Minimal/measurable residual disease (MRD) diagnostics using real-time quantitative PCR analysis of rearranged immunoglobulin and T-cell receptor gene rearrangements are nowadays implemented in most treatment protocols for patients with acute lymphoblastic leukemia (ALL). Within the EuroMRD Consortium, we aim to provide comparable, high-quality MRD diagnostics, allowing appropriate risk-group classification for patients and inter-protocol comparisons. To this end, we set up a quality assessment scheme, that was gradually optimized and updated over the last 20 years, and that now includes participants from around 70 laboratories worldwide. We here describe the design and analysis of our quality assessment scheme. In addition, we here report revised data interpretation guidelines, based on our newly generated data and extensive discussions between experts. The main novelty is the partial re-definition of the "positive below quantitative range" category by two new categories, "MRD low positive, below quantitative range" and "MRD of uncertain significance". The quality assessment program and revised guidelines will ensure reproducible and accurate MRD data for ALL patients. Within the Consortium, similar programs and guidelines have been introduced for other lymphoid diseases (e.g., B-cell lymphoma), for new technological platforms (e.g., digital droplet PCR or Next-Generation Sequencing), and for other patient-specific MRD PCR-based targets (e.g., fusion genes).

Bristol MRD Group Bristol Genetics Laboratory Southmead Hospital Bristol UK

Centro de Investigación del Cáncer Instituto de Biología Molecular y Celular del Cáncer and Department of Medicine University of Salamanca Salamanca Spain

Centro Tettamanti Fondazione IRCCS San Gerardo dei Tintori Monza Italy

CLIP Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine and University Hospital Motol Charles University Prague Czech Republic

Department of Genetics University Hospital Robert Debré Paris France

Department of Hematology University Hospital Frankfurt Frankfurt Germany

Department of Immunology LUMC Leiden The Netherlands

Department of Internal Medicine 2 University Hospital Schleswig Holstein Kiel Germany

Department of Molecular Biotechnology and health sciences Hematology Division University of Torino Torino Italy

Department of Pediatric Oncology and Hematology Charité Universitätsmedizin Berlin Berlin Germany

Department of Pediatrics University Hospital of Schleswig Holstein Campus Kiel Kiel Germany

European Scientific foundation for Laboratory Hemato Oncology Zutphen The Netherlands

German Cancer Consortium Heidelberg Germany

Hematology Laboratory Saint Louis Hospital Paris Cité University Paris France

Laboratory Medical Immunology Department of Immunology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands

Military Medical City Hospital Doha Qatar

School of Medicine University of Milano Bicocca Monza Italy

Tyks Laboratories Genomics Department Turku University Hospital Turku Finland

Université Paris Cité Paris France

University Children's Hospital Zurich Switzerland

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Minimal residual disease detection for acute lymphoblastic leukaemia in peripheral blood-Are we there yet?

The gray area of RQ-PCR-based measurable residual disease: subdividing the "positive, below quantitative range" category