Pediatric Hematology/Oncology and ImmunopathologyPediatric Hematology/Oncology and ImmunopathologyВопросы гематологии/онкологии и иммунопатологии в педиатрии1726-17082414-9314Fund Doctors, Innovations, Science for Children33810.24287/1726-1708-2020-19-2-46-53ORIGINAL ARTICLESОРИГИНАЛЬНЫЕ СТАТЬИThe influence of various doses of busulfan in conditioning regimes on outcome of allogeneic hematopoietic stem cell transplantation in children with acute myeloid leukemiaВлияние различных доз бусульфана в режимах кондиционирования на исход аллогенной трансплантации гемопоэтических стволовых клеток у детей с острым миелобластным лейкозомhttps://orcid.org/0000-0001-7263-4326PainaO. V.ПаинаО. В.
Russian Federation

Cand. of Sci. (Med.), Hematologist, Head of the 1st Pediatric Transplant Department,

Russia, 197022, Saint Petersburg, Lva Tolstogo st., 6–8

канд. мед. наук, врач-гематолог, заведующая отделением трансплантации костного мозга для детей №1,

197022, Санкт-Петербург, ул. Льва Толстого, 6–8

paina@mail.ruhttps://orcid.org/0000-0002-3386-0942RakhmanovaZ. Z.РахмановаЖ. З.
Russian Federation
https://orcid.org/0000-0002-5721-0207KozhokarP. V.КожокарьП. В.
Russian Federation
https://orcid.org/0000-0003-1143-4851FrolovaA. S.ФроловаА. С.
Russian Federation
https://orcid.org/0000-0003-4952-0704TsvetkovaL. A.ЦветковаЛ. А.
Russian Federation
https://orcid.org/0000-0002-1104-6499EkushovK. A.ЕкушовК. А.
Russian Federation
https://orcid.org/0000-0001-5861-7319MarkovaI. V.МарковаИ. В.
Russian Federation
https://orcid.org/0000-0002-1302-3311GindinaT. L.ГиндинаТ. Л.
Russian Federation
https://orcid.org/0000-0002-5402-3115AlyanskyA. L.АлянскийА. Л.
Russian Federation
https://orcid.org/0000-0002-8000-3652BarkhatovI. M.БархатовИ. М.
Russian Federation
https://orcid.org/0000-0001-5077-9225SemenovaE. V.СеменоваЕ. В.
Russian Federation
https://orcid.org/0000-0003-2594-7703ZubarovskayaL. S.ЗубаровскаяЛ. С.
Russian Federation
https://orcid.org/0000-0002-1235-4530AfanasyevB. V.АфанасьевБ. В.
Russian Federation
R.М. Gorbacheva Memorial Institute of Children Oncology, Haematology and Transplantation, I.P. Pavlov Saint-Petersburg First State Medical University, Ministry of Healthcare of Russian FederationНаучно-исследовательский институт детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова» Минздрава России0207202019246530107202001072020Copyright ©; 2020, «D. Rogachev NMRCPHOI»Copyright ©; 2020, ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России2020«D. Rogachev NMRCPHOI»ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава Россииhttps://creativecommons.org/licenses/by/4.0https://hemoncim.com/jour/article/view/338

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for patients with acute myeloid leukemia (AML). The conditioning regimen administered for this patient based on busulfan (Bu) combined with cyclophosphamide (Cy), fludarabine (Flu) or some other agents. Comparisons of myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC) have demonstrated a various results between relapse and toxicity in a few reports. We suppose, that dose intensity of Bu across regimens may affect treatment outcomes. Aim of this retrospective study was to evaluate the impact dose of busulfan to overall survival (OS), transplant-related mortality (TRM), relapse-free survival (RFS), toxicity, the incidence of primary graft failure and acute "graft versus host" disease (GvHD) in transplantation in children and adolescents with AML. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. We analyzed 110 AML pediatric patients with the median age 9 (range 1–19) y.o., who underwent first allo-HSCT with Bu based conditioning in R.M. Gorbacheva Memorial Institute from 2002 to 2018. Patients were divided into 3 groups: Bu1 – patients, who received Bu at the dose 8–10 mg/kg, n = 34 (31%), in Bu2 – dose of Bu was 12 mg/kg, n = 35 (32%), in Bu3 – dose of Bu was > 12 mg/kg, n = 41 (37%). In Bu1 Bu was combined with Flu in 31 (91%) pts and Cy in 3 (9%); in Bu2 – with Flu in 12 (34%), Cy in 7 (20%) and other agents in 16 (46%); in Bu3 – with Cy in 32 (78%), with Flu in 7 (17%) and other agents in 2 pts (5%) (p < 0.001). Patients in Bu2 received more Cy based GvHD prophylaxis regimens (69% vs 44% in Bu1, vs 29% in Bu3, p = 0.003) and more haplo grafts (51% vs 29% in Bu1, vs 15% in Bu3, p = 0.003). The complete remission at the HSCT was observed in 79 % in Bu1, 49% in Bu2, 61% in Bu3 (p = 0.02). Probabilities of OS, RFS, TRM were estimated by using the Kaplan–Meier method. Incidence of toxicity, acute GvHD and primary graft failure – by using Mann–Whitney U-test. Transplant engraftment was achieved in 95 (86%) of patients. Graft failure occurs in the 5 patients of Bu1 group (15%), in the 6 pts of Bu2 (17%) and in the 4 pts of Bu3 (10%) (p = 0.7). Median follow-up was 2 years for Bu1 and Bu3, 1 year for Bu2. Two-year OS was similar (Bu1 = 59% vs Bu2 = 60% vs Bu3 51%, p = 0.7). Two-year OS of pts with CR before HSCT was 70% in Bu1, 82% in Bu2, 60% in Bu3, p = 0,3 and 14%, 39%, 38% for pts with progression disease (PD), respectively (p = 0.5). Two-year RFS was 74% in Bu1, 82% in Bu2, 64% in Bu3 at CR (p = 0.4); 43%, 39% and 38% in pts with progression, respectively (p = 0.9). Median of RFS were also similar for the pts in PD (4 months in Bu1, 5 months in Bu2 and Bu3, p = 0.9) and not achieved for pts at CR. Drug related toxicity grade III–IV 4 experienced in 35% pts in Bu1, 29% in Bu2, in 54% in Bu3 (p = 0.04). Mucositis and toxic hepatitis were the most common adverse events. Sinusoidal obstruction syndrome (SOS) experienced in 8 pts from different group: 4 from Bu2 (11%), 3 from Bu3 (7%) and only pts from Bu1 (3%) with previously treated of inotuzumab (p = 0.4). The most pts with VOD (3/5) had PD at the HSCT. Cumulative incidence of acute GvHD grade 2 (15% vs 14% vs 10%, p = 0.8) were not different. Acute GvHD grade III–IV was observed a bit more often in Bu3 (34%), than in Bu1 (18%) and Bu2 (17%) (p = 0.09). TRM up to D+100 was also higher in Bu3 (15%), than in Bu2 (6%) and Bu1 (0%) (p = 0.05). The transplant results of children with similar disease status of AML, received MAC or RIC conditioning with various dose of Bu, were not associated with significant differences in overall outcomes. The higher dose Bu may increase incidence of toxicity grade III–IV (p = 0.04) and acute GvHD grade III–IV (p = 0.09) with increasing of early TRM (p = 0.05).

Аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК) является потенциально излечивающей терапией для детей, страдающих острым миелобластным лейкозом (ОМЛ). Выбор оптимального режима кондиционирования (РК) в соответствии с критерием «эффективность–токсичность» особенно актуален для детей и подростков. Бусульфан – основа РК при алло-ТГСК, однако сравнение миелоаблативных РК (MAК) и РК со сниженной интенсивностью (РИК) в нескольких исследованиях продемонстрировало противоречивые результаты по частоте рецидивов и токсичности. В связи с этим актуально исследование влияния различных доз бусульфана (Бу) на результаты алло-ТГСК. Цель исследования: оценить влияние различных доз Бу на общую (ОВ) и безрецидивную (БРВ) выживаемость, частоту токсических осложнений III–IV степени и острой реакции «трансплантат против хозяина» (оРТПХ) III–IV степени, раннюю трансплантационную летальность (ТЛ) и частоту первичного неприживления трансплантата (ПНТ) у детей и подростков с ОМЛ. Данное исследование одобрено независимым этическим комитетом и утверждено решением ученого совета ФГБОУ ВО ПСПбГМУ им. И.П. Павлова Минздрава России. В исследование были включены 110 пациентов с ОМЛ, медиана возраста 9 (1–19) лет, которым была проведена алло-ТГСК с кондиционированием на основе Бу (перорально и внутривенно) в НИИ ДОГиТ им. Р.М. Горбачевой с 2002 по 2018 г. Пациенты были разделены на 3 группы: Бу1 – получавшие Бу в дозе 8–10 мг/кг, n = 34 (31%); Бу2 – 12 мг/кг, n = 35 (32%); Бу3 – > 12 мг/кг, n = 41 (37%). В группе Бу1 препарат сочетали с флударабином (Флу) у 31 (91%) ребенка и циклофосфамидом (ЦФ) – у 3 (9%); в группе Бу2 – с Флу у 12 (34%) детей, ЦФ – у 7 (20%) и другими агентами – в 16 (46%) случаях; в группе Бу3 – с ЦФ у 32 (78%), Флу – у 7 (17%) и другими агентами – у 2 (5%) детей (p < 0,001). У реципиентов группы Бу2 чаще использовали в профилактике оРТПХ посттрансплантационный ЦФ (69% против 44% в Бу1 против 29% в Бу3, p = 0,003) и больше гаплоидентичных трансплантаций (51% против 29% в Бу1 против 15% в Бу3, p = 0,003). Полная ремиссия на момент ТГСК зафиксирована у 79% пациентов группы Бу1, 49% – группы Бу2, 61% – группы Бу3 (p = 0,02). ОВ, БРВ, а также ранняя ТЛ были рассчитаны, используя метод Каплана– Майера. Частота ПНТ, токсичности и оРПТХ III–IV степени была установлена с помощью критериев Манна–Уитни и Крускала–Уоллиса. Приживление трансплантата достигнуто у 95 (86%) пациентов. ПНТ диагностировано у 5 (15%) больных из группы Бу1, 6 (17%) из группы Бу2 и 4 (10%) из группы Бу3 (p = 0,7). Медиана наблюдения составила 2 года для групп Бу1 и Бу3, 1 год – для группы Бу2. ОВ не отличалась в группах: Бу1 – 59% против Бу2 – 60% против Бу3 – 51% (p = 0,7). OВ пациентов с ремиссией перед ТГСК составляла 70% в группе Бу1, 82% – в группе Бу2, 60% – в группе Бу3 (p = 0,3) и 14%, 39% и 38% соответственно для пациентов с прогрессией заболевания (ПЗ) на момент алло-ТГСК (p = 0,5). БРВ составила 74% в группе Бу1, 82% – в группе Бу2, 64% – в группе Бу3 у пациентов с ремиссией заболевания (p = 0,4); 43%, 39% и 38% соответственно у пациентов с ПЗ (p = 0,9). Медиана БРВ также была одинаковой для пациентов с ПЗ: 4 мес в группе Бу1, 5 мес в группах Бу2 и Бу3 (p = 0,9) и не была достигнута для пациентов с ремиссией перед ТГСК. Токсичность, связанная с РК, III–IV степени наблюдалась у 35% пациентов в группе Бу1, 29% – в группе Бу2, 54% – в группе Бу3 (р = 0,04). Мукозит и токсический гепатит встречались чаще других. Синдром синусоидальной обструкции наблюдался у 8 пациентов: 4 (11%) в группе Бу2, 3 (7%) в группе Бу3 и 1 (3%) в группе Бу1, которые ранее получали гемтузумаб озогамицин (p = 0,4). Большинство пациентов с данным осложнением (3/5) имели ПЗ на момент алло-ТГСК. Не было различий в кумулятивной частоте оРТПХ II степени (15% в группе Бу1 против 14% в группе Бу2 против 10% в группе Бу3, р = 0,8). оРТПХ III–IV степени наблюдалась чаще в группе Бу3 (34%), чем в группах Бу1 (18%) и Бу2 (17%) (p = 0,09). TЛ до Д+100 также была выше в группе Бу3 (15%), чем в группах Бу2 (6%) и Бу1 (0%) (p = 0,05). ОВ и БРВ после алло-ТГСК у детей с ОМЛ, получивших алло-ТГСК в одинаковом статусе болезни не были ассоциированы со значительными различиями в зависимости от дозы Бу в РК. Однако более высокая доза Бу может способствовать увеличению частоты токсичности III–IV степени (р = 0,04), оРТПХ III–IV степени (р = 0,09) и повысить раннюю ТЛ (р = 0,05).

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