Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2025; 24: 116-125
Пегилированная аспарагиназа в индукции у детей с острым лимфобластным лейкозом промежуточного риска: результаты рандомизированного исследования
https://doi.org/10.24287/1726-1708-2025-24-1-116-125Аннотация
В данном исследовании оценивались эффективность и безопасность применения пэгаспаргазы на 3-й день индукции ремиссии у детей с острым лимфобластным лейкозом (ОЛЛ) промежуточного риска. Исследование одобрено независимым этическим комитетом и утверждено решением ученого совета ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России. В исследование были включены 1470 детей с ОЛЛ промежуточного риска. Пациенты были рандомизированы на 2 группы: с введением пэгаспаргазы (1000 Е/м2) на 3-й день индукции и без применения данного препарата. В обеих группах не было обнаружено значимой разницы в бессобытийной выживаемости. В группе пациентов с введением пэгаспаргазы наблюдалась значимо более низкая кумулятивная частота рецидива: 8,3% против 13,1%, (p = 0,02). Снижение частоты рецидива было более выраженным у пациентов с B-линейным ОЛЛ, особенно у детей старше 10 лет. Между группами не было отмечено значимой разницы в ранней смертности, общей выживаемости и частоте реакций гиперчувствительности. Введение пэгаспаргазы на 3-й день индукции у пациентов с ОЛЛ промежуточного риска значимо снизило частоту рецидива без увеличения токсичности. Это привело к внедрению введения пэгаспаргазы на 3-й день индукции в протокол «Москва–Берлин 2015» (ALL-MB 2015), который в настоящий момент рутинно применяется в России у детей и подростков с ОЛЛ.
Список литературы
1. Karachunskiy A., Herold R., von Stackelberg A., Miakova N., Timakow A., Mahortih T., et al. Results of the first randomized multicentre trial on childhood acute lymphoblastic leukaemia in Russia. Leukemia 2008; 22 (6):1144–53.
2. Румянцева Ю.В., Карачунский А.И. Оптимизация терапии острого лимфобластного лейкоза у детей в России и Белоруссии: стратегия Москва–Берлин. Вопросы гематологии/онкологии и иммунопатологии в педиатрии 2007; 6 (4): 13–22.
3. Heo Y.-A., Syed Y.Y., Keam S.J. Pegaspargase: A Review in Acute Lymphoblastic Leukaemia. Drugs 2019; 79 (7): 767–77.
4. Woods D., Winchester K., Towerman A., Gettinger K., Carey C., Timmermann K., et al. From the Children’s Oncology Group: evidence-based recommendations for PEG-asparaginase nurse monitoring, hypersensitivity reaction management, and patient/family education. J Pediatr Oncol Nurs 2017; 34 (6): 387–96.
5. Karachunskiy A., Tallen G., Roumiantseva J., Lagoiko S., Chervova A., von Stackelberg A., et al Reduced vs. standard dose native E. coli-asparaginase therapy in childhood acute lymphoblastic leukemia: long-term results of the randomized trial Moscow–Berlin 2002. J Cancer Res Clin Oncol 2019; 145 (4): 1001–12.
6. Фукс О.Ю., Кондратчик К.Л., Мякова Н.В., Карачунский А.И. Ранний ответ на терапию при использовании ПЭГ-аспарагиназы в циторедуктивной фазе лечения острого лимфобластного лейкоза. Гематология и трансфузиология 2007; 52 (6): 22–6.
7. Kamisaki Y., Wada H., Yagura T., Matsushima A., Inada Y. Reduction in immunogenicity and clearance rate of Escherichia coli L-asparaginase by modification with monomethoxypolyethylene glycol. J Pharmacol Exp Ther 1981; 216 (2): 410–4.
8. Silverman L.B., Gelber R.D., Dalton V.K., Asselin B.L., Barr R.D., Clavell L.A., et al. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 2001; 97 (5): 1211–8. DOI: 10.1182/blood.v97.5.1211
9. Vrooman L., Blonquist T., Supko J.G., Supko J.G., Hunt S.K., Cronholm S.M., et al. Efficacy and toxicity of pegaspargase and calaspargase pegol in childhood acute lymphoblastic leukemia/lymphoma: Results of DFCI 11-001. J Clin Oncol 2021; 39 (31): 3496–505.
10. Avramis V.I., Sencer S., Periclou A.P., Sather H., Bostrom B.C., Cohen L.J., et al. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 2002; 99 (6): 1986–94.
11. Stock W., Luger S.M., Advani A.S., Yin J., Harvey R.C., Mullighan C.G., et al. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood 2019; 133 (14): 1548–59.
12. Bartram J., O'Connor D., Enshaei A., Moorman A.V., Harrison C., Wade R., et al. Long Term Overall Survival of Greater Than 98% in Childhood ALL Patients with Good Risk Features and Low Risk MRD: Results from a Large Multi-Center Randomized Controlled Trial, UKALL 2003, ASH 2015, Oral session. [Electronic resource] URL: https://ash.confex.com/ash/2015/webprogramscheduler/Paper84403.html (accessed 06.02.2025).
13. Popov A., Bydanov O., Roumiantseva J., et al. Peg-Asparaginase Administration on Day 3 of Remission Induction Accelerates MRD Response in Children with B-Cell Precursor Acute Lymphoblastic Leukemia. Blood 2017; 130 (Suppl 1): 3983.
14. Zhou J., Goldwasser M.A., Li A., Dahlberg S.E., Neuberg D., Wang H., et al. Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01. Blood 2007; 110 (5): 1607–11.
15. Borowitz M.J., Devidas M., Hunger S.P., Bowman W.P., Carroll A.J., Carroll W.L., et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. Blood 2008; 111 (12): 5477–85.
16. Basso G., Veltroni M., Valsecchi M.G., Dworzak M.N., Ratei R., Silvestri D., et al. Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol 2009; 27 (31): 5168–74.
17. Place A.E., Stevenson K.E., Vrooman L.M., Harris M.H., Hunt S.K., O'Brien J.E., et al. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli l-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol 2015; 16 (16): 1677–90. DOI: 10.1016/S1470-2045(15)00363-0
18. Vora A., Goulden N., Wade R., Mitchell C., Hancock J., Hough R., et al. Treatment reduction for children and young adults with lowrisk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol 2013; 14 (3): 199–209. DOI: 10.1016/S1470-2045(12)70600-9
19. Albertsen B.K., Grell K., Abrahamsson J., Lund B., Vettenranta K., Jónsson Ó.G., et al. Intermittent Versus Continuous PEG-Asparaginase to Reduce Asparaginase-Associated Toxicities: A NOPHO ALL2008 Randomized Study. J Clin Oncol 2019; 37 (19): 1638–46. DOI: 10.1200/JCO.18.01877
20. Sidhu J., Masurekar A.N., Gogoi M.P., Fong C., Ioannou T., Lodhi T., et al. Activity and toxicity of intramuscular 1000 iu/m2polyethylene glycol-E. coli L-asparaginase in the UKALL 2003 and UKALL 2011 clinical trials. Br J Haematol 2022; 198: 142–50.
21. Derman B.A., Streck M., Wynne J., Christ T.N., Curran E., Stock W., Knoebel R.W. Efficacy and toxicity of reduced vs. standard dose pegylated asparaginase in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia. Leuk Lymphoma 2020; 61 (3): 614–22.
22. Möricke A., Reiter A., Zimmermann M., Gadner H., Stanulla M., Dördelmann M., et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 2008; 111: 4477–89.
23. Карачунский А.И., Бурштейн Е.С., Варфоломеева С.Р., Тимаков А.М. Промежуточный анализ мультицентрового исследования АLL-МВ 91 и АLL-ВРМ 90: результаты терапии подростков с ОЛЛ. Вопросы гематологии/онкологии и иммунопатологии в педиатрии 2002; 2: 24–9.
24. Hunger S.P., Lu X., Devidas M., Camitta B.M., Gaynon P.S., Winick N.J., et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J Clin Oncol 2012; 30 (14): 1663–9. DOI: 10.1200/JCO.2011.37.8018
25. Woo M.H., Hak L.J., Storm M.C., Evans W.E., Sandlund J.T., Rivera G.K., et al. Hypersensitivity or development of antibodies to asparaginase does not impact treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol 2000; 18: 1525–32.
26. Zalewska-Szewczyk B., Andrzejewski W., Mlynarski W., Jedrychowska-Dańska K., Witas H., Bodalski J. The anti-asparagines antibodies correlate with L-asparagines activity and may affect clinical outcome of childhood acute lymphoblastic leukemia. Leuk Lymphoma 2007; 48: 931–6.
27. Raetz E.A., Salzer W.L. Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2010; 32: 554–63.
28. Liu C., Kawedia J.D., Cheng C., Pei D., Fernandez C.A., Cai X., et al. Clinical utility and implications of asparaginase antibodies in acute lymphoblastic leukemia. Leukemia 2012; 26: 2303–9.
29. Nachman J.B., Sather H.N., Sensel M.G., Trigg M.E., Cherlow J.M., Lukens J.N., et al. Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med 1998; 338: 1663–71.
30. Burke M.J., Devidas M., Maloney K., Angiolillo A., Schore R., Dunsmore K., et at. Severe pegaspargase hypersensitivity reaction rates (grade ≥ 3) with intravenous infusion vs intramuscular injection: analysis of 54,280 doses administered to 16,534 patients on children's oncology group (COG) clinical trials. Leuk Lymphoma 2018; 59 (7): 1624–33.
31. Brigitha L., Fiocco M., Pieters R., Klug Albertsen B., Escherich G., Lopez-Lopez E., et al. A Meta-Analysis of Hypersensitivity to Pegylated Escherichia coli Asparaginase Used As First-Line Treatment in Contemporary Pediatric Acute Lymphoblastic Leukemia Protocols. Blood 2021; 138 (Suppl 1): 2308.
Pediatric Hematology/Oncology and Immunopathology. 2025; 24: 116-125
Pegylated asparaginase during induction therapy in children with intermediate-risk acute lymphoblastic leukemia: results of a randomized study
https://doi.org/10.24287/1726-1708-2025-24-1-116-125Abstract
This study investigated the efficacy and safety of the use of pegaspargase on day 3 of remission induction in children with intermediate-risk acute lymphoblastic leukemia (ALL). The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. The study included 1470 children with intermediate-risk ALL. The patients were randomized into two groups to receive pegaspargase (1000 IU/m²) on day 3 of induction or not to receive pegaspargase. There was no significant difference in event-free survival between the pegaspargase and non-pegaspargase groups. In the pegaspargase group, the cumulative incidence of relapse was significantly lower (8.3% vs. 13.1%; p = 0.02). A particularly notable reduction in relapse incidence was seen in the patients with B-lineage ALL, especially in those over 10 years of age. There were no significant differences in early mortality, overall survival, and incidence of hypersensitivity reactions between the two groups. The administration of pegaspargase on day 3 of induction in the patients with intermediate-risk ALL significantly reduced relapse rates without increasing toxicity. This finding led to the inclusion of pegaspargase in the updated ALL MB 2015 protocol, which is now routinely used in the treatment of children and adolescents with ALL in Russia.
References
1. Karachunskiy A., Herold R., von Stackelberg A., Miakova N., Timakow A., Mahortih T., et al. Results of the first randomized multicentre trial on childhood acute lymphoblastic leukaemia in Russia. Leukemia 2008; 22 (6):1144–53.
2. Rumyantseva Yu.V., Karachunskii A.I. Optimizatsiya terapii ostrogo limfoblastnogo leikoza u detei v Rossii i Belorussii: strategiya Moskva–Berlin. Voprosy gematologii/onkologii i immunopatologii v pediatrii 2007; 6 (4): 13–22.
3. Heo Y.-A., Syed Y.Y., Keam S.J. Pegaspargase: A Review in Acute Lymphoblastic Leukaemia. Drugs 2019; 79 (7): 767–77.
4. Woods D., Winchester K., Towerman A., Gettinger K., Carey C., Timmermann K., et al. From the Children’s Oncology Group: evidence-based recommendations for PEG-asparaginase nurse monitoring, hypersensitivity reaction management, and patient/family education. J Pediatr Oncol Nurs 2017; 34 (6): 387–96.
5. Karachunskiy A., Tallen G., Roumiantseva J., Lagoiko S., Chervova A., von Stackelberg A., et al Reduced vs. standard dose native E. coli-asparaginase therapy in childhood acute lymphoblastic leukemia: long-term results of the randomized trial Moscow–Berlin 2002. J Cancer Res Clin Oncol 2019; 145 (4): 1001–12.
6. Fuks O.Yu., Kondratchik K.L., Myakova N.V., Karachunskii A.I. Rannii otvet na terapiyu pri ispol'zovanii PEG-asparaginazy v tsitoreduktivnoi faze lecheniya ostrogo limfoblastnogo leikoza. Gematologiya i transfuziologiya 2007; 52 (6): 22–6.
7. Kamisaki Y., Wada H., Yagura T., Matsushima A., Inada Y. Reduction in immunogenicity and clearance rate of Escherichia coli L-asparaginase by modification with monomethoxypolyethylene glycol. J Pharmacol Exp Ther 1981; 216 (2): 410–4.
8. Silverman L.B., Gelber R.D., Dalton V.K., Asselin B.L., Barr R.D., Clavell L.A., et al. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 2001; 97 (5): 1211–8. DOI: 10.1182/blood.v97.5.1211
9. Vrooman L., Blonquist T., Supko J.G., Supko J.G., Hunt S.K., Cronholm S.M., et al. Efficacy and toxicity of pegaspargase and calaspargase pegol in childhood acute lymphoblastic leukemia/lymphoma: Results of DFCI 11-001. J Clin Oncol 2021; 39 (31): 3496–505.
10. Avramis V.I., Sencer S., Periclou A.P., Sather H., Bostrom B.C., Cohen L.J., et al. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 2002; 99 (6): 1986–94.
11. Stock W., Luger S.M., Advani A.S., Yin J., Harvey R.C., Mullighan C.G., et al. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood 2019; 133 (14): 1548–59.
12. Bartram J., O'Connor D., Enshaei A., Moorman A.V., Harrison C., Wade R., et al. Long Term Overall Survival of Greater Than 98% in Childhood ALL Patients with Good Risk Features and Low Risk MRD: Results from a Large Multi-Center Randomized Controlled Trial, UKALL 2003, ASH 2015, Oral session. [Electronic resource] URL: https://ash.confex.com/ash/2015/webprogramscheduler/Paper84403.html (accessed 06.02.2025).
13. Popov A., Bydanov O., Roumiantseva J., et al. Peg-Asparaginase Administration on Day 3 of Remission Induction Accelerates MRD Response in Children with B-Cell Precursor Acute Lymphoblastic Leukemia. Blood 2017; 130 (Suppl 1): 3983.
14. Zhou J., Goldwasser M.A., Li A., Dahlberg S.E., Neuberg D., Wang H., et al. Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01. Blood 2007; 110 (5): 1607–11.
15. Borowitz M.J., Devidas M., Hunger S.P., Bowman W.P., Carroll A.J., Carroll W.L., et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. Blood 2008; 111 (12): 5477–85.
16. Basso G., Veltroni M., Valsecchi M.G., Dworzak M.N., Ratei R., Silvestri D., et al. Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol 2009; 27 (31): 5168–74.
17. Place A.E., Stevenson K.E., Vrooman L.M., Harris M.H., Hunt S.K., O'Brien J.E., et al. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli l-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol 2015; 16 (16): 1677–90. DOI: 10.1016/S1470-2045(15)00363-0
18. Vora A., Goulden N., Wade R., Mitchell C., Hancock J., Hough R., et al. Treatment reduction for children and young adults with lowrisk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol 2013; 14 (3): 199–209. DOI: 10.1016/S1470-2045(12)70600-9
19. Albertsen B.K., Grell K., Abrahamsson J., Lund B., Vettenranta K., Jónsson Ó.G., et al. Intermittent Versus Continuous PEG-Asparaginase to Reduce Asparaginase-Associated Toxicities: A NOPHO ALL2008 Randomized Study. J Clin Oncol 2019; 37 (19): 1638–46. DOI: 10.1200/JCO.18.01877
20. Sidhu J., Masurekar A.N., Gogoi M.P., Fong C., Ioannou T., Lodhi T., et al. Activity and toxicity of intramuscular 1000 iu/m2polyethylene glycol-E. coli L-asparaginase in the UKALL 2003 and UKALL 2011 clinical trials. Br J Haematol 2022; 198: 142–50.
21. Derman B.A., Streck M., Wynne J., Christ T.N., Curran E., Stock W., Knoebel R.W. Efficacy and toxicity of reduced vs. standard dose pegylated asparaginase in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia. Leuk Lymphoma 2020; 61 (3): 614–22.
22. Möricke A., Reiter A., Zimmermann M., Gadner H., Stanulla M., Dördelmann M., et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 2008; 111: 4477–89.
23. Karachunskii A.I., Burshtein E.S., Varfolomeeva S.R., Timakov A.M. Promezhutochnyi analiz mul'titsentrovogo issledovaniya ALL-MV 91 i ALL-VRM 90: rezul'taty terapii podrostkov s OLL. Voprosy gematologii/onkologii i immunopatologii v pediatrii 2002; 2: 24–9.
24. Hunger S.P., Lu X., Devidas M., Camitta B.M., Gaynon P.S., Winick N.J., et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J Clin Oncol 2012; 30 (14): 1663–9. DOI: 10.1200/JCO.2011.37.8018
25. Woo M.H., Hak L.J., Storm M.C., Evans W.E., Sandlund J.T., Rivera G.K., et al. Hypersensitivity or development of antibodies to asparaginase does not impact treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol 2000; 18: 1525–32.
26. Zalewska-Szewczyk B., Andrzejewski W., Mlynarski W., Jedrychowska-Dańska K., Witas H., Bodalski J. The anti-asparagines antibodies correlate with L-asparagines activity and may affect clinical outcome of childhood acute lymphoblastic leukemia. Leuk Lymphoma 2007; 48: 931–6.
27. Raetz E.A., Salzer W.L. Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2010; 32: 554–63.
28. Liu C., Kawedia J.D., Cheng C., Pei D., Fernandez C.A., Cai X., et al. Clinical utility and implications of asparaginase antibodies in acute lymphoblastic leukemia. Leukemia 2012; 26: 2303–9.
29. Nachman J.B., Sather H.N., Sensel M.G., Trigg M.E., Cherlow J.M., Lukens J.N., et al. Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med 1998; 338: 1663–71.
30. Burke M.J., Devidas M., Maloney K., Angiolillo A., Schore R., Dunsmore K., et at. Severe pegaspargase hypersensitivity reaction rates (grade ≥ 3) with intravenous infusion vs intramuscular injection: analysis of 54,280 doses administered to 16,534 patients on children's oncology group (COG) clinical trials. Leuk Lymphoma 2018; 59 (7): 1624–33.
31. Brigitha L., Fiocco M., Pieters R., Klug Albertsen B., Escherich G., Lopez-Lopez E., et al. A Meta-Analysis of Hypersensitivity to Pegylated Escherichia coli Asparaginase Used As First-Line Treatment in Contemporary Pediatric Acute Lymphoblastic Leukemia Protocols. Blood 2021; 138 (Suppl 1): 2308.
