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Leukemia. 2019 Mar 11. doi: 10.1038/s41375-019-0413-0. [Epub ahead of print]

Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1.

Author information

1
Department of Medicine, Hematology/Oncology, Goethe-University, Frankfurt, Germany. h.pfeifer@em.uni-frankfurt.de.
2
Pediatric Clinic, University of Milan Bicocca, San Gerardo Hospital, Monza, Italy.
3
Department of Immunology, Erasmus MC, University, Medical Center Rotterdam, Rotterdam, The Netherlands.
4
Hematology Laboratory and EA3518, University Hospital Saint-Louis, University Paris Diderot, Paris, France.
5
Kinderspital Zürich, Onkologie Diagnostik Labor, Zürich, Switzerland.
6
Hematology and Bone Marrow Transplant Unit, ASST-Papa Giovanni XXIII, Bergamo, Italy.
7
Regional Genetics Laboratory, Birmingham Women´s NHS Foundation Trust, Birmingham, UK.
8
Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
9
Division of Hematology and Hemotherapy, Medical School, University of São Paulo, São Paulo, Brazil.
10
Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
11
Department of Genetic Biochemistry, Hopital Robert Debré, Paris, France.
12
Department of Hematology, Laboratory of Molecular Biology, University La Sapienza, Roma, Italy.
13
Institute for Genomic Medicine, Nationwide Children's Hospital and the Ohio State University, Columbus, OH, USA.
14
Imperial Molecular Pathology, Centre for Hematology, Imperial College London, London, UK.
15
Laboratory of Molecular Biology and UMR5239, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, Lyon, France.
16
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
17
Division of Pediatric Hematology/Oncology, Department of Pediatrics, National University Hospital, Singapore, Singapore.
18
Department of Internal Medicine-Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
19
Department of Hematology, University Hospital of Salamanca (IBSAL) & Cancer Research Centre-IBMCC, (Salamanca University-CSIC), Salamanca, Spain.
20
Department of Experimental Immunhematology/Immuncytology, Sanquin Diagnostics, Amsterdam, The Netherlands.
21
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
22
TYKSLAB, Laboratory of Molecular Genetics, Turku University Hospital, Turku, Finland.
23
Abteilung für Hämatologie und internistische Onkologie, Universität Leipzig, Leipzig, Germany.
24
Childrens Cancer Research Institute, Labdia Labordiagnostik and Medical University, Vienna, Austria.
25
III. Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.
26
Azienda Ospedaliera Universitaria Federico II di Napoli Università, Naples, Italy.
27
Department of Hematology, Royal Free Campus, University College London, London, United Kingdom.
28
Department of Pediatric Hematology and Oncology, University Hospital, Justus Liebig University Giessen, Giessen, Germany.
29
Hematology Department, Jagiellonain University Krakow, Krakow, Poland.
30
MLL Munich Leukemia Laboratory, Max-Lebsche-Platz 31, Munich, Germany.
31
Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
32
Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
33
Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium.
34
CLIP, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and UH Motol, Prague, Czech Republic.
35
Department of Medicine, Hematology/Oncology, Goethe-University, Frankfurt, Germany.
36
Institut für Biostatistik und Mathematische Modellierung, Goethe Universität, Frankfurt, Germany.
37
Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands.
38
School of Medicine, Division of Cancer and Hematology, Cardiff University, Cardiff, UK.

Abstract

Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10-3 and 36/67 (53%) and 53/67 (79%) at 10-4BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.

PMID:
30858550
DOI:
10.1038/s41375-019-0413-0

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