Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2024; 23: 37-44
Результаты исследования эффективности и безопасности применения вемурафениба в сочетании с комбинированной терапией цитарабином/2-хлор-2’-дезоксиаденозином у пациентов с гистиоцитозом из клеток Лангерганса с наличием мутации V600E в гене BRAF
https://doi.org/10.24287/1726-1708-2024-23-1-37-44Аннотация
В работе представлен новый протокол терапии пациентов с BRAF-позитивным гистиоцитозом из клеток Лангерганса (ГКЛ). В целях достижения ремиссии использовалась комбинация вемурафениба (таргетный препарат) и цитарабина (Ara-С) с кладрибином (2-CdA). В исследование вошли 27 пациентов, у 18 из них была установлена мультисистемная форма ГКЛ с поражением органов риска (RO+), у 9 – мультисистемная форма без вовлечения органов риска (RO–). Терапия начиналась с 28-дневного приема вемурафениба, после чего он отменялся. На 29-е сутки начинался блок полихимиотерапии Аra-C + 2-СdA № 1. Прием вемурафениба возобновлялся на +1-е сутки после блока Ara-C + 2-CdA. Интервал между блоками – 28 дней. В таком же режиме проводились последующие 2 блока химиотерапии Аra-C + 2-СdA – № 2 и № 3. Затем прием вемурафениба прекращался, после чего следовали 3 курса 2-CdA в монорежиме. У всех пациентов наблюдался быстрый ответ на проводимую терапию: на 28-е сутки значение по шкале активности заболевания снизилось с 15 до 2 баллов в группе RO+ и с 4 до 0 баллов в группе RO–. Двухлетняя безрецидивная выживаемость в группе RO+ составила 82 % (95 % доверительный интервал 66–100), в группе RO– она достигла 89 % (95 %, доверительный интервал 71–100). Общая выживаемость в обеих группах составила 100 %. Данное исследование демонстрирует, что комбинация вемурафениба и промежуточных доз 2-CdA и Ara-C безопасна и эффективна у детей с мультисистемной формой RO+ и рефрактерных ГКЛ. Данное проспективное многоцентровое нерандомизированное исследование было одобрено независимым этическим комитетом (протокол №3e/1-18) и утверждено решением
ученого совета НМИЦ ДГОИ им. Дмитрия Рогачева. Исследование зарегистрировано на сайте Clinicaltrials.gov, номер NCT03585686. Первый пациент был включен в исследование 22. 06. 2018, дата окончания сбора данных – 30. 04. 2023.
Список литературы
1. Badalian-Very G., Vergilio J.-A., Degar B.A., MacConaill L.E., Brandner B., Calicchio M.L., et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 2010; 116 (11): 1919–23. DOI: 10.1182/blood-2010-04-279083
2. Bigenwald C., Le Berichel J., Wilk C.M., Chakraborty R., Chen S.T., Tabachnikova A., et al. BRAFV600E-induced senescence drives Langerhans cell histiocytosis pathophysiology. Nat Med 2021; 27 (5) 851. DOI: 10.1038/s41591-021-01304-x
3. Xiao Y., van Halteren A.G.S., Lei X., Borst J., Steenwijk E., de Wit T., et al. Bone marrow-derived myeloid progenitors as driver mutation carriers in high- And low-risk Langerhans cell histiocytosis. Blood 2020; 136 (19): 2188–199. DOI: 10.1182/blood.2020005209
4. Héritier S., Emile J.F., Barkaoui M.A., Thomas C., Fraitag S., Boudjemaa S., et al. BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy. J Clin Oncol 2016;34(25):3023–30. DOI: 10.1200/JCO.2015.65.9508
5. Donadieu J., Bernard F., van Noesel M., Barkaoui M., Bardet O., Mura R., et al. Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: Results of an international phase 2 study. Blood 2015; 126 (12): 1415–23. DOI: 10.1182/blood-2015-03-635151
6. Solopova G., Baidildina D., Suntsova E., et al. Front-line therapy of high-risk Langerhans cell histiocytosis with 2 chlordeoxyadenosine and cytosine arabinoside: an update of a single center experience. Pediatr Blood Cancer 2010; 55 (5).
7. Evseev D., Kalinina I., Raykina E., Osipova D., Abashidze Z., Ignatova A., et al. Vemurafenib provides a rapid and robust clinical response in pediatric Langerhans cell histiocytosis with the BRAF V600E mutation but does not eliminate low-level minimal residual disease per ddPCR using cell-free circulating DNA. Int J Hematol 2021; 114 (6): 725–34. DOI: 10.1007/s12185-021-03205-8
8. Evseev D., Osipova D., Kalinina I., Raykina E., Ignatova A., Lyudovskikh E., et al. Vemurafenib combined with cladribine and cytarabine results in durable remission of pediatric BRAF V600E–positive LCH. Blood Adv 2023; 7 (18): 5246–57. DOI: 10.1182/bloodadvances.2022009067
9. Donadieu J., Piguet C., Bernard F., Barkaoui M., Ouache M., Bertrand Y., et al. A new clinical score for disease activity in Langerhans cell histiocytosis. Pediatr Blood Cancer 2004; 43 (7): 770–6. DOI: 10.1002/pbc.20160
10. Schemper M., Smith T.L. A note on quantifying follow-up in studies of failure time. Control Clin Trials 1996; 17 (4): 343–6. DOI: 10.1016/0197-2456(96)00075-x
11. Gadner H., Grois N., Pötschger U., Minkov M., Aricò M., Braier J., et al. Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood 2008; 111 (5): 2556–62. DOI: 10.1182/blood-2007-08-106211
12. Rosso D.A., Amaral D., Latella A., Chantada G., Braier J.L. Reduced doses of cladribine and cytarabine regimen was effective and well tolerated in patients with refractory-risk multisystem Langerhans cell histiocytosis. Br J Haematol 2016; 172 (2): 287–90. DOI: 10.1111/bjh.13475
13. Salek M., Oak N., Hines M.R., Maciaszek J.L., Tatevossian R., Sharma A., et al. Development of BRAFV600E-positive acute myeloid leukemia in a patient on long-term dabrafenib for multisystem LCH. Blood Adv 2022; 6 (8): 2681–4. DOI: 10.1182/bloodadvances.2021006229
14. Milne P., Bomken S., Nicholson J., et al. Lineage-Switch of Cells Harboring BRAFV600E Alleles in Patientswith high risk Lch Treated with Inhibitors. Pediatr Blood Cancer 2022; 69 (S1): 516.
15. Ottaviano M., Giunta E.F., Tortora M., Curvietto M., Attademo L., Bosso D., et al. BRAF Gene and Melanoma: Back to the Future. Int J Mol Sci 2021;22 (7): 3474. DOI: 10.3390/ijms22073474
16. Eder S.K., Schwentner R., Soussia P.B., Abagnale G., Attarbaschi A., Minkov M., et al. Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis. Blood Adv 2022; 6 (3): 970–5. DOI: 10.1182/bloodadvances.2021005442
17. Donadieu J., Larabi I.A., Tardieu M., Visser J., Hutter C., Sieni E., et al. Vemurafenib for refractory multisystem Langerhans cell histiocytosis in children: An international observational study. J Clin Oncol 2019; 37 (31): 2857–65. DOI: 10.1200/JCO.19.00456
18. Veys P.A., Nanduri V., Baker K.S., He W., Bandini G., Biondi A., et al. Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: Outcome by intensity of conditioning. Br J Haematol 2015; 169 (5): 711–8. DOI: 10.1111/bjh.13347
Pediatric Hematology/Oncology and Immunopathology. 2024; 23: 37-44
The results of a study on the effectiveness 37 and safety of treatment with vemurafenib and cytarabine/2-chloro-2′-deoxyadenosine combination in patients with Langerhans cell histiocytosis with BRAFV600E mutation
https://doi.org/10.24287/1726-1708-2024-23-1-37-44Abstract
Here, we report on a new treatment protocol for patients with BRAF-positive Langerhans cell histiocytosis (LCH). To achieve remission in the affected patients, we used vemurafenib (a targeted drug) in combination with cytarabine (Ara-C) and cladribine (2-CdA). The study included 27 patients: 18 children with multisystem LCH with risk organ involvement (RO+) and 9 – with multisystem LCH without risk organ involvement (RO–). The treatment started with a 28-day cycle of vemurafenib, with subsequent discontinuation. On Day 29, Аra-C + 2-СdA chemotherapy cycle № 1 was initiated. Vemurafenib treatment was again started on Day +1 after the Ara-C + 2-CdA cycle. The interval between the cycles was 28 days. Similarly, the next two Аra-C + 2-СdA chemotherapy cycles (№ 2 and № 3) were carried out. Then therapy with vemurafenib was stopped and 3 cycles of 2-CdA were administered. All the patients responded to the treatment quickly: on Day 28, disease activity score decreased from 15 to 2 in the RO+ group and from 4 to 0 in the RO– group. The two-year relapse-free survival in the RO+ group was 82 % (95 % confidence interval 66–100), and 89 % (95 % confidence interval 71–100) in the RO– patients. The overall survival in both groups was 100 %. Our study demonstrates the safety and effectiveness of the treatment with vemurafenib and intermediate-dose 2-CdA and Ara-C in children with multisystem RO+ and refractory LCH. This prospective non-randomized multicenter study was approved by the Independent Ethics Committee (Minutes No. 3e/1-18) 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. It is registered at clinicaltrials.gov under the number NCT03585686. The first patient was enrolled on 22 June 2018, the data collection was stopped on 30 April 2023.
References
1. Badalian-Very G., Vergilio J.-A., Degar B.A., MacConaill L.E., Brandner B., Calicchio M.L., et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 2010; 116 (11): 1919–23. DOI: 10.1182/blood-2010-04-279083
2. Bigenwald C., Le Berichel J., Wilk C.M., Chakraborty R., Chen S.T., Tabachnikova A., et al. BRAFV600E-induced senescence drives Langerhans cell histiocytosis pathophysiology. Nat Med 2021; 27 (5) 851. DOI: 10.1038/s41591-021-01304-x
3. Xiao Y., van Halteren A.G.S., Lei X., Borst J., Steenwijk E., de Wit T., et al. Bone marrow-derived myeloid progenitors as driver mutation carriers in high- And low-risk Langerhans cell histiocytosis. Blood 2020; 136 (19): 2188–199. DOI: 10.1182/blood.2020005209
4. Héritier S., Emile J.F., Barkaoui M.A., Thomas C., Fraitag S., Boudjemaa S., et al. BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy. J Clin Oncol 2016;34(25):3023–30. DOI: 10.1200/JCO.2015.65.9508
5. Donadieu J., Bernard F., van Noesel M., Barkaoui M., Bardet O., Mura R., et al. Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: Results of an international phase 2 study. Blood 2015; 126 (12): 1415–23. DOI: 10.1182/blood-2015-03-635151
6. Solopova G., Baidildina D., Suntsova E., et al. Front-line therapy of high-risk Langerhans cell histiocytosis with 2 chlordeoxyadenosine and cytosine arabinoside: an update of a single center experience. Pediatr Blood Cancer 2010; 55 (5).
7. Evseev D., Kalinina I., Raykina E., Osipova D., Abashidze Z., Ignatova A., et al. Vemurafenib provides a rapid and robust clinical response in pediatric Langerhans cell histiocytosis with the BRAF V600E mutation but does not eliminate low-level minimal residual disease per ddPCR using cell-free circulating DNA. Int J Hematol 2021; 114 (6): 725–34. DOI: 10.1007/s12185-021-03205-8
8. Evseev D., Osipova D., Kalinina I., Raykina E., Ignatova A., Lyudovskikh E., et al. Vemurafenib combined with cladribine and cytarabine results in durable remission of pediatric BRAF V600E–positive LCH. Blood Adv 2023; 7 (18): 5246–57. DOI: 10.1182/bloodadvances.2022009067
9. Donadieu J., Piguet C., Bernard F., Barkaoui M., Ouache M., Bertrand Y., et al. A new clinical score for disease activity in Langerhans cell histiocytosis. Pediatr Blood Cancer 2004; 43 (7): 770–6. DOI: 10.1002/pbc.20160
10. Schemper M., Smith T.L. A note on quantifying follow-up in studies of failure time. Control Clin Trials 1996; 17 (4): 343–6. DOI: 10.1016/0197-2456(96)00075-x
11. Gadner H., Grois N., Pötschger U., Minkov M., Aricò M., Braier J., et al. Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood 2008; 111 (5): 2556–62. DOI: 10.1182/blood-2007-08-106211
12. Rosso D.A., Amaral D., Latella A., Chantada G., Braier J.L. Reduced doses of cladribine and cytarabine regimen was effective and well tolerated in patients with refractory-risk multisystem Langerhans cell histiocytosis. Br J Haematol 2016; 172 (2): 287–90. DOI: 10.1111/bjh.13475
13. Salek M., Oak N., Hines M.R., Maciaszek J.L., Tatevossian R., Sharma A., et al. Development of BRAFV600E-positive acute myeloid leukemia in a patient on long-term dabrafenib for multisystem LCH. Blood Adv 2022; 6 (8): 2681–4. DOI: 10.1182/bloodadvances.2021006229
14. Milne P., Bomken S., Nicholson J., et al. Lineage-Switch of Cells Harboring BRAFV600E Alleles in Patientswith high risk Lch Treated with Inhibitors. Pediatr Blood Cancer 2022; 69 (S1): 516.
15. Ottaviano M., Giunta E.F., Tortora M., Curvietto M., Attademo L., Bosso D., et al. BRAF Gene and Melanoma: Back to the Future. Int J Mol Sci 2021;22 (7): 3474. DOI: 10.3390/ijms22073474
16. Eder S.K., Schwentner R., Soussia P.B., Abagnale G., Attarbaschi A., Minkov M., et al. Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis. Blood Adv 2022; 6 (3): 970–5. DOI: 10.1182/bloodadvances.2021005442
17. Donadieu J., Larabi I.A., Tardieu M., Visser J., Hutter C., Sieni E., et al. Vemurafenib for refractory multisystem Langerhans cell histiocytosis in children: An international observational study. J Clin Oncol 2019; 37 (31): 2857–65. DOI: 10.1200/JCO.19.00456
18. Veys P.A., Nanduri V., Baker K.S., He W., Bandini G., Biondi A., et al. Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: Outcome by intensity of conditioning. Br J Haematol 2015; 169 (5): 711–8. DOI: 10.1111/bjh.13347
