Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2024; 23: 14-23
Глиомы низкой степени злокачественности ствола головного мозга у детей: стратификация на группы риска и оценка эффективности таргетной терапии
https://doi.org/10.24287/1726-1708-2024-23-3-14-23Аннотация
Глиомы низкой степени злокачественности (ГНСЗ) ствола головного мозга продолжают оставаться сложной терапевтической задачей в связи с невозможностью радикального удаления опухоли и неудовлетворительными результатами стандартной терапии. Целью нашей работы был анализ клинических и молекулярно-генетических характеристик у пациентов с ГНСЗ ствола головного мозга и результатов стандартной терапии по протоколу SIOPLGG, а также таргетной терапии BRAFи MEK-ингибиторами. В исследование включены 59 пациентов со спорадическими (вне нейрофиброматоза I типа) ГНСЗ ствола головного мозга. Исследование одобрено независимым этическим комитетом и утверждено решением ученого совета НМИЦ ДГОИ им. Дмитрия Рогачева. Законные представители пациентов подписали информированное добровольное согласие на использование информации в научных исследованиях и публикациях. Показатели 8-летней общей выживаемости составили 68% (47–96%), 5-летней выживаемости без прогрессии (ВБП) – 38% (26–57%). Основной локализацией опухоли был продолговатый мозг (n = 25; 40%), в 21 (35,5%) случае опухоль распространялась на соседние структуры ствола и головного мозга. Радикальное удаление опухоли было выполнено 14 пациентам, субтотальное – 15, частичная резекция – 14, биопсия – 16. Основным гистологическим вариантом опухоли была пилоидная астроцитома (n = 49; 83%). У большинства пациентов выявлен химерный транскрипт KIAA1549::BRAF (n = 33; 56%). Мутация BRAFV600E идентифицирована у 12 (22%) пациентов, H3K27M – у 4 (7%). Химиотерапию по протоколу SIOP-LGG (карбоплатин + винкристин) получили 12 пациентов. Показатели 2-летней ВБП составили 44% (22–87%). Локальная лучевая терапия проводилась 12 пациентам. Показатели 2-летней ВБП составили 44% (22–87%). Таргетная терапия MEKингибитором (траметиниб) была назначена 13 пациентам, комбинированная терапия BRAFи MEK-ингибиторами – 9, монотерапия BRAF-ингибитором (вемурафениб) – 1. Двухлетняя ВБП на фоне таргетной терапии в первой линии составила 88% (67–100%). Основным нежелательным явлением таргетной терапии была кожная токсичность (70%). При проведении многофакторного анализа прогностически значимыми факторами, влияющими на ВБП, оказались радикальность удаления и молекулярно-генетический драйвер: биопсия и частичное удаление опухоли, а также наличие мутаций BRAFV600E и H3K27M продемонстрировали независимое негативное прогностическое значение.
Список литературы
1. Armstrong G.T., Conklin H.M., Huang S., Srivastava D., Sanford R., Ellison D.W., et al. Survival and long-term health and cognitive outcomes after low-grade glioma. Neuro Oncol 2011; 13 (2): 223–34.
2. Ryall S., Zapotocky M., Fukuoka K., Nobre L., Stucklin A.G., Bennett J., et al. Integrated molecular and clinical analysis of 1,000 pediatric lowgrade gliomas. Cancer Cell 2020; 37 (4): 569–83.
3. Kandels D., Pietsch T., Bison B., Warmuth‐Metz M., Thomale U.W., Kortmann R.D., et al. Loss of efficacy of subsequent nonsurgical therapy after primary treatment failure in pediatric low‐grade glioma patients – Report from the German SIOP‐LGG 2004 cohort. Int J Cancer 2020; 147 (12): 3471–89.
4. Merchant T.E., Conklin H.M., Wu S., Lustig R.H., Xiong X. Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol 2009; 27 (22): 3691–7.
5. Grill J., Couanet D., Cappelli C., Habrand J.L., Rodriguez D., Sainte‐ Rose C., et al. Radiation‐induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol 1999; 45 (3): 393–6.
6. Holzapfel J., Kandels D., Schmidt R., Pietsch T., Warmuth‐Metz M., Bison B., et al. Favorable prognosis in pediatric brainstem low‐grade glioma: Report from the German SIOP‐ LGG 2004 cohort. Int J Cancer 2020; 146 (12): 3385–96.
7. Bergthold G., Bandopadhayay P., Hoshida Y., Ramkissoon S., Ramkissoon L., Rich B., et al. Expression profiles of 151 pediatric low-grade gliomas reveal molecular differences associated with location and histological subtype. Neuro Oncol 2015; 17 (11): 1486–96.
8. Lassaletta A., Zapotocky M., Mistry M., Ramaswamy V., Honnorat M., Krishnatry R., et al. Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas. J Clin Oncol 2017; 35 (25): 2934–41.
9. Upadhyaya S. A., Koschmann C., Muraszko K., Venneti S., Garton H.J., Hamstra D.A., et al. Brainstem lowgrade gliomas in children – excellent outcomes with multimodality therapy. J Child Neurol 2017; 32 (2): 194–203.
10. Schindler G., Capper D., Meyer J., Janzarik W., Omran H., Herold-Mende C., et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011; 121 (3): 397–405.
11. Papusha L., Zaytseva M., Panferova A., Salnikova E., Samarin A., Vilesova I., et al. Midline Low-Grade Gliomas of Early Childhood: Focus on Targeted Therapies. JCO Precis Oncol 2024; 8: e2300590.
12. Ryall S., Krishnatry R., Arnoldo A., Buczkowicz P., Mistry M., Siddaway R., et al. Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma. Acta Neuropathol Commun 2016; 4 (1): 93.
13. Falkenstein F., Gessi M., Kandels D., Ng H.K., Schmidt R., Warmuth‐ Metz M., et al. Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO‐grade II – Report from the German/Swiss SIOP‐LGG 2004 cohort. Int J Cancer 2020; 147 (8): 2159–75.
14. Selt F., van Tilburg C.M., Bison B., Sievers P., Harting I., Ecker J., et al. Response to trametinib treatment in progressive pediatric low-grade glioma patients. J Neurooncol 2020; 149: 499–510.
15. Bouffet E., Hansford J.R., Garrè M.L., Hara J., Plant-Fox A., Aerts I., et al. Dabrafenib plus trametinib in pediatric glioma with BRAF V600 mutations. N Engl J Med 2023; 389 (12): 1108–20.
Pediatric Hematology/Oncology and Immunopathology. 2024; 23: 14-23
Low-grade gliomas of the brainstem in children: stratification into risk groups and the assessment of the effectiveness of targeted therapy
https://doi.org/10.24287/1726-1708-2024-23-3-14-23Abstract
Low-grade gliomas (LGG) of the brainstem remain a therapeutic challenge due to the impossibility of radical tumor resection and unsatisfactory results of standard treatment. We aimed to analyse clinical molecular genetic characteristics of patients with LGG of the brainstem and the results of standard treatment according to the SIOP-LGG protocol as well as targeted therapy with BRAF and MEK inhibitors. The study included 59 patients with sporadic (non-neurofibromatosis type I) LGG of the brainstem. 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 patients' legal representatives gave their informed consent to the use of the patients' data for research purposes and in publications. The 8-year overall survival rates were 68% (47–96%) and the 5-year progression-free survival (PFS) rates were 38% (26–57%). The medulla oblongata was the most common tumor site (n = 25; 40%), in 21 (35.5%) cases, the tumor spread to the adjacent structures of the brainstem and brain. Radical resection of the tumor was performed in 14 patients, subtotal resection – in 15 patients, partial resection – in 14, and 16 patients underwent biopsy. In most cases, the histological type of the tumor was pilocytic astrocytoma (n = 49; 83%). The KIAA1549::BRAF chimeric transcript was detected in the majority of patients (n = 33; 56%). The BRAFV600E mutation was found in 12 (22%) patients, the H3K27M mutation – in 4 (7%) patients. Twelve patients received chemotherapy according to the SIOP-LGG protocol (carboplatin + vincristine). The 2-year PFS rates were 44% (22–87%). Local radiotherapy was performed in 12 patients. The 2-year PFS rates were 44% (22–87%). Targeted therapy with the MEK inhibitor (trametinib) was prescribed to 13 patients, combination therapy with the BRAF and MEK inhibitors – to 9 patients, and one patient was prescribed BRAF inhibitor (vemurafenib) monotherapy. The 2-year PFS in the patients treated with first-line targeted therapy was 88% (67–100%). The most common adverse event of targeted therapy was skin toxicity (70%). A multivariate analysis revealed that the prognostically significant factors influencing PFS were the extent of resection and a molecular genetic driver: biopsy and partial resection of the tumor, as well as the presence of the BRAFV600E and H3K27M mutations demonstrated an independent negative prognostic value.
References
1. Armstrong G.T., Conklin H.M., Huang S., Srivastava D., Sanford R., Ellison D.W., et al. Survival and long-term health and cognitive outcomes after low-grade glioma. Neuro Oncol 2011; 13 (2): 223–34.
2. Ryall S., Zapotocky M., Fukuoka K., Nobre L., Stucklin A.G., Bennett J., et al. Integrated molecular and clinical analysis of 1,000 pediatric lowgrade gliomas. Cancer Cell 2020; 37 (4): 569–83.
3. Kandels D., Pietsch T., Bison B., Warmuth‐Metz M., Thomale U.W., Kortmann R.D., et al. Loss of efficacy of subsequent nonsurgical therapy after primary treatment failure in pediatric low‐grade glioma patients – Report from the German SIOP‐LGG 2004 cohort. Int J Cancer 2020; 147 (12): 3471–89.
4. Merchant T.E., Conklin H.M., Wu S., Lustig R.H., Xiong X. Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol 2009; 27 (22): 3691–7.
5. Grill J., Couanet D., Cappelli C., Habrand J.L., Rodriguez D., Sainte‐ Rose C., et al. Radiation‐induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol 1999; 45 (3): 393–6.
6. Holzapfel J., Kandels D., Schmidt R., Pietsch T., Warmuth‐Metz M., Bison B., et al. Favorable prognosis in pediatric brainstem low‐grade glioma: Report from the German SIOP‐ LGG 2004 cohort. Int J Cancer 2020; 146 (12): 3385–96.
7. Bergthold G., Bandopadhayay P., Hoshida Y., Ramkissoon S., Ramkissoon L., Rich B., et al. Expression profiles of 151 pediatric low-grade gliomas reveal molecular differences associated with location and histological subtype. Neuro Oncol 2015; 17 (11): 1486–96.
8. Lassaletta A., Zapotocky M., Mistry M., Ramaswamy V., Honnorat M., Krishnatry R., et al. Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas. J Clin Oncol 2017; 35 (25): 2934–41.
9. Upadhyaya S. A., Koschmann C., Muraszko K., Venneti S., Garton H.J., Hamstra D.A., et al. Brainstem lowgrade gliomas in children – excellent outcomes with multimodality therapy. J Child Neurol 2017; 32 (2): 194–203.
10. Schindler G., Capper D., Meyer J., Janzarik W., Omran H., Herold-Mende C., et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011; 121 (3): 397–405.
11. Papusha L., Zaytseva M., Panferova A., Salnikova E., Samarin A., Vilesova I., et al. Midline Low-Grade Gliomas of Early Childhood: Focus on Targeted Therapies. JCO Precis Oncol 2024; 8: e2300590.
12. Ryall S., Krishnatry R., Arnoldo A., Buczkowicz P., Mistry M., Siddaway R., et al. Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma. Acta Neuropathol Commun 2016; 4 (1): 93.
13. Falkenstein F., Gessi M., Kandels D., Ng H.K., Schmidt R., Warmuth‐ Metz M., et al. Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO‐grade II – Report from the German/Swiss SIOP‐LGG 2004 cohort. Int J Cancer 2020; 147 (8): 2159–75.
14. Selt F., van Tilburg C.M., Bison B., Sievers P., Harting I., Ecker J., et al. Response to trametinib treatment in progressive pediatric low-grade glioma patients. J Neurooncol 2020; 149: 499–510.
15. Bouffet E., Hansford J.R., Garrè M.L., Hara J., Plant-Fox A., Aerts I., et al. Dabrafenib plus trametinib in pediatric glioma with BRAF V600 mutations. N Engl J Med 2023; 389 (12): 1108–20.
