Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2023; 22: 94-102
Опыт применения велаглюцеразы альфа у детей с болезнью Гоше 1-го типа в России
https://doi.org/10.24287/1726-1708-2023-22-3-94-102Аннотация
На современном этапе «золотым стандартом» лечения болезни Гоше 1-го типа у детей является ферментная заместительная терапия. Оценка эффективности и безопасности лечения велаглюцеразой альфа в педиатрической когорте больных ограничена лишь несколькими крупными исследованиями. В отечественной литературе не обнаружено публикаций по опыту применения велаглюцеразы альфа у «наивной» группы пациентов с болезнью Гоше 1-го типа. Цель исследования: оценить эффективность и безопасность применения велаглюцеразы альфа у детей с болезнью Гоше 1-го типа. Настоящее исследование одобрено независимым этическим комитетом и утверждено решением ученого совета ФГАУ «НМИЦ здоровья детей» Минздрава России. От пациентов и/или их законных представителей было получено информированное согласие на проведение исследования. Оценку эффективности терапии велаглюцеразой альфа у детей с болезнью Гоше 1-го типа проводили путем анализа данных мониторинга 15 пациентов в возрасте от 2 до 15 лет, занесенных в Российский педиатрический регистр болезни Гоше на базе ФГАУ «НМИЦ здоровья детей» Минздрава России в период 2015−2023 гг. Все пациенты на момент инициации лечения ранее не получали ферментную заместительную терапию. Медиана возраста начала лечения составила 6,5 года. Проводился учет антропометрических, лабораторных и инструментальных данных на точках 0, 6, 12, 24 и 36 мес. Доза ферментной заместительной терапии на момент инициации с учетом тяжести течения заболевания варьировала от 30 до 60 ЕД/кг с медианой 43 ЕД/кг на введение 1 раз в 2 нед. Уже через 6 мес от начала применения велаглюцеразы альфа у детей с болезнью Гоше 1-го типа отмечены статистически значимые улучшения всех показателей (p < 0,001): нормализация медианы концентрации гемоглобина (со 113 до 125 г/л) и количества тромбоцитов (со 111 до 163 × 109/л), сокращение степени увеличения объемов печени c 45,1 до 17,9% и селезенки с 39,4 до 15,5%, линейных размеров правой доли печени с 27,2 до 11,1%, длины и ширины селезенки с 73,4 до 37,8% и с 60,3 до 17,5% соответственно. При анализе активности биомаркеров гликозилсфингозина и хитотриозидазы уже через 1 год от начала терапии отмечено достоверное снижение значений, а к 3-му году лечения получено выраженное снижение медианы показателей с 204,0 (117,6; 359,2) до 35,3 (13,1; 133,6) нг/мл и с 2699 (1364; 8863,5) до 227 (287,5; 1367,5) нмоль/мл/ч соответственно (р < 0,001). Нежелательных явлений за период терапии не зарегистрировано. Таким образом, своевременно назначенная регулярная ферментная заместительная терапия велаглюцеразой альфа при адекватном режиме дозирования уже через 6 мес и 1 год от начала лечения позволяет достигнуть нормализации концентрации гемоглобина и количества тромбоцитов, снижения активности биомаркеров и сокращения увеличенных размеров печени и селезенки у детей с болезнью Гоше 1-го типа. К 3-му году лечения отмечается достижение ключевых целей терапии в виде купирования анемии и тромбоцитопении, практически полного регресса гепатоспленомегалии, нормализации денситометрических показателей минеральной плотности костей и длины тела по отношению к возрасту ребенка.
Список литературы
1. We in r e b N. J., Go k er -A l pan O., Kishnani P.S., Longo N., Burrow T.A., Bernat J.A., еt аl. The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here? Mol Genet Metab 2022; 136 (1): 4–21. DOI: 10.1016/j.ymgme.2022.03.001
2. Гундобина О.С., Комарова Е.В., Намазова-Баранова Л.С., Геворкян А.К., Мовсисян Г.Б. Болезнь Гоше у детей. Педиатрическая фармакология 2013; 10 (3): 72–5.
3. Sam R., Ryan E., Daykin E., Sidransky E. Current and emerging pharmacotherapy for Gaucher disease in pediatric populations. Expert Opin Pharmacother 2021; 22 (11): 1489–503. DOI: 10.1080/14656566.2021.1902989
4. Gupta P., Pastores G. Pharmacological treatment of pediatric Gaucher disease. Expert Rev Clin Pharmacol 2018; 11 (12): 1183–94. DOI: 10.1080/17512433.2018.15494 86
5. Гундобина О.С., Мовсисян Г.Б., Комарова Е.В., НамазоваБаранова Л.С. Эффективность и безопасность применения велаглюцеразы альфа у пациентов с болезнью Гоше 1-го типа (по данным международных исследований). Педиатрическая фармакология 2014; 11 (6): 52–5. DOI: 10.15690/pf.v11i6.1215
6. Zimran A., Pastores G.M., Tylki-Szymanska A., Hughes D.A., Elstein D., Mardach R., еt аl. Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 patients previously treated with imiglucerase. Am J Hematol 2013; 88 (3): 172–8. DOI: 10.1002/ajh.23383
7. Gonzalez D.E., Turkia H.B., Lukina E.A., Kisinovsky I., Dridi M.F., Elstein D., et al. Enzyme replacement therapy with velaglucerase alfa in Gaucher disease: Results from a randomized, double-blind, multinational, Phase 3 study. Am J Hematol 2013; 88 (3): 166–71. DOI: 10.1002/ajh.23381
8. Ben Turkia H., Gonzalez D.E., Barton N.W., Zimran A., Kabra M., Lukina E.A., et al. Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease. Am J Hematol 2013; 88 (3): 179–84. DOI: 10.1002/ajh.23382
9. Smith L., Rhead W., Charrow J., Shankar S.P., Bavdekar A., Longo N., еt al. Long-term velaglucerase alfa treatment in children with Gaucher disease type 1 naïve to enzyme replacement therapy or previously treated with imiglucerase. Mol Genet Metab 2016; 117 (2): 164–71. DOI: 10.1016/j.ymgme.2015.05.012
10. Saeki I., Tokunaga S., Matsuura T., Hayashida M., Yanagi Y., Taguchi T. A formula for determining the standard liver volume in children: a special reference for neonates and infants. Pediatr Transplant 2012; 16 (3): 244–9.
11. Prassopoulos P., Daskalogiannaki M., Raissaki M., Hatjidakis A., Gourtsoyiannis N. Determination of normal splenic volume on computed tomography in relation to age, gender and body habitus. Eur Radiol 1997; 7 (2): 246–8.
12. Детская ультразвуковая диагностика. В 5 томах. Под ред. М.И. Пыкова. Т. 5. М.: Видар; 2016. 360 с.
13. Elstein D., Burrow T.A., Charrow J., Giraldo P., Mehta A., Pastores G.M., et al. Home infusion of intravenous velaglucerase alfa: Experience from pooled clinical studies in 104 patients with type 1 Gaucher disease. Mol Genet Metab 2017; 120 (1–2): 111–5. DOI: 10.1016/j.ymgme.2016.08.005
14. Ida H., Tanaka A., Matsubayashi T., Murayama K., Hongo T., Lee H.M., Mellgard B. A multicenter, open-label extension study of velaglucerase alfa in Japanese patients with Gaucher disease: Results after a cumulative treatment period of 24months. Blood Cells Mol Dis 2016; 59: 140–7. DOI: 10.1016/j.bcmd.2015.10.002
15. Zimran A., Elstein D., Gonzalez D.E., Lukina E.A., Qin Y., Dinh Q., Turkia H.B. Treatment-naïve Gaucher disease patients achieve therapeutic goals and normalization with velaglucerase alfa by 4years in phase 3 trials. Blood Cells Mol Dis 2018; 68: 153–9. DOI: 10.1016/j.bcmd.2016.10.007
16. Hughes D.A., Gonzalez D.E., Lukina E.A., Mehta A., Kabra M., Elstein D., еt al. Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients with Gaucher disease: Long-term data from phase III clinical trials. Am J Hematol 2015; 90 (7): 584–91. DOI: 10.1002/ajh.24012
17. Pastores G.M., et al. Long-term velaglucerase alfa of enzyme replacement therapy in children with type 1 Gaucher disease. Poster presented at the SSIEM Annual Symposium, September 2–5. Innsbruck, Austria, 2014.
18. Giraldo P., et al. Safety and efficacy of velaglucerase alfa in children with type 1 Gaucher disease: 2-year experience. Poster presented at the American College of Medical Genetics (ACMG) Annual Clinical Genetics Meeting, March 27–31. Charlotte, North Carolina, USA, 2012.
19. Murugesan V., Chuang W.L., Liu J., Lischuk A., Kacena K., Lin H., et al. Glucosylsphingosine is a key biomarker of Gaucher disease. Am J Hematol 2016; 91 (11): 1082–9. DOI: 10.1002/ajh.24491
20. Hurvitz N., Dinur T., Becker-Cohen M., Cozma C., Hovakimyan M., Oppermann S., et al. Glucosylsphingosine (lyso-Gb1) as a Biomarker for Monitoring Treated and Untreated Children with Gaucher Disease. Int J Mol Sci 2019; 20 (12): 3033. DOI: 10.3390/ijms20123033
21. Elstein D., Mellgard B., Dinh Q., Lan L., Qiu Y., Cozma C., et al. Reductions in glucosylsphingosine (lyso-Gb1) in treatment-naïve and previously treated patients receiving velaglucerase alfa for type 1 Gaucher disease: Data from phase 3 clinical trials. Mol Genet Metab 2017; 122 (1–2): 113–20. DOI: 10.1016/j.ymgme.2017.08.005
22. Grabowski G.A., et al. Linear growth over 2 years of velaglucerase alfa therapy in children with type 1 Gaucher disease previously treated with imiglucerase. Poster presented at the American College of Medical Genetics (ACMG) Annual Clinical Genetics Meeting, March 27–31. Charlotte, North Carolina, USA, 2012.
23. Pastores G.M., Rosenbloom B., Weinreb N., Goker-Alpan O., Grabowski G., Cohn G.M., Zahrieh D. A multicenter open-label treatment protocol (HGT-GCB-058) of velaglucerase alfa enzyme replacement therapy in patients with Gaucher disease type 1: safety and tolerability. Genet Med 2014; 16 (5): 359–66. DOI: 10.1038/gim.2013.154
24. Goker-Alpan O., et al. Safety of velaglucerase alfa in type 1 Gaucher disease patients with anti-imiglucerase antibodies. Poster presented at the American Society of Human Genetics (ASHG) 62nd Annual meeting, November 6–10. San Francisco, CA, USA, 2012.
Pediatric Hematology/Oncology and Immunopathology. 2023; 22: 94-102
Velaglucerase alfa for treatment in children with Gaucher disease type 1: the Russian experience
https://doi.org/10.24287/1726-1708-2023-22-3-94-102Abstract
The current gold standard for the treatment of Gaucher disease type 1 in children is enzyme replacement therapy. The efficacy and safety of treatment with velaglucerase alfa have been assessed in only a few large studies involving pediatric patients as subjects of research. In the Russian literature, there are no data available on the use of velaglucerase alfa in drug-naïve patients with Gaucher disease type 1. The aim of our study was to assess the efficacy and safety of treatment with velaglucerase alfa in children with Gaucher disease type 1. The study was approved by the Independent Ethics Committee and the Scientific Council of the National Medical Research Center for Children's Health of Ministry of Healthcare of the Russian Federation. All patients and/or their legal representatives gave their informed consent to the study. The efficacy of treatment with velaglucerase alfa in children with Gaucher disease type 1 was assessed by analyzing monitoring data of 15 patients aged 2 to 15 years who had been registered in the Russian Pediatric Gaucher Registry established at National Medical Research Center for Children's Health of Ministry of Healthcare of Russia over the period from 2015 to 2023. None of the patients had ever undergone enzyme replacement therapy before they were included in this study. The median age at the start of treatment was 6.5 years. We analyzed the patients' anthropometric, laboratory and instrumental data at 0, 6, 12, 24 and 36 months. The initial dose of enzyme replacement therapy ranged from 30 to 60 units/kg (with the median of 43 units/kg per infusion) once every 2 weeks based on disease severity. In as little as 6 months after the initiation of therapy with velaglucerase alfa, patients with Gaucher disease type 1 showed a statistically significant improvement in all measured parameters (p < 0.001): normalization of the median hemoglobin concentration and platelet count (from 113 to 125 g/L and from 111 to 163 × 109/L, respectively); a reduction in degree of liver and spleen enlargement (in terms of volume, from 45.1 to 17.9% and from 39.4 to 15.5%, respectively); a reduction in degree of the right liver lobe enlargement (in terms of linear measurements, from 27.2 to 11.1%); a reduction in degree of spleen enlargement (in terms of its length and width, from 73.4 to 37.8% and from 60.3 to 17.5%, respectively). Our patients had a remarkable decrease in biomarker activity after 3 years of therapy: chitotriosidase activity decreased from 2699 to 227 nmol/mL/h and glucosylsphingosine level was reduced from 204.0 to 35.3 ng/mL (р < 0.001). There were no adverse events during the course of treatment. After 6 months and 1 year of regular enzyme replacement therapy with appropriate doses of velaglucerase alfa initiated in a timely manner, children with Gaucher disease type 1 achieve normal hemoglobin concentrations and platelet counts, a reduction in biomarker activity, and a decrease in liver and spleen volumes. After 3 years of enzyme replacement therapy, patients achieve their main therapeutic goals such as the resolution of anemia and thrombocytopenia, an almost complete regression of hepatosplenomegaly and the normalization of bone mineral density and height adjusted for age.
References
1. We in r e b N. J., Go k er -A l pan O., Kishnani P.S., Longo N., Burrow T.A., Bernat J.A., et al. The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here? Mol Genet Metab 2022; 136 (1): 4–21. DOI: 10.1016/j.ymgme.2022.03.001
2. Gundobina O.S., Komarova E.V., Namazova-Baranova L.S., Gevorkyan A.K., Movsisyan G.B. Bolezn' Goshe u detei. Pediatricheskaya farmakologiya 2013; 10 (3): 72–5.
3. Sam R., Ryan E., Daykin E., Sidransky E. Current and emerging pharmacotherapy for Gaucher disease in pediatric populations. Expert Opin Pharmacother 2021; 22 (11): 1489–503. DOI: 10.1080/14656566.2021.1902989
4. Gupta P., Pastores G. Pharmacological treatment of pediatric Gaucher disease. Expert Rev Clin Pharmacol 2018; 11 (12): 1183–94. DOI: 10.1080/17512433.2018.15494 86
5. Gundobina O.S., Movsisyan G.B., Komarova E.V., NamazovaBaranova L.S. Effektivnost' i bezopasnost' primeneniya velaglyutserazy al'fa u patsientov s bolezn'yu Goshe 1-go tipa (po dannym mezhdunarodnykh issledovanii). Pediatricheskaya farmakologiya 2014; 11 (6): 52–5. DOI: 10.15690/pf.v11i6.1215
6. Zimran A., Pastores G.M., Tylki-Szymanska A., Hughes D.A., Elstein D., Mardach R., et al. Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 patients previously treated with imiglucerase. Am J Hematol 2013; 88 (3): 172–8. DOI: 10.1002/ajh.23383
7. Gonzalez D.E., Turkia H.B., Lukina E.A., Kisinovsky I., Dridi M.F., Elstein D., et al. Enzyme replacement therapy with velaglucerase alfa in Gaucher disease: Results from a randomized, double-blind, multinational, Phase 3 study. Am J Hematol 2013; 88 (3): 166–71. DOI: 10.1002/ajh.23381
8. Ben Turkia H., Gonzalez D.E., Barton N.W., Zimran A., Kabra M., Lukina E.A., et al. Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease. Am J Hematol 2013; 88 (3): 179–84. DOI: 10.1002/ajh.23382
9. Smith L., Rhead W., Charrow J., Shankar S.P., Bavdekar A., Longo N., et al. Long-term velaglucerase alfa treatment in children with Gaucher disease type 1 naïve to enzyme replacement therapy or previously treated with imiglucerase. Mol Genet Metab 2016; 117 (2): 164–71. DOI: 10.1016/j.ymgme.2015.05.012
10. Saeki I., Tokunaga S., Matsuura T., Hayashida M., Yanagi Y., Taguchi T. A formula for determining the standard liver volume in children: a special reference for neonates and infants. Pediatr Transplant 2012; 16 (3): 244–9.
11. Prassopoulos P., Daskalogiannaki M., Raissaki M., Hatjidakis A., Gourtsoyiannis N. Determination of normal splenic volume on computed tomography in relation to age, gender and body habitus. Eur Radiol 1997; 7 (2): 246–8.
12. Detskaya ul'trazvukovaya diagnostika. V 5 tomakh. Pod red. M.I. Pykova. T. 5. M.: Vidar; 2016. 360 s.
13. Elstein D., Burrow T.A., Charrow J., Giraldo P., Mehta A., Pastores G.M., et al. Home infusion of intravenous velaglucerase alfa: Experience from pooled clinical studies in 104 patients with type 1 Gaucher disease. Mol Genet Metab 2017; 120 (1–2): 111–5. DOI: 10.1016/j.ymgme.2016.08.005
14. Ida H., Tanaka A., Matsubayashi T., Murayama K., Hongo T., Lee H.M., Mellgard B. A multicenter, open-label extension study of velaglucerase alfa in Japanese patients with Gaucher disease: Results after a cumulative treatment period of 24months. Blood Cells Mol Dis 2016; 59: 140–7. DOI: 10.1016/j.bcmd.2015.10.002
15. Zimran A., Elstein D., Gonzalez D.E., Lukina E.A., Qin Y., Dinh Q., Turkia H.B. Treatment-naïve Gaucher disease patients achieve therapeutic goals and normalization with velaglucerase alfa by 4years in phase 3 trials. Blood Cells Mol Dis 2018; 68: 153–9. DOI: 10.1016/j.bcmd.2016.10.007
16. Hughes D.A., Gonzalez D.E., Lukina E.A., Mehta A., Kabra M., Elstein D., et al. Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients with Gaucher disease: Long-term data from phase III clinical trials. Am J Hematol 2015; 90 (7): 584–91. DOI: 10.1002/ajh.24012
17. Pastores G.M., et al. Long-term velaglucerase alfa of enzyme replacement therapy in children with type 1 Gaucher disease. Poster presented at the SSIEM Annual Symposium, September 2–5. Innsbruck, Austria, 2014.
18. Giraldo P., et al. Safety and efficacy of velaglucerase alfa in children with type 1 Gaucher disease: 2-year experience. Poster presented at the American College of Medical Genetics (ACMG) Annual Clinical Genetics Meeting, March 27–31. Charlotte, North Carolina, USA, 2012.
19. Murugesan V., Chuang W.L., Liu J., Lischuk A., Kacena K., Lin H., et al. Glucosylsphingosine is a key biomarker of Gaucher disease. Am J Hematol 2016; 91 (11): 1082–9. DOI: 10.1002/ajh.24491
20. Hurvitz N., Dinur T., Becker-Cohen M., Cozma C., Hovakimyan M., Oppermann S., et al. Glucosylsphingosine (lyso-Gb1) as a Biomarker for Monitoring Treated and Untreated Children with Gaucher Disease. Int J Mol Sci 2019; 20 (12): 3033. DOI: 10.3390/ijms20123033
21. Elstein D., Mellgard B., Dinh Q., Lan L., Qiu Y., Cozma C., et al. Reductions in glucosylsphingosine (lyso-Gb1) in treatment-naïve and previously treated patients receiving velaglucerase alfa for type 1 Gaucher disease: Data from phase 3 clinical trials. Mol Genet Metab 2017; 122 (1–2): 113–20. DOI: 10.1016/j.ymgme.2017.08.005
22. Grabowski G.A., et al. Linear growth over 2 years of velaglucerase alfa therapy in children with type 1 Gaucher disease previously treated with imiglucerase. Poster presented at the American College of Medical Genetics (ACMG) Annual Clinical Genetics Meeting, March 27–31. Charlotte, North Carolina, USA, 2012.
23. Pastores G.M., Rosenbloom B., Weinreb N., Goker-Alpan O., Grabowski G., Cohn G.M., Zahrieh D. A multicenter open-label treatment protocol (HGT-GCB-058) of velaglucerase alfa enzyme replacement therapy in patients with Gaucher disease type 1: safety and tolerability. Genet Med 2014; 16 (5): 359–66. DOI: 10.1038/gim.2013.154
24. Goker-Alpan O., et al. Safety of velaglucerase alfa in type 1 Gaucher disease patients with anti-imiglucerase antibodies. Poster presented at the American Society of Human Genetics (ASHG) 62nd Annual meeting, November 6–10. San Francisco, CA, USA, 2012.
