Pediatric Hematology/Oncology and ImmunopathologyPediatric Hematology/Oncology and ImmunopathologyВопросы гематологии/онкологии и иммунопатологии в педиатрии1726-17082414-9314Fund Doctors, Innovations, Science for Children51210.24287/1726-1708-2021-20-2-97-110ORIGINAL ARTICLESОРИГИНАЛЬНЫЕ СТАТЬИA hypodiploid karyotype in childhood B-cell precursor acute lymphoblastic leukemiaГиподиплоидный кариотип при острых лимфобластных лейкозах из В-линейных предшественников у детейhttps://orcid.org/0000-0002-2352-7716OlshanskayaYu. V.ОльшанскаяЮ. В.
Russian Federation

Yuliya V. Olshanskaya, cand. med. sci., Head of the Laboratory of Cytogenetics and Molecular Genetics

1 Samory Mashela St., Moscow 117997

Ольшанская Юлия Вячеславовна, канд. мед. наук, заведующая лабораторией цитогенетики и молекулярной генетики 117997, Москва, ул. Саморы Машела, 1

yuliaolshanskaya@gmail.comhttps://orcid.org/0000-0001-7755-0228SoldatkinaO. I.СолдаткинаО. И.
Russian Federation

1 Samory Mashela St., Moscow 117997

117997, Москва, ул. Саморы Машела, 1

NikitinE. N.НикитинЕ. Н.
Russian Federation

1 Samory Mashela St., Moscow 117997

117997, Москва, ул. Саморы Машела, 1

TimofeyevaN. M.ТимофееваН. М.
Russian Federation

1 Samory Mashela St., Moscow 117997

117997, Москва, ул. Саморы Машела, 1

https://orcid.org/0000-0002-1085-4646A.KazakovaA. N.КазаковаА. Н.
Russian Federation

1 Samory Mashela St., Moscow 117997

117997, Москва, ул. Саморы Машела, 1

https://orcid.org/0000-0003-3232-2322BydanovO. I.БыдановО. И.
Russian Federation

1 Samory Mashela St., Moscow 117997

117997, Москва, ул. Саморы Машела, 1

ZharikovaL. I.ЖариковаЛ. И.
Russian Federation

1 Samory Mashela St., Moscow 117997

117997, Москва, ул. Саморы Машела, 1

https://orcid.org/0000-0002-0889-6986PopovA. M.ПоповА. М.
Russian Federation

1 Samory Mashela St., Moscow 117997

117997, Москва, ул. Саморы Машела, 1

https://orcid.org/0000-0002-8951-1127ChervovaA. A.ЧервоваА. А.
Russian Federation

1 Samory Mashela St., Moscow 117997

117997, Москва, ул. Саморы Машела, 1

LagoykoS. N.ЛагойкоС. Н.
Russian Federation

1 Samory Mashela St., Moscow 117997

117997, Москва, ул. Саморы Машела, 1

https://orcid.org/0000-0001-9634-5828ZerkalenkovaE. A.ЗеркаленковаЕ. А.
Russian Federation

1 Samory Mashela St., Moscow 117997

117997, Москва, ул. Саморы Машела, 1

https://orcid.org/0000-0001-9670-3728RumyantsevaYu. V.РумянцеваЮ. В.
Russian Federation

1 Samory Mashela St., Moscow 117997

117997, Москва, ул. Саморы Машела, 1

KarachunskiyA. I.КарачунскийА. И.
Russian Federation

1 Samory Mashela St., Moscow 117997

117997, Москва, ул. Саморы Машела, 1

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of the Russian FederationФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Минздрава России22052021202971102105202121052021Copyright ©; 2021, «D. Rogachev NMRCPHOI»Copyright ©; 2021, ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России2021«D. Rogachev NMRCPHOI»ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава Россииhttps://creativecommons.org/licenses/by/4.0https://hemoncim.com/jour/article/view/512

The detection of genetic markers associated with poor prognosis is crucial to the selection of an appropriate treatment plan for B-cell precursor acute lymphoblastic leukemia (BCP-ALL). A hypodiploid karyotype in patients with BCP-ALL has an unfavorable impact and serves as a criterion for the stratification of patients into a high-risk group. However, the survival rates of patients with a hypodiploid karyotype remain poor. Russian treatment protocols for childhood acute lymphoblastic leukemia do not include a hypodiploid karyotype in risk stratification criteria. In order to determine the prognostic value of a hypodiploid karyotype and the clinical characteristics of BCP-ALL in patients with a hypodiploid karyotype, we analyzed the survival rates of 2,700 patients included in a multicenter study. Our study was approved by the Independent Ethics Committee and the Scientific Council of the D. Rogachev NMRCPHOI of the Ministry of Healthcare of the Russian Federation. All patients underwent karyotyping and fluorescence in situhybridization (FISH) testing. A hypodiploid karyotype was detected in 27 patients. Eighteen out of 27 patients had a hypoploid clone (according to karyotyping results), 2 patients had a doubled near-haploid clone (according to karyotyping and FISH results); in 7 patients with a normal karyotype or in the absence of mitosis, hypodiploidy was determined only by FISH test. BCP-ALL with hypodiploidy is usually associated with increased WBC count at disease onset. The median WBC count in the study group was 24.2 (3.4–206.0) × 109/l vs 10.3 (0.2–1290.0) × 109/l in the control group. The number of patients with initial leukocytosis < 30 × 109/l in the study group was significantly lower than in the control group (p< 0.062). Remission was achieved in 26/27 patients. The event-free survival rates in patients with hypodiploidy were significantly lower than in those without hypodiploidy: 50 ± 11% vs 72 ± 8% (p< 0.0001). The overall survival was 64 ± 10% and 90 ± 1%, respectively (p< 0.0001). The cumulative incidence of relapse in patients with a hypodiploid karyotype was higher (42.6 ± 10.9%) than in the controls (22.3 ± 8.1%) (p< 0.0001). The patients who received more intense treatment for intermediate- and high-risk groups showed better survival rates than those in the standard-risk group: 62 ± 13% vs 40 ± 15% (р= 0.59); the cumulative incidence of relapse according to the risk group was 26.4 ± 12.1% and 60 ± 16.9%, respectively (р= 0.19).The highest risk of relapse was observed in a group that included patients with near-haploidy and low hypodiploidy (26–39 chromosomes; 52.9 ± 14.4%). The event-free survival in this group was 36 ± 13%. The results of treatment of patients with BCP-ALL and hypodiploidy according to the national guidelines turned out to be comparable to the international ones. Patients with BCP-ALL and hypodiploidy should be initially stratified to the most intense treatment arm. In order to identify patients with hypoploidy, standard karyotyping is required; where needed, it can be supplemented by FISH analysis

Выявление генетических маркеров неблагоприятного прогноза имеет принципиальное значение для выбора тактики терапии острых лимфобластных лейкозов из В-линейных предшественников (ВП-ОЛЛ). Гиподиплоидный кариотип при ВП-ОЛЛ имеет крайне неблагоприятное значение и является критерием стратификации пациентов в группу высокого риска. Несмотря на это, показатели выживаемости пациентов с гиподиплоидным кариотипом остаются невысокими. В отечественных протоколах терапии острых лимфобластных лейкозов у детей гиподиплоидный кариотип не входит в критерии стратификации пациентов на группы риска. С целью определить прогностическое значение и клинические характеристики ВП-ОЛЛ с гиподиплоидным кариотипом нами были проанализированы показатели выживаемости 2700 пациентов, включенных в многоцентровое исследование. Данное исследование одобрено независимым этическим комитетом и утверждено решением ученого совета ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России. Всем больным было проведено исследование методами кариотипирования и флуоресцентной in situгибридизации (FISH). У 27 пациентов был выявлен гиподиплоидный кариотип. У 18 из 27 больных имел место гипоплоидный клон по данным кариотипирования, у 2 – удвоение окологаплоидного клона по данным кариотипирования и FISH, у 7 пациентов с нормальным кариотипом или отсутствием митозов гиподиплоидия была установлена только на основании результатов исследования методом FISH. Для ВП-ОЛЛ с гиподиплоидией характерно повышенное число лейкоцитов в дебюте заболевания. Медиана количества лейкоцитов составила 24,2 (3,4–206,0) × 109/л против 10,3 (0,2–1290,0) × 109/л в контрольной группе. Число пациентов с инициальным лейкоцитозом менее 30 × 109/л было достоверно ниже, чем в контрольной группе (p< 0,0062). Ремиссия была достигнута у 26 из 27 больных. Бессобытийная выживаемость пациентов с гиподиплоидией была существенно ниже, чем в группе больных без гиподиплоидии: 50 ± 11% против 72 ± 8% (p< 0,0001). Общая выживаемость составила 64 ± 10% и 90 ± 1% соответственно (p< 0,0001). Кумулятивная вероятность развития рецидива при гиподиплоидном кариотипе составила 42,6 ± 10,9% против 22,3 ± 8,1% в контрольной группе (p< 0,0001). Пациенты, получавшие более интенсивную терапию согласно группам промежуточного и высокого риска, имели более высокие показатели выживаемости, нежели больные из группы стандартного риска: 62 ± 13% против 40 ± 15% (р= 0,59), кумулятивная вероятность развития рецидива в зависимости от группы риска составила 26,4 ± 12,1% и 60 ± 16,9% соответственно (р= 0,19). Наибольший риск развития рецидива наблюдался в группе, объединяющей пациентов с окологаплоидным набором хромосом и низкой гиподиплоидией (26–39 хромосом; 52,9 ± 14,4%), бессобытийная выживаемость в этой группе составила 36 ± 13%. Результаты терапии пациентов с ВП-ОЛЛ и гиподиплоидией по отечественному протоколу оказались сравнимы с общемировыми. Пациенты с ВП-ОЛЛ и гиподиплоидией изначально должны быть стратифицированы на наиболее интенсивную ветвь терапии. Для выявления гиподиплоидии обязательно выполнение стандартного кариотипирования, при необходимости дополняемого исследованием методом FISH.

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