Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2025; 24: 199-206
Современные представления о терапии классической лимфомы Ходжкина у детей и подростков
https://doi.org/10.24287/1726-1708-2025-24-1-199-206Аннотация
За последнее столетие классическая лимфома Ходжкина (ЛХ) превратилась из фатального заболевания в один из самых излечимых видов рака. Педиатрические протоколы по лечению ЛХ созданы основными мировыми консорциумами: Детской онкологической группой (COG) и Европейской группой по лечению детской ЛХ (EuroNet-PHL) и уделяют основное внимание поиску подходов к ограничению показаний и уменьшению объемов лучевой терапии и доз химиотерапевтических препаратов, которые могут вызывать долгосрочную токсичность и стать причиной ранней летальности. В их основе лежат риск-адаптированные программы, основанные на раннем ответе на химиотерапию, что стало определяющим фактором для применения лучевой терапии. Ведущее место в стадировании заболевания и оценке ответа на терапию заняла позитронно-эмиссионная томография. Целью данного обзора является обобщение современных представлений о лечении детской классической ЛХ в соответствии с подходами консорциумов COG и EuroNet-PHL.
Список литературы
1. Alaggio R., Amador C., Anagnostopoulos I., Attygalle A.D., Araujo I.B.O., Berti E., et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia 2022; 36 (7):1720–48. DOI: 10.1038/s41375-022-01620-2
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5. Satou A., Takahara T., Nakamura S. An Update on the Pathology and Molecular Features of Hodgkin Lymphoma. Cancers (Basel) 2022; 14 (11): 2647. DOI: 10.3390/cancers14112647
6. Green M.R., Monti S., Rodig S.J., Juszczynski P., Currie T., O’Donnell E., et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 2010; 116: 3268–77. DOI: 10.1182/blood-2010-05-282780
7. Roemer M.G., Advani R.H., Ligon A.H., Natkunam Y., Redd R.A., Homer H., et al. PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol. 2016; 34: 2690–7. doi: 10.1200/JCO.2016.66.4482
8. Eline Zijtregtop A.M., Zeal J., Metzger M.L., Kelly K.M., Mauz-Koerholz C., Voss S.D., et al. Significance of E-lesions in Hodgkin lymphoma and the creation of a new consensus definition: a report from SEARCH. Blood Adv 2023; 7 (20): 6303–19. DOI: 10.1182/bloodadvances.2023010024
9. Munir F., Hardit V., Sheikh I.N., Qahtani S.A., He J., Cuglievan B., et al. Classical Hodgkin Lymphoma: From Past to Future – A Comprehensive Review of Pathophysiology and Therapeutic Advances. Int J Mol Sci 2023; 24 (12): 10095. DOI: 10.3390/ijms241210095
10. Wirth A., Grigg A., Wolf M., Goldstein D., Johnson C., Davis S., et al. Risk and response adapted therapy for early stage Hodgkin lymphoma: a prospective multicenter study of the Australasian Leukaemia and Lymphoma Group/Trans-Tasman Radiation Oncology Group. Leuk Lymphoma 2011; 52 (5): 786–95. DOI: 10.3109/10428194.2010.547155
11. Cheson B.D., Fisher R.I., Barrington S.F., Cavalli F., Schwartz L.H., Zucca E., et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014; 32: 3059–67. DOI: 10.1200/jCO.2013.54.8800
12. Flerlage J.E., Kelly K.M., Beishuizen A., Cho S., De Alarcon P.A., Dieckmann U., et al. Staging evaluation and response criteria harmonization (SEARCH) for childhood, adolescent and young adult Hodgkin lymphoma (CAYAHL): methodology statement. Pediatr Blood Cancer 2017; 64: e26421. DOI: 10.1002/pbc.26421
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15. Kelly K.M., Cole P.D., Pei Q., Bush R., Roberts K.B., Hodgson D.C., et al. Response-adapted therapy for the treatment of children with newly diagnosed high risk Hodgkin lymphoma (AHOD0831): a report from the Children’s Oncology Group. Br J Haematol 2019; 187: 39–48. DOI: 10.1111/BJH.16014
16. Schwartz C.L., Chen L., McCarten K., Wolden S., Constine L.S., Hutchison R.E., et al. Childhood Hodgkin International Prognostic Score (CHIPS) predicts event-free survival in Hodgkin lymphoma: A report from the Children’s Oncology Group. Pediatr Blood Cancer 2017; 64: e26278. DOI: 10.1002/pbc.26278
17. Nadali G., Tavecchia L., Zanolin E., Bonfante V., Viviani S., Camerini E., et al. Serum level of the soluble form of the CD30 molecule identifies patients with Hodgkin's disease at high risk of unfavorable outcome. Blood 1998; 91: 3011–6. DOI: 10.1182/blood.V91.8.3011.3011_3011_3016
18. Bien E., Balcerska A., Adamkiewicz-Drozynska E., Rapala M., Krawczyk M., Stepinski J. Pre-treatment serum levels of interleukin-10, interleukin-12 and their ratio predict response to therapy and probability of event-free and overall survival in childhood soft tissue sarcomas, Hodgkin's lymphomas and acute lymphoblastic leukemias. Clin Biochem 2009; 42: 1144–57. DOI: 10.1016/j.clinbiochem.2009.04.004
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20. Jost P.J., Ruland J. Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications. Blood 2007; 109: 2700–7. DOI: 10.1182/blood-2006-07-025809
21. Ben Arush M.W., Shafat I., Ben Barak A., Shalom R.B., Vlodavsky I., Vlodavsky E., et al. Plasma heparanase as a significant marker of treatment response in children with Hodgkin lymphoma: pilot study. Pediatr Hematol Oncol 2009; 26: 157–64. DOI: 10.1080/08880010902754917
22. Kelly K.M. Hodgkin lymphoma in children and adolescents: improving the therapeutic index. Blood 2015; 126 (22): 2452–8. DOI: 10.1182/blood-2015-07-641035
23. Lo A.C., Dieckmann K., Pelz T., Gallop-Evans E., Engenhart-Cabillic R., Vordermark D., et al. Pediatric classical Hodgkin lymphoma. Pediatr Blood Cancer 2021; 68 (Suppl 2): e28562. DOI: 10.1002/pbc.28562
24. Oeffinger K.C., Stratton K.L., Hudson M.M., Leisenring W.M., Henderson T.O., Howell R.M. Impact of Risk-Adapted Therapy for Pediatric Hodgkin Lymphoma on Risk of LongTerm Morbidity: A Report from the Childhood Cancer Survivor Study. J Clin Oncol 2021; 39 (20): 2266–75. DOI: 10.1200/JCO.20.01186
25. Munir F., Hardit V., Sheikh I.N., Qahtani S.A., He J., Cuglievan B., et al. Classical Hodgkin Lymphoma: From Past to Future – A Comprehensive Review of Pathophysiology and Therapeutic Advances. Int J Mol Sci 2023; 24 (12): 10095. DOI: 10.3390/ijms241210095
26. Tebbi C.K., Mendenhall N.P., London W.B., Williams J.L., Hutchison R.E., Fitzgerald T.J., et al. Response-dependent and reduced treatment in lower risk Hodgkin lymphoma in children and adolescents, results of P9426: a report from the Children's Oncology Group. Pediatr Blood Cancer 2012; 59 (7): 1259–65. DOI: 10.1002/pbc.2427
27. Schwartz C.L., Chen L., McCarten K., Wolden S., Constine L.S., Hutchison R.E., et al. Childhood Hodgkin International Prognostic Score (CHIPS) predicts event-free survival in Hodgkin lymphoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 2016; 64 (4): e26278. DOI: 10.1002/pbc.26278
28. Henderson T.O., Hu B., Keller F., Pei Q., Wu Y., Hoppe B., et al. AHOD2131: A Randomized Phase 3 Response-Adapted Trial Comparing Standard Therapy with Immuno-Oncology Therapy for Children and Adults with Newly Diagnosed Stage I and II Classic Hodgkin Lymphoma. Blood 2023; 142 (Suppl 1): 3084. DOI: 10.1182/blood-2023-189652
29. Schwartz C., Constine L., Villaluna D. A risk-adapted, responsebased approach using ABVE-PC for children and adolescents with intermediateand high-risk Hodgkin lymphoma: The results of P9425. Blood 2009; 114: 2051–9. DOI: 10.1182/blood-2008-10-184143
30. Kelly K.M., Sposto R., Hutchinson R., Massey V., McCarten K., Perkins S., et al. BEACOPP chemotherapy is a highly effective regimen in children and adolescents with high-risk Hodgkin lymphoma: a report from the Children's Oncology Group. Blood 2011; 117 (9): 2596–603. DOI: 10.1182/blood-2010-05-285379
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32. Roth L.G., Keller F., Toledo M.M., Castellino S.M., Forlenza C.J., Catalan M.A., et al. Pembrolizumab (pembro) in Children and Young Adults with Low-Risk Classical Hodgkin Lymphoma (cHL) with Slow Early Response (SER) to Front-Line Chemotherapy (chemo): Early Results from the Phase 2 Keynote-667 Study. Blood 2023; 142 (Suppl 1): 1700. DOI: 10.1182/blood-2023-186719
33. Castellino S.M., Pei Q., Parsons S.K., Hodgson D., McCarten K., Horton T., el al. Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin’s Lymphoma. N Engl J Med 2022; 387: 1649–60. DOI: 10.1056/NEJMoa2206660
34. Mauz-Körholz C., Landman-Parker J., Balwierz W., Ammann R.A., Anderson R.A., Attarbaschi A., et al. Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in children and adolescents with intermediate-stage and advancedstage classical Hodgkin lymphoma (EuroNet-PHL-C1): a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial. Lancet Oncol 2022; 23: 125–37. DOI: 10.1016/S1470-2045(21)00470-8
35. Mauz-Körholz C., Hasenclever D., Dörffel W., Ruschke K., Pelz T., Voigt A., et al. Procarbazine-Free OEPA-COPDAC Chemotherapy in Boys and Standard OPPA-COPP in Girls Have Comparable Effectiveness in Pediatric Hodgkin's Lymphoma: The GPOH-HD-2002 Study. J Clin Oncol 2010; 28 (23): 3680–6. DOI: 10.1200/JCO.2009.26.9381
36. Dörffel W., Rühl U., Lüders H., Claviez A., Albrecht M., Bökkerink J., et al. Treatment of Children and Adolescents With Hodgkin Lymphoma Without Radiotherapy for Patients in Complete Remission After Chemotherapy: Final Results of the Multinational Trial GPOH-HD95. J Clin Oncol 2013; 31 (12): 1562–8. DOI: 10.1200/JCO.2012.45.3266
37. Kahn J.M., Mauz-Korholz C., Hernandez T., Milgrom S.A., Castellino S.M. Pediatric and Adolescent Hodgkin Lymphoma: Paving the Way for Standards of Care and Shared Decision Making. Am Soc Clin Oncol Educ Book 2024; 44(3): e432420. DOI: 10.1200/EDBK_432420
38. Lo A.C., Liu A., Liu Q., Yasui Y., Castellino S.M., Kelly K.M., et al. Late Cardiac Toxic Effects Associated With Treatment Protocols for Hodgkin Lymphoma in Children. JAMA Netw Open 2024; 7 (1): e2351062. DOI: 10.1001/jamanetworkopen.2023.51062
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40. Dörffel W., Riepenhausen M., Lüders H., Brämswig J., Schellong G. Secondary Malignancies Following Treatment for Hodgkin’s Lymphoma in Childhood and Adolescence. A Cohort Study With More Than 30 Years’ Follow-up. Dtsch Arztebl Int 2015; 112: 320–7. DOI: 10.3238/arztebl.2015.0320
Pediatric Hematology/Oncology and Immunopathology. 2025; 24: 199-206
Modern concepts in the treatment of classical Hodgkin lymphoma in children and adolescents
https://doi.org/10.24287/1726-1708-2025-24-1-199-206Abstract
Over the past century, classical Hodgkin lymphoma (HL) has evolved from a fatal disease to one of the most curable cancers. Treatment protocols for pediatric patients with HL have been developed by the world's major research consortia: the Children's Oncology Group (COG) and the European Network-Paediatric HL Study Group (EuroNet-PHL). Their efforts are devoted to identifying ways to reduce the indications for radiation therapy and to use smaller field sizes and reduced doses of radiation therapy as well as lower doses of chemotherapy with the aim to reduce early mortality and potential toxicity in the long term. These protocols rely on risk-adapted treatment programs based on early response to chemotherapy, which has become a determining factor for the use of radiotherapy. Positron emission tomography has taken a leading role in staging and evaluation of treatment response. The aim of this review is to summarize current understanding of pediatric classical HL treatment according to the approaches of the COG and EuroNet-PHL research consortia.
References
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12. Flerlage J.E., Kelly K.M., Beishuizen A., Cho S., De Alarcon P.A., Dieckmann U., et al. Staging evaluation and response criteria harmonization (SEARCH) for childhood, adolescent and young adult Hodgkin lymphoma (CAYAHL): methodology statement. Pediatr Blood Cancer 2017; 64: e26421. DOI: 10.1002/pbc.26421
13. Robertson V.L., Anderson C.S., Keller F.G., Halkar R., Goodman M., Marcus R.B., et al. Role of FDG-PET in the definition ofinvolved-field radiation therapy and management for pediatric Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 2011; 80 (2): 324–32. DOI: 10.1016/j.ijrobp.2010.02.002
14. Gallamini A., Fiore F., Sorasio R., Meignan M. Interim positron emission tomography scan in Hodgkin lymphoma: definitions, interpretation rules, and clinical validation. Leuk Lymphoma 2009; 50 (11): 1761–4. DOI: 10.3109/10428190903308072
15. Kelly K.M., Cole P.D., Pei Q., Bush R., Roberts K.B., Hodgson D.C., et al. Response-adapted therapy for the treatment of children with newly diagnosed high risk Hodgkin lymphoma (AHOD0831): a report from the Children’s Oncology Group. Br J Haematol 2019; 187: 39–48. DOI: 10.1111/BJH.16014
16. Schwartz C.L., Chen L., McCarten K., Wolden S., Constine L.S., Hutchison R.E., et al. Childhood Hodgkin International Prognostic Score (CHIPS) predicts event-free survival in Hodgkin lymphoma: A report from the Children’s Oncology Group. Pediatr Blood Cancer 2017; 64: e26278. DOI: 10.1002/pbc.26278
17. Nadali G., Tavecchia L., Zanolin E., Bonfante V., Viviani S., Camerini E., et al. Serum level of the soluble form of the CD30 molecule identifies patients with Hodgkin's disease at high risk of unfavorable outcome. Blood 1998; 91: 3011–6. DOI: 10.1182/blood.V91.8.3011.3011_3011_3016
18. Bien E., Balcerska A., Adamkiewicz-Drozynska E., Rapala M., Krawczyk M., Stepinski J. Pre-treatment serum levels of interleukin-10, interleukin-12 and their ratio predict response to therapy and probability of event-free and overall survival in childhood soft tissue sarcomas, Hodgkin's lymphomas and acute lymphoblastic leukemias. Clin Biochem 2009; 42: 1144–57. DOI: 10.1016/j.clinbiochem.2009.04.004
19. Abdelrazik N., Fouda M., Zaghloul M.H., Abbas D. Serum level of intercellular adhesion molecule-1 in children with malignant lymphoma. Med Princ Pract 2008; 17: 233–8. DOI: 10.1159/000117798
20. Jost P.J., Ruland J. Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications. Blood 2007; 109: 2700–7. DOI: 10.1182/blood-2006-07-025809
21. Ben Arush M.W., Shafat I., Ben Barak A., Shalom R.B., Vlodavsky I., Vlodavsky E., et al. Plasma heparanase as a significant marker of treatment response in children with Hodgkin lymphoma: pilot study. Pediatr Hematol Oncol 2009; 26: 157–64. DOI: 10.1080/08880010902754917
22. Kelly K.M. Hodgkin lymphoma in children and adolescents: improving the therapeutic index. Blood 2015; 126 (22): 2452–8. DOI: 10.1182/blood-2015-07-641035
23. Lo A.C., Dieckmann K., Pelz T., Gallop-Evans E., Engenhart-Cabillic R., Vordermark D., et al. Pediatric classical Hodgkin lymphoma. Pediatr Blood Cancer 2021; 68 (Suppl 2): e28562. DOI: 10.1002/pbc.28562
24. Oeffinger K.C., Stratton K.L., Hudson M.M., Leisenring W.M., Henderson T.O., Howell R.M. Impact of Risk-Adapted Therapy for Pediatric Hodgkin Lymphoma on Risk of LongTerm Morbidity: A Report from the Childhood Cancer Survivor Study. J Clin Oncol 2021; 39 (20): 2266–75. DOI: 10.1200/JCO.20.01186
25. Munir F., Hardit V., Sheikh I.N., Qahtani S.A., He J., Cuglievan B., et al. Classical Hodgkin Lymphoma: From Past to Future – A Comprehensive Review of Pathophysiology and Therapeutic Advances. Int J Mol Sci 2023; 24 (12): 10095. DOI: 10.3390/ijms241210095
26. Tebbi C.K., Mendenhall N.P., London W.B., Williams J.L., Hutchison R.E., Fitzgerald T.J., et al. Response-dependent and reduced treatment in lower risk Hodgkin lymphoma in children and adolescents, results of P9426: a report from the Children's Oncology Group. Pediatr Blood Cancer 2012; 59 (7): 1259–65. DOI: 10.1002/pbc.2427
27. Schwartz C.L., Chen L., McCarten K., Wolden S., Constine L.S., Hutchison R.E., et al. Childhood Hodgkin International Prognostic Score (CHIPS) predicts event-free survival in Hodgkin lymphoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 2016; 64 (4): e26278. DOI: 10.1002/pbc.26278
28. Henderson T.O., Hu B., Keller F., Pei Q., Wu Y., Hoppe B., et al. AHOD2131: A Randomized Phase 3 Response-Adapted Trial Comparing Standard Therapy with Immuno-Oncology Therapy for Children and Adults with Newly Diagnosed Stage I and II Classic Hodgkin Lymphoma. Blood 2023; 142 (Suppl 1): 3084. DOI: 10.1182/blood-2023-189652
29. Schwartz C., Constine L., Villaluna D. A risk-adapted, responsebased approach using ABVE-PC for children and adolescents with intermediateand high-risk Hodgkin lymphoma: The results of P9425. Blood 2009; 114: 2051–9. DOI: 10.1182/blood-2008-10-184143
30. Kelly K.M., Sposto R., Hutchinson R., Massey V., McCarten K., Perkins S., et al. BEACOPP chemotherapy is a highly effective regimen in children and adolescents with high-risk Hodgkin lymphoma: a report from the Children's Oncology Group. Blood 2011; 117 (9): 2596–603. DOI: 10.1182/blood-2010-05-285379
31. Nagpal P., Akl M.R., Ayoub N.M., Tomiyama T., Cousins T., Tai B., et al. Pediatric Hodgkin lymphoma – biomarkers, drugs, and clinical trials for translational science and medicine. Oncotarget 2016; 22; 7 (41): 67551–73. DOI: 10.18632/oncotarget.11509
32. Roth L.G., Keller F., Toledo M.M., Castellino S.M., Forlenza C.J., Catalan M.A., et al. Pembrolizumab (pembro) in Children and Young Adults with Low-Risk Classical Hodgkin Lymphoma (cHL) with Slow Early Response (SER) to Front-Line Chemotherapy (chemo): Early Results from the Phase 2 Keynote-667 Study. Blood 2023; 142 (Suppl 1): 1700. DOI: 10.1182/blood-2023-186719
33. Castellino S.M., Pei Q., Parsons S.K., Hodgson D., McCarten K., Horton T., el al. Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin’s Lymphoma. N Engl J Med 2022; 387: 1649–60. DOI: 10.1056/NEJMoa2206660
34. Mauz-Körholz C., Landman-Parker J., Balwierz W., Ammann R.A., Anderson R.A., Attarbaschi A., et al. Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in children and adolescents with intermediate-stage and advancedstage classical Hodgkin lymphoma (EuroNet-PHL-C1): a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial. Lancet Oncol 2022; 23: 125–37. DOI: 10.1016/S1470-2045(21)00470-8
35. Mauz-Körholz C., Hasenclever D., Dörffel W., Ruschke K., Pelz T., Voigt A., et al. Procarbazine-Free OEPA-COPDAC Chemotherapy in Boys and Standard OPPA-COPP in Girls Have Comparable Effectiveness in Pediatric Hodgkin's Lymphoma: The GPOH-HD-2002 Study. J Clin Oncol 2010; 28 (23): 3680–6. DOI: 10.1200/JCO.2009.26.9381
36. Dörffel W., Rühl U., Lüders H., Claviez A., Albrecht M., Bökkerink J., et al. Treatment of Children and Adolescents With Hodgkin Lymphoma Without Radiotherapy for Patients in Complete Remission After Chemotherapy: Final Results of the Multinational Trial GPOH-HD95. J Clin Oncol 2013; 31 (12): 1562–8. DOI: 10.1200/JCO.2012.45.3266
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