bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2023-68-2-166-181bloodjour-453Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESПрименение пэгаспаргазы у взрослых больных Ph-негативными острыми лимфобластными лейкозами в рамках лечения по протоколу «ОЛЛ-2016»The use of pegaspargase in adult Ph-negative acute lymphoblastic leukemia patients in the treatment according to the all-2016 protocolhttps://orcid.org/0000-0002-9969-8482АлешинаО. А.AleshinaO. A.

Алешина Ольга Александровна, кандидат  медицинских наук, заведующая отделением гематологии и химиотерапии острых лейкозов и лимфом

125167, Москва

Olga A. Aleshina, Cand. Sci. (Med.), Head of the Department of Hematology and Chemotherapy of Acute Leukemias and Lymphomas

125167, Moscow

dr.gavrilina@mail.ruhttps://orcid.org/0000-0002-7968-1923КотоваЕ. С.KotovaE. S.

Котова Екатерина Сергеевна, гематолог дневного стационара онкологии и химиотерапии гемобластозов и депрессий кроветворения

125167, Москва

Ekaterina  S.  Kotova, Hematologist, Department of Oncology and Chemotherapy for Hemoblastosis and Hematopoietic Depressions

125167, Moscow

https://orcid.org/0000-0003-2763-5391ИсиноваГ. А.IsinovaG. A.

Исинова Галина Александровна, кандидат медицинских наук, гематолог отделения интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения с блоком трансплантации гемопоэтических стволовых клеток и костного мозга

125167, Москва

Galina A. Isinova, Cand. Sci. (Med.), Hematologist, Department of Intensive High-Dose Chemotherapy for Hemoblastosis and Hematopoietic Depressions with Hematopoietic Stem Cell and Bone Marrow Transplantation Unit

125167, Moscow

https://orcid.org/0000-0002-2663-7128ГришунинаМ. Е.GrishuninaM. E.

Гришунина Мария Евгеньевна, гематолог

603126, Нижний Новгород

Maria E. Grishunina, Hematologist

603126, Nizhny Novgorod

https://orcid.org/0000-0001-6371-6792СвешниковаЮ. В.SveshnikovaJ. V.

Свешникова Юлия Валентиновна, гематолог отделения гематологии, химиотерапии и трансплантации костного мозга

620102, Екатеринбург

Julia V. Sveshnikova, Hematologist, Department of Hematology, Chemotherapy and Bone Marrow Transplantation

620102, Ekaterinburg

https://orcid.org/0000-0001-6574-0518КаплановК. Д.KaplanovK. D.

Капланов Камиль Даниялович, кандидат медицинских наук, заведующий гематологическим отделением №  11

125284, Москва

Kamil D. Kaplanov, Cand. Sci. (Med.), Head of the Hematology Department No 11

125284, Moscow

https://orcid.org/0000-0002-2446-8092БондаренкоС. Н.BondarenkoS. N.

Бондаренко Сергей Николаевич, доктор медицинских наук, доцент, кафедры гематологии, трансфузиологии и трансплантологии с курсом детской онкологии ФПО имени профессора Б.В. Афанасьева

197022, Санкт-Петербург

Sergey N. Bondarenko, Dr. Sci. (Med.), Associate Professor, Department of Hematology, Transfusiology and Transplantology with a Course in Pediatric Oncology, named Professor B.V. Afanasyev

197022, Saint-Petersburg

https://orcid.org/0000-0002-3981-8024ЗининаЕ. Е.ZininaE. E.

Зинина Елена Евгеньевна, заведующая клинико-диагностическим (гематологическим) центром;главный внештатный гематолог департамента здравоохранения Ханты-Мансийского автономного округа Югры

628408, Сургут

Elena E. Zinina, Head of the Clinical Diagnostic (Hematological) Center

628408, Surgut

https://orcid.org/0000-0001-8044-598XЧабаеваЮ. А.ChabaevaYu. A.

Чабаева Юлия Александровна, кандидат технических наук, старший научный сотрудник информационно-аналитического отдела

125167, Москва

Yulia A. Chabaeva, Cand. Sci. (Tech.), Deputy Head of the Information and Analysis Department

125167, Moscow

https://orcid.org/0000-0001-6177-3566ПаровичниковаЕ. Н.ParovichnikovaE. N.

Паровичникова Елена Николаевна, доктор медицинских наук, генеральный директор

125167, Москва

Elena N. Parovichnikova, Dr. Sci. (Med.), Head of the National Medical Research Center for Hematology

125167, Moscow

ФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской ФедерацииРоссияNational Research Center for HematologyRussian FederationГБУЗ Нижегородской области «Нижегородская областная клиническая больница им. Н.А. Семашко»РоссияN.A. Semashko Regional Clinical HospitalRussian FederationГАУ здравоохранения Свердловской области «Свердловская областная клиническая больница № 1»РоссияRegional Clinical Hospital No. 1Russian FederationГБУЗ «Городская клиническая больница им. С.П. Боткина» Департамента здравоохранения г. МосквыРоссияS.P. Botkin City Clinical HospitalRussian FederationФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова» Министерства здравоохранения Российской ФедерацииРоссияRaisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation, I.P. Pavlov First Saint-Petersburg State Medical UniversityRussian FederationБУ «Сургутская окружная клиническая больница»РоссияRegional Clinical HospitalRussian Federation202317072023682166181Copyright © Алешина О.А., Котова Е.С., Исинова Г.А., Гришунина М.Е., Свешникова Ю.В., Капланов К.Д., Бондаренко С.Н., Зинина Е.Е., Чабаева Ю.А., Паровичникова Е.Н., 20232023Алешина О.А., Котова Е.С., Исинова Г.А., Гришунина М.Е., Свешникова Ю.В., Капланов К.Д., Бондаренко С.Н., Зинина Е.Е., Чабаева Ю.А., Паровичникова Е.Н.Aleshina O.A., Kotova E.S., Isinova G.A., Grishunina M.E., Sveshnikova J.V., Kaplanov K.D., Bondarenko S.N., Zinina E.E., Chabaeva Y.A., Parovichnikova E.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.htjournal.ru/jour/article/view/453Введение

Введение. Существует несколько форм препаратов L-аспарагиназы, которые различаются по фармакокинетике, токсичности и другим характеристикам.

Цель — определить частоту развития различных видов токсичности L-аспарагиназы у взрослых больных Ph-негативными острыми лимфобластными лейкозами (ОЛЛ) при лечении по протоколу «ОЛЛ-2016».

Материалы и методы

Материалы и методы. В многоцентровое проспективное рандомизированное исследование «ОЛЛ-2016» включено 313 больных с впервые установленным диагнозом «Ph-негативный ОЛЛ». В электронную базу была введена информация по токсичности L-аспарагиназы у 256 больных. Соотношение мужчин и женщин — 155:101. Медиана возраста — 32 (18–54) года. Выполнен анализ 1253 курсов, которые включали введение L-аспарагиназы.

Результаты

Результаты. Токсичность и развитие побочных реакций L-аспарагиназы были диагностированы у 67  (26  %) из 256 больных. При проведении 102 (8 %) из 1253 курсов были осложнения, обусловленные введением L-аспарагиназы. Токсичность и развитие побочных реакций L-аспарагиназы 1–2-й степени были у 34 (51 %) больных: аллергические реакции — у 6 (18 %), тромбозы брахицефальных вен, ассоциированные с установкой венозного катетера, — у 2 (6 %), увеличение концентраций панкреатической амилазы в сыворотке крови и диастазы в моче без клинических признаков панкреатита — у 3 (9 %), нарушение белково-синтетической функции печени — у 23 (68 %), гепатотоксичность — у 15 (44 %). Токсичность L-аспарагиназы 3–4-й степени развилась у 33 (49 %) больных, из них 22 (67 %) потребовалась отмена препарата (медиана отмены — 3-е введение). Ни один больной не умер вследствие токсичности нативной формы препарата. Показатели 5-летней общей выживаемости (ОВ) и вероятности развития рецидива (ВРР) у больных, у которых была отмена препарата на этапах индукции ремиссии, по сравнению с больными, которым было продолжено лечение с включением L-аспарагиназы на этапах консолидации ремиссии и поддерживающей терапии, достоверно не различались: ОВ —89 % vs 70 % (р = 0,0921), ВРР — 47 % vs. 33 % (р = 0,8633).

Заключение

Заключение. У взрослых больных отмена L-аспарагиназы по причине токсичности в большинстве случаев была произведена на этапе индукции ремиссии. Возможно, замена нативной формы препарата на пегилированную форму позволит улучшить долгосрочные показатели выживаемости у этой группы больных.

Introduction

Introduction. There are several forms of the L-asparaginase which are characterized by differences in the half-life, the spectrum of toxicity as well as other factors.

Aim — to determine the incidence of different types of L-asparaginase toxicity in adult patients with Ph-negative acute lymphoblastic leukemia (ALL) treated according to the ALL-2016 protocol.

Materials and methods

Materials and methods. From December 2016 to February 2023 the multicenter prospective randomized study “ALL-2016” included 313 patients with newly diagnosed Ph-negative ALL. Information about the 256 patients who had toxicity of native L-asparaginase was entered into an electronic database. The ratio of men and women was 155:101. The median age was 32  (18–54) years. We analyzed 1253  courses of therapy that included the administration of L-asparaginase.

Results

Results. L-asparaginase toxicity and adverse reactions were diagnosed in 67 (26 %) of 256 patients. Of the 1253 courses, 102 (8 %) had complications associated with the administration of this drug. Grade 1–2 toxicity of L-asparaginase was diagnosed in 34 (51 %) patients: allergic reaction — in 6 (18 %), thrombosis of brachiocephalic veins associated with the installation of a central venous catheter — in 2 (6 %), increased pancreatic amylase in blood serum and diastase in urine, without clinical signs of pancreatitis — in 3 (9 %), lower protein-synthesis function of liver — in 23 (68 %), hepatotoxicity — in 15 (44 %). Grade 3–4 toxicity of L-asparaginase was diagnosed in 33 (49 %) patients, of which 22 (67 %) required discontinuation of the drug. The median of the development of complications of L-asparaginase was the third administration. None of the patients died as the result of the toxicity of native form of the drug. The 5-year overall survival (OS) and the probability of relapse (PR) in the group of patients in which L-asparaginase was discontinued at the stage of induction of remission and in the group of patients who continued L-asparaginase treatment at remission consolidation and maintenance therapy did not differ significantly: OS — 89 % vs 70 % (p = 0.0921), PR — 47 % vs 33 % (р = 0.8633).

Conclusion

Conclusion. In adult patients, L-asparaginase withdrawal due to toxicity, in most cases, occurs at the stage of the remission induction. It is possible that the replacement of the native form the drug to the pegylated one in adult patients with ALL, in whom L-asparaginase is canceled at the stage of remission induction, improves long-term survival rates.

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The authors declare that there are no conflicts of interest present.