Практические аспекты применения карфилзомиба при множественной миеломе

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; = 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; = 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; < 0,0001) и ОВ (47,6 vs 40 мес.; ОР 0,79; = 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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ЛИТЕРАТУРА

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Эволюция противоопухолевой терапии и ее влияние на суррогатные факторы прогноза множественной миеломы

А.С. Лучинин1, С.В. Семочкин2, Н.В. Минаева1, Н.М. Поздеев1, И.В. Парамонов1

1 ФГБУН «Кировский НИИ гематологии и переливания крови ФМБА», ул. Красноармейская, д. 72, Киров, Российская Федерация, 610027

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

Для переписки: Александр Сергеевич Лучинин, ул. Красноармейская, д. 72, Киров, Российская Федерация, 610027; тел.: +7(919)506-87-86; e-mail: glivec@mail.ru

Для цитирования: Лучинин А.С., Семочкин С.В., Минаева Н.В. и др. Эволюция противоопухолевой терапии и ее влияние на суррогатные факторы прогноза множественной миеломы. Клиническая онкогематология. 2018;11(2):175-81.

DOI: 10.21320/2500-2139-2018-11-2-175-181


РЕФЕРАТ

Цель. Оценить прогностическое значение отдельных суррогатных клинико-лабораторных маркеров у пациентов со множественной миеломой (MM) при проведении современной терапии.

Материалы и методы. В анализ включено 567 пациентов (215 мужчин и 352 женщины), жителей Кировской области, с впервые диагностированной ММ в период с 1.01.1994 г. по 31.12.2016 г. Медиана возраста составила 64 года (диапазон 29–90 лет). Пациенты разделены на две группы: 1-ю группу составили больные, получавшие лечение в 1994–2005 гг. (n = 269), 2-ю — в 2006–2016 гг. (n = 298). Влияние отдельных факторов на общую выживаемость (ОВ) оценивали с помощью многофакторного логистического регрессионного анализа по методу Кокса.

Результаты. В период 2006–2016 гг. доля пациентов, получавших традиционную химиотерапию, снизилась с 78,4 до 32,5 %. В то же время увеличилось количество больных, получающих бортезомиб-содержащие схемы, с 1,9 до 56,3 % и протоколы с трансплантацией аутологичных гемопоэтических стволовых клеток (аутоТГСК) с 1,4 до 14,0 %. Медиана ОВ в 1994–2005 гг. составила 27 мес. Этот показатель увеличился до 55 мес. в 2006–2016 гг. В сравниваемых десятилетиях 5-летняя ОВ увеличилась с 21 (95%-й доверительный интервал [95% ДИ] 17–27 %) до 47 % (95% ДИ 39–55 %) соответственно (отношение рисков [ОР] 0,51; 95% ДИ 0,41–0,64; < 0,0001). У пациентов, получавших лечение в 2006–2016 гг. с использованием бортезомиб-содержащих программ, медиана ОВ увеличилась до 73 мес. в сравнении с 27 мес. в 1994–2005 гг. При выполнении аутоТГСК у пациентов ≤ 65 лет медиана ОВ не достигнута, а в группе больных без аутоТГСК медиана ОВ составила 54 мес.

Выводы. Суррогатные прогностические маркеры, такие как возраст старше 65 лет, уровень гемоглобина < 100 г/л, β2-микроглобулина ≥ 6 мг/л, креатинина сыворотки ≥ 177 мкмоль/л и III стадия по системам ISS и Durie—Salmon, остаются неблагоприятными предикторами выживаемости при ММ.

Ключевые слова: множественная миелома, прогноз, бортезомиб, аутоТГСК, общая выживаемость.

Получено: 21 декабря 2017 г.

Принято в печать: 25 февраля 2018 г.

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ЛИТЕРАТУРА

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Бортезомиб в программной терапии рецидивов и рефрактерных форм острого лимфобластного лейкоза у детей

Н.А. Батманова, М.А. Шервашидзе, А.В. Попа, Л.Ю. Гривцова, И.Н. Серебрякова, Г.Л. Менткевич

ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» Минздрава России, Каширское ш., д. 24, Москва, Российская Федерация, 115478

Для переписки: Наталья Андреевна Батманова, Каширское ш., д. 24, Москва, Российская Федерация, 115478; тел.: +7(925)321-26-42; e-mail: Batmanova_nataly@mail.ru

Для цитирования: Батманова Н.А., Шервашидзе М.А., Попа А.В. и др. Бортезомиб в программной терапии рецидивов и рефрактерных форм острого лимфобластного лейкоза у детей. Клиническая онкогематология. 2017;10(3):381–9.

DOI: 10.21320/2500-2139-2017-10-3-381-389


РЕФЕРАТ

Актуальность и цели. Несмотря на существенные успехи в лечении острого лимфобластного лейкоза (ОЛЛ) у детей, рецидивы и рефрактерность к стандартной химиотерапии — основная причина неудач в лечении данной категории больных. Включение бортезомиба в программную терапию рецидивов ОЛЛ с целью изменить чувствительность бластных клеток, возможно, станет одним из путей излечения пациентов. Цель — оценить эффективность и токсичность противорецидивных протоколов ALL REZ BFM 95/96 без включения бортезомиба и COG AALL07P1 с включением бортезомиба при рецидивах и рефрактерных ОЛЛ у детей.

Материалы и методы. В исследование включено 54 ребенка с подтвержденным рецидивом ОЛЛ различных локализаций. С 1995 по 2011 г. лечение по протоколу ALL REZ BFM 95/96 без бортезомиба проведено 26 больным. С 2011 по 2016 г. лечение по программе COG AALL07P1 c бортезомибом получило 28 детей.

Результаты. Непосредственная эффективность лечения была существенно выше у больных, получивших лечение по программе с бортезомибом, — 85,7 vs 57,6 % после индукционной химиотерапии по протоколу ALL REZ BFM 95/96. При оценке отдаленных результатов лечения (безрецидивная, бессобытийная, общая выживаемость) между группами больных значимых различий не выявлено. Бессобытийная выживаемость больных с изолированными костномозговыми рецидивами на срок 2 года составила 20,3 ± 17,5 %. Переносимость программы была приемлемой, осложнения развивались в период миелосупрессии и не были связаны с введением бортезомиба.

Заключение. Интенсификация индукционной химиотерапии при повторной ремиссии по программе COG AALL07P1 c включением бортезомиба позволяет увеличить количество полных ремиссий, включая МОБ-отрицательные.

Ключевые слова: острый лимфобластный лейкоз, рефрактерность, рецидивы, бортезомиб.

Получено: 24 февраля 2017 г.

Принято в печать: 2 мая 2017 г.

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ЛИТЕРАТУРА

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

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

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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Современные методы лечения AL амилоидоза: обзор литературы и собственные данные

А.Г. Смирнова1, С.Н. Бондаренко1, А.А. Кисина2, А.В. Смирнов2, А. Цандер3, Б.В. Афанасьев1

1 Институт детской гематологии, онкологии и трансплантологии им. Р.М. Горбачевой СПбГМУ им. акад. И.П. Павлова, Санкт-Петербург, Российская Федерация

2 Научно-исследовательский институт нефрологии СПбГМУ им. акад. И.П. Павлова, Санкт-Петербург, Российская Федерация

3 Центр трансплантации костного мозга Медицинского университета Гамбург-Эппендорф, Гамбург, Германия


РЕФЕРАТ

AL амилоидоз — достаточно редкое заболевание из группы плазмоклеточных дискразий, имеющее крайне неоднородную клиническую картину и плохой прогноз. В статье представлено краткое описание данной патологии, проведен обзор современных методов лечения, представлены собственные результаты терапии. В исследование включено 46 больных с диагнозом AL амилоидоза, которые получали лечение как с использованием аутологичной трансплантации гемопоэтических стволовых клеток, так и стандартной химиотерапии, включающей комбинацию мелфалана с дексаметазоном и бортезомиба с дексаметазоном.


Ключевые слова: AL амилоидоз, лечение, трансплантация гемопоэтических стволовых клеток, мелфалан, бортезомиб.

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Множественная миелома: 7 лет таргетной терапии и ее результаты в Новосибирске

 Поспелова Т.И.1,  Скворцова Н.В.1, Нечунаева И.Н. 2

1 ГБОУ «Государственный медицинский университет», Красный пр-т, д. 52, Новосибирск, Российская Федерация, 630091

2 ГБУ «Городская клиническая больница № 2», Городской гематологический центр, ул. Ползунова, д. 21, Новосибирск, Российская Федерация, 630051

Адрес для переписки: Наталия Валерьевна Скворцова, канд. мед. наук, доцент, Красный пр-т, д. 52, Новосибирск, Российская Федерация, 630091; тел.: +8(383)279-94-06; e-mail: nata_sk78@mail.ru

Для цитирования: Поспелова Т.И., Скворцова Н.В., Нечунаева И.Н. Множественная миелома: 7 лет таргетной терапии и ее результаты в Новосибирске. Клиническая онкогематология. 2015;8(3):267–73.


РЕФЕРАТ

Цель. Оценить 7-летние результаты терапии множественной миеломы (ММ) ингибитором протеасом в Городском гематологическом центре Новосибирска.

Методы. В исследование включено 199 пациентов с ММ, наблюдавшихся в Городском гематологическом центре Новосибирска с июля 2006 г. по декабрь 2014 г. Медиана возраста составила 68 лет (диапазон 36–81 год). В первой линии терапии бортезомиб получало 98 больных, во второй — 101.

Результаты. Общая эффективность терапии первой линии составила 78,5 %, причем у 25 % пациентов достигнута полная и почти полная ремиссия. Медиана времени до достижения ответа была 72 дня. При прогрессировании или рефрактерной ММ эффективность бортезомиба в составе схем противоопухолевой терапии была 68,3 %. Бортезомиб оказался эффективен и при повторном назначении у пациентов, ранее получавших его и другие компоненты комбинированного режима (общий ответ 68,4 %). Медиана общей выживаемости не достигнута, а 7-летняя выживаемость составила 70 %. Побочные эффекты бортезомиба были предсказуемыми и контролируемыми, наиболее значимые из них: гастроинтестинальные, гематологические, астения и периферическая нейропатия.

Заключение. Бортезомиб является высокоэффективным лечебным средством, играющим важную роль в терапии ММ в качестве первой и последующих линий и приводит к достоверному улучшению показателей общей выживаемости пациентов.


Ключевые слова: множественная миелома, эффективность лечения, бортезомиб, общая выживаемость.

Получено: 16 февраля 2015 г.

Принято в печать: 28 мая 2015 г.

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