Samples from patients with AML show high concordance in detection of mutations by NGS at local institutions vs central laboratories

Uma Borate, Fei Yang, Richard Press, Amy S Ruppert, Dan Jones, Sean Caruthers, Weiqiang Zhao, Jo-Anne Vergilio, Dean C Pavlick, Luke Juckett, Brianna Norris, Taylor Bucy, Amy Burd, Eytan M Stein, Prapti Patel, Maria R Baer, Wendy Stock, Gary Schiller, William Blum, Tibor Kovacsovics, Mark Litzow, James Foran, Nyla A Heerema, Leonard Rosenberg, Sonja Marcus, Ashley Yocum, Mona Stefanos, Brian Druker, John C Byrd, Ross L Levine, Alice Mims, Uma Borate, Fei Yang, Richard Press, Amy S Ruppert, Dan Jones, Sean Caruthers, Weiqiang Zhao, Jo-Anne Vergilio, Dean C Pavlick, Luke Juckett, Brianna Norris, Taylor Bucy, Amy Burd, Eytan M Stein, Prapti Patel, Maria R Baer, Wendy Stock, Gary Schiller, William Blum, Tibor Kovacsovics, Mark Litzow, James Foran, Nyla A Heerema, Leonard Rosenberg, Sonja Marcus, Ashley Yocum, Mona Stefanos, Brian Druker, John C Byrd, Ross L Levine, Alice Mims

Abstract

Next-generation sequencing (NGS) to identify pathogenic mutations is an integral part of acute myeloid leukemia (AML) therapeutic decision-making. The concordance in identifying pathogenic mutations among different NGS platforms at different diagnostic laboratories has been studied in solid tumors but not in myeloid malignancies to date. To determine this interlaboratory concordance, we collected a total of 194 AML bone marrow or peripheral blood samples from newly diagnosed patients with AML enrolled in the Beat AML Master Trial (BAMT) at 2 academic institutions. We analyzed the diagnostic samples from patients with AML for the detection of pathogenic myeloid mutations in 8 genes (DNMT3A, FLT3, IDH1, IDH2, NPM1, TET2, TP53, and WT1) locally using the Hematologic Neoplasm Mutation Panel (50-gene myeloid indication filter) (site 1) or the GeneTrails Comprehensive Heme Panel (site 2) at the 2 institutions and compared them with the central results from the diagnostic laboratory for the BAMT, Foundation Medicine, Inc. The overall percent agreement was over 95% each in all 8 genes, with almost perfect agreement (κ > 0.906) in all but WT1, which had substantial agreement (κ = 0.848) when controlling for site. The minimal discrepancies were due to reporting variants of unknown significance (VUS) for the WT1 and TP53 genes. These results indicate that the various NGS methods used to analyze samples from patients with AML enrolled in the BAMT show high concordance, a reassuring finding given the wide use of NGS for therapeutic decision-making in AML.

Conflict of interest statement

Conflict-of-interest disclosure: U.B. has been a consultant for Genentech, Daiichi Sankyo, Takeda, Pfizer, AbbVie/Genentech and Novartis. A.S.R. served on an independent data monitoring committee for Telios Pharma, Inc, and is currently employed and holds stock with Eli Lilly and Company. E.M.S. has served on the advisory boards of Astellas Pharma, AbbVie, Genentech, Daiichi Sankyo, Novartis, Amgen, Seattle Genetics, Syros Pharmaceuticals, Syndax Pharmaceuticals, Agios Pharmaceuticals and Celgene; is an equity holder in Auron Therapeutics. G.S. has commercial interests in Bristol Myers Squibb, Amgen, J&J; has received fees from AbbVie, Agios, Amgen, Astellas, Bristol Myers Squibb, Incyte, Janssen, Jazz, Karyopharm, Kite, Pharmacyclics, Sanofi/Genzyme, Stemline; has received research funds from AbbVie, Actinium, Actuate, Arog, Astellas, AltruBio, AVM Bio, BMS/Celgene, Celator, Constellation, Daiichi-Sankyo, Deciphera, Delta-Fly, Forma, FujiFilm, Gamida, Genentech-Roche, GlycoMimetics, Geron, Incyte, Karyopharm, Kiadis, Kite/Gilead, Kura, Marker, Mateon, Onconova, Pfizer, PrECOG, Regimmune, Samus, Sangamo, Sellas, Stemline, Syros, Takeda, Tolero, Trovagene, Agios, Amgen, Jazz, ORCA, Ono-UK, Novartis. J.F. has received research funding from Takeda/Millennium. P.P. has served on the advisory board of Agios Pharmaceuticals and is currently an employee of Servier. J.-A.V. is an employee at Foundation Medicine Inc with equity in Roche. D.C.P. is an employee at Foundation Medicine Inc with equity in Roche. R.L.L. is on the supervisory board of Qiagen and is a scientific adviser to Imago, Mission Bio, Zentalis, Ajax, Auron, Prelude, C4 Therapeutics and Isoplexis; receives research support from and consulted for Celgene and Roche and has consulted for Incyte, Janssen, Astellas, Morphosys and Novartis; has received honoraria from Astra Zeneca, Roche, Lilly and Amgen for invited lectures and from Gilead for grant reviews. B.D. has potential competing interests in SAB: Adela Bio, Aileron Therapeutics, Therapy Architects/ALLCRON (inactive), Cepheid, Celgene, DNA SEQ, Nemucore Medical Innovations, Novartis, RUNX1 Research Program, Vivid Biosciences (inactive); SAB & Stock: Aptose Biosciences, Blueprint Medicines, Enliven Therapeutics, Iterion Therapeutics, GRAIL, Recludix Pharma; is a member of board of directors & stock for Amgen, Vincerx Pharma; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; advisory committee: Multicancer Early Detection Consortium; founder: VB Therapeutics; sponsored research agreement: Enliven Therapeutics, Recludix Pharma; clinical trial funding: Novartis, AstraZeneca; royalties from patent 6958335 (Novartis exclusive license) and OHSU and Dana-Farber Cancer Institute (1 Merck exclusive license, 1 CytoImage, Inc exclusive license, and 1 Sun Pharma Advanced Research Company nonexclusive license); US Patents 4326534, 6958335, 7416873, 7592142, 10473667, 10664967, 11049247. J.C.B. is a current equity holder in Vincerx Pharma Inc (a publicly traded company); holds membership on the board of directors or advisory committees of Vincerx, Newave, Orange Grove Bio; and holds consultancy, honoraria on Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, and Syndax. A.M. has served on the advisory boards of Jazz Pharmaceuticals, AbbVie/Genentech, Astellas Pharma, PTC Therapeutics, Novartis, Agios Pharmaceuticals and Syndax Pharmaceuticals. The remaining authors declare no competing financial interests.

© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Schematic for the analysis of patient samples between central and institutional laboratories.

References

    1. Shumilov E, Flach J, Kohlmann A, et al. Current status and trends in the diagnostics of AML and MDS. Blood Rev. 2018;32(6):508–519.
    1. Bacher U, Shumilov E, Flach J, et al. Challenges in the introduction of next-generation sequencing (NGS) for diagnostics of myeloid malignancies into clinical routine use. Blood Cancer J. 2018;8(11):113.
    1. Voso MT, Ottone T, Lavorgna S, et al. MRD in AML: the role of new techniques. Front Oncol. 2019;9
    1. Rowe JM. AML in 2017: advances in clinical practice. Best Pract Res Clin Haematol. 2017;30(4):283–286.
    1. Jongen-Lavrencic M, Grob T, Hanekamp D, et al. Molecular minimal residual disease in acute myeloid leukemia. N Engl J Med. 2018;378(13):1189–1199.
    1. Burd A, Levine RL, Ruppert AS, et al. Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the beat AML master trial. Nat Med. 2020;26(12):1852–1858.
    1. Burd A, Levine RL, Ruppert AS, et al. Precision medicine treatment in older AML: results of Beat AML Master Trial. Blood. 2019;134(Supplement_1):175.
    1. Glenn TC. Field guide to next-generation DNA sequencers. Mol Ecol Resour. 2011;11(5):759–769.
    1. Fox EJ, Reid-Bayliss KS, Emond MJ, Loeb LA. Accuracy of next generation sequencing platforms. Next Gener Seq Appl. 2014;1
    1. Stetson D, Ahmed A, Xu X, et al. Orthogonal comparison of four plasma NGS tests with tumor suggests technical factors are a major source of assay discordance. JCO Precis Oncol. 2019;3:1–9.
    1. Shin S, Park J. Characterization of sequence-specific errors in various next-generation sequencing systems. Mol Biosyst. 2016;12(3):914–922.
    1. Weiss GJ, Hoff BR, Whitehead RP, et al. Evaluation and comparison of two commercially available targeted next-generation sequencing platforms to assist oncology decision making. Onco Targets Ther. 2015;8:959–967.
    1. Squillace RM, Frampton GM, Stephens PJ, Ross JS, Miller VA. Comparing two assays for clinical genomic profiling: the devil is in the data. Onco Targets Ther. 2015;8:2237–2242.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する