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Review Article

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Korean J Hematol 2012; 47(4):

Published online December 31, 2012

https://doi.org/10.5045/kjh.2012.47.4.245

© The Korean Society of Hematology

Measurements of treatment response in childhood acute leukemia

Dario Campana*, and Elaine Coustan-Smith

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Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Correspondence to : Correspondence to Dario Campana, M.D., Ph.D. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, Level 9 South, 117599, Singapore. Tel: +65-6601-2666, Fax: +65-6779-7486, paedc@nus.edu.sg

Received: October 26, 2012; Accepted: November 14, 2012

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Measuring response to chemotherapy is a backbone of the clinical management of patients with acute leukemia. This task has historically relied on the ability to identify leukemic cells among normal bone marrow cells by their morphology. However, more accurate ways to identify leukemic cells have been developed, which allow their detection even when they are present in small numbers that would be impossible to be recognized by microscopic inspection. The levels of such minimal residual disease (MRD) are now widely used as parameters for risk assignment in acute lymphoblastic leukemia (ALL) and increasingly so in acute myeloid leukemia (AML). However, different MRD monitoring methods may produce discrepant results. Moreover, results of morphologic examination may be in stark contradiction to MRD measurements, thus creating confusion and complicating treatment decisions. This review focusses on the relation between results of different approaches to measure response to treatment and define relapse in childhood acute leukemia.

Keywords Acute lymphoblastic leukemia, Acute myeloid leukemia, Flow cytometry, Polymerase chain reaction, Minimal residual disease, Remission

Article

Review Article

Korean J Hematol 2012; 47(4): 245-254

Published online December 31, 2012 https://doi.org/10.5045/kjh.2012.47.4.245

Copyright © The Korean Society of Hematology.

Measurements of treatment response in childhood acute leukemia

Dario Campana*, and Elaine Coustan-Smith

Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Correspondence to: Correspondence to Dario Campana, M.D., Ph.D. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, Level 9 South, 117599, Singapore. Tel: +65-6601-2666, Fax: +65-6779-7486, paedc@nus.edu.sg

Received: October 26, 2012; Accepted: November 14, 2012

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Measuring response to chemotherapy is a backbone of the clinical management of patients with acute leukemia. This task has historically relied on the ability to identify leukemic cells among normal bone marrow cells by their morphology. However, more accurate ways to identify leukemic cells have been developed, which allow their detection even when they are present in small numbers that would be impossible to be recognized by microscopic inspection. The levels of such minimal residual disease (MRD) are now widely used as parameters for risk assignment in acute lymphoblastic leukemia (ALL) and increasingly so in acute myeloid leukemia (AML). However, different MRD monitoring methods may produce discrepant results. Moreover, results of morphologic examination may be in stark contradiction to MRD measurements, thus creating confusion and complicating treatment decisions. This review focusses on the relation between results of different approaches to measure response to treatment and define relapse in childhood acute leukemia.

Keywords: Acute lymphoblastic leukemia, Acute myeloid leukemia, Flow cytometry, Polymerase chain reaction, Minimal residual disease, Remission

Fig 1.

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Figure 1.

Relation between morphologic and flow cytometric detection of residual disease during and after treatment in childhood AML. (A) Percentage of bone marrow mononucleated cells expressing leukemia-associated immunophenotypes as measured by flow cytometry within groups defined by the percentage of myeloblasts counted by morphology. Gray area corresponds to measurements below the 0.1% threshold used to define MRD positivity. (B) Flow cytometric MRD data within groups defined by the hemopathologists' judgement regarding the presence of leukemic myeloblasts. From Inaba et al. [73] with permission.

Blood Research 2012; 47: 245-254https://doi.org/10.5045/kjh.2012.47.4.245

Fig 2.

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Figure 2.

Relation between event-free survival (EFS) for patients with childhood AML according to flow cytometry and morphology after Induction I. (A) EFS of patients who were MRD-negative (<0.1%) by flow cytometry according to percentage of blasts by morphology. (B) EFS of patients who were MRD-positive (≥0.1%) by flow cytometry according to percentage of blasts by morphology. (C) EFS of patients with <5% blasts by morphology according to MRD levels by flow cytometry. (D) EFS of patients with ≥5% blasts by morphology according to MRD levels by flow cytometry. From Inaba et al. [73] with permission.

Blood Research 2012; 47: 245-254https://doi.org/10.5045/kjh.2012.47.4.245

Fig 3.

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Figure 3.

Possible scenarios that may explain concordant or discordant MRD results by flow cytometry and PCR after chemotherapy. This can either be ineffective (top), result in leukemia cell death (middle), or induce leukemic cell differentiation (bottom). In the latter case, MRD by flow cytometry might be negative, owing to the loss of aberrant immunophenotypes but MRD by PCR would be positive as the cells retain leukemia fusion transcripts. However, these cells may also lack clonogenic potential.

Blood Research 2012; 47: 245-254https://doi.org/10.5045/kjh.2012.47.4.245

Table 1 . Antibody and fluorochrome combinations currently used in our laboratory for MRD monitoring in B-lineage ALL by flow cytometry.a).

a)Using the markers listed in this table, a leukemia-associated signature can be identified in virtually all cases of B-lineage ALL at diagnosis. For the few remaining cases, additional markers that can be tested include CD133, CD15, anti-NG2, CD164, CD304, CD97, CD102, CD99, and CD300a [80]..

Abbreviations: FITC, Fluorescein Isothiocyanate; PE, R-Phycoerythrin; PerCP, Peridinin Chlorophyll Protein; APC, Allophycocyanin; PE-Cy7, Phycoerythrin-Cyanine 7; APC-H7, Allophycocyanin-Cyanine 7 analog; BV421, Brilliant Violet 421; v450, BD Horizon v450..

Table 2 . Prevalence of MRD positivity at the end of remission induction therapy in patients with newly diagnosed childhood ALL enrolled in different treatment protocols..

a)Treatment intensification for patients with MRD ≥1% on day 19. On the preceding Total XIII study, 42 of 165 patients studied were MRD-positive on day 46 [12]..

Abbreviations: COG, Children's Oncology Group; St. Jude, St. Jude Children's Research Hospital; DFCI, Dana-Farber Cancer Institute; BFM, Berlin-Frankfurt-Münster; EORTC, European Organization for Research and Treatment of Cancer; UKALL, United Kingdom Medical Research Council acute lymphoblastic leukaemia; Ma-Spore, Malaysia-Singapore Acute Lymphoblastic Leukemia Study; AIEOP-BFM, Associazione Italiana di Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster; NOPHO, the Nordic Society of Pediatric Haematology and Oncology..

Table 3 . Antibody and fluorochrome combinations currently used in our laboratory for MRD monitoring in AML by flow cytometry.a).

a)The FITC, PE, BV421 and V500/BV510 antibody conjugates can be changed between tubes for the final MRD combinations according to the abnormal patterns defined at diagnosis. In addition, CD41 may be useful in some cases of AML M7..

Abbreviations: FITC, Fluorescein Isothiocyanate; PE, R-Phycoerythrin; PerCP, Peridinin Chlorophyll Protein; APC, Allophycocyanin; PE-Cy7, Phycoerythrin-Cyanine 7; APC-H7, Allophycocyanin-Cyanine 7 analog; BV421, Brilliant Violet 421; BV510, Brilliant Violet 510; v500, BD Horizon v500..
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