Pediatric Hematology/Oncology and ImmunopathologyPediatric Hematology/Oncology and ImmunopathologyВопросы гематологии/онкологии и иммунопатологии в педиатрии1726-17082414-9314Fund Doctors, Innovations, Science for Children13110.24287/1726-1708-2016-15-4-34-41ЛЕЙКОЗЫMonitoring of minimal residual disease in the perspective of treatment of acute lymphoblastic leukemias in childrenМониторинг минимальной остаточной болезни в перспективе лечения острых лимфобластных лейкозов у детейZakharovaElena S.ЗахароваЕлена Сергеевна
Russian Federation
eszakh@gmail.comGnuchevNikolay V.ГнучевНиколай Васильевич
Russian Federation
gnuchev@igb.ac.ruGeorgievGeorgiy P.ГеоргиевГеоргий Павлович
Russian Federation
georgiev@igb.ac.ruLarinSergey S.ЛаринСергей Сергеевич
Russian Federation
sergei_larin@mail.ruDmitry Rogachev Federal Research Centre of Paediatric Haematology, Oncology and Immunology, Ministry of Health of the Russian FederationФедеральный научно-клинический центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева Минздрава РоссииInstitute of Gene Biology, Russian Academy of Medical SciencesИнститут биологии гена РАНN.I.Pirogov Russian National Research Medical University, Research Institute of Translational MedicineРоссийский национальный исследовательский медицинский университет им. Н.И.Пирогова, Научно-исследовательский институт трансляционной медицины19122016154344119092018Copyright ©; 2016, «D. Rogachev NMRCPHOI»Copyright ©; 2016, ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России2016«D. Rogachev NMRCPHOI»ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава Россииhttps://creativecommons.org/licenses/by/4.0https://hemoncim.com/jour/article/view/131

Treatment and diagnosis of acute lymphoblastic leukemias (ALL) in children have achieved much progress in the past years. Highly effective protocols for treatment of ALL have been developed, permitting to obtain remission in more than 90% of patients. Study of the level of minimal residual disease (MRD) permits to refer a patient to a certain group of risk, requiring a particular scheme of therapy and also to choose the optimal terms for bone marrow transplantation (BMT). Bone marrow (BM) samples of MRD-positive patients are very important for clarification of the mechanisms of tumour resistance to therapy. Introduction of new generation methods (high throughput sequencing, proteomics, bioinformatics) will permit to determine additional genetic and protein markers associated with higher levels of MRD, which in its turn might lead to creation of new effective markers and target therapeutic preparations.

Лечение и диагностика острых лимфобластных лейкозов (ОЛЛ) у детей достигли большого прогресса в последние годы. Разработаны высокоэффективные протоколы лечения ОЛЛ, позволяющие достичь ремиссии у более 90% пациентов. Исследование уровня минимальной остаточной болезни (МОБ) позволяет отнести пациента к определенной группе риска, что предполагает конкретную схему терапии, а также выбрать оптимальные сроки для проведения трансплантации костного мозга (ТКМ). Образцы костного мозга (КМ) МОБ-положительных пациентов очень важны для выяснения механизмов устойчивости опухоли к терапии. Внедрение методов нового поколения (высокопродуктивное секвенирование, протеомика, биоинформатика) позволит выявить дополнительные генетические и белковые маркеры, связанные с повышенным уровнем МОБ, что, в свою очередь, может привести к созданию новых эффективных маркеров и таргетных терапевтических препаратов.

минимальная остаточная болезнь (МОБ)острый лимфобластный лейкоз (ОЛЛ)полимерно-цепная реакция (ПЦР)проточная цитометрияреаранжировки генов иммуноглобулинов _и Т-клеточного рецептораminimal residual disease (MRD)acute lymphoblastic leukemia (ALL)polymerase chain reaction (PCR)flow cytometryimmunoglobulin and Т-cell receptor gene rearrangementЗлокачественные новообразования в России в 2013 году (заболеваемость и смертность). Под ред. Каприна АД, Старинского ВВ, Петрова ГВ. М.: МНИОИ им. П.А.Герцена, 2015Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grümayer R, Möricke A, et al. Molecular response to treatment redefines 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;115(16):3206-14Gaipa G, Basso G, Biond A, Campana D. Detection of Minimal Residual Disease in Pediatric Acute Lymphoblastic Leukemia. Cytometry Part B (Clinical Cytometry). 2013;84(6):359-69van Dongen JJM, van der Velden VHJ, Bruggemann M, Orfao A. Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood. 2015;125(26):3996-4008.Brüggemann M, Schrauder A, Raff T, Pfeifer H, Dworzak M., Ottmann OG, et al. European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL); Internation al. Berlin-Frankfurt-Münster Study Group (I-BFM-SG). Standardized MRD quantification in European ALL trials: proceed ings of the second international symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. Leukemia. 2010;24(3):521-35.Pongers-Willemse MJ, Seriu T, Stolz F, d’Aniello E, Gameiro P, Pisa P, et al. Primers and protocols for standardized detection of minimal residual disease in acute lymphoblastic leukemia using immunoglobulin and T cell receptor gene rearrangements and TAL1 deletions as PCR targets. Report of the BIOMED-1 CONCERTED ACTION: Investigation of minimal residual disease in acute leukemia. Leukemia. 1999;13(1):110-8.van Dongen JJM, Langerak AW, Bruggemann M, Evans PAS, Humme M, Lavender FL, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003;17(12):2257-317.van der Velden VHJ, Willemse MJ, van der Schoot CE, Haehlen K, van Wering ER, van Dongen JJM. Immunoglobulin kappa deleting element rearrangements in precursor-B acute lymphoblastic leukemia are stable targets for detection of minimal residual disease by real-time quantitative PCR. Leukemia. 2002;16(5): 928-36.van der Velden VHJ, Wijkhuijs JM, Jacobs DCH, van Wering ER, van Dongen JJM. T cell receptor gamma gene rearrangements as targets for detection of minimal residual disease in acute lymphoblastic leukemia by real-time quantitative PCR analysis. Leukemia. 2002;16(7):1372-80.van Dongen JJ, Seriu T, Panzer-Grümayer ER, Biondi A, Pongers-Willemse MJ, Corral L, et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet. 1998;352(9142):1731-8.Cave H, van der Werff ten Bosch J, Suciu S, Guidal C, Waterkeyn C, Otten J, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. N Engl J Med. 1998;339(9):591-8.Flohr T, Schrauder A, Cazzaniga G, Panzer-Grümayer R, van der Velden V, Fischer S, et al. International BFM Study Group (I-BFM-SG). Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia. 2008;22(4):771-82.Bartram CR, Schrauder A, Köhler R, Schrappe M. Acute lymphoblastic leukemia in children: treatment planning via minimal residual disease assessment. Dtsch Arztebl Int. 2012 Oct;109(40):652-8. doi: 10.3238/arztebl.2012.0652. Epub 2012 Oct 5.van der Velden VH, Cazzaniga G, Schrauder A, Hancock J, Bader P, Panzer-Grumayer ER, et al. Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia. 2007;21(14):604-11.Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grümayer R, Möricke A, et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood. 2011;118(8):2077-84.Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Childrens' Oncology Group study. Blood. 2008;111(12):5477-85.Stow P, Key L, Chen X, Pan Q, Neale GA, Coustan-Smith E, et al. Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia. Blood. 2010;115(23):4657-63.Bassan R, Spinelli O, Oldani E, Intermesoli T, Tosi M, Peruta B, et al. Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood. 2009;113(18):4153-62.Gokbuget N, Kneba M, Raff T, Trautmann H, Bartram CR, Arnold R, et al. Adults with acute lymphoblastic leukemia and molecular failure display a poor diagnosis and are candidates for stem cell transplantation and targeted therapies. Blood. 2012;120(9):1868-76.Neale GA, Coustan-Smith E, Pan Q, Chen X, Gruhn B, Stow P, et al. Tandem application of flow cytometry and polymerase chain reaction for comprehensive detection of minimal residual disease in childhood acute lymphoblastic leukemia. Leukemia. 1999;13(8):1221-6.Malec M, van der Velden VH, Björklund E, Wijkhuijs JM, Söderhäll S, Mazur J, et al. Analysis of minimal residual disease in childhood ison between RQ-PCR analysis of Ig/TCR gene rearrangements and multicolor flow cytometric immunophenotyping. Leukemia. 2004;18(10):630-6.Kerst G, Kreyenberg H, Roth C, Well C, Dietz K, Coustan-Smith E, et al. Concurrent detection of minimal residual disease (MRD) in childhood acute lymphoblastic leukaemia by flow cytometry and real-time PCR. Br J Haematol. 2005;128(6): 774-82.Ryan J, Quinn F, Meunier A, Boublikova L, Crampe M, Tewari P, et al. Minimal residual disease detection in childhood acute lymphoblastic leukaemia patients at multiple time points reveals high levels of concordance between molecular and immunophenotypic approaches. Br J Haematol. 2009;144(1):107-15.Gaipa G, Cazzaniga G, Valsecchi MG, Panzer-Grümayer R, Buldini B, Silvestri D, et al. Time point-dependent concordance of flow cytometry and real-time quantitative polymerase chain reaction for minimal residual disease detection in childhood acute lymphoblastic leukemia. Haematologica. 2012;97(10):1586-93.Neale GA, Coustan-Smith E, Stow P, Pan Q, Chen X, Pui CH, et al. Comparative analysis of flow cytometry and polymerase chain reaction for the detection of minimal residual disease in childhood acute lymphoblastic leukemia. Leukemia. 2004;18(5):934-8.Eckert C, Hagedorn N, Sramkova L, Mann G, Panzer-Grümayer R, Peters C, et al. Monitoring minimal residual disease in children with high-riskrelapses of acute lymphoblastic leukemia: Prognostic relevanceof early and late assessment. Leukemia. 2015;29(8):1648-55.Zhou J, Goldwasser MA, Li A, Dahlberg SE, Neuberg D, Wang H, et al.; Dana-Farber Cancer Institute ALL Consortium. Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01. Blood. 2007;110(5):1607-11.Stow P, Key L, Chen X, Pan Q, Neale GA, Coustan-Smith E, et al. Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia. Blood. 2010; 115(23):4657-63.Yamaji K, Okamoto T, Yokota S, Watanabe A, Horikoshi Y, Asami K, et al. Japanese Childhood Cancer Leukemia Study Group. Minimal residual disease-based augmented therapy in childhood acute lymphoblastic leukemia: A report from the Japanese Childhood Cancer and Leukemia Study Group. Pediatr Blood Cancer. 2010;55(7):1287-95.Katsibardi K, Moschovi MA, Braoudaki M, Papadhimitriou SI, Papathanasiou C, Tzortzatou-Stathopoulou F. Sequential monitoring of minimal residual disease in acute lymphoblastic leukemia: 7-year experience in a pediatric hematology/ oncology unit. Leuk Lymphoma. 2010;51(5):46-52.Meleshko AN, Savva NN, Fedasenka UU, Romancova AS, Krasko OV, Eckert C, et al. Prognostic value of MRD-dynamics in childhood acute lymphoblastic leukemia treated according to the MB-2002/2008 protocols. Leuk Res. 2011;35(10): 1312-20.Eckert C, Biondi A, Seeger K, Cazzaniga G, Hartmann R, Beyermann B, et al. Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia. Lancet. 2001;358(9289):1239-41.Paganin M, Zecca M, Fabbri G, Polato K, Biondi A, Rizzari C, et al. Minimal residual disease is an important predictive factor of outcome in children with relapsed ’high-risk’ acute lymphoblastic leukemia. Leukemia. 2008;22(12):2193-200.Raetz EA, Borowitz MJ, Devidas M, Linda SB, Hunger SP, Winick NJ, et al. Reinduction platform for children with first marrow relapse in acute lymphoblastic lymphoma. J Clin Oncol. 2008;26(24):3971-78.Krejci O, van der Velden VH, 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 Transplant. 2003; 32(8):849-51.Bader P, Kreyenberg H, Henze GH, Eckert C, Reising M, Willasch A, et al. ALL-REZ BFM Study Group. Prognostic value of minimal residual disease quantification before allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia: The ALL-REZ BFM Study Group. J Clin Oncol. 2009; 27(3):377-84.Leung W, Campana D, Yang J, Pei D, Coustan-Smith E, Gan K, et al. High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood. 2011;118:223-30.Zhao XS, Liu YR, Zhu HH, Xu LP, Liu DH, Liu KY, et al. Monitoring MRD with flow cytometry: An effective method to predict relapse for ALL patients after allogeneic hematopoietic stem cell transplantation. Ann Hematol. 2012;91(2):183-92.Dworzak MN, Gaipa G, Ratei R, Veltroni M, Schumich A, Maglia O, et al. Standardization of flow cytometric minimal residual disease evaluation in acute lymphoblastic leukemia: multicentric assessment is feasible. Cytometry B Clin Cytom. 2008;74(6):331-40.Basso G, Veltroni M, Valsecchi MG, Dworzak MN, Ratei R, Silvetri D, et al. Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol. 2009;27(31):5168-74.da Costa ES, Peres RT, Almeida J, Lecrevisse Q, Arroyo ME, Teodosio C, et al. Harmonization of light scatter and fluorescence flow cytometry profiles obtained after staining peripheral blood leucocytes for cell surface-only versus intracellular antigens with the Fix & Perm reagent. Cytometry B Clin Cytom. 2010;78(1 ):11 -20.Pedreira CE, Costa ES, Almeida J, Fernandez C, Quijano S, Flores J, et al. A probabilistic approach for the evaluation of minimal residual disease by multiparameter flow cytometry in leukemic B-cell chronic lymphoproliferative disorders. Cytometry A. 2008;73A(12):1141-50.Sitthi-Amorn J, Herrington B, Megason G, Pullen J, Gordon C, Hogan S, et al. Transcriptome Analysis of Minimal Residual Disease in Subtypes of Pediatric B Cell Acute Lymphoblastic Leukemia. Clin Med Insights Oncol. 2015 May 24;9: 51-60. doi: 10.4137/CMO.S17049. eCollection 2015.Pedreira CE, Costa ES, Barrena S, Lecrevisse Q, Almeida J, van Dongen JJM, et al. Generation of flow cytometry data files with a potentially infinite number of dimensions. Cytometry A. 2008;73(9):834-46.Mullighan CG. Molecular genetics of B-precursor acute lymphoblastic leuke-mia. J Clin Invest. 2012;122(10):3407-15.Harvey RC, Mullighan CG, Wang X, Dobbin KK, Davidson GS, Bedrick EJ, et al. Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood. 2010;116(23):4874-84.Kang H, Chen IM, Wilson CS, Bedrick EJ, Harvey RC, Atlas SR, et al. Gene expression classifiers for relapse-free survival and minimal residual disease improve risk classification and outcome prediction in pediatric B-precursor acute lymphoblastic leukemia. Blood. 2010;115(7):1394-405.