Применение антибиотиков при фебрильной нейтропении у больных острыми лейкозами

В.А. Охмат, Г.А. Клясова, Е.Н. Паровичникова, В.В. Троицкая, Е.О. Грибанова, В.Г. Савченко

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

Для переписки: Владимир Александрович Охмат, канд. мед. наук, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167; тел.: +7(495)614-92-72; e-mail: okhmatvladimir@mail.ru

Для цитирования: Охмат В.А., Клясова Г.А., Паровичникова Е.Н. и др. Применение антибиотиков при фебрильной нейтропении у больных острыми лейкозами. Клиническая онкогематология. 2018;11(1):100-9.

DOI: 10.21320/2500-2139-2018-11-1-100-109


РЕФЕРАТ

Цель. Оценить результаты применения антибиотиков при фебрильной нейтропении у больных острыми миелоидными (ОМЛ) и острыми лимфобластными лейкозами (ОЛЛ).

Материалы и методы. В проспективное исследование (2013–2015 гг.) включено 66 больных ОМЛ и 44 — ОЛЛ, получивших 480 курсов химиотерапии в течение 6 мес.

Результаты. Фебрильную нейтропению регистрировали в 242 (50 %) курсах химиотерапии, чаще у больных ОМЛ, чем ОЛЛ (93 vs 18 %; p < 0,0001). У больных ОМЛ инфекции преобладали в индукции и консолидации (98 vs 89 %), при ОЛЛ — в индукции (55 %). У больных ОМЛ в сравнении с больными ОЛЛ излечение от инфекций было реже при использовании антибиотиков 1-го этапа в режиме монотерапии (24 vs 57 %; p < 0,0001), но чаще при добавлении препаратов других групп (37 vs 18 %; p = 0,01). Эффект при назначении β-лактамных антибиотиков у больных ОМЛ был реже на этапе индукции, чем в консолидации (47 vs 72 %; p = 0,0004). При гранулоцитопении более 14 дней частота ответа при использовании антибиотиков 1-го этапа и карбапенемов составила 23–24 %, а в 47 % случаев его регистрировали при добавлении других противомикробных препаратов, чаще противогрибковых (21 %). При лихорадке неясной этиологии ответ отмечался при применении антибиотиков 1-го этапа в режиме монотерапии (45 %). При клинически и микробиологически доказанной инфекции весомая доля излечений наблюдалась при сочетании β-лактамных антибиотиков с другими препаратами (43 %).

Заключение. У больных ОЛЛ и при лихорадке неясной этиологии оптимальной следует признать эскалационную стратегию применения антибиотиков. У больных ОМЛ на этапе индукции, в случаях продолжительной нейтропении (> 14 дней), при клинически и микробиологически доказанных инфекциях эффективность β-лактамных антибиотиков в режиме монотерапии ниже. В 37–48 % случаев излечение регистрировали при добавлении других противомикробных препаратов.

Ключевые слова: острый лейкоз, ОМЛ, ОЛЛ, фебрильная нейтропения, лихорадка неясной этиологии, клинически и микробиологически доказанная инфекция, антибиотики.

Получено: 2 июля 2017 г.

Принято в печать: 20 октября 2017 г.

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Прогностическое значение и корреляция динамики гиперэкспрессии гена WT1 и мутации гена NPM1 у пациентов с острым миелобластным лейкозом

Л.Л. Гиршова, И.Г. Будаева, Е.Г. Овсянникова, С.О. Кузин, Д.В. Моторин, Р.Ш. Бадаев, Д.Б. Заммоева, В.В. Иванов, К.В. Богданов, О.С. Писоцкая, Ю.В. Миролюбова, Т.С. Никулина, Ю.А. Алексеева, А.Ю. Зарицкий

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

Для переписки: Ирина Гармаевна Будаева, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341; тел.: +7(931)351-07-06; e-mail: irina2005179@mail.ru

Для цитирования: Гиршова Л.Л., Будаева И.Г., Овсянникова Е.Г. и др. Прогностическое значение и корреляция динамики гиперэкспрессии гена WT1 и мутации гена NPM1 у пациентов с острым миелобластным лейкозом. Клиническая онкогематология. 2017;10(4):485–93.

DOI: 10.21320/2500-2139-2017-10-4-485-493


РЕФЕРАТ

Актуальность. Острый миелобластный лейкоз (ОМЛ) с мутацией NPM1 составляет 30 % всех ОМЛ и характеризуется благоприятным прогнозом, за исключением случаев с мутацией FLT3-ITD. Несмотря на благоприятный прогноз, вероятность развития рецидивов у пациентов с мутацией NPM1 может принципиально отличаться. В связи с этим все большую актуальность приобретает возможность оценки минимальной остаточной болезни (МОБ) на фоне программной химиотерапии и на этапе последующего наблюдения. Такой подход позволит прогнозировать чувствительность опухолевого клона к химиотерапии.

Цель. Оценить результаты использования высокоспецифичного (мутации NPM1) и более универсального неспецифичного (гиперэкспрессия гена WT1) маркеров для оценки МОБ, а также выявить корреляцию в динамике изменений уровней NPM1 и WT1 на разных этапах терапии и после ее окончания в период наблюдения.

Материалы и методы. В исследование включено 14 пациентов c ОМЛ. У всех больных имели место мутация NPM1 и гиперэкспрессия гена WT1. У 50 % пациентов обнаруживались дополнительные молекулярные маркеры (гиперэкспрессия BAALC, мутации FLT3-ITD, DNMT3A, MLL). Представлен длительный мониторинг уровней экспрессии WT1 и мутации NPM1 методом ПЦР в режиме реального времени.

Результаты. Медиана редукции уровня NPM1 после индукционной терапии составила 3 log. У всех пациентов данной группы развились рецидивы, присутствовала мутация NPM1, отмечались более низкие показатели общей (ОВ) и безрецидивной выживаемости (БРВ), что статистически значимо коррелирует с наличием прогностически неблагоприятных молекулярных маркеров. Не отмечено статистически значимых различий БРВ в группах с редукцией уровня экспрессии WT1 < или > 2 log на 28-й день лечения. В то же время при редукции уровня экспрессии WT1 ≥ 2 log выявлена статистически значимая разница в развитии раннего рецидива в зависимости от уровня снижения NPM1 (≥ или < 3 log). БРВ была более долгосрочной у пациентов с уровнем экспрессии WT1 < 100/104 копий ABL на 28-й день и WT1 < 250/104 копий ABL на 14-й день от начала терапии. Уровень экспрессии WT1 был значительно ниже на 14-й и 28-й дни у пациентов с редукцией NPM1 > 3 log на 28-й день. Снижение экспрессии WT1 < 100/104 копий ABL на 28-й день чаще встречалось у пациентов с изолированной мутацией NPM1 в отличие от больных с дополнительными неблагоприятными молекулярными маркерами.

Заключение. Уровень редукции NPM1 после индукционной терапии может служить достоверным предиктором, влияющим на показатели БРВ и ОВ. Выявлена корреляция между степенью редукции NPM1 и наличием дополнительных молекулярных маркеров. При сравнении универсального (гиперэкспрессия WT1) и высокоспецифичного (мутация NPM1) маркеров NPM1 оказался более чувствительным маркером. В работе подтверждено прогностическое значение более низкого порогового уровня WT1 на 28-й день лечения (100/104 копий ABL) и впервые показано влияние на результаты терапии ранней оценки редукции экспрессии WT1 на 14-й день индукционного курса.

Ключевые слова: острый миелобластный лейкоз, ОМЛ, NPM1, WT1, молекулярный мониторинг.

Получено: 22 февраля 2017 г.

Принято в печать: 26 мая 2017 г.

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Цитогенетические и молекулярно-генетические факторы прогноза острых миелоидных лейкозов

А.В. Мисюрин

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

Для переписки: Андрей Витальевич Мисюрин, канд. биол. наук, Каширское ш., д. 24, Moсква, Российская Федерация, 115478; e-mail: and@genetechnology.ru

Для цитирования: Мисюрин А.В. Цитогенетические и молекулярно-генетические факторы прогноза острых миелоидных лейкозов. Клиническая онкогематология. 2017;10(2):227–34.

DOI: 10.21320/2500-2139-2017-10-2-227-234


РЕФЕРАТ

В обзоре приведены данные о диагностическом и прогностическом значении цитогенетических и молекулярно-генетических маркеров острых миелоидных лейкозов (ОМЛ). Показано, что в ряде случаев выделенные ранее на основе клинико-морфоцитохимических характеристик варианты ОМЛ можно разграничить благодаря обнаружению специфических генетических и хромосомных дефектов. Тем не менее, некоторые одинаковые повторяющиеся хромосомные аномалии могут быть обнаружены у больных ОМЛ, заболевание у которых согласно клинико-морфоцитохимическим признакам можно отнести к разным вариантам миелоидного лейкоза. В настоящее время признается, что изменение кариотипа является определяющим фактором прогноза, имеющим более существенное значение, чем критерии, основанные на морфологических и цитохимических признаках. В связи с этим выбор риск-адаптированной программы лечения ОМЛ следует проводить с учетом результатов цитогенетического исследования. В обзоре особый раздел посвящен известным к настоящему времени мутациям генов, которые могут влиять на результаты лечения ОМЛ.

Ключевые слова: ОМЛ, хромосомная аномалия, химерный онкоген, экспрессия гена, мутация гена.

Получено: 16 сентября 2016 г.

Принято в печать: 3 января 2017 г.

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Молекулярный мониторинг уровня транскрипта RUNX1-RUNX1T1 при острых миелобластных лейкозах на фоне терапии

Л.Л. Гиршова, Е.Г. Овсянникова, С.О. Кузин, Е.Н. Горюнова, Р.И. Вабищевич, А.В. Петров, Д.В. Моторин, Д.В. Бабенецкая, В.В. Иванов, К.В. Богданов, И.В. Холопова, Т.С. Никулина, Ю.В. Миролюбова, Ю.А. Алексеева, А.Ю. Зарицкий

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

Для переписки: Екатерина Геннадьевна Овсянникова, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341; тел.: +7(921)313-68-35; e-mail: katrin51297@mail.ru

Для цитирования: Гиршова Л.Л., Овсянникова Е.Г., Кузин С.О. и др. Молекулярный мониторинг уровня транскрипта RUNX1-RUNX1T1 при острых миелобластных лейкозов на фоне терапии. Клиническая онкогематология. 2016;9(4):456–64.

DOI: 10.21320/2500-2139-2016-9-4-456-464


РЕФЕРАТ

Актуальность. Современные подходы к терапии острых миелобластных лейкозов (ОМЛ) заключаются в достижении максимальной редукции опухоли и, соответственно, эрадикации лейкозного клона. За исключением случаев изолированной молекулярной перестройки RUNX1-RUNX1T1, целью терапии является достижение неопределяемого уровня таргетного (исследуемого) гена.

Цель. Оценить динамику уровня RUNX1-RUNX1T1 и соответствующих клинических проявлений в ходе мониторинга на различных этапах программной терапии и после ее завершения.

Методы. В работе представлено описание 10 наблюдений ОМЛ с изолированной экспрессией RUNX1-RUNX1T1 (n = 4) и в сочетании с различными молекулярными и цитогенетическими аномалиями (n = 6). Кроме того, представлено наблюдение длительного мониторинга экспрессии гена методом количественного определения RUNX1-RUNX1T1 с помощью ПЦР в реальном времени.

Результаты. Частота рецидивов в группе со снижением уровня экспрессии RUNX1-RUNX1T1 ³ 2 log составила 75 % в сравнении с пациентами, у которых был меньше уровень снижения транскрипта с частотой рецидивов 0 % (= 0,05). Нарастание уровня RUNX1-RUNX1T1 на фоне сохранения костномозговой ремиссии более чем на 1 log совпадало с развитием костномозгового рецидива в течение 5–18 нед. Кроме того, возможно длительное сохранение определенного уровня транскрипта после завершения программной терапии без развития рецидивов.

Заключение. В работе подвергнуты анализу возможные молекулярные предпосылки различных клинических исходов ОМЛ у больных с длительной персистенцией транскрипта RUNX1-RUNX1T1. Это, возможно, позволит сформировать индивидуализированный подход к пациентам с ОМЛ.


Ключевые слова: острый миелобластный лейкоз, ОМЛ, RUNX1-RUNX1T1, молекулярный мониторинг.

Получено: 5 апреля 2016 г.

Принято в печать: 18 апреля 2016 г.

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Мутации генов при острых миелоидных лейкозах

О.В. Блау

Клиника Шарите, Берлинский медицинский университет, ул. Хинденбургдамм, д. 30, Берлин, Германия, 12200

Для переписки: Ольга Владимировна Блау, д-р мед. наук, Department of Hematology, Oncology and Tumorimmunology, Charite University School of Medicine, Hindenburgdamm 30, 12200, Berlin, Germany; e-mail: olga.blau@charite.de.

Для цитирования: Блау О.В. Мутации генов при острых миелоидных лейкозах. Клиническая онкогематология. 2016;9(3):245-56.

DOI: 10.21320/2500-2139-2016-9-3-245-256


РЕФЕРАТ

Острый миелобластный лейкоз (ОМЛ) — клональное злокачественное заболевание, характеризующееся неэффективным гемопоэзом. Большинство больных ОМЛ имеют различные цитогенетические и молекулярно-генетические повреждения, которые сочетаются с определенными биологическими и клиническими особенностями заболевания. Примерно у 50–60 % больных de novo и у 80–95 % больных вторичными ОМЛ обнаруживаются хромосомные изменения. Следует отметить, что структурные цитогенетические аберрации являются наиболее частыми маркерами и встречаются примерно в 40 % случаев ОМЛ de novo. Достаточно большая группа больных с нормальным кариотипом (НК-ОМЛ), формально относящаяся к категории промежуточного риска, является крайне гетерогенной в отношении прогноза течения заболевания. В действующие прогностические классификации ОМЛ включены сегодня только некоторые мутации, характеризующиеся известным прогностическим значением, в частности NPM1, FLT3 и C/EBPa. Пациенты с NPM1, но без мутаций FLT3-ITD или с мутациями C/EBPa характеризуются благоприятным прогнозом заболевания, а с мутацией FLT3-ITD — неблагоприятным. Недавно выявлен новый класс мутаций, при которых повреждаются гены, ответственные за эпигенетические процессы регуляции генома, в частности метилирование ДНК или модификацию гистонов. Среди них наиболее изученными к настоящему времени являются мутации в генах DNMT3A, IDH1/2, TET2 и некоторых других. В целом ряде исследований показан неблагоприятный прогностический эффект мутации DNMT3A при ОМЛ. Что касается прогностического значения IDH1/2, то данный вопрос еще не до конца ясен. На прогноз заболевания влияет ряд биологических факторов, в т. ч. сочетание с цитогенетическими аберрациями и другими мутациями, особенно FLT3 и NPM1. Число исследований, посвященных генетическим мутациям при ОМЛ, постоянно растет. Накопленные к настоящему времени знания о генетических изменениях при ОМЛ подтверждают их роль в возникновении и развитии заболевания.


Ключевые слова: острый миелобластный лейкоз, ОМЛ, кариотип, цитогенетические аберрации, мутации генов, прогноз.

Получено: 23 января 2016 г.

Принято в печать: 4 апреля 2016 г.

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Стойкое восстановление донорского гемопоэза у больной с посттрансплантационным рецидивом острого миеломонобластного лейкоза с inv(3)(q21q26), –7 и экспрессией онкогена EVI1 после трансфузий донорских лимфоцитов и использования гипометилирующих агентов

Н.Н. Мамаев, А.В. Горбунова, Т.Л. Гиндина, О.А. Слесарчук, В.Н. Овечкина, С.Н. Бондаренко, О.В. Голощапов, В.М. Кравцова, Б.В. Афанасьев

Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова, Институт детской онкологии, гематологии и трансфузиологии им. Р.М. Горбачевой, Санкт-Петербург, Российская Федерация


РЕФЕРАТ

Представлено наблюдение успешного лечения посттрансплантационного рецидива острого миеломонобластного лейкоза (М4-вариант по ФАБ) с прогностически неблагоприятными аномалиями: инверсией inv(3)(q21q26), моносомией 7 и гиперэкспрессией гена EVI1. Достигнуто стойкое восстановление донорского гемопоэза после 1-го курса высокодозной терапии цитарабином, повторных инфузий донорских лимфоцитов и нескольких курсов гипометилирующих препаратов (децитабин, азацитидин). Обсуждаются возможные молекулярные механизмы этой эффективной терапии с целью ее воспроизведения в будущем у пациентов с аналогичными клиническими ситуациями.

Ключевые слова: ОМЛ, inv(3)(q21q26), гиперэкспрессия гена EVI1, аллогенная трансплантация гемопоэтических стволовых клеток, рецидивы, лечение, инфузии донорских лимфоцитов, гипометилирующие агенты.

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ЛИТЕРАТУРА

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