Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2022; 21: 66-71
Значительное снижение количества кровотечений у детей с ингибиторной формой гемофилии А в реальной клинической практике применения эмицизумаба
https://doi.org/10.24287/1726-1708-2022-21-1-66-71Аннотация
Данные по применению эмицизумаба у детей с ингибиторной формой гемофилии А (ИГА) в реальной клинической практике на территории нашей страны немногочисленны и представлены описанием единичных случаев. Цель исследования: оценить эффективность и безопасность профилактического применения эмицизумаба у детей с тяжелым течением ИГА. Проведен ретроспективный анализ данных медицинской документации детей с ИГА, получавших эмицизумаб в условиях 11 центров на территории Российской Федерации. Данное исследование не требовало одобрения этическим комитетом, так как в нем использовались обобщенные ретроспективные деперсонифицированные данные, полученные в ходе рутинной клинической практики. Оценивали среднегодовые показатели частоты кровотечений (ГЧК), спонтанных (ГЧСК), суставных (ГЧКС) и кровотечений, требующих дополнительного введения концентрата фактора VIII или терапии препаратами шунтирующего действия (ГЧКТ) до и после назначения эмицизумаба, а также наличие и тяжесть нежелательных явлений во время терапии. Медиана возраста пациентов на момент начала лечения эмицизумабом составляла 65 (11–170) месяцев. До начала лечения эмицизумабом ГЧК составляла 19,9 (95% доверительный интервал (ДИ) 15,4–26,1) эпизода, ГЧСК – 13,6 (95% ДИ 10,6–17,8) эпизода, ГЧКС – 6,6 (95% ДИ 4,7–9,7) эпизода и ГЧКТ – 16,6 (95% ДИ 12,4–22,7) эпизода. После начала лечения эмицизумабом частота кровотечений резко снизилась: ГЧК на 98,6% (95% ДИ 96,7–99,4), ГЧКС на 99,4% (95% ДИ 95,3–99,9) и ГЧКТ на 98,8% (95% ДИ 96,8–99,6) без каких-либо спонтанных кровотечений в течение 10 (1–32) мес лечения. Нежелательных явлений, которые привели бы к прерыванию или прекращению лечения эмицизумабом, зарегистрировано не было. В реальной клинической практике применение эмицизумаба у детей с ИГА приводит к выраженному и безопасному снижению всех эпизодов кровотечений более чем на 98% при абсолютном отсутствии спонтанных кровотечений.
Список литературы
1. Giangrande P.L.F., Hermans C., O’Mahony B., de Kleijn P., Bedford M., Batorova A., et al. European principles of inhibitor management in patients with haemophilia. Orphanet J Rare Dis 2018; 13 (1): 66.
2. Данные исследования MAR Consult: опрос врачей, наблюдающих пациентов с гемофилией А, в регионах России в 2018 г.
3. Lenting P.J., Denis C.V., Christophe O.D. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII? Blood 2017; 130 (23): 2463–8.
4. Инструкция по медицинскому применению препарата Эмицизумаб. [Электронный ресурс]: URL: https://www.rlsnet.ru/tn_index_id_96727 (дата обращения 01.10.2021).
5. Mahlangu J., Oldenburg J., Paz-Priel I., Negrier C., Niggli M., Mancuso M.E., et al. Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. N Engl J Med 2018; 379 (9): 811– 22.
6. Oldenburg J., Mahlangu J.N., Kim B., Schmitt C., Callaghan M.U., Young G., et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med 2017; 377 (9): 809–18.
7. Young G., Liesner R., Chang T., Sidonio R., Oldenburg J., Jiménez-Yuste V., et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood 2019; 134 (24): 2127–38. DOI: 10.1182/blood.2019001869
8. Pipe S.W., Shima M., Lehle M., Shapiro A., Chebon S., Fukutake K., et al. Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. Lancet Haematol 2019; 6 (6): e295–305.
9. Зозуля Н.И., Кумскова М.А., Полянская Т.Ю., Свирин П.В., Мамаев А.Н., Галстян Г.М. Гемофилия А. Клинические рекомендации, 2018. С. 19. 10. Белкина Ю.Е. Опыт применения эмицизумаба у пациента с неэффективной индукцией иммунной толерантности. Российский журнал детской гематологии и онкологии 2020; 7 (4s): 7–9.
10. Лебедев В.В., Асекретова Т.В. Опыт применения эмицизумаба у пациента с повторным нарастанием титра ингибирующих антител после индукции иммунной толерантности с частичным ответом. Российский журнал детской гематологии и онкологии 2020; 7 (4s): 14–5.
11. Петров В.Ю., Вдовин В.В., Лаврентьева И.Н. Опыт применения эмицизумаба у ребенка с тяжелой формой ингибиторной гемофилии А и затрудненным венозным доступом. Российский журнал детской гематологии и онкологии 2020; 7 (4s): 16–7.
12. Зинина Е.Е., Спичак О.В. Применение эмицизумаба для профилактической терапии у пациента с анафилактической реакцией на первое введение концентрата фактора VIII. Российский журнал детской гематологии и онкологии 2020; 7 (4s): 18–9.
13. Андреева Т.А., Лавриченко И.А., Крашенинникова О.А. Сложности ведения пациента с гемофилией А и анафилактическими реакциями на препараты фактора VIII и препараты шунтирующего действия. Российский журнал детской гематологии и онкологии 2020; 7 (4s): 20–2.
14. Abarca-Villaseca V., Soto-Arellano V. Breakthrough Bleeding Episodes at Minimum and Improvement in Quality of Life in a Child with Severe Hemophilia A with Inhibitors Treated with Emicizumab: A Case Report from Chile. Am J Case Rep 2021; 22: e929598.
15. Barg A.A., Livnat T., Budnik I., Avishai E., Brutman-Barazani T., Tamarin I., et al. Emicizumab treatment and monitoring in a paediatric cohort: real-world data. Br J Haematol 2020; 191: 282–90.
16. McCary I., Guelcher C., Kuhn J., Butler R., Massey G., Guerrera M.F., et al. Real-world use of emicizumab in patients with haemophilia A: Bleeding outcomes and surgical procedures. Haemophilia 2020; 26 (4): 631–6.
17. Cohen C.T., Diaz R. Emicizumab in pediatric hemophilia: Bleeding and surgical outcomes from a single-center retrospective study. Pediatr Blood Cancer 2021; 68 (11): e29325.
18. Barg A.A., Avishai E., Budnik I., Levy-Mendelovich S., Barazani T.B., Kenet G., et al. Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors-a single-center cohort. Pediatr Blood Cancer 2019; 66 (11): e27886.
19. Catarino C., Campanico S., Rodrigues F., Campaniço S., Santos S., Antunes M., et al. Prophylaxis with emicizumab in children and adults with hemophilia A and inhibitors: preliminary data on 7 patients of a portuguese hemophilia center. Res Pract Thromb Haemost 2019; 3 (Suppl 1): 299.
20. Garcia J., Zia A. Real-world case series and summary of current literature of infants and toddlers with severe hemophilia A with inhibitor on prophylaxis with emicizumab. Pediatr Blood Cancer 2021; 68 (5): e28942.
21. Hassan E., Jonathan L., Jayashree M. Real-world experience on the tolerability and safety of emicizumab prophylaxis in paediatric patients with severe haemophilia A with and without FVIII inhibitors. Haemophilia 2021; 27 (6): e698–703. DOI: 10.1111/hae.14432
22. Oldenburg J., Shima M., Kruse-Jarres R., Santagostino E., Mahlangu J., Lehle M., et al. Outcomes in children with hemophilia A with inhibitors: Results from a noninterventional study. Pediatr Blood Cancer 2020; 67: e28474.
23. Srivastava A., Santagostino E., Dougall A., Kitchen S., Sutherland M., Pipe S.W., et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia 2020; 26 Suppl 6: 1–158.
24. Callaghan M., Negrier C., Paz-Priel I., Chebon S., Lehle M., Mahlangu J., et al. Emicizumab Treatment is Efficacious and Well Tolerated Long Term in Persons with Haemophilia A (PwHA) with or without FVIII Inhibitors: Pooled Data from Four HAVEN Studies (ISTH 2019 OC 60.2).
25. Yiménez-Yuste V., Peyvandi F., Klamroth R., Castaman G., Shanmukhaiah C., Rangarajan S., et al. Final Analysis of the STASEY Trial: A Single-arm, Multicenter, Open-label, Phase III Clinical Trial Evaluating the Safety and Tolerability of Emicizumab Prophylaxis in Persons with Hemophilia A (PwHA) with Factor (F) VIII Inhibitors [abstract]. Res Pract Thromb Haemost 2021; 5 (Suppl 2).
Pediatric Hematology/Oncology and Immunopathology. 2022; 21: 66-71
Bleeding rate reduction in children with hemophilia A and inhibitors treated with emicizumab in the real-world clinical setting
https://doi.org/10.24287/1726-1708-2022-21-1-66-71Abstract
There are only limited data coming from isolated case reports regarding the real-world use of emicizumab for the treatment of children with hemophilia A and inhibitors (HAI) in Russia. The aim of the study was to evaluate the efficacy and safety of emicizumab prophylaxis in children with severe HAI. Ethical approval was not required since the study only involved the use of anonymized and generalized retrospective data obtained during routine clinical practice. We retrospectively analyzed medical records of children with HAI who had been treated with emicizumab at 11 institutions located in Russia, taking into consideration such parameters as annualized bleeding rates (ABR), annualized spontaneous bleeding rates (ASBR), annualized joint bleeding rates (AJBR) and annualized bleeding rates for bleeds requiring additional therapy (ABRRT), as well as the presence and severity of adverse events during the treatment. The median age of patients at the time of initiation of emicizumab prophylaxis was 65 (11–170) months. Before the treatment, ABR was 19.9 (95% confidence interval (CI), 15.4–26.1), ASBR – 13.6 (95% CI, 10.6–17.8), AJBR – 6.6 (95% CI, 4.7–9.7), ABRRT – 16.6 (95% CI, 12.4–22.7). After the initiation of the treatment, bleeding rates changed dramatically: ABR decreased by 98.6% (95% CI, 96.7–99.4), AJBR – by 99.4% (95% CI, 95.3–99.9), ABRRT – by 98.8% (95% CI, 96.8–99.6); and there were no signs of spontaneous bleeding during 10 (1–32) months of treatment. No adverse events leading to the interruption or discontinuation of the treatment with emicizumab were reported. The use of emicizumab in children with HAI in the real-world clinical setting results in a significant (> 98%) and safe reduction in bleeding episodes without any signs of spontaneous bleeding.
References
1. Giangrande P.L.F., Hermans C., O’Mahony B., de Kleijn P., Bedford M., Batorova A., et al. European principles of inhibitor management in patients with haemophilia. Orphanet J Rare Dis 2018; 13 (1): 66.
2. Dannye issledovaniya MAR Consult: opros vrachei, nablyudayushchikh patsientov s gemofiliei A, v regionakh Rossii v 2018 g.
3. Lenting P.J., Denis C.V., Christophe O.D. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII? Blood 2017; 130 (23): 2463–8.
4. Instruktsiya po meditsinskomu primeneniyu preparata Emitsizumab. [Elektronnyi resurs]: URL: https://www.rlsnet.ru/tn_index_id_96727 (data obrashcheniya 01.10.2021).
5. Mahlangu J., Oldenburg J., Paz-Priel I., Negrier C., Niggli M., Mancuso M.E., et al. Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. N Engl J Med 2018; 379 (9): 811– 22.
6. Oldenburg J., Mahlangu J.N., Kim B., Schmitt C., Callaghan M.U., Young G., et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med 2017; 377 (9): 809–18.
7. Young G., Liesner R., Chang T., Sidonio R., Oldenburg J., Jiménez-Yuste V., et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood 2019; 134 (24): 2127–38. DOI: 10.1182/blood.2019001869
8. Pipe S.W., Shima M., Lehle M., Shapiro A., Chebon S., Fukutake K., et al. Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. Lancet Haematol 2019; 6 (6): e295–305.
9. Zozulya N.I., Kumskova M.A., Polyanskaya T.Yu., Svirin P.V., Mamaev A.N., Galstyan G.M. Gemofiliya A. Klinicheskie rekomendatsii, 2018. S. 19. 10. Belkina Yu.E. Opyt primeneniya emitsizumaba u patsienta s neeffektivnoi induktsiei immunnoi tolerantnosti. Rossiiskii zhurnal detskoi gematologii i onkologii 2020; 7 (4s): 7–9.
10. Lebedev V.V., Asekretova T.V. Opyt primeneniya emitsizumaba u patsienta s povtornym narastaniem titra ingibiruyushchikh antitel posle induktsii immunnoi tolerantnosti s chastichnym otvetom. Rossiiskii zhurnal detskoi gematologii i onkologii 2020; 7 (4s): 14–5.
11. Petrov V.Yu., Vdovin V.V., Lavrent'eva I.N. Opyt primeneniya emitsizumaba u rebenka s tyazheloi formoi ingibitornoi gemofilii A i zatrudnennym venoznym dostupom. Rossiiskii zhurnal detskoi gematologii i onkologii 2020; 7 (4s): 16–7.
12. Zinina E.E., Spichak O.V. Primenenie emitsizumaba dlya profilakticheskoi terapii u patsienta s anafilakticheskoi reaktsiei na pervoe vvedenie kontsentrata faktora VIII. Rossiiskii zhurnal detskoi gematologii i onkologii 2020; 7 (4s): 18–9.
13. Andreeva T.A., Lavrichenko I.A., Krasheninnikova O.A. Slozhnosti vedeniya patsienta s gemofiliei A i anafilakticheskimi reaktsiyami na preparaty faktora VIII i preparaty shuntiruyushchego deistviya. Rossiiskii zhurnal detskoi gematologii i onkologii 2020; 7 (4s): 20–2.
14. Abarca-Villaseca V., Soto-Arellano V. Breakthrough Bleeding Episodes at Minimum and Improvement in Quality of Life in a Child with Severe Hemophilia A with Inhibitors Treated with Emicizumab: A Case Report from Chile. Am J Case Rep 2021; 22: e929598.
15. Barg A.A., Livnat T., Budnik I., Avishai E., Brutman-Barazani T., Tamarin I., et al. Emicizumab treatment and monitoring in a paediatric cohort: real-world data. Br J Haematol 2020; 191: 282–90.
16. McCary I., Guelcher C., Kuhn J., Butler R., Massey G., Guerrera M.F., et al. Real-world use of emicizumab in patients with haemophilia A: Bleeding outcomes and surgical procedures. Haemophilia 2020; 26 (4): 631–6.
17. Cohen C.T., Diaz R. Emicizumab in pediatric hemophilia: Bleeding and surgical outcomes from a single-center retrospective study. Pediatr Blood Cancer 2021; 68 (11): e29325.
18. Barg A.A., Avishai E., Budnik I., Levy-Mendelovich S., Barazani T.B., Kenet G., et al. Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors-a single-center cohort. Pediatr Blood Cancer 2019; 66 (11): e27886.
19. Catarino C., Campanico S., Rodrigues F., Campaniço S., Santos S., Antunes M., et al. Prophylaxis with emicizumab in children and adults with hemophilia A and inhibitors: preliminary data on 7 patients of a portuguese hemophilia center. Res Pract Thromb Haemost 2019; 3 (Suppl 1): 299.
20. Garcia J., Zia A. Real-world case series and summary of current literature of infants and toddlers with severe hemophilia A with inhibitor on prophylaxis with emicizumab. Pediatr Blood Cancer 2021; 68 (5): e28942.
21. Hassan E., Jonathan L., Jayashree M. Real-world experience on the tolerability and safety of emicizumab prophylaxis in paediatric patients with severe haemophilia A with and without FVIII inhibitors. Haemophilia 2021; 27 (6): e698–703. DOI: 10.1111/hae.14432
22. Oldenburg J., Shima M., Kruse-Jarres R., Santagostino E., Mahlangu J., Lehle M., et al. Outcomes in children with hemophilia A with inhibitors: Results from a noninterventional study. Pediatr Blood Cancer 2020; 67: e28474.
23. Srivastava A., Santagostino E., Dougall A., Kitchen S., Sutherland M., Pipe S.W., et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia 2020; 26 Suppl 6: 1–158.
24. Callaghan M., Negrier C., Paz-Priel I., Chebon S., Lehle M., Mahlangu J., et al. Emicizumab Treatment is Efficacious and Well Tolerated Long Term in Persons with Haemophilia A (PwHA) with or without FVIII Inhibitors: Pooled Data from Four HAVEN Studies (ISTH 2019 OC 60.2).
25. Yiménez-Yuste V., Peyvandi F., Klamroth R., Castaman G., Shanmukhaiah C., Rangarajan S., et al. Final Analysis of the STASEY Trial: A Single-arm, Multicenter, Open-label, Phase III Clinical Trial Evaluating the Safety and Tolerability of Emicizumab Prophylaxis in Persons with Hemophilia A (PwHA) with Factor (F) VIII Inhibitors [abstract]. Res Pract Thromb Haemost 2021; 5 (Suppl 2).
