Тромбогеморрагические осложнения при лечении больных острым лимфобластным лейкозом L-аспарагиназой

Г.М. Галстян, О.А. Полеводова, А.В. Баженов, В.В. Троицкая, О.А. Гаврилина, Д.Г. Гительзон, А.Э. Васильев, Е.Н. Паровичникова

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

Для переписки: Геннадий Мартинович Галстян, д-р мед. наук, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167; тел.: +7(916)488-50-73; e-mail: gengalst@gmail.com

Для цитирования: Галстян Г.М., Полеводова О.А., Баженов А.В. и др. Тромбогеморрагические осложнения при лечении больных острым лимфобластным лейкозом L-аспарагиназой. Клиническая онкогематология. 2018;11(1):89-99.

DOI: 10.21320/2500-2139-2018-11-1-89-99


РЕФЕРАТ

Настоящая статья представляет собой обзор литературы, посвященный применению L-аспарагиназы (АСП) при остром лимфобластном лейкозе (ОЛЛ), с описанием 2 собственных клинических наблюдений. Лечение АСП при проведении индукции ремиссии осложнилось у пациентов венозными тромбозами и кровоизлиянием в ЦНС. В обоих случаях эти осложнения возникли на фоне сниженной плазменной активности антитромбина III (АТ), гипофибриногенемии и тромбоцитопении. Обсуждаются факторы риска возникновения тромбогеморрагических осложнений у больных ОЛЛ во время лечения АСП, роль в их развитии сочетанной терапии АСП с антрациклинами, пероральными контрацептивами, глюкокортикостероидами, наличия тромбофилии и центрального венозного катетера. Описаны возможные механизмы развития тромбозов, определены наиболее вероятные сроки их возникновения, локализация. В статье приводятся различные варианты профилактики и лечения тромбогеморрагических осложнений у больных ОЛЛ во время лечения АСП. Рекомендуется у всех больных ОЛЛ, получающих АСП, исследовать в плазме концентрацию фибриногена и активность АТ до начала лечения, на 3-й день после введения препарата и далее каждые 5–7 дней на протяжении 3 нед. после введения. Новые пероральные антикоагулянты не зависят от активности АТ в крови и могут использоваться для профилактики и лечения тромботических осложнений, связанных с АСП. Приводятся рекомендации по коррекции содержания АТ и гипофибриногенемии.

Ключевые слова: L-аспарагиназа, осложнения, тромбоз, тромбоэластография, антитромбин III, гипофибриногенемия, тромбоцитопения, новые пероральные антикоагулянты.

Получено: 16 августа 2017 г.

Принято в печать: 27 октября 2017 г.

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ЛИТЕРАТУРА

  1. Савченко В.Г., Паровичникова Е.Н., Афанасьев Б.В. и др. Национальные клинические рекомендации по диагностике и лечению острых миелоидных лейкозов взрослых. Гематология и трансфузиология. 2014;59(1):1–32. [Savchenko VG, Parovichnikova EN, Afanas’ev BV, et al. National clinical recommendations for the diagnosis and treatment of acute myeloid leukemia in adults. Gematologiya i transfuziologiya. 2014;59(1):1–32. (In Russ)]
  2. Asselin BL. The three asparaginases. In: Kaspers GJL, Pieters R, Veerman AJP, eds. Drug Resistance in Leukemia and Lymphoma III. Advances in Experimental Medicine and Biology, vol. 457. Boston: Springer; 1999. pp. 621–9. doi: 10.1007/978-1-4615-4811-9_69.
  3. Попа А.В. Возможности адекватного выбора различных препаратов аспарагиназы. Онкогематология. 2007;1:52–6. [Popa AV. The abilities of adequate choice of different asparaginase products. Onkogematologiya. 2007;1:52–6. (In Russ)]
  4. Priest JR, Ramsay NK, Steinherz PG, et al. A syndrome of thrombosis and hemorrhage complicating L-asparaginase therapy for childhood acute lymphoblastic leukemia. J Pediatr. 1982;100(6):984–9. doi: 10.1016/s0022-3476(82)80535-0.
  5. Caruso V, Iacoviello L, Castelnuovo A Di, et al. Thrombotic complications in childhood acute lymphoblastic leukemia : a meta-analysis of 17 prospective studies comprising 1752 pediatric patients. Blood. 2006;108(7):2216–22. doi: 10.1182/blood-2006-04-015511.
  6. Rozen L, Noubouossie D, Dedeken L, et al. Different profile of thrombin generation in children with acute lymphoblastic leukaemia treated with native or pegylated asparaginase: A cohort study. Pediatr Blood Cancer. 2017;26(2):294–301. doi: 10.1002/pbc.26228.
  7. Caruso V, Iacoviello L, Di Castelnuovo A, et al. Venous thrombotic complications in adults undergoing induction treatment for acute lymphoblastic leukemia: results from a meta-analysis. J Thromb Haemost. 2007;5(3):621–3. doi: 10.1111/j.1538-7836.2007.02383.x.
  8. Ranta S, Heyman MM, Jahnukainen K, et al. Antithrombin deficiency after prolonged asparaginase treatment in children with acute lymphoblastic leukemia. Blood Coagul Fibrinol.  2013;24(7):749–56. doi: 10.1097/mbc.0b013e328363b147.
  9. Abbott LS, Deevska M, Fernandez CV, et al. The impact of prophylactic fresh-frozen plasma and cryoprecipitate on the incidence of central nervous system thrombosis and hemorrhage in children with acute lymphoblastic leukemia receiving asparaginase. Blood. 2009;114(25):5146–51. doi: 10.1182/blood-2009-07-231084.
  10. Grace RF, Dahlberg SE, Neuberg D, et al. The frequency and management of asparaginase-related thrombosis in paediatric and adult patients with acute lymphoblastic leukaemia treated on Dana-Farber Cancer Institute consortium protocols. Br J Haematol. 2011;152(4):452–9. doi: 10.1111/j.1365-2141.2010.08524.x.
  11. Merlen C, Bonnefoy A, Wagner E, et al. L-Asparaginase Lowers Plasma Antithrombin and Mannan-Binding-Lectin Levels: Impact on Thrombotic and Infectious Events in Children With Acute Lymphoblastic Leukemia. Pediatr Blood Cancer. 2015;62(8):1381–7. doi: 10.1002/pbc.25515.
  12. Mizrahi T, Leclerc J-M, David M, et al. ABO Group as a Thrombotic Risk Factor in Children With Acute Lymphoblastic Leukemia: A Retrospective Study of 523 Patients. J Pediatr Hematol Oncol. 2015;37(5):e328–32. doi: 10.1097/mph.0000000000000333.
  13. Lauw MN, Van der Holt B, Middeldorp S, et al. Venous thromboembolism in adults treated for acute lymphoblastic leukaemia: Effect of fresh frozen plasma supplementation. Thromb Haemost. 2013;109(4):633–42. doi: 10.1160/th12-11-0845.
  14. Mitchell LG, Andrew M, Hanna K, et al. A prospective cohort study determining the prevalence of thrombotic events in children with acute lymphoblastic leukemia and a central venous line who are treated with L-asparaginase: results of the Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated with Asparaginase (PARKAA) Study. Cancer. 2003;97(2):508–16. doi: 10.1002/cncr.11042.
  15. Sibai H, Seki JT, Wang TQ, et al. Venous thromboembolism prevention during asparaginase-based therapy for acute lymphoblastic leukemia. Curr Oncol. 2016;23(4):e355–61. doi: 10.3747/co.23.3077.
  16. Goyal G, Bhatt VR. L-asparaginase and venous thromboembolism in acute lymphocytic leukemia. Fut Oncol. 2015;11(17):2459–70. doi: 10.2217/fon.15.114.
  17. Couturier M-A, Huguet F, Chevallier P, et al. Cerebral venous thrombosis in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma during induction chemotherapy with l-asparaginase: The GRAALL experience. Am J Hematol. 2015;90(11):986–91. doi: 10.1002/ajh.24130.
  18. Wani NA, Kosar T, Pala NA, Qureshi UA. Sagittal sinus thrombosis due to L-asparaginase. J Pediatr Neurosci. 2010;5(1):32–5. doi: 10.4103/1817-1745.66683.
  19. Guzman-Uribe P, Vargas-Ruiz AG. Thrombosis in Leukemia: Incidence, Causes, and Practical Management. Curr Oncol Rep. 2015;17(5):444. doi: 10.1007/s11912-015-0444-2.
  20. Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in adults with philadelphia chromosome-negative acute lymphoblastic leukemia: The GRAALL-2003 study. J Clin Oncol. 2009;27(6):911–8. doi: 10.1200/jco.2008.18.6916.
  21. Santoro N, Colombini A, Silvestri D, et al. Screening for coagulopathy and identification of children with acute lymphoblastic leukemia at a higher risk of symptomatic venous thrombosis: an AIEOP experience. J Pediatr Hematol Oncol. 2013;35(5):348–55. doi: 10.1097/mph.0b013e31828dc614.
  22. Pui C, Chesney CM, Bergum PW, et al. Lack of pathogenetic role of proteins C and S in thrombosis associated with asparaginase-prednisone-vincristine therapy for leukaemia. Br J Haematol. 1986;64(2):283–90. doi: 10.1111/j.1365-2141.1986.tb04121.x.
  23. Mauz-Korholz C, Junker R, Gobel U, Nowak-Gottl U. Prothrombotic risk factors in children with acute lymphoblastic leukemia treated with delayed E. coli asparaginase (COALL-92 and 97 protocols). Thromb Haemost. 2000;83(6):840–3.
  24. Risseeuw-Appel IM, Dekker I, Hop WC, Hahlen K. Minimal effects of E. coli and Erwinia asparaginase on the coagulation system in childhood acute lymphoblastic leukemia: a randomized study. Med Pediatr Oncol. 1994;23(4):335–43. doi: 10.1002/mpo.2950230404.
  25. Domenech C, Thomas X, Chabaud S, et al. L-asparaginase loaded red blood cells in refractory or relapsing acute lymphoblastic leukaemia in children and adults: Results of the GRASPALL 2005-01 randomized trial. Br J Haematol. 2011;153(1):58–65. doi: 10.1111/j.1365-2141.2011.08588.x.
  26. Nowak-Gottl U, Ahlke E, Fleischhack G, et al. Thromboembolic events in children with acute lymphoblastic leukemia (BFM protocols): prednisone versus dexamethasone administration. Blood. 2003;101(7):2529–33. doi: 10.1182/blood-2002-06-1901.
  27. Hernandez-Espinosa D, Minano A, Ordonez A, et al. Dexamethasone induces a heat-stress response that ameliorates the conformational consequences on antithrombin of L-asparaginase treatment. J Thromb Haemostasis. 2009;7(7):1128–33. doi: 10.1111/j.1538-7836.2009.03449.x.
  28. Hunault-Berger M, Chevallier P, Delain M, et al. Changes in antithrombin and fibrinogen levels during induction chemotherapy with L-asparaginase in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma. Use of supportive coagulation therapy and clinical outcome: The CAPELAL study. Haematologica. 2008;93(10):1488–94. doi: 10.3324/haematol.12948.
  29. Ueno T, Ohtawa K, Mitsui K, et al. Cell cycle arrest and apoptosis of leukemia cells induced by L-asparaginase. Leukemia. 1997;11(11):1858–61. doi: 10.1038/sj.leu.2400834.
  30. Sugimoto K, Suzuki HI, Fujimura T, et al. A clinically attainable dose of L-asparaginase targets glutamine addiction in lymphoid cell lines. Cancer Sci. 2015;106(11):1534–43. doi: 10.1111/cas.12807.
  31. De Stefano V, Za T, Ciminello A, et al. Haemostatic alterations induced by treatment with asparaginases and clinical consequences. Thromb Haemost. 2015;113(2):247–61. doi: 10.1160/th14-04-0372.
  32. Giordano P, Molinari AC, Del Vecchio GC, et al. Prospective study of hemostatic alterations in children with acute lymphoblastic leukemia. Am J Hematol. 2010;85(5):325–30. doi: 10.1002/ajh.21665.
  33. Nowak-Gottl U, Boos J, Wolff J, et al. Asparaginase decreases clotting factors in vitro: a possible pitfall? Int J Clin Lab Res. 1995;25(3):146–8. doi: 10.1007/bf02592556.
  34. Bushman JE, Palmieri D, Whinna HC, Church FC. Insight into the mechanism of asparaginase-induced depletion of antithrombin III in treatment of childhood acute lymphoblastic leukemia. Leuk Res. 2000;24(7):559–65. doi: 10.1016/s0145-2126(00)00017-5.
  35. Priest JR, Ramsay NKC, Bennett AJ, et al. The effect of L-asparaginase on antithrombin, plasminogen, and plasma coagulation during therapy for acute lymphoblastic leukemia. J Pediatr. 1982;100(6):990–5. doi: 10.1016/s0022-3476(82)80536-2.
  36. Mazzucconi MG, Gugliotta L, Leone G, et al. Antithrombin III infusion suppresses the hypercoagulable state in adult acute lymphoblastic leukaemia patients treated with a low dose of Escherichia coli L-asparaginase. A GIMEMA study. Blood Coagul Fibrinol. 1994;5(1):23–8. doi: 10.1097/00001721-199402000-00004.
  37. Mitchell L, Andrew M, Hanna K, et al. Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study. Thromb Haemost. 2003;90(2):235–44. doi: 10.1160/th02-11-0283.
  38. Farrell K, Fyfe A, Allan J, et al. An antithrombin replacement strategy during asparaginase therapy for acute lymphoblastic leukemia is associated with a reduction in thrombotic events. Leuk Lymphoma. 2016;57(11):2567–74. doi: 10.3109/10428194.2016.1165815.
  39. Elhasid R, Lanir N, Sharon R, et al. Prophylactic therapy with enoxaparin during L-asparaginase treatment in children with acute lymphoblastic leukemia. Blood Coagul Fibrinol. 2001;12(5):367–70. doi: 10.1097/00001721-200107000-00005.
  40. Meister B, Kropshofer G, Klein-Franke A, et al. Comparison of low-molecular-weight heparin and antithrombin versus antithrombin alone for the prevention of symptomatic venous thromboembolism in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2008;50(2):298–303. doi: 10.1002/pbc.21222.
  41. Plander M, Szendrei T, Bodo I, Ivanyi JL. Successful treatment with rivaroxaban of an extended superficial vein thrombosis in a patient with acquired antithrombin deficiency due to Peg-asparaginase treatment. Ann Hematol. 2015;94(7):1257–8. doi: 10.1007/s00277-015-2368-1.