Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2023; 22: 36-42
Профилактика ингибиторной формы тяжелой гемофилии А у детей в Республике Беларусь: 12-летний опыт работы
https://doi.org/10.24287/1726-1708-2023-22-3-36-42Аннотация
Поиск мероприятий по снижению риска образования ингибиторов у ранее не леченных пациентов (РНЛП) с тяжелой гемофилией А к вводимому фактору VIII определил актуальность исследования. Цель – определить эффективность профилактики возникновения патологических ингибиторов свертывания у РНЛП (или минимально леченных пациентов) с тяжелой гемофилией А путем введения плазменного концентрата фактора свертывания крови (КФСК) VIII в дозе 25 МЕ/кг 1 раз/нед на протяжении 1 года. Настоящее исследование одобрено независимым этическим комитетом и утверждено решением ученого совета ГУ «Республиканский научно-практический центр детской онкологии, гематологии и иммунологии» (Республика Беларусь). За период с 2010 по 2022 г. тяжелая форма гемофилии А впервые была выявлена у 56 мальчиков. КФСК VIII для остановки кровотечения в режиме «по требованию» получил 21 пациент (1-я группа). В режиме профилактики ингибиторной формы гемофилии КФСК VIII в дозе 25 МЕ/кг массы тела 1 раз/нед на протяжении первых 50 нед лечения получили 35 мальчиков (2-я группа). Применение разрешенного для введения с периода новорожденности плазменного КФСК VIII в дозе 25 МЕ/кг 1 раз/нед у РНЛП (или минимально леченных пациентов) способствовало снижению кумулятивной частоты возникновения патологических ингибиторов до 15,9 ± 7,7% (4 из 35 пациентов) по сравнению с 43,7 ± 11,8% (8 из 21 пациента) среди детей, получавших гемостатическую терапию в связи с необходимостью остановки кровотечения (log-rank-тест, p = 0,041). Таким образом, введение плазменного КФСК VIII в дозе 25 МЕ/кг 1 раз/нед на протяжении первых 50 нед сопровождается снижением кумулятивной частоты возникновения ингибиторов (р = 0,009) к нему до 15,9 ± 7,7%.
Список литературы
1. Gouw S.C., van der Bom J.G., Marijke van den Berg H. Treatment related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood 2007; 109: 4648–54.
2. Kurnik K., Bidlingmaier C., Engl W., Chehadeh H., Reipert B., Auerswald G. New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development. Haemophilia 2010; 16: 256–62.
3. Auerswald G., Kurnik K., Aledort L.M., Chehadeh H., LoewBaselli A., Steinitz K., et al.; EPIC Clinical Study Group. The EPIC study: a lesson to learn. Haemophilia 2015; 21: 622–8.
4. Peyvandi F., Mannucci P.M., Garagiola I., El-Beshlawy А., Elalfy М., Ramanan V., et al. Randomized trial of Factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med 2016; 374: 2054–64.
5. Rossetti L.C., Radic C.P., Larripa I.B., De Brasi C.D. Genotyping the Hemophilia Inversion Hotspot by Use of Inverse PCR. Clin Chem 2005; 51 (7): 1154–8.
6. Rossetti L.C., Radic C.P., Larripa I.B., De Brasi C.D. Developing a new generation of tests for genotyping hemophilia-causative rearrangements involving int 22h and int1h hotspots in the factor VIII gene. J Thromb Haemost 2008; 6: 830–6.
7. Bagnall R.D., Waseem N., Green P.M., Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood 2002; 99 (1): 168–74.
8. Hay C.R.М., Broun S., Collins P.W., Keeling D.M., Liesner R. The diagnosis and management of factor VIII and IX inhibitots: a guideline from the United Kingdom Hemophilia Centre Doctors Organisation. Br J Haematol 2006; 133: 591–605.
9. Rosendaal F.R., Palla R., Garagiola I., Mannucci P.M., Peyvandi F.; SIPPET Study Group. Genetic risk stratification to reduce inhibitor development in the early treatment of hemophilia A: a SIPPET analysis. Blood 2017; 130 (15): 1757–9. DOI: 10.1182/blood-2017-06-791756
10. Keipert C., Drechsel-Bäuerle U., Oberle D., Müller-Olling M., Hilger A. Epidemiological Challenges in Rare Bleeding Disorders: FVIII Inhibitor Incidence in Haemophilia A Patients – A Known Issue of Unknown Origin. Int J Environ Res Public Health 2021; 18: 225. DOI: 10.3390/ijerph18010225
11. Liesner R.J., Abraham A., Altisent C., Belletrutti M.J., Carcao M., Carvalho M., et al. Simoctocog Alfa (Nuwiq) in Previously UntreatedPatients with Severe Haemophilia A: Final Results of the NuProtect Study. Thromb Haemost 2021; 121 (11): 1400–8. DOI: 10.1055/s-0040-1722623
12. Halimeh S., Rott H., Siebert M. et al. Аn individualized approach to reduce inhibitor risk in pups with severe hemophilia А. EAHAD congress 2022, poster 27. DOI: 10.1111/hae.14479
13. Maclean P.S., Richards M., Williams M., Collins P., Liesner R., Keeling D.M., et al.; Paediatric Working Party of UKHCDO. Treatment related factors and inhibitor development in children with severe haemophilia A. Haemophilia 2011; 17: 282–7.
Pediatric Hematology/Oncology and Immunopathology. 2023; 22: 36-42
The prophylaxis of severe hemophilia A with inhibitors in children in the Republic of Belarus: a 12-year experience
https://doi.org/10.24287/1726-1708-2023-22-3-36-42Abstract
The development of inhibitory antibodies against FVIII is the most serious complication associated with the use of FVIII concentrates in hemophilia A patients. There is a need for more research on measures that could reduce the risk of inhibitor formation in previously untreated patients (PUPs) with severe hemophilia A. The purpose of this study was to determine the effectiveness of the prevention of clotting inhibitor development in PUPs (or minimally treated patients) with severe hemophilia A by administering plasma-derived factor VIII concentrate (pdFVIII) at a dose of 25 IU/kg once a week for a year. The study was approved by the Independent Ethics Committee and the Scientific Council of the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (the Republic of Belarus). Between 2010 and 2022, 56 boys were newly diagnosed with severe hemophilia A. Twenty-one of them received pdFVIII as on-demand treatment to stop bleeding (Group 1). Thirty-five boys received pdFVIII at a dose of 25 IU/kg body weight once a week during the first 50 weeks of treatment for the prevention of inhibitor development (Group 2). The administration of pdFVIII at a dose of 25 IU/kg once a week in the PUPs (or minimally treated patients) contributed to a decrease in the cumulative incidence of inhibitors to 15.9 ± 7.7% (4 out of the 35 patients who had been treated prophylactically) compared with 43.7 ± 11.8% (8 out of the 21 patients who had received hemostatic therapy to stop bleeding) (log-rank test, p = 0.041). Thus, the administration of pdFVIII concentrate at a dose of 25 IU/kg once a week for the first 50 weeks of treatment lead to a decrease (p = 0.009) in the cumulative incidence of inhibitors against the administered coagulation factor VIII to 15.9 ± 7.7%.
References
1. Gouw S.C., van der Bom J.G., Marijke van den Berg H. Treatment related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood 2007; 109: 4648–54.
2. Kurnik K., Bidlingmaier C., Engl W., Chehadeh H., Reipert B., Auerswald G. New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development. Haemophilia 2010; 16: 256–62.
3. Auerswald G., Kurnik K., Aledort L.M., Chehadeh H., LoewBaselli A., Steinitz K., et al.; EPIC Clinical Study Group. The EPIC study: a lesson to learn. Haemophilia 2015; 21: 622–8.
4. Peyvandi F., Mannucci P.M., Garagiola I., El-Beshlawy A., Elalfy M., Ramanan V., et al. Randomized trial of Factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med 2016; 374: 2054–64.
5. Rossetti L.C., Radic C.P., Larripa I.B., De Brasi C.D. Genotyping the Hemophilia Inversion Hotspot by Use of Inverse PCR. Clin Chem 2005; 51 (7): 1154–8.
6. Rossetti L.C., Radic C.P., Larripa I.B., De Brasi C.D. Developing a new generation of tests for genotyping hemophilia-causative rearrangements involving int 22h and int1h hotspots in the factor VIII gene. J Thromb Haemost 2008; 6: 830–6.
7. Bagnall R.D., Waseem N., Green P.M., Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood 2002; 99 (1): 168–74.
8. Hay C.R.M., Broun S., Collins P.W., Keeling D.M., Liesner R. The diagnosis and management of factor VIII and IX inhibitots: a guideline from the United Kingdom Hemophilia Centre Doctors Organisation. Br J Haematol 2006; 133: 591–605.
9. Rosendaal F.R., Palla R., Garagiola I., Mannucci P.M., Peyvandi F.; SIPPET Study Group. Genetic risk stratification to reduce inhibitor development in the early treatment of hemophilia A: a SIPPET analysis. Blood 2017; 130 (15): 1757–9. DOI: 10.1182/blood-2017-06-791756
10. Keipert C., Drechsel-Bäuerle U., Oberle D., Müller-Olling M., Hilger A. Epidemiological Challenges in Rare Bleeding Disorders: FVIII Inhibitor Incidence in Haemophilia A Patients – A Known Issue of Unknown Origin. Int J Environ Res Public Health 2021; 18: 225. DOI: 10.3390/ijerph18010225
11. Liesner R.J., Abraham A., Altisent C., Belletrutti M.J., Carcao M., Carvalho M., et al. Simoctocog Alfa (Nuwiq) in Previously UntreatedPatients with Severe Haemophilia A: Final Results of the NuProtect Study. Thromb Haemost 2021; 121 (11): 1400–8. DOI: 10.1055/s-0040-1722623
12. Halimeh S., Rott H., Siebert M. et al. An individualized approach to reduce inhibitor risk in pups with severe hemophilia A. EAHAD congress 2022, poster 27. DOI: 10.1111/hae.14479
13. Maclean P.S., Richards M., Williams M., Collins P., Liesner R., Keeling D.M., et al.; Paediatric Working Party of UKHCDO. Treatment related factors and inhibitor development in children with severe haemophilia A. Haemophilia 2011; 17: 282–7.
