OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press34410.17650/1818-8346-2019-14-2-13-23HEMATOLOGIC MALIGNANCIES: TREATMENT, SUPPORTIVE CAREГЕМОБЛАСТОЗЫ: ЛЕЧЕНИЕ, СОПРОВОДИТЕЛЬНАЯ ТЕРАПИЯVenous thrombosis in children, adolescents and young adults with acute lymphoblastic leukemia receiving chemotherapy in the Republic of BelarusВенозные тромбозы у детей, подростков и молодых взрослых с острым лимфобластным лейкозом, получающих программную химиотерапию в Республике Беларусьhttps://orcid.org/0000-0002-2738-429XDmitrievV. V.ДмитриевВ. В.
Belarus

43 Frunzenskaya St., Borovlyany, Minsk region 223053, Republic of Belarus

Республика Беларусь, 223053 Минский район, д. Боровляны, ул. Фрунзенская, 43

dmitrievhaematol@mail.ruMigalN. V.МигальН. В.
Belarus

43 Frunzenskaya St., Borovlyany, Minsk region 223053, Republic of Belarus

Республика Беларусь, 223053 Минский район, д. Боровляны, ул. Фрунзенская, 43

BydanovO. I.БыдановО. И.
Belarus

43 Frunzenskaya St., Borovlyany, Minsk region 223053, Republic of Belarus

Республика Беларусь, 223053 Минский район, д. Боровляны, ул. Фрунзенская, 43

https://orcid.org/0000-0002-8304-1005LipayN. V.ЛипайН. В.
Belarus

43 Frunzenskaya St., Borovlyany, Minsk region 223053, Republic of Belarus

Республика Беларусь, 223053 Минский район, д. Боровляны, ул. Фрунзенская, 43

https://orcid.org/0000-0003-0233-7718DmitrievE. V.ДмитриевЕ. В.
Belarus

43 Frunzenskaya St., Borovlyany, Minsk region 223053, Republic of Belarus

Республика Беларусь, 223053 Минский район, д. Боровляны, ул. Фрунзенская, 43

Belarusian Research Center for Pediatric Oncology, Hematology and ImmunologyГУ «Республиканский научно-практический центр детской онкологии, гематологии и иммунологии» Минздрава Республики Беларусь2607201914213232507201925072019https://oncohematology.abvpress.ru/ongm/article/view/344

Objective: to clarify the conditions for the occurrence of thrombosis and assess the effect of anticoagulant therapy on the survival and outcome of thrombosis in children, adolescents and young adults with acute lymphoblastic leukemia (ALL) receiving program chemotherapy.

Materials and methods. The study included 592 patients with ALL received program chemotherapy from 2008 to 2017 in the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (Minsk, Belarus). Of them, in 42 patients various localization venous thrombosis was detected at different therapy phase.

Results. The cumulative detection rate of thrombosis was 7.5 ± 1.1 %. The use of pegelated asparaginase (PEG-asp) at a dose of 1000 IU/m2 in induction therapy increased the relative risk of thrombosis in the first 5 weeks of treatment by 3 times (relative risk 3.4; 95 % confidence  interval 0.98–11.9), compared to patients not receiving PEG-asp. The cumulative detection rate of thrombosis in patients with the post-induction L-asparaginase (L-asp) 25,000 IU/m2 regimen was 14.7 ± 2.6 %, which was higher (p = 0.0536) than when using L-asp in other dosing regimens. In addition to ALL as the main disease, taking chemotherapy drugs, other risk factors for thrombosis (thrombophilia, the presence of antiphospholipid antibodies, a decrease of natural anticoagulants activity) in various combinations were in half (23 of 42) patients with venous thrombosis. Therapeutic dose of low molecular weight heparins (LMWH) 150–200 IU/kg received 30 patients. Reduced for the period of thrombocytopenia from 100 to 35 × 109/L for up to 4 weeks, a daily dose of LMWH was received by 12 patients. The dose of LMWH was reduced in proportion to the blood platelets count. After the recovery of the platelet count of more than 100 × 109/L, patients continued treatment of LMWH in a daily dose of 150–200 anti-Xa IU/kg. Reducing of LMWH dose during thrombocytopenia period did not affect the outcome of thrombosis (χ2 = 0.494; p = 0.78). Among 42 patients with thrombosis, 38 completed maintenance therapy, eventfree survival was 83.0 ± 8.0%, which did not differ (p = 0.654) from that (81.0 ± 2.0 %) in patients without thrombosis. 

Conclusion. The presence of venous thrombosis with the use of LMWH as antithrombotic therapy did not lead to a decrease in the event-free survival of ALL patients, compared with those without thrombosis. Reducing the therapeutic dose of LMWH did not affect the outcome of thrombosis in the analyzed groups.

Цель исследования – уточнить условия возникновения тромбозов и оценить влияние антикоагулянтной терапии на выживаемость и исход тромбоза у детей, подростков и молодых взрослых с острым лимфобластным лейкозом (ОЛЛ), получающих программную химиотерапию.

Материалы и методы. В исследование включены 592 пациента, получавших терапию по поводу ОЛЛ в РНПЦ ДОГИ (Минск, Беларусь) с 2008 по 2017 г. Из них у 42 пациентов на различных этапах терапии зарегистрировано развитие венозного тромбоза различной локализации.

Результаты. Кумулятивная частота выявления тромбоза составила 7,5 ± 1,1 %. Применение пегилированной аспарагиназы (PEG-asp) в дозе 1000 МЕ / м2 на этапе индукционной терапии увеличило относительный риск возникновения тромбоза в первые 5 нед лечения в 3 раза (относительный риск 3,4; 95 % доверительный интервал 0,98–11,9) по сравнению с пациентами, не получавшими PEG-asp. Кумулятивная частота выявления тромбозов у пациентов с режимом постиндукционной L-аспарагиназы (L-asp) в дозе 25 000 МЕ / м2 составила 14,7 ± 2,6 %, что было выше (р = 0,0536), чем при использовании L-asp в других режимах дозирования. Кроме ОЛЛ как основного заболевания, приема химиопрепаратов, другие факторы риска развития тромбоза (тромбофилия, наличие антифосфолипидных антител, снижение активности естественных антикоагулянтов) в различном сочетании были у половины (23 из 42) пациентов с венозным тромбозом. Терапевтическую дозу низкомолекулярных гепаринов (НМГ) 150–200 МЕ / кг получали 30 пациентов. На период тромбоцитопении от 100 до 35 × 109 / л продолжительностью до 4 нед редуцированную суточную дозу НМГ получали 12 пациентов. Редукция дозы НМГ проводилась пропорционально содержанию тромбоцитов в крови. После восстановления содержания тромбоцитов более 100 × 109 / л пациенты продолжали лечение НМГ в суточной дозе 150–200 анти-Ха МЕ / кг. Редуцирование дозы НМГ на этапе химиоиндуцированной тромбоцитопении не повлияло на исход тромбоза (χ2 = 0,494; p = 0,78). Завершили поддерживающую терапию 38 из 42 пациентов с тромбозом, бессобытийная выживаемость составила 83,0 ± 8,0 %, что не отличалось (р = 0,654) от таковой у пациентов без тромбозов (81,0 ± 2,0 %).

Заключение. Наличие венозного тромбоза на фоне предлагаемой схемы противотромботической терапии с применением НМГ не привело к снижению бессобытийной выживаемости пациентов с ОЛЛ по сравнению с пациентами, не имевшими тромбозов. Редуцирование терапевтической дозы НМГ не повлияло на исход тромбоза в анализируемых группах. 

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DOI: 01.2005/JCPSP.1517.Kenet G., Lütkhoff L.K., Albisetti M. et al. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies. Circulation 2010;121(16):1838–47. DOI: 10.1161/CIRCULATIONAHA.109.913673.Kenet G., Lütkhoff L.K., Albisetti M. et al. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies. Circulation 2010;121(16):1838–47. DOI: 10.1161/CIRCULATIONAHA.109.913673.Mannucci P.M., Franchini M. Classic thrombophilic gene variants (2015). Thromb Haemost 2015;114(5):885–9. DOI: 10.1160/TH15-02-0141.Mannucci P.M., Franchini M. Classic thrombophilic gene variants (2015). Thromb Haemost 2015;114(5):885–9. DOI: 10.1160/TH15-02-0141.Zharkov P.A., Roitman E.V., Svirin P.V. et al. The risk of venous thromboembolism in children сarrying prothrombotic polymorphisms. Gematologiya i transfuziologiya = Hematology and Transfusiology 2012;57(4):27–34. (In Russ.).Zharkov P.A., Roitman E.V., Svirin P.V. et al. The risk of venous thromboembolism in children сarrying prothrombotic polymorphisms. Gematologiya i transfuziologiya = Hematology and Transfusiology 2012;57(4):27–34. (In Russ.).Babilonia K.M., Golightly L.K., Gutman J.A. et al. Antithrombotic therapy in patients with thrombocytopenic cancer: outcomes associated with reduced-dose, low-molecular-weight heparin during hospitalization. Clin Appl Thromb Hemost 2014;20(8):799–806. DOI: 10.1177/1076029614543140.Babilonia K.M., Golightly L.K., Gutman J.A. et al. Antithrombotic therapy in patients with thrombocytopenic cancer: outcomes associated with reduced-dose, low-molecular-weight heparin during hospitalization. Clin Appl Thromb Hemost 2014;20(8):799–806. DOI: 10.1177/1076029614543140.Dmitriev E.V. Nadroparin and dalteparin pharmacokinetics in thromboses complicated the treatment of children with on - cological diseases. The Book of Abstracts The Congress on Open Is - sues in Thrombosis and Hemostasis 2018 jointly with the 9th Russian Conference on Clinical Hemostasiology and Hemorheology, Saint Petersburg, Russia October 4–6, 2018, p 60. www.coith2018.com.Dmitriev E.V. Nadroparin and dalteparin pharmacokinetics in thromboses complicated the treatment of children with on - cological diseases. The Book of Abstracts The Congress on Open Is - sues in Thrombosis and Hemostasis 2018 jointly with the 9th Russian Conference on Clinical Hemostasiology and Hemorheology, Saint Petersburg, Russia October 4–6, 2018, p 60. www.coith2018.com.