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      Early Response to Dexamethasone as Prognostic Factor: Result from Indonesian Childhood WK-ALL Protocol in Yogyakarta

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          Abstract

          Early response to treatment has been shown to be an important prognostic factor of childhood acute lymphoblastic leukemia (ALL) patients in Western studies. We studied this factor in the setting of a low-income province in 165 patients treated on Indonesian WK-ALL-2000 protocol between 1999 and 2006. Poor early response, defined as a peripheral lymphoblasts count of ≥1000/ μL after 7 days of oral dexamethasone plus one intrathecal methotrexate (MTX), occurred in 19.4% of the patients. Poor responders showed a higher probability of induction failures compared to good responders (53.1% versus 23.3%, P < 0.01), higher probability of resistant disease (15.6% versus 4.5%, P = 0.02), shorter disease-free survival ( P = 0.034; 5-year DFS: 24.9% ± 12.1% versus 48.6% ± 5.7%), and shorter event-free survival ( P = 0.002; 5-year EFS: 9.7% ± 5.3% versus 26.3% ± 3.8%). We observed that the percentage of poor responders in our setting was higher than reported for Western countries with prednisone or prednisolone as the steroids. The study did not demonstrate a significant additive prognostic value of early response over other known risk factors (age and white blood cell count) for DFS and only a moderately added value for EFS.

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          Risk- and response-based classification 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).

          The Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) joined to form the Children's Oncology Group (COG) in 2000. This merger allowed analysis of clinical, biologic, and early response data predictive of event-free survival (EFS) in acute lymphoblastic leukemia (ALL) to develop a new classification system and treatment algorithm. From 11 779 children (age, 1 to 21.99 years) with newly diagnosed B-precursor ALL consecutively enrolled by the CCG (December 1988 to August 1995, n=4986) and POG (January 1986 to November 1999, n=6793), we retrospectively analyzed 6238 patients (CCG, 1182; POG, 5056) with informative cytogenetic data. Four risk groups were defined as very high risk (VHR; 5-year EFS, 45% or below), lower risk (5-year EFS, at least 85%), and standard and high risk (those remaining in the respective National Cancer Institute [NCI] risk groups). VHR criteria included extreme hypodiploidy (fewer than 44 chromosomes), t(9;22) and/or BCR/ABL, and induction failure. Lower-risk patients were NCI standard risk with either t(12;21) (TEL/AML1) or simultaneous trisomies of chromosomes 4, 10, and 17. Even with treatment differences, there was high concordance between the CCG and POG analyses. The COG risk classification scheme is being used for division of B-precursor ALL into lower- (27%), standard- (32%), high- (37%), and very-high- (4%) risk groups based on age, white blood cell (WBC) count, cytogenetics, day-14 marrow response, and end induction minimal residual disease (MRD) by flow cytometry in COG trials.
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            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.

            Detection of minimal residual disease (MRD) is the most sensitive method to evaluate treatment response and one of the strongest predictors of outcome in childhood acute lymphoblastic leukemia (ALL). The 10-year update on the I-BFM-SG MRD study 91 demonstrates stable results (event-free survival), that is, standard risk group (MRD-SR) 93%, intermediate risk group (MRD-IR) 74%, and high risk group (MRD-HR) 16%. In multicenter trial AIEOP-BFM ALL 2000, patients were stratified by MRD detection using quantitative PCR after induction (TP1) and consolidation treatment (TP2). From 1 July 2000 to 31 October 2004, PCR target identification was performed in 3341 patients: 2365 (71%) patients had two or more sensitive targets ( or =10(-3) at TP2), and 52% as MRD-IR. The remaining 823 patients were stratified according to clinical risk features: HR (n=108) and IR (n=715). In conclusion, MRD-PCR-based stratification using stringent criteria is feasible in almost 80% of patients in an international multicenter trial.
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              Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow.

              Speed of blast clearance is an indicator of outcome in childhood acute lymphoblastic leukemia (ALL). Availability of measurement of minimal residual disease (MRD) at an early time point with a reduced-cost method is of clinical relevance. In the AIEOP-BFM-ALL (Associazione Italiana Ematologia Oncologia Pediatrica and Berlin-Frankfurt-Münster Study Group) 2000 trial, patients were stratified by levels of polymerase chain reaction (PCR) MRD at day +33 and +78. AIEOP studied the prognostic impact of MRD measured by flow cytometry (FCM) at day 15 of induction therapy. Bone marrow samples from 830 Italian patients were collected on day 15, after 14 days of steroids, and one dose of intrathecal methotrexate, vincristine, daunorubicine, and asparaginase. Cells were analyzed by four-color FCM for detection of leukemia-associated immunophenotypes. Three patient risk groups were identified by FCM: standard ( or = 10%; 11%). Their 5-year cumulative incidences of relapse were 7.5% (SE, 1.5), 17.5% (SE, 2.1), and 47.2% (SE, 5.9), respectively. In multivariate analysis, FCM was the most important prognostic factor among those available by day 15, with two-fold and five-fold increase in the risk of relapse compared with patients with less than 0.1%. PCR MRD, when added to the model, had significant prognostic impact; yet high levels of FCM MRD retained an independent ability to detect a significantly higher risk of relapse. Measurement of FCM MRD in day 15 bone marrow was the most powerful early predictor of relapse, applicable to virtually all patients; it may complement PCR MRD-based stratification including later time points, thus allowing additional treatment tailoring.
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                Author and article information

                Journal
                J Oncol
                J Oncol
                JO
                Journal of Oncology
                Hindawi Publishing Corporation
                1687-8450
                1687-8469
                2012
                3 April 2012
                : 2012
                : 417941
                Affiliations
                1Pediatric Hematology and Oncology Division, Department of Pediatrics, Dr. Sardjito Hospital, Medical Faculty, Universitas Gadjah Mada, Yogyakarta, Indonesia
                2Department of Epidemiology and Biostatistics, VU University Medical Center, 1007MB Amsterdam, The Netherlands
                3Pediatric Oncology/Hematology Division, Department of Pediatrics, VU University Medical Center, 1007MB Amsterdam, The Netherlands
                Author notes
                *Pudjo H. Widjajanto: pudjo007@ 123456yahoo.com

                Academic Editor: A. J. M. Balm

                Article
                10.1155/2012/417941
                3324166
                22548058
                60abe978-2d81-41c3-bfb8-ce271de595d3
                Copyright © 2012 Pudjo H. Widjajanto et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 November 2011
                : 24 January 2012
                : 25 January 2012
                Categories
                Clinical Study

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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