леналидомид

Перспективы применения иммуномодулирующих препаратов и модуляторов цереблон Е3-лигазы в лечении множественной миеломы

ОБЗОРЫ , , , , ,

С.В. Семочкин1,2

1 МНИОИ им. П.А. Герцена — филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2-й Боткинский пр-д, д. 3, Москва, Российская Федерация, 125284

2 ФГАОУ ВО «РНИМУ им. Н.И. Пирогова» Минздрава России, ул. Островитянова, д. 1, Москва, Российская Федерация, 117997

Для переписки: Сергей Вячеславович Семочкин, д-р мед. наук, профессор, 2-й Боткинский пр-д, д. 3, Москва, Российская Федерация, 125284; e-mail: semochkin_sv@rsmu.ru

Для цитирования: Семочкин С.В. Перспективы применения иммуномодулирующих препаратов и модуляторов цереблон Е3-лигазы в лечении множественной миеломы. Клиническая онкогематология. 2023;16(3):229–41.

DOI: 10.21320/2500-2139-2023-16-3-229-241

РЕФЕРАТ

За последние десятилетия прогресс в лечении множественной миеломы (ММ) связан с лучшим пониманием биологии этого заболевания и внедрением в практику новых классов лекарственных средств, таких как иммуномодулирующие препараты (IMiD), ингибиторы протеасом (ИП) и моноклональные антитела (МАТ). Современные IMiD (леналидомид, помалидомид) являются производными талидомида, которые, несмотря на сходство химической структуры, проявляют лишь относительную перекрестную резистентность. Леналидомид — иммуномодулятор 2-го поколения с высокой противоопухолевой активностью и благоприятным профилем безопасности. В 2006 г. применение леналидомида в комбинации с дексаметазоном (схема Rd) было одобрено FDA (США) для лечения рецидивов/рефрактерной MM, а через 9 лет, в 2015 г., — для впервые диагностированной ММ. В 2015–2019 гг. для лечения рецидивов MM были разработаны схемы, построенные на комбинации Rd с бортезомибом (VRd), карфилзомибом (KRd), иксазомибом (IRd), элотузумабом (ERd) и даратумумабом (DRd), — так называемые триплеты. Помалидомид — препарат 3-го поколения, используемый у пациентов с рефрактерностью к леналидомиду. Для лечения пациентов с рецидивами/рефрактерной ММ, которые получили не менее двух линий терапии, включавших леналидомид и бортезомиб, в практику внедрены схемы из трех препаратов на основе помалидомида и дексаметазона в комбинации с элотузумабом (EPd), изатуксимабом (Isa-Pd) и даратумумабом (DPd). В 2010 г. была открыта молекулярная мишень действия IMiD — белок цереблон (CRBN), входящий в ферментный комплекс CRBN E3-лигазы. Понимание данного механизма позволило создать новое семейство производных талидомида, получившее название модуляторов CRBN E3-лигазы (CELMoD). Два препарата этой группы (ибердомид, мезигдомид) в исследованиях I–II фазы продемонстрировали обнадеживающую активность при ММ с рефрактерностью к трем классам противоопухолевых препаратов (IMiD, ИП и анти-CD38 МАТ). Фокус представленного обзора направлен на проспективные исследования IMiD и CELMoD на разных этапах лечения ММ.

Ключевые слова: множественная миелома, иммуномодулирующие препараты, модуляторы цереблон Е3-лигазы, леналидомид, помалидомид, ибердомиб, мезигдомид.

Получено: 25 января 2023 г.

Принято в печать: 28 мая 2023 г.

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Статистика Plumx русский

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Эффективность и токсичность индукционной терапии у пациентов с впервые диагностированным системным AL-амилоидозом: результаты проспективного одноцентрового клинического исследования

КЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯ , , , ,

И.Г. Рехтина, В.A. Хышова, М.В. Соловьев, Л.П. Менделеева

ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167

Для переписки: Виктория Александровна Хышова, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167; тел.: +7(983)413-02-00; e-mail: viktoria2102@icloud.com

Для цитирования: Рехтина И.Г., Хышова В.A., Соловьев М.В., Менделеева Л.П. Эффективность и токсичность индукционной терапии у пациентов с впервые диагностированным системным AL-амилоидозом: результаты проспективного одноцентрового клинического исследования. Клиническая онкогематология. 2023;16(2):166–73.

DOI: 10.21320/2500-2139-2023-16-2-166-173

РЕФЕРАТ

Цель. Оценить результаты индукционной терапии у пациентов с впервые диагностированным системным AL-амилоидозом (AL-А).

Материалы и методы. В проспективное одноцентровое клиническое исследование включено 60 пациентов (32 женщины, 28 мужчин) с впервые диагностированным системным AL-A I–IIIA стадии. Медиана возраста составила 59 лет (диапазон 34–74 года). В качестве терапии первой линии у 57 пациентов применялась программа BorСyDex (бортезомиб, циклофосфамид, дексаметазон). У 3 пациентов лечение проводилось по схеме RCd (леналидомид, циклофосфамид, дексаметазон). При недостаточной эффективности или выраженной токсичности пациентов (n = 24) переводили на вторую линию индукционной терапии леналидомидом или мелфаланом в сочетании с дексаметазоном. Высокодозная химиотерапия с трансплантацией аутологичных гемопоэтических стволовых клеток (аутоТГСК) выполнена 11 (18 %) пациентам.

Результаты. Целевая степень гематологического ответа (полная ремиссия [ПР] и очень хорошая частичная ремиссия [охЧР]) на терапию BorCyDex достигнута у 62 % пациентов. В результате всех линий индукционной терапии, включая аутоТГСК, целевая степень ответа повысилась до 69 %, в т. ч. у 7/51 (14 %) — строгая ПР (сПР), у 8/51 (16 %) — ПР, у 20/51 (39 %) — охЧР. Почечный ответ после терапии BorCyDex констатирован у 10/38 (26 %) пациентов, сердечный — у 6/31 (19 %), печеночный — у 4/5 (80 %). После всех линий терапии с аутоТГСК органный ответ (по ≥ 1 органа) наблюдался у 15/46 (32 %) больных. Клинический ответ отмечался у всех пациентов при достижении сПР, у 67 % — при ПР, у 47 % — при охЧР (p = 0,04). При меньшей степени гематологического ответа клинического улучшения не наблюдалось. Медиана безрецидивной выживаемости (без признаков гематологического и клинического прогрессирования) при сроке наблюдения 36 мес. не достигнута. 3-летняя общая выживаемость составила 80 %. Летальность во время индукционной терапии составила 10 % (умерло 6 пациентов, в т. ч. 2 на фоне инфекции COVID-19). Планируемые 6 курсов BorCyDex удалось провести лишь у 13 (23 %) из 55 пациентов. Во время индукционной терапии по программе BorCyDex умерло 4 пациента. Терапия была досрочно прекращена у 7 (12 %) из 55 больных ввиду ее неэффективности, у 22 (39 %) — из-за развития тяжелой периферической и автономной полинейропатии. У 9/55 (16 %) пациентов отмечалось резкое нарастание NT-proBNP при достигнутом гематологическом ответе, что сопровождалось сердечно-сосудистыми осложнениями и послужило причиной отмены противоопухолевого лечения.

Заключение. Низкая обратимость органных дисфункций остается краеугольным камнем в проблеме лечения AL-A. Глубина гематологического ответа (достижение ПР) имеет основополагающее значение для достижения клинического эффекта. Полученные данные подтвердили высокую токсичность схемы BorCyDex у больных AL-A. Несмотря на достигнутые успехи в терапии AL-А, связанные с применением ингибиторов протеасом, необходимы новые, более эффективные подходы к лечению этого заболевания.

Ключевые слова: AL-амилоидоз, бортезомиб, леналидомид, эффективность, токсичность.

Получено: 31 октября 2022 г.

Принято в печать: 3 марта 2023 г.

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Статистика Plumx русский

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Практические аспекты применения карфилзомиба при множественной миеломе

НОВЫЕ ПРЕПАРАТЫ , , , , , ,

С.В. Семочкин1,2, Г.Н. Салогуб3, С.С. Бессмельцев4, К.Д. Капланов5

1 ФГБОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России, ул. Островитянова, д. 1, Москва, Российская Федерация, 117997

2 ГБУЗ «Городская клиническая больница № 52 ДЗМ», ул. Пехотная, д. 3, Москва, Российская Федерация, 123182

3 ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341

4 ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА», ул. 2-я Советская, д. 16, Санкт-Петербург, Российская Федерация, 191024

5 ГБУЗ «Волгоградский областной клинический онкологический диспансер № 1», ул. Землячки, д. 78, Волгоград, Российская Федерация, 400138

Для переписки: Сергей Вячеславович Семочкин, д-р мед. наук, профессор, ул. Пехотная, д. 3, Москва, Российская Федерация, 123182; тел./факс: +7(495)369-00-36; e-mail: semochkin_sv@rsmu.ru

Для цитирования: Семочкин С.В., Салогуб Г.Н., Бессмельцев С.С., Капланов К.Д. Практические аспекты применения карфилзомиба при множественной миеломе. Клиническая онкогематология. 2019;12(1):21–31.

DOI: 10.21320/2500-2139-2019-12-1-21-31

РЕФЕРАТ

Карфилзомиб (Кипролис®, Amgen) — ингибитор протеасомы второго поколения, способный ковалентно связывать и необратимо ингибировать химотрипсин-подобную активность протеасомы 20S. Препарат одобрен в 2016 г. в России в качестве монотерапии при рецидивирующей и рефрактерной множественной миеломе (ММ), а также в сочетании с леналидомидом и дексаметазоном (схема KRd) или только дексаметазоном (Kd) для лечения пациентов с рецидивами ММ, получивших как минимум одну линию предшествующей терапии. В настоящем обзоре представлены механизм действия, клиническая эффективность и профиль нежелательных явлений карфилзомиба по данным исследований II фазы (монотерапия) и двум ключевым рандомизированным исследованиям III фазы (комбинация карфилзомиба с другими препаратами). В исследовании ASPIRE было продемонстрировано, что добавление карфилзомиба к комбинации леналидомида и дексаметазона (KRd) привело к значительному улучшению выживаемости без прогрессирования (ВБП) по сравнению с исходной схемой Rd (медиана 26,3 vs 17,6 мес.; отношение рисков [ОР] 0,69; p = 0,0001). Медиана общей выживаемости (ОВ) составила 48,3 мес. (95%-й доверительный интервал [95% ДИ] 42,4–52,8 мес.) для KRd vs 40,4 мес. (95% ДИ 33,6–44,4 мес.) для Rd (ОР 0,79; p = 0,0045). В исследовании ENDEAVOR показано, что терапия по схеме карфилзомиб + дексаметазон (Kd) по сравнению с комбинацией бортезомиба и дексаметазона (Vd) также значительно улучшает ВБП (медиана 18,7 vs 9,4 мес.; ОР 0,53; p < 0,0001) и ОВ (47,6 vs 40 мес.; ОР 0,79; p = 0,010). В обзоре обсуждаются особенности применения карфилзомиба в особых группах пациентов (с почечной недостаточностью, высоким цитогенетическим риском).

Ключевые слова: карфилзомиб, ингибитор протеасомы, леналидомид, бортезомиб, множественная миелома, почечная недостаточность, цитогенетический риск.

Получено: 12 мая 2018 г.

Принято в печать: 28 декабря 2018 г.

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Заготовка гемопоэтических стволовых клеток у больных множественной миеломой: влияние предшествующей аутоТГСК терапии леналидомидом и режима мобилизации

ТРАНСПЛАНТАЦИЯ КОСТНОГО МОЗГА , , , , , ,

И.И. Кострома, А.А. Жернякова, Ж.В. Чубукина, И.М. Запреева, С.А. Тиранова, А.В. Сельцер, Н.Ю. Семенова, С.С. Бессмельцев, А.В. Чечеткин, С.В. Грицаев

ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА», ул. 2-я Советская, д. 16, Санкт-Петербург, Российская Федерация, 191024

Для переписки: Иван Иванович Кострома, канд. мед. наук, ул. 2-я Советская, д. 16, Санкт-Петербург, Российская Федерация, 191024; тел.: +7(921)784-82-82; e-mail: obex@rambler.ru

Для цитирования: Кострома И.И., Жернякова А.А., Чубукина Ж.В. и др. Заготовка гемопоэтических стволовых клеток у больных множественной миеломой: влияние предшествующей аутоТГСК терапии леналидомидом и режима мобилизации. Клиническая онкогематология. 2018;11(2):192–7.

DOI: 10.21320/2500-2139-2018-11-2-192-197

РЕФЕРАТ

Актуальность. Своевременное приживление трансплантата — одно из условий эффективности трансплантации аутологичных гемопоэтических стволовых клеток (аутоТГСК) у больных множественной миеломой (ММ). Быстрое и надежное восстановление кроветворения связано с количеством клеток CD34+ в трансплантате. Несмотря на выделение показателей, сопряженных с низкой клеточностью аутотрансплантата, внедрение в практику новых лекарственных средств и режимов мобилизации ГСК обосновывает целесообразность определения их возможного влияния на качество трансплантата.

Цель. Выделить факторы, связанные с низкой эффективностью аутотрансплантата у больных ММ, и оценить прогностическую значимость леналидомида, назначаемого в индукционный период, и винорелбина в составе режима мобилизации.

Материалы и методы. Проведен ретроспективный анализ результатов заготовки аутотрансплантата у 68 больных ММ с применением двух режимов мобилизации: циклофосфамид 3 г/м2 с гранулоцитарным колониестимулирующим фактором (Г-КСФ) и винорелбин 30 мг/м2 с Г-КСФ. Цель мобилизации — заготовка не менее 2–4 × 106 клеток CD34+/кг массы тела. Подсчет клеток CD34+ выполняли с помощью 4-цветного анализа на лазерном проточном цитометре Cytomics FC 500.

Результаты. Не выявлено влияния возраста и иммунохимического варианта ММ на количество клеток CD34+ в трансплантате. Обнаружена тенденция к снижению числа CD34+ при предшествующем приеме леналидомида: 4,1 × 106/кг vs 7,76 × 106/кг без терапии иммуномодуляторами (р = 0,066). Установлено значимое увеличение количества клеток CD34+ при включении в режим мобилизации циклофосфамида по сравнению с винорелбином — 6,8 × 106/кг vs 3,96 × 106/кг соответственно (р = 0,022).

Заключение. Снижение числа клеток CD34+ в аутотрансплантате больных ММ, получавших леналидомид в период до заготовки аутоГСК, и более низкая мобилизационная активность винорелбина дают основание для дифференцированного выбора режима мобилизации. Винорелбин может быть рекомендован больным, у которых планируется однократная аутоТГСК: лицам пожилого возраста или с полным ответом. В случае значительной терапии леналидомидом, предшествующей аутоТГКС, предпочтительнее использовать промежуточные дозы циклофосфамида.

Ключевые слова: аутоТГСК, множественная миелома, режим мобилизации, циклофосфамид, винорелбин, леналидомид, предикторы.

Получено: 29 ноября 2017 г.

Принято в печать: 9 февраля 2018 г.

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Множественная миелома (лечение рецидивов и рефрактерных форм): обзор литературы и собственные данные. Часть III

КЛИНИКА, ДИАГНОСТИКА И ЛЕЧЕНИЕ ЛИМФОИДНЫХ ОПУХОЛЕЙ , , , , , , , , , , ,

С.С. Бессмельцев

ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург, Российская Федерация

РЕФЕРАТ

Использование новых подходов в лечении рецидивов/рефрактерных форм множественной миеломы (ММ) привело к существенному увеличению общей выживаемости больных, достижению качественного ответа и более длительной ремиссии по сравнению с пациентами, получавшими стандартную химиотерапию. Эти изменения связаны главным образом с применением новых препаратов: бортезомиба, талидомида, леналидомида, каждый из которых обладает выраженной противомиеломной активностью. Бортезомиб, талидомид и леналидомид используются в комбинации как с химиотерапевтическими препаратами, так и друг с другом, что существенно повышает эффективность лечения больных ММ. Однако, если больные не отвечают на бортезомиб и иммуномодуляторы, прогноз ухудшается. В настоящее время число препаратов, которые используются при ММ, достаточно большое, причем спектр их все более расширяется. Тем не менее результаты лечения больных с рецидивами/рефрактерными формами ММ не вполне удовлетворительные, что свидетельствует о трудностях разработки эффективных лекарственных средств. Появилось большое количество препаратов второго и третьего поколений, которые становятся все более доступными для клинического применения. Проводятся клинические исследования I, II и III фаз по оценке эффективности карфилзомиба, помалидомида, вориностата, панобиностата, ромидепсина, перифосина, танеспимицина, бендамустина и элотузумаба при рецидивах/рефрактерных формах ММ. В обзоре представлены современные подходы к ведению пациентов с рецидивами и рефрактерным течением ММ, основанные на результатах клинических исследований и собственных данных, целью которых было оптимизировать результаты лечения. Представлена эффективность различных классов новых лекарственных средств, обсуждены все «за» и «против», полученные в доклинических и клинических исследованиях. Подробно освещены побочные эффекты новых препаратов.

Ключевые слова: множественная миелома, рецидив, рефрактерное течение, бортезомиб, талидомид, леналидомид, карфилзомиб, помалидомид, лечение, полная ремиссия, общая выживаемость, нейропатия.

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Множественная миелома (лечение первичных больных): обзор литературы и собственные данные. Часть II

КЛИНИКА, ДИАГНОСТИКА И ЛЕЧЕНИЕ ЛИМФОИДНЫХ ОПУХОЛЕЙ , , , , , , , ,

С.С. Бессмельцев

ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург, Российская Федерация

РЕФЕРАТ

В последние десятилетия в результате широкого применения аутологичной трансплантации гемопоэтических стволовых клеток (аутоТГСК) и новых, весьма эффективных лекарственных средств существенно улучшились показатели выживаемости пациентов с множественной миеломой (ММ) в возрасте до 65 лет (молодые пациенты). У пациентов с ММ в возрасте старше 65 лет традиционно используется комбинация мелфалана и преднизолона (MP). Внедрение новых препаратов, в частности иммуномодулирующих средств (ИМС) и ингибиторов протеасомы, значительно изменило подходы к лечению этого заболевания. У больных с впервые выявленной ММ была изучена эффективность многих двух-, трех- и четырехкомпонентных комбинаций. Установлено, что достижение полной ремиссии (ПР) служит независимым предиктором длительной выживаемости (ВБП, ОВ). Результаты проведенных проспективных исследований свидетельствуют о том, что для достижения высокого значения ПР и увеличения ее продолжительности необходимо индукционное лечение с использованием трехкомпонентных режимов, содержащих бортезомиб или иммуномодуляторы, с последующей аутоТГСК, консолидацией/поддерживающей терапией ИМС или ингибиторами протеасомы. В преобладающем большинстве случаев пожилые пациенты не являются кандидатами на аутоТГСК. Внедрение в лечебную практику новых препаратов — талидомида, бортезомиба, леналидомида — значительно улучшило результаты лечения этих больных. Программы MP + талидомид (MPT), MP + бортезомиб (VMP) и MP + леналидомид с последующей поддерживающей терапией леналидомидом (MPR-R) в настоящее время рассматриваются в качестве новых стандартов лечения пожилых пациентов с ММ. Прогноз ММ зависит от множества факторов, которые следует учитывать до начала терапии. В обзоре представлены современные подходы к ведению пациентов с впервые выявленной ММ, основанные на проводимых в настоящее время исследованиях, цель которых заключается в оптимизации результатов лечения.

Ключевые слова: множественная миелома, бортезомиб, талидомид, леналидомид, лечение, полная ремиссия, общая выживаемость, нейропатия, аутологичная трансплантация гемопоэтических стволовых клеток.

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