Фидарова З.Т., Пономарев Р.В., и др. Оценка гематологического ответа на терапию ингибиторами С5-компонента комплемента у пациентов с пароксизмальной ночной гемоглобинурией. Онкогематология. 2024;19(1):83-91 [Latyshev VD, Fidarova ZT, Ponomarev RV, et al. Hematological response in patients with paroxysmal nocturnal hemoglobinuria treated with C5‑inhibitor. Onkogematolog iya = Oncohematology. 2024;19(1):83-91 (in Russian)]. DOI:10.17650/1818‑8346‑2024‑19‑1‑83‑91
31. Bodó I, Amine I, Boban A, et al. Complement Inhibition in Paroxysmal Nocturnal Hemoglobinuria (PNH): A Systematic Review and Expert Opinion from Central Europe on Special Patient Populations. Adv Ther. 2023;40(6):2752-72. DOI:10.1007/s12325-023-02510-4
________________________________________________
2. de Latour RP, Mary JY, Salanoubat C, et al.; French Society of Hematology; French Association of Young Hematologists. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood. 2008;112(8):3099-106. DOI:10.1182/blood-2008-01-133918
3. Bessler M, Mason PJ, Hillmen P, et al. Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene. EMBO J. 1994;13(1):110-7. DOI:10.1002/j.1460-2075.1994.tb06240.x
4. Hillmen P, Bessler M, Mason PJ, et al. Specific defect in N acetylglucosamine incorporation in the biosynthesis of the glycosylphosphatidylinositol anchor in cloned cell lines from patients with paroxysmal nocturnal hemoglobinuria. Proc Natl Acad Sci USA. 1993;90(11):5272-6. DOI:10.1073/pnas.90.11.5272
5. Nicholson-Weller A, March JP, Rosenfeld SI, Austen KF. Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria are deficient in the complement regulatory protein, decay accelerating factor. Proc Natl Acad Sci USA. 1983;80(16):5066-70. DOI:10.1073/pnas.80.16.5066
6. Hosokawa K, Nakao S. Somatic mutations and clonal expansions in paroxysmal nocturnal hemoglobinuria. Semin Hematol. 2022;59(3):143-9. DOI:10.1053/j.seminhematol.2022.08.004
7. Kulagin AD, Klimova OU, Dobronravov AV, et al. Clinical manifestation and diagnostic errors of classical paroxysmal nocturnal hemoglobinuria: analysis of 150 observations. Klinicheskaya onkogematologiya. 2017;10(3):333-41 (in Russian). DOI:10.21320/2500-2139-2017-10-3-333-34114
8. Kulagin AD, Klimova OU, Dobronravov AV, et al. Paroxysmal nocturnal hemoglobinuria in children and adults: a comparative clinical profile and long-term prognosis. Voprosy gematologii/onkologii i immunopatologii v pediatrii. 2018;17(3):11-21 (in Russian). DOI:10.24287/1726-1708-2018-17-3-11-2115
9. Paroksizmal'naia nochnaia gemoglobinuriia. Klinicheskie rekomendatsii (odobreny Minzdravom Rossii). Available at: https://www.consultant.ru/document/cons_doc_LAW_489062/d30cb2687ade8f5cac6743fcab379c986113b3c7/Acce...: 16.12.2024 (in Russian).
10. Hillmen P, Muus P, Dührsen U, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007;110(12):4123-8. DOI:10.1182/blood-2007-06-095646
11. Brodsky RA, Young NS, Antonioli E, et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008;111(4):1840-7. DOI:10.1182/blood-2007-06-094136
12. Kulasekararaj A, Brodsky R, Kulagin A, Jang JH. Biosimilars in rare diseases: a focus on paroxysmal nocturnal hemoglobinuria. Haematologica. 2023;108(5):1232-43. DOI:10.3324/haematol.2022.281562
13. Ptushkin VV, Kulagin AD, Lukina EA, et al. Results of phase Ib open multicenter clinical trial of the safety, pharmacokinetics and pharmacodynamics of first biosimilar of eculizumab in untreated patients with paroxysmal nocturnal hemoglobinuria during induction of therapy. Terapevticheskii Arkhiv (Ter. Arkh.). 2020;92(7):77-84 (in Russian). DOI:10.26442/00403660.2020.07.000818
14. Kulagin AD, Ptushkin VV, Lukina EA, et al. Results of long-term therapy with a biosimilar of eculizumab in patients with paroxysmal nocturnal hemoglobinuria. Acta Haematol. 2024:1-9. DOI: 10.1159/000542294
15. Kulasekararaj AG, Griffin M, Langemeijer S, et al. Long-term safety and efficacy of ravulizumab in patients with paroxysmal nocturnal hemoglobinuria: 2-year results from two pivotal phase 3 studies. Eur J Haematol. 2022;109(3):205-14. DOI:10.1111/ejh.13783
16. Chonat S, Kulagin A, Maschan A, et al. Pharmacokinetics, pharmacodynamics, efficacy, and safety of ravulizumab in pediatric paroxysmal nocturnal hemoglobinuria. Blood Adv. 2024;8(11):2813-24. DOI:10.1182/bloodadvances.2023012267
17. Kulagin A, Klimova O, Rudakova T, et al. Benefits and limitations of long-term eculizumab treatment for paroxysmal nocturnal hemoglobinuria (PNH): Real-world data from large cohort study in Russia. Blood. 2018;132(Suppl. 1):2589. DOI:10.1182/blood-2018-99-120139
18. Debureaux PE, Kulasekararaj AG, Cacace F, et al. Categorizing hematological response to eculizumab in paroxysmal nocturnal hemoglobinuria: a multicenter real-life study. Bone Marrow Transplant. 2021;56(10):2600-2. DOI:10.1038/s41409-021-01372-0
19. Kelly RJ, Holt M, Vidler J, et al. Treatment outcomes of complement protein C5 inhibition in 509 UK patients with paroxysmal nocturnal hemoglobinuria. Blood. 2024;143(12):1157-66. DOI:10.1182/blood.2023021762
20. Notaro R, Sica M. C3-mediated extravascular hemolysis in PNH on eculizumab: Mechanism and clinical implications. Semin Hematol. 2018;55(3):130-5. DOI:10.1053/j.seminhematol.2018.05.014
21. Risitano AM, Marotta S, Ricci P, et al. Anti-complement Treatment for Paroxysmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper From the SAAWP of the EBMT. Front Immunol. 2019;10:1157. DOI:10.3389/fimmu.2019.01157
22. Hillmen P, Szer J, Weitz I, et al. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2021;384(11):1028-37. DOI:10.1056/NEJMoa2029073
23. Marchenko MV, Klimova OU, Anikina EV, et al. Complement C3 inhibitor in patients with paroxysmal nocturnal hemoglobinuria with suboptimal response to C5 inhibitor therapy. Oncohematology. 2024;19(3):68-78 (in Russian). DOI:10.17650/1818-8346-2024-19-3-68-78
24. Lee JW, Griffin M, Kim JS, et al. Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial. Lancet Haematol. 2023;10(12):e955-65. DOI:10.1016/S2352-3026(23)00315-0
25. Schubart A, Anderson K, Mainolfi N, et al. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc Natl Acad Sci USA. 2019;116(16):7926-31. DOI:10.1073/pnas.1820892116
26. Peffault de Latour R, Roeth A, Kulasekararaj AG, et al. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2024;390(11):994-1008. DOI:10.1056/NEJMoa2308695
27. Xu B, Kang B, Chen J, et al. Factor B inhibitor iptacopan for the treatment of paroxysmal nocturnal hemoglobinuria. Blood Rev. 2024;66:101210. DOI:10.1016/j.blre.2024.101210
28. Sipol AA, Babenko EV, Borisov VI, et al. An inter-laboratory comparison of PNH clone detection by high-sensitivity flow cytometry in a Russian cohort. Hematology. 2015;20(1):31-8. DOI:10.1179/1607845414Y.0000000162
29. Notaro R, Luzzatto L. Breakthrough Hemolysis in PNH with Proximal or Terminal Complement Inhibition. N Engl J Med. 2022;387(2):160-6. DOI:10.1056/NEJMra2201664
30. Latyshev VD, Fidarova ZT, Ponomarev RV, et al. Hematological response in patients with paroxysmal nocturnal hemoglobinuria treated with C5‑inhibitor. Onkogematolog iya = Oncohematology. 2024;19(1):83-91 (in Russian). DOI:10.17650/1818‑8346‑2024‑19‑1‑83‑91
31. Bodó I, Amine I, Boban A, et al. Complement Inhibition in Paroxysmal Nocturnal Hemoglobinuria (PNH): A Systematic Review and Expert Opinion from Central Europe on Special Patient Populations. Adv Ther. 2023;40(6):2752-72. DOI:10.1007/s12325-023-02510-4
Авторы
О.У. Климова*, И.К. Голубовская, Ю.Н. Кузнецов, М.В. Марченко, А.Д. Кулагин
ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова» Минздрава России, Санкт-Петербург, Россия
*ou_klimova@mail.ru
Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia
*ou_klimova@mail.ru
ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова» Минздрава России, Санкт-Петербург, Россия
*ou_klimova@mail.ru
________________________________________________
Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia
*ou_klimova@mail.ru
Цель портала OmniDoctor – предоставление профессиональной информации врачам, провизорам и фармацевтам.