bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2023-68-1-21-34bloodjour-429Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESОтдаленные результаты наблюдения больных хроническим миелолейкозом в ремиссии без леченияA long-term follow-up of observation in treatment-free remission in patients with chronic myeloid leukemiahttps://orcid.org/0000-0001-5730-2593ПетроваА. Н.PetrovaA. N.

Анна Николаевна Петрова, кандидат медицинских наук, научный сотрудник

отдел диагностики и лечения гематологических заболеваний

125167

Москва

Anna N. Petrova, Cand. Sci. (Med.), Researcher

Department of Diagnostics and Treatment of Hematology Diseases

125167

Moscow

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

Екатерина Юрьевна Челышева, доктор медицинских наук, ведущий научный сотрудник

отдел диагностики и лечения гематологических заболеваний

125167

Москва

Ekaterina Yu. Chelysheva, Dr. Sci. (Med.), Leading Researcher

Department of Diagnostics and Treatment of Hematology Diseases,

125167

Moscow

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

Ирина Семеновна Немченко, кандидат медицинских наук, гематолог

научно-клиническое отделение гематологии миелопролиферативных заболеваний

125167

Москва

Irina S. Nemchenko, Cand. Sci. (Med.), Hematologist

Scientific Clinical Department of Hematology of Myeloproliferative Disorders

125167

Moscow

isn1965@mail.ruhttps://orcid.org/0000-0002-3123-8316БыковаА. В.BykovaA. V.

Анастасия Витальевна Быкова, гематолог

научно-клиническое отделение гематологии миелопролиферативных заболеваний

125167

Москва

Anastasiya V. Bykova, Hematologist

Scientific Clinical Department of Hematology of Myeloproliferative Disorders

125167

Moscow

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

Марина Анатольевна Гурьянова, гематолог

отделение химиотерапии гематологических заболеваний

125167

Москва

Margarita A. Gurianova, Hematologist

Department of Chemotherapy of Неmatological Disorders

125167

Moscow

margarita.samtcova@yandex.ruhttps://orcid.org/0000-0002-9181-6050КузьминаЕ. А.KuzminaE. A.

Елена Андреевна Кузьмина, аспирант, гематолог

научно-клиническое отделение гематологии миелопролиферативных заболеваний

125167

Москва

Elena A. Kuzmina, Postgraduate, Hematologist

Scientific Clinical Department of Hematology of Myeloproliferative Disorders

125167

Moscow

111ekuzmina@gmail.comhttps://orcid.org/0000-0001-7816-808XЦыбаН. Н.TsybaN. N.

Николай Николаевич Цыба, доктор медицинских наук, аналитик

отдел диагностики и лечения гематологических заболеваний

125167

Москва

Nikolay N. Tsyba, Dr. Sci. (Med.), Analyst

Department of Diagnostics and Treatment of Hematology Diseases

125167

Moscow

tsyba2007@yandex.ruhttps://orcid.org/0000-0003-0261-5941КохноА. В.KokhnoA. V.

Алина Владимировна Кохно, кандидат медицинских наук, заведующаяотделом

отдел диагностики и лечения гематологических заболеваний

125167

Москва

Alina V. Kokhno, Cand. Sci. (Med.), Head of the Department

Department of Diagnostics and Treatment of Hematology Diseases

125167

Moscow

kohno.a@blood.ruhttps://orcid.org/0000-0001-9947-2371ТуркинаА. Г.TurkinaA. G.

Анна Григорьевна Туркина, доктор медицинских наук, профессор,руководитель отделения

научно-клиническое отделение гематологии миелопролиферативных заболеваний

125167

Москва

Anna G. Turkina, Dr. Sci. (Med.), Professor, Head of the Department

Scientific Clinical Department of Hematology of Myeloproliferative Disorders

125167

Moscow

turkianna@yandex.ruФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской ФедерацииРоссияNational Medical Research Center for HematologyRussian Federation2023110520236812134Copyright © Петрова А.Н., Челышева Е.Ю., Немченко И.С., Быкова А.В., Гурьянова М.А., Кузьмина Е.А., Цыба Н.Н., Кохно А.В., Туркина А.Г., 20232023Петрова А.Н., Челышева Е.Ю., Немченко И.С., Быкова А.В., Гурьянова М.А., Кузьмина Е.А., Цыба Н.Н., Кохно А.В., Туркина А.Г.Petrova A.N., Chelysheva E.Y., Nemchenko I.S., Bykova A.V., Gurianova M.A., Kuzmina E.A., Tsyba N.N., Kokhno A.V., Turkina A.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/429

   Введение. Опция наблюдения больных хроническим миелолейкозом (ХМЛ) без терапии ингибиторами тирозинкиназ (ИТК) включена в российские и международные клинические рекомендации и применяется в клинической практике. Тем не менее вопросы, касающиеся ремиссии без лечения (РБЛ), все еще являются предметом исследования.   Цель — представить отдаленные результаты наблюдения в РБЛ больных ХМЛ, участвующих в исследовании RU-SKI.   Больные и методы. В исследование включены 98 больных ХМЛ с длительностью терапии любыми ИТК ≥ 3 лет, с глубоким молекулярным ответом (МО, BCR-ABL ≤ 0,01 % IS) длительностью ≥ 2 лет. Терапию возобновляли при потере большого МО (БМО, BCR-ABL ≥ 0,1 % IS).   Результаты. При медиане наблюдения после отмены ИТК 64 мес. (51–86 мес.) выживаемость без потери БМО через 3 и 5 лет после отмены ИТК составила 51 % (95%-ный доверительный интервал (95% ДИ): 41–61 %) и 46 % (95% ДИ: 36–57 %) соответственно. C 3-го по 5-й годы наблюдения без терапии потеря БМО произошла у 2 (4 %) больных. После 5 лет наблюдения потери БМО не зарегистрировано. Выживаемость без потери БМО у больных с повторной попыткой прекращения лечения достоверно ниже — 12,5 % против 50 % с первой отменой (р = 0,039). У всех 50 больных, возобновивших лечение в связи с молекулярным рецидивом, были восстановлены БМО и глубокий МО4. В группе больных, сохранявших РБЛ к моменту анализа (n = 47), у 62 % (n = 29) отмечались колебания уровня BCR::ABL1 в пределах 0,01–0,1 % за время наблюдения без терапии. У 38 (42 %) из 90 больных с первой отменой ИТК была зафиксирована потеря глубокого МО4 после отмены ИТК. Выживаемость без потери БМО от момента потери МО4 составила 24 % к 5-му году наблюдения. Потеря глубокого МО4 в первые 3 месяца после отмены терапии ассоциирована с высокой вероятностью дальнейшей потери БМО (8 % против 54 % у больных с потерей МО4 на сроке > 3 мес., р = 0,00015).   Заключение. Небольшая частота поздних рецидивов (4 % после 3 лет наблюдения) и возможность длительного персистирования минимальной остаточной болезни (МОБ) после отмены терапии определяют необходимость оптимизации сроков молекулярного мониторинга с учетом статуса МОБ.

   Introduction. The option of observation without therapy with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) patients is already included in Russian and international clinical guidelines. Evaluation of long-term follow-up results of treatment free remission (TFR) in CML patients is relevant for the introduction of this approach into routine clinical practice.   Aim — to demonstrate the outcomes in a long-term follow-up of CML patients who discontinued TKI therapy in the RU-SKI trial.   Patients and methods. The prospective study included 98 CML patients with TKI therapy duration ≥ 3 years and a deep molecular response (DMR, BCR::ABL1 ≤ 0.01 %) duration ≥ 2 years. TKI therapy was resumed with the loss of a major MR (MMR, BCR::ABL1 > 0,1 %).   Results. Median time of follow-up after TKI discontinuation was 64 months (range of 51–86 months). Survival without MMR loss at 3 and 5 years after TKI discontinuation was 51 % (CI 41–61 %) and 46 % (CI 36–57 %) respectively. From 3 to 5 years of follow-up without therapy, the loss of MMR occurred in 2 (4 %) patients. There was no MMR loss observed after 5 years of follow-up. In patients with first and second treatment discontinuation, survival without MMR loss was 50 % versus 12,5 %(р = 0,039). All 50 patients with molecular relapses regained MMR and MR4 after TKI therapy resumption. BCR::ABL1 level fluctuations 0,01–0,1 % were in 62 % (n = 29) patients, who were in TFR at the time of analysis. Loss of MR4 was observed in 38 (42 %) from 90 patients with first TKI discontinuation. Survival without MMR loss from MO4 loss was 24 % at 5 years after TKI discontinuation. Loss of MO4 in the first 3 months after TKI cessation was associated with a high probability of further MMR loss (8 % versus 54 % in patients with loss of MO4 for > 3 months, p = 0.00015).   Conclusion. The low frequency of late relapses (4 % after 3 years of follow-up) and the possibility of long-term persistence of minimal residual disease (MRD) after discontinuation of therapy determine the need to optimize the timing of molecular monitoring, taking into account the MRD status of patients.

хронический миелолейкозремиссия без леченияглубокий молекулярный ответchronic myeloid leukemiadeep molecular responsetreatment-free remissionИсследование проводилось в ФГБУ «НМИЦ гематологии» Минздрава России в качестве протокола клинической апробации МЗ РФ «Метод наблюдения больных хроническим миелолейкозом с глубокой молекулярной ремиссией без воздействия ингибиторов тирозинкиназ под контролем молекулярно-генетических методов исследования», ID № 18-10. Дополнительных финансовых средств не привлекалосьThe study was conducted at the National Research Center for Hematology of the Ministry of Health of Russia as a protocol for clinical testing of the Ministry of Health of the Russian Federation “Method of monitoring patients with chronic myeloid leukemia with deep molecular remission without exposure to tyrosine kinase inhibitors under the control of molecular genetic research methods”, ID No. 18-10. 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The authors declare that there are no conflicts of interest present.