множественная миелома

Опыт применения помалидомида в комбинации с низкими дозами дексаметазона при множественной миеломе с «двойной рефрактерностью»

ЛИМФОИДНЫЕ ОПУХОЛИ , , ,

А.В. Петров2, Д.В. Моторин2, О.С. Покровская1, Е.С. Урнова1, М.В. Нарейко1, Д.В. Бабенецкая2, Ю.А. Алексеева2, Л.Л. Гиршова2, Л.П. Менделеева1, А.Ю. Зарицкий2

1 ФГБУ «Гематологический научный центр» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167

2 ФГБУ «Северо-Западный федеральный медицинский исследовательский центр им. В.А. Алмазова» Минздрава России, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341

Для переписки: Алексей Владиленович Петров, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341; тел.: +7(921)317-28-02; e-mail: avlpetrov@mail.ru

Для цитирования: Петров А.В., Моторин Д.В., Покровская О.С. и др. Опыт применения помалидомида в комбинации с низкими дозами дексаметазона при множественной миеломе с «двойной рефрактерностью». Клиническая онкогематология. 2017;10(3):372–80.

DOI: 10.21320/2500-2139-2017-10-3-372-380

РЕФЕРАТ

Актуальность. Проблема поиска радикальной терапии множественной миеломы (ММ) до настоящего времени остается нерешенной. Заболевание характеризуется прогрессирующим течением и необходимостью проведения повторных курсов терапии с использованием препаратов, не обладающих перекрестной резистентностью. Прогноз заболевания с «двойной рефрактерностью» к ключевым противоопухолевым препаратам — ингибиторам протеасом первого поколения и иммуномодулирующим средствам — остается пессимистичным. Медиана выживаемости без прогрессирования (ВБП) и общей выживаемости (ОВ) в этой когорте больных составляет 5 и 9 мес. соответственно.

Цель. Оценить эффективность и переносимость помалидомида в комбинации с низкими дозами дексаметазона при рецидивах и рефрактерных формах множественной миеломы (РРММ), осложненной «двойной рефрактерностью».

Материалы и методы. С сентября 2015 г. по июль 2016 г. на базе ФГБУ «Гематологический научный центр» МЗ РФ и ФГБУ «Северо-Западный федеральный медицинский исследовательский центр им. В.А. Алмазова» МЗ РФ в исследование по протоколу включено 10 больных РРММ. Медиана возраста составила 62,5 года (диапазон 48–76 лет), а предшествующих линий терапии — 4 (диапазон 3–5). У всех больных имело место прогрессирование заболевания после применения бортезомиба, леналидомида, режимов с включением алкилирующих препаратов. Кроме того, 6 (60 %) из 10 больным проведена высокодозная химиотерапия мелфаланом с последующей аутоТГСК. Медиана курсов терапии — 6 (диапазон 4–15).

Результаты. Общий ответ составил 60 %, минимальный ответ/стабилизация заболевания — 40 % (критерии IMWG). Медиана ВБП составила 7,8 мес.; ОВ за 18 мес. — 70 % (медиана не достигнута). Гематологическая токсичность III–IV степени, связанная с терапией, наблюдалась у 2 больных (5 эпизодов). Негематологические нежелательные явления III–IV степени включали острый коронарный синдром, тромбоз глубоких вен нижних конечностей, нейропатическую боль, а также острое бредовое расстройство в 1 наблюдении, потребовавшее прекращения терапии. Наличие исходной цитопении и почечной недостаточности до начала терапии помалидомидом не потребовало редукции доз препарата и/или прекращения лечения.

Заключение. Исследуемый режим, включающий помалидомид и малые дозы дексаметазона, продемонстрировал высокий уровень общего ответа при РРММ, а также приемлемый профиль токсичности.

Ключевые слова: множественная миелома, «двойная рефрактерность», иммуномодулирующие препараты, помалидомид.

Получено: 24 января 2017 г.

Принято в печать: 6 мая 2017 г.

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Миелоидные супрессорные клетки при некоторых онкогематологических заболеваниях

ОБЗОРЫ , , , ,

А.В. Пономарев

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

Для переписки: Александр Васильевич Пономарев, аспирант, Каширское ш., д. 24, Moсква, Российская Федерация, 115478; e-mail: kl8546@yandex.ru

Для цитирования: Пономарев А.В. Миелоидные супрессорные клетки при некоторых онкогематологических заболеваниях. Клиническая онкогематология. 2017;10(1):29–38.

DOI: 10.21320/2500-2139-2017-10-1-29-38

РЕФЕРАТ

Миелоидные супрессорные клетки — это незрелые клетки миелоидного происхождения, обладающие иммуносупрессивными свойствами. В обзоре приведена характеристика миелоидных супрессорных клеток, в т. ч. варианты фенотипа, механизмы супрессивного воздействия на иммунную систему, механизмы рекрутирования опухолью миелоидных супрессоров. Дано краткое описание работ, в которых исследовались миелоидные супрессоры при онкогематологических заболеваниях, включая множественную миелому, лимфомы и лейкозы.

Ключевые слова: миелоидные супрессоры, супрессорные клетки миелоидного происхождения, множественная миелома, лимфомы, лейкозы.

Получено: 8 сентября 2016 г.

Принято в печать: 3 декабря 2016 г.

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Отдельные аспекты аутологичной трансплантации гемопоэтических стволовых клеток при множественной миеломе

ОБЗОРЫ , , ,

С.В. Грицаев, А.А. Кузяева, С.С. Бессмельцев

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

Для переписки: Сергей Васильевич Грицаев, д-р мед. наук, 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024; тел.: +7(812)717-58-57; e-mail: gritsaevsv@mail.ru

Для цитирования: Грицаев С.В., Кузяева А.А., Бессмельцев С.С. Отдельные аспекты аутологичной трансплантации гемопоэтических стволовых клеток при множественной миеломе. Клиническая онкогематология. 2017;10(1):7–12.

DOI: 10.21320/2500-2139-2017-10-1-7-12

РЕФЕРАТ

В обзоре рассматриваются отдельные вопросы режимов мобилизации и режимов кондиционирования, а также проведения аутологичной трансплантации гемопоэтических стволовых клеток (аутоТГСК) у больных с множественной миеломой. Цель — определить на этой основе новые научные направления по повышению эффективности аутоТГСК.

Ключевые слова: множественная миелома, аутологичная трансплантация гемопоэтических стволовых клеток, режим мобилизации, режим кондиционирования.

Получено: 13 июля 2016 г.

Принято в печать: 12 ноября 2016 г.

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Элотузумаб в лечении множественной миеломы (обзор литературы)

ЛИМФОИДНЫЕ ОПУХОЛИ , , ,

О.М. Вотякова

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

Для переписки: Ольга Михайловна Вотякова, канд. мед. наук, Каширское ш., д. 24, Москва, Российская Федерация, 115478; тел.: +7(499)324-92-09; e-mail: omvtk@yandex.ru

Для цитирования: Вотякова О.М. Элотузумаб в лечении множественной миеломы (обзор литературы). Клиническая онкогематология. 2016;9(4):438–45.

DOI: 10.21320/2500-2139-2016-9-4-438-445

РЕФЕРАТ

Основным методом лечения множественной миеломы на протяжении десятилетий была химиотерапия. Однако значительное увеличение продолжительности жизни больных отмечено после внедрения в клиническую практику талидомида, бортезомиба и леналидомида. Тем не менее болезнь остается неизлечимой и необходима разработка принципиально новых лечебных подходов. Элотузумаб — это гуманизированное моноклональное антитело IgG1, специфической мишенью которого является антиген SLAMF7. Он относится к семейству сигнальных молекул, активирующих лимфоциты. Высокая экспрессия этого антигена выявляется на миеломных клетках. В обзоре представлены механизм действия элотузумаба, доклинические данные и основные клинические исследования.

Ключевые слова: моноклональные антитела, элотузумаб, клинические исследования, множественная миелома.

Получено: 25 мая 2016 г.

Принято в печать: 15 июня 2016 г.

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Клиническое значение иммунофенотипирования клеток костного мозга при множественной миеломе

ЛИМФОИДНЫЕ ОПУХОЛИ , , , ,

О.Ю. Якимович, О.М. Вотякова, Н.В. Любимова, Н.Н. Тупицын

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

Для переписки: Оксана Юрьевна Якимович, аспирант, Каширское ш., д. 24, Москва, Российская Федерация, 115478; тел.: +7(499)324-28-54; e-mail: ronc_ramn@mail.ru

Для цитирования: Якимович О.Ю., Вотякова О.М., Любимова Н.В., Тупицын Н.Н. Клиническое значение иммунофенотипирования клеток костного мозга при множественной миеломе. Клиническая онкогематология. 2016;9(3):296-301.

DOI: 10.21320/2500-2139-2016-9-3-296-301

РЕФЕРАТ

Цель. Анализ взаимосвязи между экспрессией аберрантных маркеров CD45, CD19 и CD56 на плазматических клетках и клинико-лабораторными и прогностически значимыми показателями у больных множественной миеломой (ММ).

Методы. В настоящее исследование включены данные клинического анализа и иммунофенотипирования клеток костного мозга 64 больных ММ, наблюдавшихся в ФГБУ «РОНЦ им. Н.Н. Блохина» МЗ РФ с 2004 по 2015 г. Проточную трехцветную цитометрию проводили с использованием диагностической панели первично меченных флюорохромами моноклональных антител (CD38-PerCP, CD138-FITC) и конъюгированных с РЕ-моноклональными антителами к CD45, CD19 и CD56.

Результаты. При сравнении средних значений общего количества клеток плазмоцитарного ряда, числа плазмобластов, проплазмоцитов и зрелых плазматических клеток по данным миелограммы, а также сопоставлении этих данных с уровнем экспрессии маркера CD19 выявлены определенные закономерности. Отмечена статистически значимая взаимосвязь CD19-негативного иммунофенотипа с более высоким уровнем как общего количества элементов плазмоцитарного ряда, так и молодых форм плазматических клеток. Выявлена статистически значимая корреляция CD19-негативного иммунофенотипа с более высоким уровнем С-реактивного белка — важного прогностического параметра при ММ. Кроме того, обнаружена взаимосвязь CD19-негативного фенотипа с более высоким числом (%) молодых форм нейтрофилов в крови, т. е. с более частым левым сдвигом в лейкоцитарной формуле. Для CD56-негативного фенотипа характерна плазмобластная морфология опухолевых клеток, а также наличие плазматических клеток в крови. Плазмоклеточный лейкоз чаще диагностируется у больных с СD56-негативным фенотипом опухолевых клеток. При CD45-негативном иммунофенотипе миеломных клеток в сравнении CD45-позитивным наблюдались более высокий уровень свободных легких цепей k-типа, протеинурия Бенс-Джонса, а также более высокий уровень креатинина в сыворотке.

Заключение. Исследование иммунофенотипа плазматических клеток при ММ имеет важное научно-практическое значение и требует дальнейшего изучения.

Ключевые слова: множественная миелома, аберрантный иммунофенотип плазматических клеток, маркеры CD45, CD19 и CD56, клинико-лабораторные показатели.

Получено: 17 марта 2016 г.

Принято в печать: 1 апреля 2016 г.

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Помалидомид в лечении рецидивов и рефрактерных форм множественной миеломы

КЛИНИКА, ДИАГНОСТИКА И ЛЕЧЕНИЕ ЛИМФОИДНЫХ ОПУХОЛЕЙ , ,

С.В. Семочкин

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

Для переписки: Сергей Вячеславович Семочкин, д-р мед. наук, профессор, ул. Островитянова, д. 1, Москва, Российская Федерация, 117997; тел.: +7(495)653-14-78; e-mail: s.semochkin@gmail.com

Для цитирования: Семочкин С.В. Помалидомид в лечении рецидивов и рефрактерных форм множественной миеломы. Клиническая онкогематология. 2015;8(4):379–389.

DOI: 10.21320/2500-2139-2015-8-4-379-389

РЕФЕРАТ

Помалидомид — иммуномодулирующий препарат третьего поколения, рекомендованный для лечения пациентов с множественной миеломой, рефрактерной к леналидомиду и бортезомибу. Профиль побочных явлений оптимизирован для применения у пациентов с интенсивным и длительным противоопухолевым лечением. Помалидомид одобрен в 2013 г. Управлением по контролю за качеством пищевых продуктов и лекарственных средств США (FDA) и Европейским агентством по лекарственным средствам (EMA) для лечения пациентов с рецидивами и рефрактерной множественной миеломой, которые получили не менее двух линий лечения, включая леналидомид и бортезомиб, с прогрессированием непосредственно при последней терапии либо в пределах 60 дней после ее окончания. Регистрация помалидомида с аналогичными показаниями ожидается в России в 2015 г. Помалидомид обладает сходным механизмом действия с другими иммуномодуляторами. Препарат оказывает как прямое цитостатическое воздействие, так и вызывает опосредованный эффект через воздействие на микроокружение костного мозга и T/NK-клеточный иммунитет. Рекомендуемая стартовая доза помалидомида составляет 4 мг/сут (в дни 1–21/28) в комбинации с низкими дозами дексаметазона (40 мг в неделю для молодых пациентов и 20 мг для пациентов старше 75 лет). Лечение рекомендуется проводить вплоть до прогрессирования болезни или появления неприемлемой токсичности. В обзоре представлены рекомендации по коррекции дозы препарата в зависимости от переносимости и профилактике тромботических осложнений. В статье представлено собственное клиническое наблюдение, которое демонстрирует успешное применение помалидомида у больного из группы высокого цитогенетического риска с двойной рефрактерностью — к бортезомибу и леналидомиду, интенсивным предшествующим противоопухолевым лечением. Продолжительность жизни после начала терапии помалидомидом составила около 16 мес., что соответствует литературным данным.

Ключевые слова: помалидомид, иммуномодулирующие агенты, множественная миелома.

Получено: 8 апреля 2015 г.

Принято в печать: 20 октября 2015 г.

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Бендамустин в лечении множественной миеломы

КЛИНИКА, ДИАГНОСТИКА И ЛЕЧЕНИЕ ЛИМФОИДНЫХ ОПУХОЛЕЙ , ,

О.М. Вотякова

ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» РАМН, Москва, Российская Федерация

Для цитирования: Вотякова О.М. Бендамустин в лечении множественной миеломы. Клин. онкогематол. 2014; 7(3): 301–10.

РЕФЕРАТ

Бендамустин — противоопухолевый препарат с двойным механизмом действия, сочетающий свойства алкилирующего соединения и пуринового аналога, с многообещающей активностью при множественной миеломе (ММ). В 2013 г. в России бендамустин (Рибомустин) зарегистрирован для лечения больных старше 65 лет с впервые диагностированной ММ, не являющихся кандидатами на проведение высокодозной химиотерапии с аутологичной трансплантацией гемопоэтических стволовых клеток (ВДХТ с аутоТГСК), с клиническими проявлениями нейропатии, препятствующей использованию талидомида и бортезомиба. В обзоре приводятся данные по эффективности и безопасности применения бендамустина как в монорежиме, так и в сочетании с глюкокортикоидами и таргетными препаратами (бортезомиб, талидомид, леналидомид) у первичных больных и при рецидивах ММ. Представленные в обзоре данные позволяют рекомендовать бендамустин в сочетании с глюкокортикоидами и новыми препаратами у больных ММ с повторными рецидивами, а также в качестве терапии первой линии у отдельных первичных пациентов с полинейропатией, не являющихся кандидатами на проведение ВДХТ с аутоТГСК.

Ключевые слова: множественная миелома, бендамустин, Рибомустин.

Принято в печать: 23 мая 2014 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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Множественная миелома (патогенез, клиника, диагностика, дифференциальный диагноз). Часть I

ОБЗОРЫ , , , ,

С.С. Бессмельцев

Российский научно-исследовательский институт гематологии и трансфузиологии, Санкт-Петербург, Российская Федерация

РЕФЕРАТ

Множественная миелома (ММ) — опухолевое заболевание, характеризующееся инфильтрацией костного мозга плазматическими клетками и обширным поражением костей скелета, что сопровождается болью и переломами костей. В обзоре представлены лабораторные признаки и клинические симптомы, характерные для ММ. Диагноз ММ не вызывает сомнений при обнаружении в костном мозге больных 10 % и более клональных плазматических клеток, M-протеина в сыворотке или моче (кроме несекретирующей миеломы), гиперкальциемии, почечной недостаточности, анемии или очагов лизиса в костях скелета. Для выявления М-протеина используют электрофорез сывороточных белков и иммунофиксацию. Кроме того, необходимы электрофорез и иммунофиксация мочевых белков или определение свободных легких цепей иммуноглобулинов. Международная система стадирования в зависимости от уровня b2-микроглобулина и альбумина в сыворотке подразделяет больных ММ на три группы риска: стандартного, промежуточного и высокого. Анализ хромосомных нарушений позволяет более надежно стратифицировать больных на группы риска. Установлено, что del(13), t(4;14) или t(14;16), del(17p), гиподиплоидия и индекс метки плазматических клеток 3 % и более существенно ухудшают прогноз ММ.

В обзоре представлены лабораторные признаки и клинические симптомы моноклональной гаммапатии неясного генеза/неопределенного значения, асимптоматической миеломы (тлеющей миеломы), несекретирующей миеломы, солитарной плазмоцитомы кости, экстрамедуллярной плазмоцитомы, плазмоклеточного лейкоза, макроглобулинемии Вальденстрема, амилоидоза и других заболеваний.

Ключевые слова: множественная миелома, моноклональные гаммапатии неясного генеза, асимптоматическая миелома, M-протеин, клональные плазматические клетки.

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