bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2020-65-4-370-385bloodjour-241Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESРезультаты проспективного исследования по наблюдению больных хроническим миелолейкозом после прекращения терапии ингибиторами тирозинкиназA prospective study of the monitoring of patients with chronic myeloid leukemia upon withdrawal of tyrosine kinase inhibitor therapyhttps://orcid.org/0000-0001-9947-2371ТуркинаА. Г.TurkinaA. G.

Туркина Анна Григорьевна, доктор медицинских наук, профессор, руководитель научно-консультативного отделения химиотерапии миелопролиферативных заболеваний

125167, Москва

Anna G. Turkina, Dr. Sci. (Med.), Professor, Head of the Scientific Advisory Department of Chemotherapy of Myeloproliferative Disorders

125167, Moscow

turkianna@yandex.ruhttps://orcid.org/0000-0001-5730-2593ПетроваА. Н.PetrovaA. N.

Петрова Анна Николаевна, аспирант научно-консультативного отделения химиотерапии миелопролиферативных заболеваний

125167, Москвател.: +7 (495) 612-16-36, +7 (917) 519-32-66 

Anna N. Petrova, Postgraduate Student, Scientific Advisory Department of Chemotherapy of Myeloproliferative Disorders

125167, Moscowtel.: +7 (495) 612-16-36, +7 (917) 519-32-66 

ap996@mail.ruhttps://orcid.org/0000-0001-6423-1789ЧелышеваЕ. Ю.ChelyshevaE. Yu.

Челышева Екатерина Юрьевна, кандидат медицинских наук, ведущий научный сотрудник научно-консультативного отделения химиотерапии миелопролиферативных заболеваний

125167, Москва

Ekaterina Yu. Chelysheva, Cand. Sci. (Med.), Leading Researcher, Scientific Advisory Department of Chemotherapy of Myeloproliferative Disorders

125167, Moscow

denve@bk.ruhttps://orcid.org/0000-0001-5393-0816ШуховО. А.ShukhovO. A.

Шухов Олег Александрович, кандидат медицинских наук, старший научный сотрудник научно-консультативного отделения химиотерапии миелопролиферативных заболеваний

125167, Москва

Oleg A. Shukhov, Cand. Sci. (Med.), Senior Researcher, Scientific Advisory Department of Chemotherapy of Myeloproliferative Disorders

125167, Moscow

shuhov@list.ruhttps://orcid.org/0000-0001-7816-808XЦыбаН. Н.TsybaO. N.

Цыба Николай Николаевич, доктор медицинских наук, аналитик научно-консультативного отделения химиотерапии миелопролиферативных заболеваний

125167, Москва

Nikolay N. Tsyba, Dr. Sci. (Med.), Analyst, Scientific Advisory Department of Chemotherapy of Myeloproliferative Disorders

125167, Moscow

tsyba2007@yandex.ruhttps://orcid.org/0000-0002-6523-9157ГоленковА. К.GolenkovA. K.

Голенков Анатолий Константинович, доктор медицинских наук, профессор, руководитель отделения клинической гематологии и иммунотерапии

129110, Москва

Anatolii K. Golenkov, Dr. Sci. (Med.), Professor, Head of the Department of Clinical Hematology and Immunotherapy

129110, Moscow

a.golenkov@monikiweb.ruhttps://orcid.org/0000-0002-4604-2842ВысоцкаяЛ. Л.VysotskaiaL. L.

Высоцкая Людмила Леонидовна, кандидат медицинских наук, старший научный сотрудник отделения клинической гематологии и иммунотерапии

129110, Москва

Liudmila L. Vysotskaia, Cand. Sci. (Med.), Senior Researcher, Department of Clinical Hematology and Immunotherapy

129110, Moscow

nora-mila@yandex.ruhttps://orcid.org/0000-0002-3123-8316БыковаА. В.BykovaA. V.

Быкова Анастасия Витальевна, врач научно-консультативного отделения химиотерапии миелопролиферативных заболеваний

125167, Москва

Anastasiya V. Bykova, Physician, Scientific Advisory Department of Chemotherapy of Myeloproliferative Disorders

125167, Moscow

ivlutaya@mail.ruhttps://orcid.org/0000-0001-9178-1428НемченкоИ. С.NemchenkoI. S.

Немченко Ирина Семеновна, кандидат медицинских наук, врач научноконсультативного отделения химиотерапии миелопролиферативных заболеваний

125167, Москва

Irina S. Nemchenko, Cand. Sci. (Med.), Physician, Scientific Advisory Department of Chemotherapy of Myeloproliferative Disorders

125167, Moscow

isn1965@mail.ruhttps://orcid.org/0000-0001-5244-5819ГусароваГ. А.GusarovaG. A.

Гусарова Галина Анатольевна, кандидат медицинских наук, врач научно-консультативного отделения химиотерапии миелопролиферативных заболеваний

125167, Москва

Galina A. Gusarova, Cand. Sci. (Med.), Physician, Scientific Advisory Department of Chemotherapy of Myeloproliferative Disorders

125167, Moscow

galina1966@bk.ruhttps://orcid.org/0000-0002-5762-9171ПоспеловаО. М.PospelovaO. M.

Поспелова Ольга Михайловна, врач научно-консультативного отделения химиотерапии миелопролиферативных заболеваний

125167, Москва

Olga M. Pospelova, Physician, Scientific Advisory Department of Chemotherapy of Myeloproliferative Disorders

125167, Moscow

pospelova.olga@mail.ruhttps://orcid.org/0000-0001-9984-389XГурьяноваМ. А.GurianovaM. A.

Гурьянова Марина Анатольевна, врач научно-консультативного отделения химиотерапии миелопролиферативных заболеваний

125167, Москва

Margarita A. Gurianova, Physician, Scientific Advisory Department of Chemotherapy of Myeloproliferative Disorders

125167, Moscow

margarita.samtcova@yandex.ruhttps://orcid.org/0000-0001-5958-0490МартынкевичИ. С.MartynkevichI. S.

Мартынкевич Ирина Степановна, доктор биологических наук, руководитель лаборатории молекулярной генетики

191024, Санкт-Петербург

Irina S. Martynkevich, Dr. Sci. (Biol.), Head of the Laboratory of Molecular Genetics

191024, St. Petersburg

genetics.spb@mail.ruhttps://orcid.org/0000-0003-2530-808XАбдуллаевА. О.AbdullaevA. O.

Абдуллаев Адхамжон Одилович, кандидат медицинских наук, старший научный сотрудник лаборатории молекулярной гематологии заболеваний

125167, Москва

Adkhamzhon O. Abdullaev, Cand. Sci. (Med.), Senior Researcher, Laboratory of Molecular Hematology

125167, Moscow

adham_abdullaev@mail.ruhttps://orcid.org/0000-0001-9463-9187СудариковА. Б.SudarikovA. B.

Судариков Андрей Борисович, доктор биологических наук, руководитель лаборатории молекулярной гематологии заболеваний

125167, Москва

Andrei B. Sudarikov, Dr. Sci. (Biol.), Head of the Laboratory of Molecular Hematology

125167, Moscow

andrey@sudarikov.nethttps://orcid.org/0000-0002-6288-7570КуликовС. М.KulikovS. M.

Куликов Сергей Михайлович, кандидат технических наук, руководитель информационно-аналитического отдела заболеваний

125167, Москва

Sergei M. Kulikov, Cand. Sci. (Tech.), Head of the Information and Analytical Department

125167, Moscow

smkulikov@mail.ruhttps://orcid.org/0000-0001-8188-5557СавченкоВ. Г.SavchenkoV. G.

Савченко Валерий Григорьевич, академик РАН, доктор медицинских наук, профессор, генеральный директор

125167, Москва

Valeriy G. Savchenko, Dr. Sci. (Med), Full Member of the Russian Academy of Sciences, Professor, Director

125167, Moscow

director@blood.ruФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской ФедерацииРоссияNational Research Center for HematologyRussian FederationГБУЗ МО «Московский областной научно-исследовательский клинический институт им. М. В. Владимирского»РоссияVladimirsky Moscow Regional Research and Clinical InstituteRussian FederationФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства»РоссияRussian Scientific Research Institute of Hematology and TransfusiologyRussian Federation202009122020654370385Copyright © Туркина А.Г., Петрова А.Н., Челышева Е.Ю., Шухов О.А., Цыба Н.Н., Голенков А.К., Высоцкая Л.Л., Быкова А.В., Немченко И.С., Гусарова Г.А., Поспелова О.М., Гурьянова М.А., Мартынкевич И.С., Абдуллаев А.О., Судариков А.Б., Куликов С.М., Савченко В.Г., 20202020Туркина А.Г., Петрова А.Н., Челышева Е.Ю., Шухов О.А., Цыба Н.Н., Голенков А.К., Высоцкая Л.Л., Быкова А.В., Немченко И.С., Гусарова Г.А., Поспелова О.М., Гурьянова М.А., Мартынкевич И.С., Абдуллаев А.О., Судариков А.Б., Куликов С.М., Савченко В.Г.Turkina A.G., Petrova A.N., Chelysheva E.Y., Shukhov O.A., Tsyba O.N., Golenkov A.K., Vysotskaia L.L., Bykova A.V., Nemchenko I.S., Gusarova G.A., Pospelova O.M., Gurianova M.A., Martynkevich I.S., Abdullaev A.O., Sudarikov A.B., Kulikov S.M., Savchenko V.G.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/241Введение

Введение. Внедрение в клиническую практику ингибиторов тирозинкиназ (ИТК) привело к радикальному изменению прогноза у больных хроническим миелолейкозом (ХМЛ). В связи с нежелательными явлениями терапии ИТК и затратами, связанными с лечением, актуальным является вопрос о возможности прекращения терапии ИТК. Цель: оценить результаты наблюдения больных ХМЛ после прекращения терапии ИТК.

Материалы и методы

Материалы и методы. В проспективное исследование было включено 98 больных ХМЛ в хронической фазе, соответствующих следующим критериям: терапия любыми ИТК длительностью ≥ 3 лет, глубокий молекулярный ответ (МО, BCR-ABL ≤ 0,01 % IS) длительностью ≥ 2 лет. После прекращения терапии ИТК количественная оценка BCR-ABL проводилась ежемесячно в первые 6 месяцев наблюдения, каждые 2 месяца до 1 года и каждые 3 месяца, начиная со второго года наблюдения. Терапию возобновляли при потере большого МО (БМО, BCR-ABL ≥ 0,1 % IS).

Результаты

Результаты. Потеря БМО после отмены ИТК отмечалась у 48 (49 %) больных. Выживаемость без потери БМО после прекращения терапии составила 52 % через 24 месяца при медиане наблюдения 35 месяцев (23–52 месяца). Факторами, достоверно связанными с сохранением БМО после отмены терапии, были длительность терапии ИТК, длительность глубокого МО и глубина МО на момент прекращения лечения. Не обнаружено достоверного влияния на вероятность сохранения ремиссии без молекулярного рецидива следующих факторов: пол, возраст, группа риска по Sokal, вид и линия терапии ИТК на момент отмены, а также резистентность к иматинибу в анамнезе. БМО был восстановлен у всех 48 больных, возобновивших терапию ИТК вследствие молекулярного рецидива. У 65 % больных перед прекращением лечения наблюдались нежелательные явления терапии ИТК, которые полностью разрешились у всех больных к 6 месяцам наблюдения. У 42 % больных наблюдался скелетно-мышечный болевой синдром («синдром отмены») в период наблюдения без терапии ИТК, который не привел к возобновлению ИТК ни у одного больного. Развитие «синдрома отмены» ассоциировалось со старшим возрастом и более длительным сроком терапии ИТК перед прекращением лечения.

Заключение

Заключение. Выживаемость без молекулярного рецидива у больных ХМЛ в ремиссии без лечения (РБЛ) сопоставима с данными других исследований. Безопасность наблюдения в РБЛ подтверждается отсутствием случаев прогрессии заболевания и восстановлением БМО после возобновления терапии ИТК у 100 % больных.

Introduction

Introduction. The advent of tyrosine kinase inhibitors (TKIs) in clinical practice drastically improved prognosis in patients with chronic myeloid leukaemia (CML). Adverse events of the TKI therapy and its high financial burden warrant the trend to gradually abandon this treatment.

Aim

Aim. To assess the results of CML patient monitoring after the withdrawal of TKI therapy.

Patients and methods

Patients and methods. This prospective study included 98 chronic phase CML patients satisfying the criteria: any receiving of TKI therapy for ≥3 years; deep molecular response (DMR, BCR-ABL ≤ 0.01 % IS) during ≥ 2 years. The withdrawal was followed by quantitative BCR-ABL estimation performed monthly for the first 6 months of the survey, bimonthly for 1 year and every 3 months from the second year onwards. Therapy was resumed at a loss of major molecular response (MMR, BCR-ABL ≥ 0.1 % IS).

Results

Results. The MMR loss upon the TKI withdrawal was observed in 48 (49 %) patients. Survival without MMR loss was 52 % past 24 months since withdrawal, with a median of 35 months (23–52). The duration of therapy, MR and the MR depth at the time of withdrawal significantly correlated with a conserved post-therapy MMR. Gender, age, a Sokal risk group, type and line of TKI therapy at withdrawal, and imatinib resistance in history were not observed to significantly impact molecular relapse-free remission. MMR was recovered in all 48 patients with TKI therapy resumed in molecular relapse. In 65 % of the patients, adverse therapy events observed during treatment completely resolved by 6 months of post-therapy monitoring. Musculoskeletal pain (withdrawal syndrome, WS) was reported in 42 % patients in the post-therapeutic period, which did not lead to TKI resumption. The WS development correlated with an elder age and longer therapy prior to withdrawal.

Conclusion

Conclusion. Molecular relapse-free survival in CML patients with treatment-free remission (TFR) is comparable to other published evidence. Monitoring safety during TFR is attested by the lack of disease progression and MMR recovery upon TKI resumption in all patients.

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