vestimИзвестия Национальной академии наук Беларуси. Серия медицинских наукProceedings of the National Academy of Sciences of Belarus, Medical series1814-60232524-2350The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1814-6023-2019-16-2-202-215vestim-497Research ArticleКЛИНИЧЕСКАЯ И ЭКСПЕРИМЕНТАЛЬНАЯ МЕДИЦИНАCLINICAL AND EXPERIMENTAL MEDICINEВлияние показателей минимальной остаточной болезни на риск развития рецидива у пациентов с острым лимфобластным лейкозомInfluence of value of minimal residual disease at risk of developing recurrence of relapse in patients with acute lymphoblastic leukemiaСтоляроваЕ. А.StolyarovaE. A.

Столярова Елена Александровна – врач-гематолог

ул. Фрунзенская, 43, 223053, д. Боровляны, Минский р-н

Elena A. Stolyarova – Hematologist

43, Frunzenskaya Str., 223053, v. Borovliany, Minsk Region

EA.Stolyarova@yandex.ruМигальН. В.MigalN. V.

Мигаль Наталья Владимировна – канд. мед. наук, доцент, заведующий отделением

ул. Фрунзенская, 43, 223053, д. Боровляны, Минский р-н

Nataliya V. Migal – Ph. D. (Med.), Assistant Professor, Head of the Department

43, Frunzenskaya Str., 223053, v. Borovliany, Minsk Region

migaldanuta1@yandex.ruБелевцевМ. В.BelevtsevM. V.

Белевцев Михаил Владимирович – канд. биол. наук, доцент, заместитель директора

ул. Фрунзенская, 43, 223053, д. Боровляны, Минский р-н

Mikhail V. Belevtsev – Ph. D. (Biol.), Assistant Professor, Deputy Director

43, Frunzenskaya Str., 223053, v. Borovliany, Minsk Region

belevtsev@mail.ruМовчанЛ. В.MovchanL. V.

Мовчан Людмила Викторовна – канд. биол. наук, врач-иммунолог

ул. Фрунзенская, 43, 223053, д. Боровляны, Минский р-н

Ludmila V. Movchan – Ph. D. (Biol.), Immunologist

43, Frunzenskaya Str., 223053, v. Borovliany, Minsk Region

movchan-1@mail.ruБыдановО. И.BudanovO. I.

Быданов Олег Иванович – мед. статистик

ул. Фрунзенская, 43, 223053, д. Боровляны, Минский р-н

Oleg I. Budanov – Medical statistic

43, Frunzenskaya Str., 223053, v. Borovliany, Minsk Region

budanov@oncology.byПоповА. М.PopovA. M.

Попов Александр Михайлович – канд. мед. наук, заведующий лабораторией

ул. Саморы Машела, 1, 117997, г. Москва

Aleksandr M. Popov – Ph. D. (Med.), Head of the Laboratory

1, Zamora Machel Str., 117997, Moscow

uralcytometry@gmail.comФечинаЛ. Г.FechinaL. G.

Фечина Лариса Геннадьевна – канд. мед. наук, руководитель отдела, заместитель глав. врача

ул. С. Дерябиной, 32, 620149, г. Екатеринбург

Larisa G. Fechina – Ph. D. (Med.), Head of the Department, Deputy Chief Doctor

32, Serafma Deryabina str., 620149, Yekaterinburg

childrens_oncology@mail.ruАлейниковаО. В.AleinikovaO, V.

Алейникова Ольга Витальевна – член-корреспондент, д-р мед. наук, профессор, директор

ул. Фрунзенская, 43, 223053, д. Боровляны, Минский р-н

Olga V. Aleinikova – Corresponding Member, D. Sc. (Med.), Professor, Director

43, Frunzenskaya Str., 223053, v. Borovliany, Minsk Region

aleinikova2004@mail.ruРеспубликанский научно-практический центр детской онкологии, гематологии и иммунологииRepublican Research Center for Pediatric Oncology, Hematology and ImmunologyНациональный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия РогачеваNational Medical Research Center of Pediatric Hematology, Oncology and Immunology named after Dmitry RogachevОбластная детская клиническая больница № 1Regional Children’s Clinical Hospital no. 1201901072019162202215Copyright © Столярова Е.А., Мигаль Н.В., Белевцев М.В., Мовчан Л.В., Быданов О.И., Попов А.М., Фечина Л.Г., Алейникова О.В., 20192019Столярова Е.А., Мигаль Н.В., Белевцев М.В., Мовчан Л.В., Быданов О.И., Попов А.М., Фечина Л.Г., Алейникова О.В.Stolyarova E.A., Migal N.V., Belevtsev M.V., Movchan L.V., Budanov O.I., Popov A.M., Fechina L.G., Aleinikova O.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestimed.belnauka.by/jour/article/view/497

Минимальная остаточная болезнь (МОБ) – наиболее значимый прогностический фактор риска развития рецидива у пациентов с острым лимфобластным лейкозом (ОЛЛ). Оценка МОБ необходима не только для прогноза рецидива заболевания, но и для дополнительной стратификации пациентов на группы риска с целью индивидуализации терапии и оценки ее качества. В данном исследовании проведен анализ показателей МОБ у пациентов с ОЛЛ на 15-й и 36-й день индукционной терапии, а также оценено их влияние на показатели выживаемости и риск развития рецидива у пациентов с ОЛЛ, получающих лечение согласно протоколу ОЛЛ-МБ 2008.

Minimal residual disease (MRD) is the most significant predictor of the relapse in patients with acute lymphoblastic leukemia (ALL). MRD evaluation is necessary not only for the prediction of the relapse, but for additional stratification of patients by the risk groups in order to address the issue of the therapy individualization and to evaluate the therapy quality. This study analyzes the MRD parameters in patients with ALL at the stage of induction therapy and evaluates the effect of the value of the minimum residual disease on survival rates and the risk of relapse in patients with ALL treated according to protocol ALL-MB 2008.

острый лимфобластный лейкозминимальная остаточная болезньклиренс лейкемических клетокбессобытийная выживаемостькумулятивная частота рецидиваacute lymphoblastic leukemiaminimal residual diseaseclearance of leukemic cellsevent-free survival (EFS)cumulative incidence of relapse (CIR)ReferencesThe childhood leukemia international consortium / C. Metayer [et al.] // Cancer Epidemiol. – 2013. – Vol. 37, N 3. – P. 336–347. https://doi.org/10.1016/j.canep.2012.12.011Metayer C., Milne E., Clavel J., Infante-Rivard C., Petridou E., Taylor M. [et al.]. The childhood leukemia international consortium. Cancer Epidemiology, 2013, vol. 37, no. 3, pp. 336–347. https://doi.org/10.1016/j.canep.2012.12.011Childhood and adolescent cancer statistics, 2014 / E. Ward [et al.] // CA: а Cancer J. Clin. – 2014. – Vol. 64, N 2. – P. 83–103. https://doi.org/10.3322/caac.21219Ward E., DeSantis C., Robbins A., Kohler B., Jemal A. Childhood and adolescent cancer statistics, 2014. CA: a Cancer Journal for Clinicians, 2014, vol. 64, no. 2, pp. 83–103. https://doi.org/10.3322/caac.21219Belson, M. Risk factors for acute leukemia in children: a review / M. Belson, B. Kingsley, A. Holmes // Environ. Health Perspect. – 2007. – Vol. 115, N 1. – P. 138–145. https://doi.org/10.1289/ehp.9023Belson M., Kingsley B., Holmes A. Risk factors for acute leukemia in children: a review. Environmental Health Perspectives, 2007, vol. 115, no. 1, pp. 138–145. https://doi.org/10.1289/ehp.9023Cools, J. Improvements in the survival of children and adolescents with acute lymphoblastic leukemia / J. Cools // Haematologica. – 2012. – Vol. 97, N 5. – P. 635. https://doi.org/10.3324/haematol.2012.068361Cools J. Improvements in the survival of children and adolescents with acute lymphoblastic leukemia. Haematologica, 2012, vol. 97, no. 5, pp. 635. https://doi.org/10.3324/haematol.2012.068361Pui, C. H. Acute lymphoblastic leukemia / C.-H. Pui, W. E. Evans // N. Engl. J. Med. – 1998. – Vol. 339, N 9. – P. 605–615. https://doi.org/10.1056/NEJM199808273390907Pui C.-H., Evans W. E. Acute lymphoblastic leukemia. New England Journal of Medicine, 1998, vol. 339, no. 9, pp. 605–615. https://doi.org/10.1056/NEJM199808273390907Cooper, S. L. Treatment of pediatric acute lymphoblastic leukemia / S. L. Cooper, P. A. Brown // Pediatr. Clin. North Am. – 2015. – Vol. 62, N 1. – P. 61–73. https://doi.org/10.1016/j.pcl.2014.09.006Cooper S. L., Brown P. A. Treatment of pediatric acute lymphoblastic leukemia. Pediatric Clinics of North America, 2015, vol. 62, no. 1, pp. 61–73. https://doi.org/10.1016/j.pcl.2014.09.006How I treat relapsed childhood acute lymphoblastic leukemia / F. Locatelli [et al.] // Blood. – 2012. – Vol. 120, N 14. – P. 2807–2816. https://doi.org/10.1182/blood-2012-02-265884Locatelli F., Schrappe M., Bernardo M. E., Rutella S. How I treat relapsed childhood acute lymphoblastic leukemia. Blood, 2012, vol. 120, no. 14, pp. 2807–2816. https://doi.org/10.1182/blood-2012-02-265884Lee, J. W. Prognostic factors and treatment of pediatric acute lymphoblastic leukemia / J. W. Lee, B. Cho // Korean J. Pediatr. – 2017. – Vol. 60, N 5. – P. 129–137. https://doi.org/10.3345/kjp.2017.60.5.129Lee J. W., Cho B. Prognostic factors and treatment of pediatric acute lymphoblastic leukemia. Korean Journal of Pediatrics, 2017, vol. 60, no. 5, pp. 129–137. https://doi.org/10.3345/kjp.2017.60.5.129Teachey, D. T. Predicting relapse risk in childhood acute lymphoblastic leukaemia / D. T. Teachey, S. P. Hunger // Br. J. Haematol. – 2013. – Vol. 162, N 5. – P. 606–620. https://doi.org/10.1111/bjh.12442Teachey D. T., Hunger S. P. Predicting relapse risk in childhood acute lymphoblastic leukaemia. British Journal of Haematology, 2013, vol. 162, no. 5, pp. 606–620. https://doi.org/10.1111/bjh.12442Detection of minimal residual disease in pediatric acute lymphoblastic leukemia / G. Gaipa [et al.] // Cytometry B Clin. Cytom. – 2013. – Vol. 84, N 6. – P. 359–369. https://doi.org/10.1002/cyto.b.21101Gaipa G., Basso G., Biondi A., Campana D. Detection of minimal residual disease in pediatric acute lymphoblastic leukemia. Cytometry Part B Clinical Cytometry, 2013, vol. 84, nо. 6, pp. 359–369. https://doi.org/10.1002/cyto.b.21101Risk- and response-based classifcation of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG) / K. R. Schultz [et al.] // Blood. – 2007. – Vol. 109, N 3. – P. 926–935. https://doi.org/10.1182/blood-2006-01-024729Schultz K. R., Pullen D. J, Sather H. N., Shuster J. J., Devidas M., Borowitz M. J. [et al.]. Risk- and response-based classifcation of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG). Blood, 2007, vol. 109, no. 3, pp. 926–935. https://doi.org/10.1182/blood-2006-01-024729Prediction of outcome by early bone marrow response in childhood acute lymphoblastic leukemia treated in the ALL-BFM 95 trial: differential effects in precursor B-cell and T-cell leukemia / M. Lauten [et al.] // Haematologica. – 2012. – Vol. 97, N 7. – P. 1048–1056. https://doi.org/10.3324/haematol.2011.047613Lauten M., Möricke A., Beier R., Zimmermann M., Stanulla M., Meissner B. [et al.]. Prediction of outcome by early bone marrow response in childhood acute lymphoblastic leukemia treated in the ALL-BFM 95 trial: differential effects in precursor B-cell and T-cell leukemia. Haematologica, 2012, vol. 97, no. 7, pp. 1048–1056. https://doi.org/10.3324/haematol.2011.047613Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90 / M. Schrappe [et al.] // Blood. – 2000. – Vol. 95, N 11. – P. 3310–3322.Schrappe M., Reiter A., Ludwig W. D., Harbott J., Zimmermann M., Hiddemann W. [et al.]. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALLBFM 90. Blood, 2000, vol. 95, no. 11, pp. 3310–3322.Minimal residual disease in leukaemia patients / T. Szczepańsk [et al.] // Lancet Oncol. – 2001. – Vol. 2, N 7. – P. 409–417.Szczepański T., Orfão A., van der Velden V. H., San Miguel J. F., van Dongen J. J. Minimal residual disease in leukaemia patients. Lancet Oncology, 2001, vol. 2, no. 7, pp. 409–417.Campana, D. Determination of minimal residual disease in leukaemia patients / D. Campana // Br. J. Haematol. – 2003. – Vol. 121, N 6. – P. 823–838. https://doi.org/10.1046/j.1365-2141.2003.04393.xCampana D. Determination of minimal residual disease in leukaemia patients. British Journal of Haematology, 2003, vol. 121, no. 6, pp. 823–838. https://doi.org/10.1046/j.1365-2141.2003.04393.xMinimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies / J. J. van Dongen [et al.] // Blood. – 2015. – Vol. 125, N 26. – P. 3996–4009. https://doi.org/10.1182/blood-2015-03-580027van Dongen J. J., van der Velden V. H., Brüggemann M., Orfao A. Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood, 2015, vol. 125, no. 26, pp. 3996–4009. https://doi.org/10.1182/blood-2015-03-580027Brüggemann, M. Has MRD monitoring superseded other prognostic factors in adult ALL? / M. Brüggemann, T. Raff, M. Kneba // Blood. – 2012. – Vol. 120, N 23. – P. 4470–4481. https://doi.org/10.1182/blood-2012-06-379040Brüggemann M., Raff T., Kneba M. Has MRD monitoring superseded other prognostic factors in adult ALL? Blood, 2012, vol. 120, no. 23, pp. 4470–4481. https://doi.org/10.1182/blood-2012-06-379040Chatterjee, T. Minimal residual disease detection using flow cytometry: applications in acute leukemia / T. Chatterjee, R. S. Mallhi, S. Venkatesan // Med. J. Armed Forces India. – 2016. – Vol. 72, N 2. – P. 152–156. https://doi.org/10.1016/j.mjaf.2016.02.002Chatterjee T., Mallhi R. S., Venkatesan S. Minimal residual disease detection using flow cytometry: applications in acute leukemia. Medical Journal Armed Forces India, 2016, vol. 72, no. 2, pp. 152–156. https://doi.org/10.1016/j.mjaf.2016.02.002Proposal for the standardization of flow cytometry protocols to detect minimal residual disease in acute lymphoblastic leukemia / M. R. V. Ikoma [et al.] // Rev. Bras. de Hematol. Hemoter. – 2015. – Vol. 37, N 6. – P. 406–413. https://doi.org/10.1016/j.bjhh.2015.07.012Ikoma M. R.V., Beltrame M. P., Ferreira S. I., Souto E. X., Malvezzi M., Yamamoto M. Proposal for the standardization of flow cytometry protocols to detect minimal residual disease in acute lymphoblastic leukemia. Revista Brasileira de Hematologia e Hemoterapia, 2015, vol. 37, no. 6, pp. 406–413. https://doi.org/10.1016/j.bjhh.2015.07.012Campana, D. Minimal residual disease-guided therapy in childhood acute lymphoblastic leukemia / D. Campana, C.-H. Pui // Blood. – 2017. – Vol. 129, N 4. – P. 1913–1918. https://doi.org/10.1182/blood-2016-12-725804Campana D., Pui C.-H. Minimal residual disease-guided therapy in childhood acute lymphoblastic leukemia. Blood, 2017, vol. 129, no. 4, pp. 1913–1918. https://doi.org/10.1182/blood-2016-12-725804Campana, D. Molecular determinants of treatment response in acute lymphoblastic leukemia / D. Campana // Hematol. Am. Soc. of Hematol. Educ. Program. – 2008. – Vol. 2008, N 1. – P. 366–373. https://doi.org/10.1182/asheducation-2008.1.366Campana D. Molecular determinants of treatment response in acute lymphoblastic leukemia. Hematology. American Society of Hematology. Education Program, 2008, no. 1, pp. 366–373. https://doi.org/10.1182/asheducation-2008.1Clinical signifcance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study / M. J. Borowitz [et al.] // Blood. – 2008. – Vol. 111, N 12. – P. 5477–5485. https://doi.org/10.1182/blood-2008-01-132837Borowitz M. J., Devidas M., Hunger S. P., Bowman W. P., Carroll A. J., Carroll W. L. [et al.]. Clinical signifcance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study. Blood, 2008, vol. 111, no. 12, pp. 5477–5485. https://doi.org/10.1182/blood-2008-01-132837Clinical signifcance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer-Childhood Leukemia Cooperative Group / H. Cavé [et al.] // N. Engl. J. Med. – 1998. – Vol. 339, N 9. – P. 591–598. https://doi.org/10.1056/NEJM199808273390904Cavé H., van der Werff ten Bosch J., Suciu S., Guidal C., Waterkeyn C., Otten J. [et al.]. Clinical signifcance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer-Childhood Leukemia Cooperative Group. New England Journal of Medicine, 1998, vol. 339, no. 9, pp. 591–598. https://doi.org/10.1056/NEJM199808273390904Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood / J. J. van Dongen [et al.] // Lancet. – 1998. – Vol. 352, N 9142. – P. 1731–1738. https://doi.org/10.1016/S0140-6736(98)04058-6Van Dongen J. J., Seriu T., Panzer-Grümayer E. R., Biondi A., Pongers-Willemse M. J., Corral L. [et al.]. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet, 1998, vol. 352, no. 9142, pp. 1731–1738. https://doi.org/10.1016/S0140-6736(98)04058-6Level of minimal residual disease prior to haematopoietic stem cell transplantation predicts prognosis in paediatric patients with acute lymphoblastic leukaemia: a report of the Pre-BMT MRD Study Group / O. Krejci [et al.] // Bone Marrow Transplant. – 2003. – Vol. 32, N 8. – P. 849–851. https://doi.org/10.1038/sj.bmt.1704241Krejci O., van der Velden V. H., Bader P., Kreyenberg H., Goulden N., Hancock J. [et al.]. Level of minimal residual disease prior to haematopoietic stem cell transplantation predicts prognosis in paediatric patients with acute lymphoblastic leukaemia: a report of the Pre-BMT MRD Study Group. Bone Marrow Transplantation, 2003, vol. 32, no. 8, pp. 849–851. https://doi.org/10.1038/sj.bmt.1704241Prognostic value of minimal residual disease quantifcation before allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia: the ALL-REZ BFM Study Group / P. Bader [et al.] // J. Clin. Oncol. – 2009. – Vol. 27, N 3. – P. 377–384. https://doi.org/10.1200/JCO.2008.17.6065Bader P., Kreyenberg H., Henze G. H., Eckert C., Reising M., Willasch A. [et al.]. Prognostic value of minimal residual disease quantifcation before allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia: the ALL-REZ BFM Study Group. Journal of Clinical Oncology, 2009, vol. 27, no. 3, pp. 377–384. https://doi.org/10.1200/JCO.2008.17.6065UKALL 2003, a randomised trial investigating treatment intensifcation for children and young adults with minimal residual disease defned high risk acute lymphoblastic leukaema / A. J. Vora [et al.] // Blood. – 2012. – Vol. 120, N 21. – P. 136.Vora A. J., Goulden N., Mitchell C. D., Hough R., Rowntree C., Richards S. M. UKALL 2003, a randomised trial investigating treatment intensifcation for children and young adults with minimal residual disease defned high risk acute lymphoblastic leukaema. Blood, 2012, vol. 120, no. 21, pp. 136–136.Molecular response to treatment redefnes all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study / V. Conter [et al.] // Blood. – 2010. – Vol. 115, N 16. – P. 3206–3214. https://doi.org/10.1182/blood-2009-10-248146Conter V., Bartram C. R., Valsecchi M. G., Schrauder A., Panzer-Grümayer R., Möricke A. [et al.]. Molecular response to treatment redefnes all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood, 2010, vol. 115, no. 16, pp. 3206–3214. https://doi.org/10.1182/blood-2009-10-248146Румянцев, А. Г. Результаты проспективных кооперированных исследований эффективности лечения рака у детей в России [Электронный ресурс] / А. Г. Румянцев // DOCPLAYER. – Режим доступа : https://docplayer.ru/91149045-Rezultaty-prospektivnyh-kooperirovannyh-issledovaniy-effektivnosti-lecheniya-raka-u-detey-v-rossii.html. – Дата доступа : 03.12.2018.Rumyantsev A. G. Results of prospective cooperative studies of the effectiveness of cancer treatment in children in Russia. Available at: https://docplayer.ru/91149045-Rezultaty-prospektivnyh-kooperirovannyh-issledovaniy-effektivnostilecheniya-raka-u-detey-v-rossii.html (accessed 7 February 2011) (in Russian).

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