OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press18410.17650/1818-8346-2016-11-1-62-74BASIC RESEARCHФУНДАМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯ В ПРАКТИЧЕСКОЙ МЕДИЦИНЕ НА СОВРЕМЕННОМ ЭТАПЕMethodological aspects of diagnostics and minimal residual disease monitoring in infant acute leukemiasМетодические основы диагностики и мониторинга минимальной остаточной болезни при острых лейкозах у детей первого года жизниTsaurG. A.ЦаурГ. А.
Russian Federation
tsaur@mail.ruPopovA. M.ПоповА. М.
Russian Federation
FechinaL. G.ФечинаЛ. Г.
Russian Federation
RumyantsevS. A.РумянцевС. А.
Russian Federation
Regional Children Clinical Hospital No 1ГБУЗ СО ОДКБ № 132 S. Deryabinoy St., Ekaterinburg, 620149, Russia Institute of Medical Cell TechnologiesРоссия, 620149, Екатеринбург, ул. С. Дерябиной, 32 ГАУЗ СО «Институт медицинских клеточных технологий»22a Karla Marksa St., Ekaterinburg, 620026, Russia Ural Federal University named after the first President of Russia B. N. Yel’tsinРоссия, 620026, Екатеринбург, ул. Карла Маркса, 22а ФГАОУ ВПО «УрФУ им. первого Президента России Б. Н. Ельцина»19 Mira St., Ekaterinburg, 620002, RussiaРоссия, 620002, Екатеринбург, ул. Мира, 19Federal Research Center of Pediatric Hematology, Oncology and Immunology named after Dmitriy Rogachev, Ministry of Health of RussiaФГБУ «ФНКЦ ДГОИ им. Дмитрия Рогачева» Минздрава России1 Samory Mashela St., Moscow, 117998, RussiaРоссия, 117998, Москва, ул. Саморы Машела, 132 S. Deryabinoy St., Ekaterinburg, 620149, RussiaРоссия, 620149, Екатеринбург, ул. С. Дерябиной, 321 Samory Mashela St., Moscow, 117998, Russia N.I. Pirogov Russian National Research Medical University, Ministry of Health of RussiaРоссия, 117998, Москва, ул. Саморы Машела, 1 ГБОУ ВПО «РНИМУ им. Н. И. Пирогова» Минздрава России1 Ostrovityanova St., Moscow, 117997, RussiaРоссия, 117997, Москва, ул. Островитянова, 13103201611162743103201631032016https://oncohematology.abvpress.ru/ongm/article/view/184

Hereby we present methodological aspects and prognostic significance of minimal residual disease (MRD) monitoring in infant acute leukemias. Based on our own experience we made algorithm for detection of MRD in this group of patients. We conclude that general concordance between MRD detection by flow cytometry and real-time polymerase chain reaction (PCR) for fusion gene transcripts achieved 87.0 %. Concordance was significantly lower during induction in comparison to consolidation/intensification and relapse treatment (78.6; 90.4 and 93.4 %, correspondingly; p = 0.002). It was not dependent on presence of normal B-cell precursors. Concordance between MRD results obtained by qualitative real-time PCR in bone marrow and peripheral blood samples was 84.5 %. Interestingly, all discrepant results (22 samples 15.5 %) were MRD-positive in bone marrow, but negative in peripheral blood. Despite high qualitative concordance rate between MRD detection in bone marrow and peripheral blood samples we could not show prognostic value of MRD monitoring in peripheral blood by fusion gene transcripts. Multivariate analysis revealed that MRD-positivity at time-point 4 in bone marrow was the only significant and independent prognostic factor of unfavorable outcome in the observed group of patients (hazard ratio 7.326; 95 % confidence interval 2.378–22.565).

11q23/MLL rearrangementsinfant acute leukemiasminimal residual diseaseперестройки 11q23/MLLострые лейкозы у детей первого года жизниминимальная остаточная болезнь1. Cimino G., Moir D.T., Canaani O. et al. Cloning of ALL-1, the locus involved in leukemias with the t(4;11)(q21;q23), t(9;11)(p22;q23), and t(11;19)(q23;p13) chromosome translocations. Cancer Res 1991;51(24):6712–4.Cimino G., Moir D.T., Canaani O. et al. Cloning of ALL-1, the locus involved in leukemias with the t(4;11)(q21;q23), t(9;11)(p22;q23), and t(11;19)(q23;p13) chromosome translocations. Cancer Res 1991;51(24):6712–4.2. Ziemin-van der Poel S., McCabe N., Gill H. J. et al. Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias. Proc Natl Acad Sci USA 1991;88(23):10735–9.Ziemin-van der Poel S., McCabe N., Gill H. J. et al. Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias. Proc Natl Acad Sci USA 1991;88(23):10735–9.3. Tkachuk D., Kohler S., Cleary M. Involvement of a homolog of Drosophila tritorax by 11q23 chromosomal translocations in acute leukemias. Cell 1992;71(4):691–700.Tkachuk D., Kohler S., Cleary M. Involvement of a homolog of Drosophila tritorax by 11q23 chromosomal translocations in acute leukemias. Cell 1992;71(4):691–700.4. Шориков Е. В. Результаты программного лечения острого лимфобластного лейкоза у детей первого года жизни. Автореф. дис. ... канд. мед. наук. М., 2005. 34 с. [Shorikov E. V. Treatment results of acute lymphoblastic leukemia in infants. Author’s abstract of thesis … of candidate of medicine. Moscow, 2005. 34 p. (In Russ.)].Шориков Е. В. Результаты программного лечения острого лимфобластного лейкоза у детей первого года жизни. Автореф. дис. ... канд. мед. наук. М., 2005. 34 с. [Shorikov E. V. Treatment results of acute lymphoblastic leukemia in infants. Author’s abstract of thesis … of candidate of medicine. Moscow, 2005. 34 p. (In Russ.)].5. Pieters R., Schrappe M., De Lorenzo P. et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 2007;370(9583):240–50.Pieters R., Schrappe M., De Lorenzo P. et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 2007;370(9583):240–50.6. Hilden J., Dinndorf P., Meerbaum S. et al. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children’s Oncology Group. Blood 2006;108(2):441–51.Hilden J., Dinndorf P., Meerbaum S. et al. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children’s Oncology Group. Blood 2006;108(2):441–51.7. Ferster A., Bertrand Y., Benoit Y. et al. Improved survival for acute lymphoblastic leukaemia in infancy: the experience of EORTC-Childhood Leukaemia Cooperative Group. Br J Haematol 1994;86(2):284–90.Ferster A., Bertrand Y., Benoit Y. et al. Improved survival for acute lymphoblastic leukaemia in infancy: the experience of EORTC-Childhood Leukaemia Cooperative Group. Br J Haematol 1994;86(2):284–90.8. Silverman L., McLean T., Gelber R. et al. Intensified therapy for infants with acute lymphoblastic leukemia: results from the Dana-Farber Cancer Institute Consortium. Cancer 1997;80(12):2285–95.Silverman L., McLean T., Gelber R. et al. Intensified therapy for infants with acute lymphoblastic leukemia: results from the Dana-Farber Cancer Institute Consortium. Cancer 1997;80(12):2285–95.9. Lauer S., Camitta B., Leventhal B. et al. Intensive alternating drug pairs after remission induction for treatment of infants with acute lymphoblastic leukemia: A Pediatric Oncology Group pilot study. J Pediatr Hematol Oncol 1998;20(3):229–33.Lauer S., Camitta B., Leventhal B. et al. Intensive alternating drug pairs after remission induction for treatment of infants with acute lymphoblastic leukemia: A Pediatric Oncology Group pilot study. J Pediatr Hematol Oncol 1998;20(3):229–33.10. Tomizawa D., Koh K., Sato T. et al. Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group. Leukemia 2007;22(11):2258–63.Tomizawa D., Koh K., Sato T. et al. Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group. Leukemia 2007;22(11):2258–63.11. Dördelmann M., Reiter A., Borkhardt A. et al. Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood 1999;94(4):1209–17.Dördelmann M., Reiter A., Borkhardt A. et al. Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood 1999;94(4):1209–17.12. Biondi A., Rizzari C., Valsecchi M. G. et al. Role of treatment intensification in infants with acute lymphoblastic leukemia: results of two consecutive AIEOP studies. Haematologica 2006;91(4):534–7.Biondi A., Rizzari C., Valsecchi M. G. et al. Role of treatment intensification in infants with acute lymphoblastic leukemia: results of two consecutive AIEOP studies. Haematologica 2006;91(4):534–7.13. Frankel L., Ochs J., Shuster J. J. et al. Therapeutic trial for infant acute lymphoblastic leukemia: the Pediatric Oncology Group experience (POG 8493). J Pediatr Hematol Oncol 1997;19(1):35–42.Frankel L., Ochs J., Shuster J. J. et al. Therapeutic trial for infant acute lymphoblastic leukemia: the Pediatric Oncology Group experience (POG 8493). J Pediatr Hematol Oncol 1997;19(1):35–42.14. Chessells J., Harrison C., Watson S. et al. Treatment of infants with lymphoblastic leukaemia: results of the UK Infant Protocols 1987–1999. Br J Haematol 2002;117(2):306–14.Chessells J., Harrison C., Watson S. et al. Treatment of infants with lymphoblastic leukaemia: results of the UK Infant Protocols 1987–1999. Br J Haematol 2002;117(2):306–14.15. de Zen L., Bicciato S., te Kronnie G. et al. Computational analysis of flow cytometry antigen expression profiles in childhood acute lymphoblastic leukemia: an MLL/AF4 identification. Leukemia 2003;17(8):1557–65.de Zen L., Bicciato S., te Kronnie G. et al. Computational analysis of flow cytometry antigen expression profiles in childhood acute lymphoblastic leukemia: an MLL/AF4 identification. Leukemia 2003;17(8):1557–65.16. Borkhardt A., Wuchter C., Viehmann S. et al. Infant acute lymphoblastic leukemia –combined cytogenetic, immunophenotypical and molecular analysis of 77 cases. Leukemia 2002;16(9):1685–90.Borkhardt A., Wuchter C., Viehmann S. et al. Infant acute lymphoblastic leukemia –combined cytogenetic, immunophenotypical and molecular analysis of 77 cases. Leukemia 2002;16(9):1685–90.17. Попов А.М., Вержбицкая Т. Ю., Цаур Г. А. и др. Алгоритм применения проточной цитометрии для мониторинга минимальной остаточной болезни при CD10-негативном остром лимфобластном лейкозе из В-линейных предшественников. Вопросы диагностики в педиатрии 2012;(5):31–6. [Popov A. M., Verzhbitskaya T. Yu., Tsaur G. A. et al. Methodology of flow cytometry application for minimal residual disease monitoring in childhood CD10-negative B-cell precursor acute lymphoblastic leukemia. Voprosy diagnostiki v pediatrii = Diagnostic Issues in Pediatrics 2012;(5):31–6. (In Russ.)].Попов А.М., Вержбицкая Т. Ю., Цаур Г. А. и др. Алгоритм применения проточной цитометрии для мониторинга минимальной остаточной болезни при CD10-негативном остром лимфобластном лейкозе из В-линейных предшественников. Вопросы диагностики в педиатрии 2012;(5):31–6. [Popov A. M., Verzhbitskaya T. Yu., Tsaur G. A. et al. Methodology of flow cytometry application for minimal residual disease monitoring in childhood CD10-negative B-cell precursor acute lymphoblastic leukemia. Voprosy diagnostiki v pediatrii = Diagnostic Issues in Pediatrics 2012;(5):31–6. (In Russ.)].18. Попов А. М., Вержбицкая Т. Ю., Цаур Г. А. и др. Изменения иммунофено- типа опухолевых бластов при CD10-позитивном остром лимфобластном лейкозе у детей к 15-му дню индукционной терапии по протоколу ALL-MB-2008. Иммунология 2010; 2):60–4. [Popov A. M., Verzhbitskaya T. Yu., Tsaur G. A. et al. Changes in blasts immunophenotype in CD10-positive children acute lymphoblastic leukemia by 15th day of induction therapy according ALLMB- 2008 protocol. Immunologiya = Immunology 2010;(2):60–4. (In Russ.)].Попов А. М., Вержбицкая Т. Ю., Цаур Г. А. и др. Изменения иммунофено- типа опухолевых бластов при CD10-позитивном остром лимфобластном лейкозе у детей к 15-му дню индукционной терапии по протоколу ALL-MB-2008. Иммунология 2010; 2):60–4. [Popov A. M., Verzhbitskaya T. Yu., Tsaur G. A. et al. Changes in blasts immunophenotype in CD10-positive children acute lymphoblastic leukemia by 15th day of induction therapy according ALLMB- 2008 protocol. Immunologiya = Immunology 2010;(2):60–4. (In Russ.)].19. Pui C. H., Carroll W., Meshinchi S. et al. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol 2011;29(5):551–65.Pui C. H., Carroll W., Meshinchi S. et al. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol 2011;29(5):551–65.20. Biondi A., Cimino G., Pieters R. et al. Biological and therapeutic aspects of infant leukemia. Blood 2000;96(1):24–33.Biondi A., Cimino G., Pieters R. et al. Biological and therapeutic aspects of infant leukemia. Blood 2000;96(1):24–33.21. Chen C. S., Sorensen P., Domer P. et al. Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood 1993;81(9):2386–93.Chen C. S., Sorensen P., Domer P. et al. Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood 1993;81(9):2386–93.22. Beillard E., Pallisgaard N., van der Velden V. et al. Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using “real-time” quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) – a Europe Against Cancer Program. Leukemia 2003;17(12):2474–86.Beillard E., Pallisgaard N., van der Velden V. et al. Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using “real-time” quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) – a Europe Against Cancer Program. Leukemia 2003;17(12):2474–86.23. Gabert J., Beillard E., van der Velden V. et al Standardization and quality control studies of “real-time” quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – a Europe Against Cancer Program. Leukemia 2003;17(12):2318–57.Gabert J., Beillard E., van der Velden V. et al Standardization and quality control studies of “real-time” quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – a Europe Against Cancer Program. Leukemia 2003;17(12):2318–57.24. van Dongen J., Macintyre E., Gabert J. et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Leukemia 1999;13(12):1901–18.van Dongen J., Macintyre E., Gabert J. et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Leukemia 1999;13(12):1901–18.25. Zaliova M., Fronkova E., Krejcikova K. et al. Quantification of fusion transcript reveals a subgroup with distinct biological properties and predicts relapse in BCR/ABL-positive ALL: implications for residual disease monitoring. Leukemia 2009;23(5):944–51.Zaliova M., Fronkova E., Krejcikova K. et al. Quantification of fusion transcript reveals a subgroup with distinct biological properties and predicts relapse in BCR/ABL-positive ALL: implications for residual disease monitoring. Leukemia 2009;23(5):944–51.26. Taube T., Eckert C., Körner G. et al. Real-time quantification of TEL-AML1 fusion transcripts for MRD detection in relapsed childhood acute lymphoblastic leukaemia. Comparison with antigen receptor-based MRD quantification methods. Leuk Res 2004;28(7):699–706.Taube T., Eckert C., Körner G. et al. Real-time quantification of TEL-AML1 fusion transcripts for MRD detection in relapsed childhood acute lymphoblastic leukaemia. Comparison with antigen receptor-based MRD quantification methods. Leuk Res 2004;28(7):699–706.27. Попов А. М., Цаур Г. А., Вержбицкая Т. Ю. и др. Сравнение результатов определения минимальной остаточной болезни методом проточной цитометрии и выявления химерного транскрипта полимеразной цепной реакцией у детей, больных B-линейным острым лимфобластным лейкозом. Гематология и трансфузиология 2010;55(2):3–9. [Popov A. M., Tsaur G. A., Verzhbitskaya T. Yu. et al. Comparison of the results of evaluating the minimal residual disease by flow cytometry and by detecting of chimeric transcript by the polymerase chain reaction in children with B-cell acute lymphoblastic leukemia. Gematologiya i transfuziologiya = Hematology and Transfusiology 2010;55(2):3–9. (In Russ.)].Попов А. М., Цаур Г. А., Вержбицкая Т. Ю. и др. Сравнение результатов определения минимальной остаточной болезни методом проточной цитометрии и выявления химерного транскрипта полимеразной цепной реакцией у детей, больных B-линейным острым лимфобластным лейкозом. Гематология и трансфузиология 2010;55(2):3–9. [Popov A. M., Tsaur G. A., Verzhbitskaya T. Yu. et al. Comparison of the results of evaluating the minimal residual disease by flow cytometry and by detecting of chimeric transcript by the polymerase chain reaction in children with B-cell acute lymphoblastic leukemia. Gematologiya i transfuziologiya = Hematology and Transfusiology 2010;55(2):3–9. (In Russ.)].28. Brüggemann M., Schrauder A., Raff T. et al. Standardized MRD quantification in European ALL trials: proceedings of the second international symposium on MRD assessment in Kiel, Germany, 18–20 September 2008. Leukemia 2010;24(3):521–35.Brüggemann M., Schrauder A., Raff T. et al. Standardized MRD quantification in European ALL trials: proceedings of the second international symposium on MRD assessment in Kiel, Germany, 18–20 September 2008. Leukemia 2010;24(3):521–35.29. Szczepanski T. Why and how to quantify minimal residual disease in acute lymphoblastic leukaemia. Leukemia 2007;21(4):622–6.Szczepanski T. Why and how to quantify minimal residual disease in acute lymphoblastic leukaemia. Leukemia 2007;21(4):622–6.30. Fechina L., Shorikov E., Tsaur G. et al. Contribution of all-trans retinoic acid to improved early relapse-free outcome in infant acute lymphoblastic leukemia comparing to the chemotherapy alone. Blood 2007;110(11):832А, abstract 2828.Fechina L., Shorikov E., Tsaur G. et al. Contribution of all-trans retinoic acid to improved early relapse-free outcome in infant acute lymphoblastic leukemia comparing to the chemotherapy alone. Blood 2007;110(11):832А, abstract 2828.31. Meyer С., Kowarz E., Hofmann J. et al. New insights to the MLL recombinome of acute leukemias. Leukemia 2009;23(8):1490–9.Meyer С., Kowarz E., Hofmann J. et al. New insights to the MLL recombinome of acute leukemias. Leukemia 2009;23(8):1490–9.32. Pieters R. Biology and treatment of infant leukemias. In: Treatment of acute leukemias: new directions for clinical research. Ed. by C. H. Pui. Totowa: Humana Press, 2003. Pp. 61–73.Pieters R. Biology and treatment of infant leukemias. In: Treatment of acute leukemias: new directions for clinical research. Ed. by C. H. Pui. Totowa: Humana Press, 2003. Pp. 61–73.33. Reaman G. Biology and treatment of infant leukemias. In: Treatment of acute leukemias: new directions for clinical research. Ed C. H. Pui. Totowa: Humana Press, 2003. Pp. 75–83.Reaman G. Biology and treatment of infant leukemias. In: Treatment of acute leukemias: new directions for clinical research. Ed C. H. Pui. Totowa: Humana Press, 2003. Pp. 75–83.34. Цаур Г. А., Флейшман Е. В., Попов А. М. и др. Цитогенетическая и молекулярно-генетическая характеристика острых лейкозов у детей первого года жизни. Клиническая онкогематология 2011;4(2):134–41. [Tsaur G. A., Fleyshman E. V., Popov A. M. et al. Cytogenetics and molecular genetics of infant acute leukemias. Klinicheskaya onkogematologiya = Clinical Oncohematology 2011;4(2):134–41. (In Russ.)].Цаур Г. А., Флейшман Е. В., Попов А. М. и др. Цитогенетическая и молекулярно-генетическая характеристика острых лейкозов у детей первого года жизни. Клиническая онкогематология 2011;4(2):134–41. [Tsaur G. A., Fleyshman E. V., Popov A. M. et al. Cytogenetics and molecular genetics of infant acute leukemias. Klinicheskaya onkogematologiya = Clinical Oncohematology 2011;4(2):134–41. (In Russ.)].35. Цаур Г. А., Попов А. М., Алейникова О. В. и др. Характеристика перестроек 11q23(MLL) у детей первого года жизни с острым лимфобластным лейкозом. Онкогематология 2011;(3):57–64. [Tsaur G. A., Popov A. M., Aleynikova O. V. et al. Detection of 11q23(MLL) rearrangements in infant acute lymphoblastic leukemia. Onkogematologiya = Oncohematology 2011;(3):57–64. (In Russ.)].Цаур Г. А., Попов А. М., Алейникова О. В. и др. Характеристика перестроек 11q23(MLL) у детей первого года жизни с острым лимфобластным лейкозом. Онкогематология 2011;(3):57–64. [Tsaur G. A., Popov A. M., Aleynikova O. V. et al. Detection of 11q23(MLL) rearrangements in infant acute lymphoblastic leukemia. Onkogematologiya = Oncohematology 2011;(3):57–64. (In Russ.)].36. Цаур Г. А., Плеханова О. М., Гиндина Т. Л. и др. Применение метода флуоресцентной гибридизации in situ для выявления перестроек гена MLL при острых лейкозах у детей первого года жизни. Медицинская генетика 2012;(7):35–45. [Tsaur G. A., Plekhanova O. M., Gindina T. L. et al. Detection of MLL gene rearrangements in infants under 12 month of age with acute leukemias by fluorescence in situ hybridization. Meditsinskaya genetika = Medical Genetics 2012;(7):35–45. (In Russ.)].Цаур Г. А., Плеханова О. М., Гиндина Т. Л. и др. Применение метода флуоресцентной гибридизации in situ для выявления перестроек гена MLL при острых лейкозах у детей первого года жизни. Медицинская генетика 2012;(7):35–45. [Tsaur G. A., Plekhanova O. M., Gindina T. L. et al. Detection of MLL gene rearrangements in infants under 12 month of age with acute leukemias by fluorescence in situ hybridization. Meditsinskaya genetika = Medical Genetics 2012;(7):35–45. (In Russ.)].37. Цаур Г. А., Флейшман Е. В., Гиндина Т. Л. и др. Характеристика перестроек 11q23/MLL при остром миелоидном лейкозе у детей первого года жизни. Клиническая онкогематология 2012;5(4):365–70. [Tsaur G. A., Fleyshman E. V., Gindina T. L. et al. Detection of 11q23(MLL) rearrangements in infant acute myeloid leukemia. Klinicheskaya onkogematologiya = Clinical Oncohematology 2012;5(4):365–70. (In Russ.)].Цаур Г. А., Флейшман Е. В., Гиндина Т. Л. и др. Характеристика перестроек 11q23/MLL при остром миелоидном лейкозе у детей первого года жизни. Клиническая онкогематология 2012;5(4):365–70. [Tsaur G. A., Fleyshman E. V., Gindina T. L. et al. Detection of 11q23(MLL) rearrangements in infant acute myeloid leukemia. Klinicheskaya onkogematologiya = Clinical Oncohematology 2012;5(4):365–70. (In Russ.)].38. Цаур Г. А., Флейшман Е. В., Плеханова О. М. и др. Редкие перестройки хромосомного района 11q23 и гена MLL при острых лейкозах у детей первого года жизни. Вопросы диагностики в педиатрии 2012;(6):16–24. [Tsaur G. A., Fleyshman E. V., Plekhanova O. M. et al. Rare 11q23/MLL rearrangements in infant acute leukemia. Voprosy diagnostiki v pediatrii = Diagnostic Issues in Pediatrics 2012;(6):16– 24. (In Russ.)].Цаур Г. А., Флейшман Е. В., Плеханова О. М. и др. Редкие перестройки хромосомного района 11q23 и гена MLL при острых лейкозах у детей первого года жизни. Вопросы диагностики в педиатрии 2012;(6):16–24. [Tsaur G. A., Fleyshman E. V., Plekhanova O. M. et al. Rare 11q23/MLL rearrangements in infant acute leukemia. Voprosy diagnostiki v pediatrii = Diagnostic Issues in Pediatrics 2012;(6):16– 24. (In Russ.)].39. Balgobind B., Raimondi S., Harbott J. et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood 2009;114(12):2489–96.Balgobind B., Raimondi S., Harbott J. et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood 2009;114(12):2489–96.40. Pui C. H., Gaynon P., Boyett J. et al. Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 2002;359(9321):1909–15.Pui C. H., Gaynon P., Boyett J. et al. Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 2002;359(9321):1909–15.41. Meyer C., Hofmann J., Burmeister T. et al. The MLL recombinome of acute leukemias in 2013. Leukemia 2013;27(11):2165–76.Meyer C., Hofmann J., Burmeister T. et al. The MLL recombinome of acute leukemias in 2013. Leukemia 2013;27(11):2165–76.42. Felix C., Hosler M., Slater D. et al. MLL genomic breakpoint distribution within the breakpoint cluster region in de novo leukemia in children. J Pediatr Hematol Oncol 1998;20(4):299–308.Felix C., Hosler M., Slater D. et al. MLL genomic breakpoint distribution within the breakpoint cluster region in de novo leukemia in children. J Pediatr Hematol Oncol 1998;20(4):299–308.43. Попов А. М., Вержбицкая Т. Ю., Цаур Г. А. и др. Особенности мониторинга минимальной остаточной болезни при B-линейных острых лимфобластных лейкозах методом проточной цитометрии у детей первого года жизни. Детская онкология 2008;(2):32–5. [Popov A. M., Verzhbitskaya T. Yu., Tsaur G. A. et al. Peculiarities of minimal residual disease monitoring by flow cytometry in infants with B-lineage acute lymphoblastic leukemia Detskaya onkologiya = Pediatric Oncology 2008;(2):32–5. (In Russ.)].Попов А. М., Вержбицкая Т. Ю., Цаур Г. А. и др. Особенности мониторинга минимальной остаточной болезни при B-линейных острых лимфобластных лейкозах методом проточной цитометрии у детей первого года жизни. Детская онкология 2008;(2):32–5. [Popov A. M., Verzhbitskaya T. Yu., Tsaur G. A. et al. Peculiarities of minimal residual disease monitoring by flow cytometry in infants with B-lineage acute lymphoblastic leukemia Detskaya onkologiya = Pediatric Oncology 2008;(2):32–5. (In Russ.)].44. Цаур Г. А., Наседкина Т. В., Попов А. М. и др. Время достижения молекулярной ремиссии как фактор прогноза у детей первого года жизни острым лимфобластным лейкозом. Онкогематология 2010;(2):46–54.Цаур Г. А., Наседкина Т. В., Попов А. М. и др. Время достижения молекулярной ремиссии как фактор прогноза у детей первого года жизни острым лимфобластным лейкозом. Онкогематология 2010;(2):46–54.[Tsaur G. A., Nasedkina T. V., Popov A. M. et al. Time to molecular remission as prognostic factor in infant acute lymphoblastic leukemia. Onkogematologiya = Oncohematology 2010;(2):46–54. (In Russ.)].45. Цаур Г. А., Друй А. Е., Попов А. М. и др. Возможность использования микроструйных биочипов для оценки качества и количества РНК у пациентов с онкологическими и онкогематологическими заболеваниями. Вестник уральской медицинской академической науки 2011;(4):107–11. [Tsaur G. A., Druy А. Е., Popov А. М. et al. Microfluidic biochips for RNA quantity and quality evaluation in patients with oncological disorders. Vestnik ural’skoy meditsinskoy akademicheskoy nauki = Bulletin of the Ural Medical Academic Research 2011;(4):107–11. (In Russ.)].Цаур Г. А., Друй А. Е., Попов А. М. и др. Возможность использования микроструйных биочипов для оценки качества и количества РНК у пациентов с онкологическими и онкогематологическими заболеваниями. Вестник уральской медицинской академической науки 2011;(4):107–11. [Tsaur G. A., Druy А. Е., Popov А. М. et al. Microfluidic biochips for RNA quantity and quality evaluation in patients with oncological disorders. Vestnik ural’skoy meditsinskoy akademicheskoy nauki = Bulletin of the Ural Medical Academic Research 2011;(4):107–11. (In Russ.)].46. van Dongen J. J., Seriu T., Panzer-Grumayer R. et al. Prognostic value of minimal residual disease in acute lymphoblastic leukemia in childhood. Lancet 1998;352(9142):1731–8.van Dongen J. J., Seriu T., Panzer-Grumayer R. et al. Prognostic value of minimal residual disease in acute lymphoblastic leukemia in childhood. Lancet 1998;352(9142):1731–8.47. Dworzak M. N., Froschl G., Printz D. et al. Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia. Blood 2002;99(6):1952–8.Dworzak M. N., Froschl G., Printz D. et al. Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia. Blood 2002;99(6):1952–8.48. Campana D. Minimal residual disease studies in acute leukaemia. Am J Clin Pathol 2004;122:S47–57.Campana D. Minimal residual disease studies in acute leukaemia. Am J Clin Pathol 2004;122:S47–57.49. Flohr T., Schrauder A., Cazzaniga G. et al. 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 AIEOPBFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia 2008;22(4):771–82.Flohr T., Schrauder A., Cazzaniga G. et al. 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 AIEOPBFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia 2008;22(4):771–82.50. Borowitz M., Devidas M., Hunger S. et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study. Blood 2008;111(12):5477–85.Borowitz M., Devidas M., Hunger S. et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study. Blood 2008;111(12):5477–85.51. Цаур Г. А., Попов А. М., Наседкина Т. В. и др. Прогностическое значение минимальной остаточной болезни, определенной путем выявления химерных транскриптов у детей первого года жизни, больных острым лимфобластным лейкозом, получающих терапию по протоколу MLL-Baby. Гематология и трансфузиология 2012;57(4):12–22. [Tsaur G. A., Popov A. M., Nasedkina T. V. et al. Prognostic significance of minimal residual disease detected by PCR for fusion gene transcripts in infant acute lymphoblastic leukemia treated by MLL-baby protocol. Gematologiya i transfuziologiya = Hematology and Transfusiology 2012;57(4):12–22. (In Russ.)].Цаур Г. А., Попов А. М., Наседкина Т. В. и др. Прогностическое значение минимальной остаточной болезни, определенной путем выявления химерных транскриптов у детей первого года жизни, больных острым лимфобластным лейкозом, получающих терапию по протоколу MLL-Baby. Гематология и трансфузиология 2012;57(4):12–22. [Tsaur G. A., Popov A. M., Nasedkina T. V. et al. Prognostic significance of minimal residual disease detected by PCR for fusion gene transcripts in infant acute lymphoblastic leukemia treated by MLL-baby protocol. Gematologiya i transfuziologiya = Hematology and Transfusiology 2012;57(4):12–22. (In Russ.)].52. van der Velden V., Cazzaniga G., Schrauder A. et al. Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia 2007;21(4):604–11.van der Velden V., Cazzaniga G., Schrauder A. et al. Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia 2007;21(4):604–11.53. van der Velden V., Panzer-Grumayer E. R., Cazzaniga G. et al. Optimization of PCRbased minimal residual disease diagnostics for childhood acute lymphoblastic leukemia in a multi-center setting. Leukemia 2007;21(4):706–13.van der Velden V., Panzer-Grumayer E. R., Cazzaniga G. et al. Optimization of PCRbased minimal residual disease diagnostics for childhood acute lymphoblastic leukemia in a multi-center setting. Leukemia 2007;21(4):706–13.54. van der Velden V., Corral L., Valsecchi M. G. et al. Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia 2009;23(6):1073–9.van der Velden V., Corral L., Valsecchi M. G. et al. Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia 2009;23(6):1073–9.55. Garand R., Beldjord K., Cavé H. et al. Flow cytometry and IgH/TCR quantitative PCR for minimal residual disease quantitation in acute lymphoblastic leukemia: a French multicenter prospective study on behalf of the FRALLE, EORTC and GRAALL. Leukemia 2013;27(2):370–6.Garand R., Beldjord K., Cavé H. et al. Flow cytometry and IgH/TCR quantitative PCR for minimal residual disease quantitation in acute lymphoblastic leukemia: a French multicenter prospective study on behalf of the FRALLE, EORTC and GRAALL. Leukemia 2013;27(2):370–6.56. Schrappe M., Valsecchi M. G., Bartram C. 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.Schrappe M., Valsecchi M. G., Bartram C. 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):2077–84.57. Eckert C., Biondi A., Seeger K. et al. Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia. Lancet 2001;358(9289): 1239–41.Eckert C., Biondi A., Seeger K. et al. Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia. Lancet 2001;358(9289): 1239–41.58. Bader P., Kreyenberg H., Henze G. et al. 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.Bader P., Kreyenberg H., Henze G. et al. 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): 377–84.59. Meyer C., Schneider B., Reichel M. et al. Diagnostic tool for the identification of MLL rearrangements including unknown partner genes. Proc Natl Acad Sci USA 2005;102(2):449–54.Meyer C., Schneider B., Reichel M. et al. Diagnostic tool for the identification of MLL rearrangements including unknown partner genes. Proc Natl Acad Sci USA 2005;102(2):449–54.60. Burmeister T., Meyer C., Schwartz S. et al. Monitoring minimal residual disease by quantification of genomic chromosomal breakpoint sequences in acute leukemias with MLL aberrations. Leukemia 2006;20(3):451–7.Burmeister T., Meyer C., Schwartz S. et al. Monitoring minimal residual disease by quantification of genomic chromosomal breakpoint sequences in acute leukemias with MLL aberrations. Leukemia 2006;20(3):451–7.61. Elia L., Gottardi E., Floriddia G. et al. Retrospective comparison of qualitative and quantitative reverse transcriptase polymerase chain reaction in diagnosing and monitoring the ALL1-AF4 fusion transcript in patients with acute lymphoblastic leukaemia. Leukemia 2004;18(11):1824–30.Elia L., Gottardi E., Floriddia G. et al. Retrospective comparison of qualitative and quantitative reverse transcriptase polymerase chain reaction in diagnosing and monitoring the ALL1-AF4 fusion transcript in patients with acute lymphoblastic leukaemia. Leukemia 2004;18(11):1824–30.62. Elia L., Grammatico S,, Paoloni F. et al. Clinical outcome and monitoring of minimal residual disease in patients with acute lymphoblastic leukemia expressing the MLL/ENL fusion gene. Am J Hematol 2011;86(12):993–7.Elia L., Grammatico S,, Paoloni F. et al. Clinical outcome and monitoring of minimal residual disease in patients with acute lymphoblastic leukemia expressing the MLL/ENL fusion gene. Am J Hematol 2011;86(12):993–7.63. Popov A., Buldini B., de Lorenzo P. et al. Identification of low risk group in infants with acute lymphoblastic leukemia by flow cytometric minimal residual disease measurement at day 15 of Interfant-99 and Interfant-06 protocols treatment. Blood 2013;122(21):abstract 1333.Popov A., Buldini B., de Lorenzo P. et al. Identification of low risk group in infants with acute lymphoblastic leukemia by flow cytometric minimal residual disease measurement at day 15 of Interfant-99 and Interfant-06 protocols treatment. Blood 2013;122(21):abstract 1333.