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Leukemia. 2014 Jun;28(6):1299-307. doi: 10.1038/leu.2013.375. Epub 2013 Dec 17.

Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders.

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Division of Hematology, A.O. Azienda Ospedaliera Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.
Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Sequenta Inc, San Francisco, CA, USA.
Division of Nuclear Medicine, Statistical Consultant, University of Torino, Torino, Italy.
Department of Internal Medicine II, Hematology and Oncology, Goethe University Hospital, Frankfurt, Germany.


In this study, we compared immunoglobulin heavy-chain-gene-based minimal residual disease (MRD) detection by real-time quantitative PCR (RQ-PCR) and next-generation sequencing (NGS) to assess whether NGS could overcome some limitations of RQ-PCR and further increase sensitivity, specificity, accuracy and reproducibility. In total, 378 samples from 55 patients with acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) or multiple myeloma (MM) were investigated for clonotype identification, clonotype identity and comparability of MRD results. Forty-five clonotypes were identified by RQ-PCR and 49 by NGS. Clonotypes identified by both tools were identical or >97% homologous in 96% of cases. Both tools were able to routinely reach a sensitivity level of 1 × E-05. A good correlation of MRD results was observed (R=0.791, P<0.001), with excellent concordance in 79.6% of cases. Few discordant cases were observed across all disease subtypes. NGS showed at least the same level of sensitivity as allele-specific oligonucleotides-PCR, without the need for patient-specific reagents. We conclude that NGS is an effective tool for MRD monitoring in ALL, MCL and MM. Prospective comparative analysis of unselected cases is required to validate the clinical impact of NGS-based MRD assessment.

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