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      Day 15 and Day 33 Minimal Residual Disease Assessment for Acute Lymphoblastic Leukemia Patients Treated According to the BFM ALL IC 2009 Protocol: Single-Center Experience of 133 Cases

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          Abstract

          Introduction: Childhood acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by the acquisition of several genetic lesions in the lymphoid progenitors with subsequent proliferation advantage and lack of maturation. Along the years, it has been repeatedly shown that minimal residual disease (MRD) plays an important role in prognosis and therapy choice. The aim of the current study was to determine the prognostic role of MRD in childhood ALL patients in conjunction with other relevant patient and disease characteristics, thus showing the real-life scenario of childhood ALL.

          Patients and Methods: The retrospective study includes childhood ALL patients that were treated according to the BFM ALL IC 2009 between January 2016 and December 2018 at the Fundeni Clinical Institute, Bucharest, Romania.

          Results: None of the variables significantly influenced the induction-related death in our study. None of the variables independently predicted relapse-free survival (RFS) with the highest tendency for statistical significance being represented by poor prednisone response. Non-relapse mortality (NRM) was independently predicted by age, prednisone response, and day 33 flow cytometry-MRD (FCM-MRD). Overall survival (OS) was independently predicted by prednisone response and day 33 FCM-MRD. Event-free survival (EFS) was independently predicted by age, prednisone response, and day 33 FCM-MRD.

          Conclusion : Prednisone response, day 15 FCM-MRD, day 33 FCM-MRD, and the risk group represent the most important factors that in the current study independently predict childhood ALL prognosis.

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          Most cited references15

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          Acute lymphoblastic leukaemia.

          Acute lymphoblastic leukaemia occurs in both children and adults but its incidence peaks between 2 and 5 years of age. Causation is multifactorial and exogenous or endogenous exposures, genetic susceptibility, and chance have roles. Survival in paediatric acute lymphoblastic leukaemia has improved to roughly 90% in trials with risk stratification by biological features of leukaemic cells and response to treatment, treatment modification based on patients' pharmacodynamics and pharmacogenomics, and improved supportive care. However, innovative approaches are needed to further improve survival while reducing adverse effects. Prognosis remains poor in infants and adults. Genome-wide profiling of germline and leukaemic cell DNA has identified novel submicroscopic structural genetic changes and sequence mutations that contribute to leukaemogenesis, define new disease subtypes, affect responsiveness to treatment, and might provide novel prognostic markers and therapeutic targets for personalised medicine. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study.

            Minimal residual disease (MRD) is an important predictor of relapse in acute lymphoblastic leukemia (ALL), but its relationship to other prognostic variables has not been fully assessed. The Children's Oncology Group studied the prognostic impact of MRD measured by flow cytometry in the peripheral blood at day 8, and in end-induction (day 29) and end-consolidation marrows in 2143 children with precursor B-cell ALL (B-ALL). The presence of MRD in day-8 blood and day-29 marrow MRD was associated with shorter event-free survival (EFS) in all risk groups; even patients with 0.01% to 0.1% day-29 MRD had poor outcome compared with patients negative for MRD patients (59% +/- 5% vs 88% +/- 1% 5-year EFS). Presence of good prognostic markers TEL-AML1 or trisomies of chromosomes 4 and 10 still provided additional prognostic information, but not in National Cancer Institute high-risk (NCI HR) patients who were MRD(+). The few patients with detectable MRD at end of consolidation fared especially poorly, with only a 43% plus or minus 7% 5-year EFS. Day-29 marrow MRD was the most important prognostic variable in multi-variate analysis. The 12% of patients with all favorable risk factors, including NCI risk group, genetics, and absence of days 8 and 29 MRD, had a 97% plus or minus 1% 5-year EFS with nonintensive therapy. These studies are registered at www.clinicaltrials.gov as NCT00005585, NCT00005596, and NCT00005603.
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              Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group.

              Outcome of childhood acute lymphoblastic leukemia (ALL) improved greatly by intensifying chemotherapy for all patients. Minimal residual disease (MRD) levels during the first months predict outcome and may select patients for therapy reduction or intensification.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                30 June 2020
                2020
                : 10
                : 923
                Affiliations
                [1] 1Department of Medicine, Carol Davila University of Medicine and Pharmacy , Bucharest, Romania
                [2] 2Department of Stem Cell Transplantation, Fundeni Clinical Institute , Bucharest, Romania
                [3] 3Department of Hematology, Coltea Hospital , Bucharest, Romania
                [4] 4Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy , Cluj Napoca, Romania
                [5] 5Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy , Cluj Napoca, Romania
                [6] 6Department of Hematology, Oncology Institute Prof. Dr. Ion Chiricuta , Cluj Napoca, Romania
                [7] 7Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy , Cluj Napoca, Romania
                Author notes

                Edited by: Gabriel Ghiaur, The Johns Hopkins Hospital, Johns Hopkins Medicine, United States

                Reviewed by: Jonathan Webster, The Johns Hopkins Hospital, Johns Hopkins Medicine, United States; Laura M. Wake, The Johns Hopkins Hospital, Johns Hopkins Medicine, United States

                *Correspondence: Ciprian Tomuleasa ciprian.tomuleasa@ 123456umfcluj.ro

                This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2020.00923
                7338564
                32695667
                c5e70a28-c261-4e05-9ef3-ea6f675151c0
                Copyright © 2020 Radu, Colita, Pasca, Tomuleasa, Popa, Serban, Gheorghe, Serbanica, Jercan, Marcu, Bica, Teodorescu, Constantinescu, Petrushev, Asan, Jardan, Dragomir, Tanase and Colita.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 February 2020
                : 11 May 2020
                Page count
                Figures: 5, Tables: 1, Equations: 0, References: 19, Pages: 9, Words: 4387
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                children,all,mrd,flow cytometry,survival
                Oncology & Radiotherapy
                children, all, mrd, flow cytometry, survival

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