bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2021-66-2-192-205bloodjour-281Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESМониторинг минимальной остаточной болезни и В-клеточных субпопуляций у больных острым B-лимфобластным лейкозом, леченных по протоколу «ОЛЛ-2016»Minimal residual disease and b-cell subpopulation monitoring in acute b-lymphoblastic leukaemia patients treated on rall-2016 protocolhttps://orcid.org/0000-0002-8490-6066ГальцеваИ. В.GaltsevaI. V.

Гальцева Ирина Владимировна, кандидат медицинских наук, заведующая лабораторией иммунофенотипирования клеток крови и костного мозга

125167, Москва

Irina V. Galtseva, Cand. Sci. (Med.), Head of the Laboratory of Blood and Bone Marrow Immunophenotyping

125167, Moscow

irinagaltseva@gmail.comhttps://orcid.org/0000-0001-5932-0285ДавыдоваЮ. О.DavydovaY. O.

Давыдова Юлия Олеговна, кандидат медицинских наук, врач клинической лабораторной диагностики лаборатории иммунофенотипирования клеток крови и костного мозга

125167, Москва

Yulia O. Davydova, Cand. Sci. (Med.) Physician (clinical diagnostics), Laboratory of Blood and Bone Marrow Immunophenotyping

125167, Moscow

davydova.y@blood.ruhttps://orcid.org/0000-0001-6177-3566ПаровичниковаЕ. Н.ParovichnikovaE. N.

Паровичникова Елена Николаевна, доктор медицинских наук, заведующая отделом химиотерапии гемобластозов, депрессий кроветворения и трансплантации костного мозга

125167, Москва

Elena N. Parovichnikova, Dr. Sci. (Med.), Head of the Department of Chemotherapy for Hemoblastoses, Hematopoietic Depressions and Bone Marrow Transplantation

125167, Moscow

parovichnikova.e@blood.ruhttps://orcid.org/0000-0002-9969-8482ГаврилинаО. А.GavrilinaO. A.

Гаврилина Ольга Александровна, кандидат медицинских наук, старший научный сотрудник отделения интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения

125167, Москва

Olga A. Gavrilina, Cand. Sci. (Med.), Senior Researcher, Department of Intensive High-Dose Chemotherapy for Hemoblastoses and Hematopoietic Depressions

125167, Moscow

dr.gavrilina@mail.ruhttps://orcid.org/0000-0002-4827-8947ТроицкаяВ. В.TroitskayaV. V.

Троицкая Вера Витальевна, кандидат медицинских наук, заместитель генерального директора по лечебной работе, заведующая отделением интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения

125167, Москва

Vera V. Troitskaya, Cand. Sci. (Med.), Deputy Director General for Therapy, Head of the Department of Intensive High-Dose Chemotherapy for Hemoblastoses and Hematopoietic Depressions

125167, Moscow

troitskaya.v@blood.ruhttps://orcid.org/0000-0002-6512-910XКапрановН. М.KapranovN. M.

Капранов Николай Михайлович, кандидат биологических наук, медицинский физик лаборатории иммунофенотипирования клеток крови и костного мозга

125167, Москва

Nikolay M. Kapranov, Cand. Sci. (Biol.) Medical Physicist, Laboratory of Blood and Bone Marrow Immunophenotyping

125167, Moscow

kapranov.n@blood.ruhttps://orcid.org/0000-0002-4119-7175НикифороваК. А.NikiforovaK. A.

Никифорова Ксения Александровна, биолог лаборатории иммунофенотипирования клеток крови и костного мозга

125167, Москва

Ksenia A. Nikiforova, Biologist, Laboratory of Blood and Bone Marrow Immunophenotyping

125167, Moscow

nikiforova.k@blood.ruhttps://orcid.org/0000-0003-2763-5391ИсиноваГ. А.IsinovaG. A.

Исинова Галина Александровна, кандидат медицинских наук, врачгематолог отделения интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения

125167, Москва

Galina A. Isinova, Cand. Sci. (Med.), Physician (haematology), Department of Intensive High-Dose Chemotherapy for Hemoblastoses and Hematopoietic Depressions

125167, Moscow

rara4v1s@gmail.comhttps://orcid.org/0000-0003-2947-6398ЗарубинаК. И.ZarubinaK. I.

Зарубина Ксения Игоревна, врач-гематолог отделения интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения

125167, Москва

Ksenia I. Zarubina, Physician (haematology), Department of Intensive HighDose Chemotherapy for Hemoblastoses and Hematopoietic Depressions

125167, Moscow

ksenijazarubina@mail.ruhttps://orcid.org/0000-0003-1494-7978СоколовА. Н.SokolovA. N.

Соколов Андрей Николаевич, кандидат медицинских наук, старший научный сотрудник отделения интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения

125167, Москва

Andrey N. Sokolov, Cand. Sci. (Med.), Senior Researcher, Department of Intensive High-Dose Chemotherapy for Hemoblastoses and Hematopoietic Depressions

125167, Moscow

sokolov.a@blood.ruhttps://orcid.org/0000-0001-8188-5557СавченкоВ. Г.SavchenkoV. G.

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

125167, Москва

Valery G. Savchenko, Dr. Sci. (Med.), Prof., Full Member of the Russian Academy of Sciences, Director General

125167, Moscow

svg@blood.ruФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской ФедерацииРоссияNational Research Center for HematologyRussian Federation202131082021662192205Copyright © Гальцева И.В., Давыдова Ю.О., Паровичникова Е.Н., Гаврилина О.А., Троицкая В.В., Капранов Н.М., Никифорова К.А., Исинова Г.А., Зарубина К.И., Соколов А.Н., Савченко В.Г., 20212021Гальцева И.В., Давыдова Ю.О., Паровичникова Е.Н., Гаврилина О.А., Троицкая В.В., Капранов Н.М., Никифорова К.А., Исинова Г.А., Зарубина К.И., Соколов А.Н., Савченко В.Г.Galtseva I.V., Davydova Y.O., Parovichnikova E.N., Gavrilina O.A., Troitskaya V.V., Kapranov N.M., Nikiforova K.A., Isinova G.A., Zarubina K.I., Sokolov A.N., 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/281Введение

Введение. В  рамках Российского многоцентрового исследования по  терапии острых лимфобластных лейкозов (ОЛЛ) у взрослых «ОЛЛ-2016» предусмотрено централизованное определение минимальной остаточной болезни (МОБ) на 70-й (конец индукции II), 133-й (конец консолидации III) и 190-й (конец консолидации V) дни.

Цель  — оценить клиренс опухолевых клеток и  динамику нормальных В-клеточных предшественников, зрелых В-клеток и плазматических клеток.

Материалы и методы

Материалы и методы. С декабря 2016 г. по август 2019 г. в исследование было включено 59 больных В-ОЛЛ, в  контрольную группу вошло 4  донора аллогенных стволовых клеток крови. Определение МОБ проводили в образцах костного мозга методом проточной цитометрии.

Результаты

Результаты. В  контрольных точках МОБ-негативного статуса достигало большинство больных: 60,4 %  — на  70-й день, 75,6 %  — на  133-й день, а  на  190-й день  — 91,2 %. Не  обнаружено зависимости величины МОБ от иммунофенотипа опухолевых клеток. В-клеточные предшественники не определялись у 54,4 % больных на 70-й день, у 38,8 % — на 133-й день и у 59,4 % — на 190-й день. «Зрелых» В-клеток у больных было меньше на 133-й день, 190-й день по сравнению с донорами. Доля плазматических клеток значимо не изменялась на протяжении терапии и не отличалась у больных и доноров.

Заключение

Заключение. Протокол «ОЛЛ-2016» позволяет добиться МОБ-негативного статуса у  большинства больных, несмотря на снижение интенсивности цитостатического воздействия.

Introduction

Introduction. The Russian multicentre trial on treatment of Acute Lymphoblastic Leukaemia (ALL) in adults (RALL-2016) regulates a centralised detection of minimal residual disease (MRD) on days 70 (end of induction II), 133 (end of consolidation III) and 190 (end of consolidation V).

Aim — the assessment of tumour cell clearance and normal B-cell precursor, mature B-cell and plasma cell dynamics.

Materials and methods

Materials and methods. The study period of December 2016 — August 2019 covered 59 B-ALL patients; the control cohort included four allogeneic blood stem cell donors. The MRD detection was performed with bone marrow samples in flow cytometry.

Results

Results. The patient majority have reached MRD-negativity at control timepoints, 60.4, 75.6 and 91.2% on days 70, 133 and 190, respectively. No correlation was observed between MRD values and tumour cell immunophenotype. B-cell precursors were undetected in 54.4, 38.8 and 59.4% patients on days 70, 133 and 190, respectively. Mature B-cells were fewer compared to donors’ on days 133 and 190. The relative plasma cell count did not differ significantly over therapy and between patients and donors.

Conclusion

Conclusion. The RALL-2016 protocol facilitates MRD-negativity in the patient majority despite reduced cytostatic intensity.

острый лимфобластный лейкозминимальная остаточная болезньпроточная цитометрияиммунофенотипированиеacute lymphoblastic leukaemiaminimal residual diseaseflow cytometryimmunophenotypingReferencesSchuurhuis G.J., Heuser M., Freeman S., et al. Minimal/measurable residual disease in AML: A consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018; 131(12): 1275–1291. DOI: 10.1182/blood-2017-09-801498.Schuurhuis G.J., Heuser M., Freeman S., et al. Minimal/measurable residual disease in AML: A consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018; 131(12): 1275–1291. DOI: 10.1182/blood-2017-09-801498.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): 771–782. DOI: 10.1038/leu.2008.5.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): 771–782. DOI: 10.1038/leu.2008.5.Basso G., Veltroni M., Valsecchi M.G., et al. Risk of relapse of childhood acute lymphoblastic leukemia is predicted by fl ow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol. 2009; 27(31): 5168–5174. DOI: 10.1200/JCO.2008.20.8934.Basso G., Veltroni M., Valsecchi M.G., 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): 5168–5174. DOI: 10.1200/JCO.2008.20.8934.Borowitz M.J., Pullen D.J., Shuster J.J., et al. Minimal residual disease detection in childhood precursor-B-cell acute lymphoblastic leukemia: Relation to other risk factors. A Children’s Oncology Group study. Leukemia. 2003; 17(8): 1566– 1572. DOI: 10.1038/sj.leu.2403001.Borowitz M.J., Pullen D.J., Shuster J.J., et al. Minimal residual disease detection in childhood precursor-B-cell acute lymphoblastic leukemia: Relation to other risk factors. A Children’s Oncology Group study. Leukemia. 2003; 17(8): 1566– 1572. DOI: 10.1038/sj.leu.2403001.Björklund E., Mazur J., Söderhäll S., Porwit-MacDonald A. Flow cytometric follow-up of minimal residual disease in bone marrow gives prognostic information in children with acute lymphoblastic leukemia. Leukemia. 2003; 17(1): 138–148. DOI: 10.1038/sj.leu.2402736.Björklund E., Mazur J., Söderhäll S., Porwit-MacDonald A. Flow cytometric follow-up of minimal residual disease in bone marrow gives prognostic information in children with acute lymphoblastic leukemia. Leukemia. 2003; 17(1): 138–148. DOI: 10.1038/sj.leu.2402736.Treatment of High Risk Adult Acute Lymphoblastic Leukemia (LAL-AR/2003). ClinicalTrials.gov (database of privately and publicly funded clinical studies), 2009. https://clinicaltrials.gov/ct2/show/NCT00853008Treatment of High Risk Adult Acute Lymphoblastic Leukemia (LAL-AR/2003). ClinicalTrials.gov (database of privately and publicly funded clinical studies), 2009. https://clinicaltrials.gov/ct2/show/NCT00853008Gökbuget N., Kneba M., Raff T., et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood. 2012; 120(9): 1868– 1876. DOI: 10.1182/blood-2011-09-377713.Gökbuget N., Kneba M., Raff T., et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood. 2012; 120(9): 1868– 1876. DOI: 10.1182/blood-2011-09-377713.Brüggemann M., Kotrova M. Minimal residual disease in adult ALL: Technical aspects and implications for correct clinical interpretation. Hematol Am Soc Hematol Educ Progr. 2017; 2017(1): 13–21. DOI: 10.1182/asheducation-2017.1.13.Brüggemann M., Kotrova M. Minimal residual disease in adult ALL: Technical aspects and implications for correct clinical interpretation. Hematol Am Soc Hematol Educ Progr. 2017; 2017(1): 13–21. DOI: 10.1182/asheducation-2017.1.13.Clinical trials AIEOP-BFM ALL 2009 (2007-004270-43). EU Clinical Trials Register, 2010. https://www.clinicaltrialsregister.eu/Clinical trials AIEOP-BFM ALL 2009 (2007-004270-43). EU Clinical Trials Register, 2010. https://www.clinicaltrialsregister.eu/Beldjord K., Chevret S., Asnafi V., et al. Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia. Blood. 2014; 123(24): 3739–3749. DOI: 10.1182/blood-2014-01-547695.Beldjord K., Chevret S., Asnafi V., et al. Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia. Blood. 2014; 123(24): 3739–3749. DOI: 10.1182/blood-2014-01-547695.Паровичникова Е.Н., Троицкая В.В., Соколов А.Н. и др. Промежуточные результаты по лечению острых Ph-негативных лимфобластных лейкозов у взрослых больных (итоги Российской исследовательской группы по лечению острых лимфобластных лейкозов (RALL)). Онкогематология. 2014; 3(9): 6–15. DOI: 10.17650/1818-8346-2014-9-3-6-15.Parovichnikova E.N., Troitskaya V.V., Sokolov A.N., et al. Interim results of the Ph-negative acute lymphoblastic leukemia treatment in adult patients (results of Russian research group of ALL treatment (RALL)). Onkogematologiya. 2014; 3(9): 6–15. DOI: 10.17650/1818-8346-2014-9-3-6-15. (In Russian).Паровичникова Е.Н., Соколов А.Н., Троицкая В.В. и др. Острые Ph-негативные лимфобластные лейкозы взрослых: факторы риска при использовании протокола ОЛЛ-2009. Терапевтический архив. 2016; 88(7): 15–24. DOI: 10.17116/terarkh201688715-24.Parovichnikova E.N., Sokolov A.N., Troitskaya V.V., et al. Acute Ph-negative lymphoblastic leukemias in adults: Risk factors in the use of the ALL-2009 protocol. Terapevticheskii arkhiv. 2016; 88(7): 15–24. DOI: 10.17116/terarkh201688715-24. (In Russian).Multicenter Clinical Trial for Adult Ph-negative ALL. Non-intensive But Noniterruptive Treatment. ClinicalTrials.gov (database of privately and publicly funded clinical studies), 2010. https://clinicaltrials.gov/ct2/show/NCT01193933Multicenter Clinical Trial for Adult Ph-negative ALL. Non-intensive But Noniterruptive Treatment. ClinicalTrials.gov (database of privately and publicly funded clinical studies), 2010. https://clinicaltrials.gov/ct2/show/NCT01193933De-escalated Treatment Approach for Adult Ph-negative Acute Lymphoblastic Leukemia (ALL). ClinicalTrials.gov (database of privately and publicly funded clinical studies), 2018. https://clinicaltrials.gov/ct2/show/NCT03462095De-escalated Treatment Approach for Adult Ph-negative Acute Lymphoblastic Leukemia (ALL). ClinicalTrials.gov (database of privately and publicly funded clinical studies), 2018. https://clinicaltrials.gov/ct2/show/NCT03462095Wood B.L. Principles of minimal residual disease detection for hematopoietic neoplasms by flow cytometry. Cytometry B Clin Cytom. 2016; 90(1): 47–53. DOI: 10.1002/cyto.b.21239.Wood B.L. Principles of minimal residual disease detection for hematopoietic neoplasms by flow cytometry. Cytometry B Clin Cytom. 2016; 90(1): 47–53. DOI: 10.1002/cyto.b.21239.Wood B. Multicolor immunophenotyping: human immune system hematopoiesis. Methods Cell Biol. 2004; 75: 559–576. DOI: 10.1016/S0091-679X(04)75023-2.Wood B. Multicolor immunophenotyping: human immune system hematopoiesis. Methods Cell Biol. 2004; 75: 559–576. DOI: 10.1016/S0091-679X(04)75023-2.Wood B.L. Flow cytometric monitoring of residual disease in acute leukemia. In: Methods in Molecular Biology (Clifton N.J.). 2013; 999: 123–136. DOI: 10.1007/978-1-62703-357-2_8.Wood B.L. Flow cytometric monitoring of residual disease in acute leukemia. In: Methods in Molecular Biology (Clifton N.J.). 2013; 999: 123–136. DOI: 10.1007/978-1-62703-357-2_8.Dworzak M.N., Buldini B., Gaipa G., et al. AIEOP-BFM consensus guidelines 2016 for flow cytometric immunophenotyping of Pediatric acute lymphoblastic leukemia. Cytometry Part B. 2018; 94B: 82–93. DOI: 10.1002/cyto.b.21518.Dworzak M.N., Buldini B., Gaipa G., et al. AIEOP-BFM consensus guidelines 2016 for flow cytometric immunophenotyping of Pediatric acute lymphoblastic leukemia. Cytometry Part B. 2018; 94B: 82–93. DOI: 10.1002/cyto.b.21518.Попов А.М., Вержбицкая Т.Ю., Фечина Л.Г. и др. Острые лейкозы: различия иммунофенотипа бластных клеток и их неопухолевых аналогов в костном мозге. Клиническая онкогематология. 2016; 9(3): 302–313. DOI: 10.21320/2500-2139-2016-9-3-302-313.Popov A.M., Verzhbitskaya T.Yu., Fechina L.G., et al. Acute leukemias: Immunophenotypic differences between blast cells and their nonneoplastic analogues in bone marrow. Klinicheskaya onkogematologiya. 2016; 9(3): 302–313. DOI: 10.21320/2500-2139-2016-9-3-302-313. (In Russian).Dworzak M.N., Gaipa G., Ratei R., et al. Standardization of flow cytometric minimal residual disease evaluation in acute lymphoblastic leukemia: Multicentric assessment is feasible. Cytometry Part B. 2008; 74B: 331–340. DOI: 10.1002/cyto.b.20430.Dworzak M.N., Gaipa G., Ratei R., et al. Standardization of flow cytometric minimal residual disease evaluation in acute lymphoblastic leukemia: Multicentric assessment is feasible. Cytometry Part B. 2008; 74B: 331–340. DOI: 10.1002/cyto.b.20430.Borowitz M.J., Devidas M., Hunger S.P., 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): 5477–5485. DOI: 10.1182/blood-2008-01-132837.Borowitz M.J., Devidas M., Hunger S.P., 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): 5477–5485. DOI: 10.1182/blood-2008-01-132837.Ribera J.-M., Oriol A., Morgades M., et al. Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescents and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial. J Clin Oncol. 2014; 32(15): 1595–1604. DOI: 10.1200/JCO.2013.52.2425.Ribera J.-M., Oriol A., Morgades M., et al. Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescents and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial. J Clin Oncol. 2014; 32(15): 1595–1604. DOI: 10.1200/JCO.2013.52.2425.Bassan R., Spinelli O., Oldani E., et al. Improved risk classification for riskspecific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood. 2009; 113(18): 4153–4162. DOI: 10.1182/blood-2008-11-185132.Bassan R., Spinelli O., Oldani E., et al. Improved risk classification for riskspecific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood. 2009; 113(18): 4153–4162. DOI: 10.1182/blood-2008-11-185132.Patel B., Rai L., Buck G., et al. Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: Final results of the international trial UKALL XII/ECOG2993. Br J Haematol. 2010; 148(1): 80–89. DOI: 10.1111/j.1365-2141.2009.07941.x.Patel B., Rai L., Buck G., et al. Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: Final results of the international trial UKALL XII/ECOG2993. Br J Haematol. 2010; 148(1): 80–89. DOI: 10.1111/j.1365-2141.2009.07941.x.Ravandi F., Jorgensen J.L., O’Brien S.M., et al. Minimal residual disease assessed by multi-parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia. Br J Haematol. 2016; 172(3): 392–400. DOI: 10.1111/bjh.13834.Ravandi F., Jorgensen J.L., O’Brien S.M., et al. Minimal residual disease assessed by multi-parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia. Br J Haematol. 2016; 172(3): 392–400. DOI: 10.1111/bjh.13834.van Lochem E.G., Wiegers Y.M., van den Beemd R., et al. Regeneration pattern of precursor-B-cells in bone marrow of acute lymphoblastic leukemia patients depends on the type of preceding chemotherapy. Leukemia. 2000; 14(4): 688– 695. DOI: 10.1038/sj.leu.2401749.van Lochem E.G., Wiegers Y.M., van den Beemd R., et al. Regeneration pattern of precursor-B-cells in bone marrow of acute lymphoblastic leukemia patients depends on the type of preceding chemotherapy. Leukemia. 2000; 14(4): 688– 695. DOI: 10.1038/sj.leu.2401749.van Wering E.R., van der Linden-Schrever B.E., Szczepański T., et al. Regenerating normal B-cell precursors during and after treatment of acute lymphoblastic leukaemia: Implications for monitoring of minimal residual disease. Br J Haematol. 2000; 110(1): 139–146. DOI: 10.1046/j.1365-2141.2000.02143.x.van Wering E.R., van der Linden-Schrever B.E., Szczepański T., et al. Regenerating normal B-cell precursors during and after treatment of acute lymphoblastic leukaemia: Implications for monitoring of minimal residual disease. Br J Haematol. 2000; 110(1): 139–146. DOI: 10.1046/j.1365-2141.2000.02143.x.Theunissen P.M.J., van den Branden A., van der Sluijs-Gelling A., et al. Understanding the reconstitution of the B-cell compartment in bone marrow and blood after treatment for B-cell precursor acute lymphoblastic leukaemia. Br J Haematol. 2017; 178(2): 267–278. DOI: 10.1111/bjh.14685.Theunissen P.M.J., van den Branden A., van der Sluijs-Gelling A., et al. Understanding the reconstitution of the B-cell compartment in bone marrow and blood after treatment for B-cell precursor acute lymphoblastic leukaemia. Br J Haematol. 2017; 178(2): 267–278. DOI: 10.1111/bjh.14685.Liao H., Zheng Q., Jin Y., et al. The prognostic significance of hematogones and CD34+ myeloblasts in bone marrow for adult B-cell lymphoblastic leukemia without minimal residual disease. Sci Rep. 2019; 9(1): 19722. DOI: 10.1038/s41598-019-56126-2.Liao H., Zheng Q., Jin Y., et al. The prognostic significance of hematogones and CD34+ myeloblasts in bone marrow for adult B-cell lymphoblastic leukemia without minimal residual disease. Sci Rep. 2019; 9(1): 19722. DOI: 10.1038/s41598-019-56126-2.

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