Прогностическое значение генетических маркеров в оценке эффективности индукционной терапии, включающей аутологичную трансплантацию гемопоэтических стволовых клеток, у больных множественной миеломой

Е.Л. Назарова, Н.В. Минаева, М.Н. Хоробрых, Э.Е. Сухорукова, В.И. Шардаков, И.В. Парамонов, Н.А. Зорина

ФГБУН «Кировский научно-исследовательский институт гематологии и переливания крови ФМБА», Красноармейская ул., д. 72, Киров, Российская Федерация, 610027

Для переписки: Елена Львовна Назарова, канд. мед. наук, Красноармейская ул., д. 72, Киров, Российская Федерация, 610027; e-mail: nazarova@niigpk.ru

Для цитирования: Назарова Е.Л., Минаева Н.В., Хоробрых М.Н. и др. Прогностическое значение генетических маркеров в оценке эффективности индукционной терапии, включающей аутологичную трансплантацию гемопоэтических стволовых клеток, у больных множественной миеломой. Клиническая онкогематология. 2018;11(1):54-69.

DOI: 10.21320/2500-2139-2018-11-1-54-69


РЕФЕРАТ

Цель. Установить значение полиморфизма генов иммунного ответа в оценке результатов лечения больных множественной миеломой (ММ) с использованием высокодозной химиотерапии (ВДХТ) и аутологичной трансплантации гемопоэтических стволовых клеток (аутоТГСК).

Методы. В исследование включено 20 больных ММ: 8 мужчин и 12 женщин с медианой возраста 51,5 года (диапазон 32–67 лет). Клинико-лабораторное обследование проводилось до начала режима кондиционирования высокими дозами мелфалана (200 мг/м2). В соответствии с достигнутым противоопухолевым ответом на индукционную терапию выделено три группы больных: 1-я — с частичной ремиссией (= 7); 2-я — с очень хорошей частичной ремиссией (= 9); 3-я — с полной ремиссией (= 4). Генотипирование 20 полиморфных локусов 14 генов иммунного ответа выполняли методом ПЦР.

Результаты. Группу пациентов с очень хорошей частичной ремиссией отличало от группы пациентов с полным ответом на индукционную терапию отсутствие мутантных гомозигот АА гена IL10 в полиморфном локусе G-1082A, а от группы с частичным ответом на индукционную терапию — мутантных гомозигот ТТ гена TLR6 (Ser249Pro). У пациентов с более выраженным мукозитом (II–III) в отличие от больных с мукозитом более легкой степени тяжести (0–I) характеризовали недостаток мутантных гомозигот СС гена IL1β в позиции G-1473C и меньшее число носителей гетеро- и гомозиготных гаплотипов (CT+TT) гена IL10 с мутантным аллелем T в точке мутации C-819T. При многофакторном анализе генетическим маркером, статистически значимо влияющим на показатели общей выживаемости у больных ММ после ВДХТ и аутоТГСК, является полиморфный статус генов IL10 (G-1082A), TNF (G-308A), TLR4 (Thr399Ile) и TLR9 в полиморфных локусах Т-1237С и А2848. На показатели выживаемости без прогрессирования дополнительно воздействовал мутационный статус генов IL1β (T-511C), IL2 (T-330G), IL6 (C-174G), CD14 (C-159T), TLR3 (Phe421Leu) и TLR4 (Asp299Gly).

Заключение. Полученные нами данные свидетельствуют о взаимосвязи 14 полиморфизмов 10 генов иммунного ответа с непосредственными результатами индукционной терапии, а также со степенью тяжести мукозита в ранний посттрансплантационный периоде, показателями общей и выживаемости без прогрессирования у больных ММ. Небольшой объем выборки требует дальнейших исследований для подтверждения выявленных тенденций. Предложенная гипотеза о влиянии полиморфизма генов иммунного ответа на прогноз заболевания может служить важным звеном при формировании индивидуализированных подходов к терапии ММ.

Ключевые слова: множественная миелома, полиморфизм генов, иммунный ответ, цитокины, Toll-подобные рецепторы, высокодозная химиотерапия, аутологичная трансплантация гемопоэтических стволовых клеток.

Получено: 18 августа 2017 г.

Принято в печать: 7 ноября 2017 г.

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