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Letters to the Editor
NPM1-based MRD log reduction in peripheral blood greater than 4-logs defines a group of patients with a very low risk of relapse when treated with chemotherapy alone whatever the type of NPM1 mutation. Additionally, this study highlights the robustness and accuracy of dPCR for detecting MRD in patients for whom standard MRD markers are not available.15 The dPCR assay reliably detected five copies of mutated NPM1 transcript (the limit-of-detection assay was per- formed with type A, B and D transcripts). The detection limit was therefore 0.01% for a sample containing 50,000 copies of the housekeeping ABL1 gene, which is equiva- lent to the RT-qPCR assay used in most laboratories. Thus, dPCR could be informative for the early detection of relapses and be used for MRD follow-up in patients. Considering its sensitivity and ease of use (especially the absolute quantification without the need for standard curves), dPCR may represent an alternative method equivalent to RT-qPCR for MRD monitoring of classical NPM1-type A, B and D mutations.
Auriane Lesieur,1 Xavier Thomas,2 Olivier Nibourel,1,3 Nicolas Boissel,4 Laurène Fenwarth,1,3 Stéphane De Botton,5 Elise Fournier,1,3 Karine Celli-Lebras,4 Emmanuel Raffoux,4 Christian Recher,6 Juliette Lambert,7 Céline Berthon,3,8 Arnaud Pigneux,9 Raphael Itzykson,4 Pascal Turlure,10 Cécile Pautas,11 Jacques Vargaftig,12 Claude Preudhomme,1,3 Hervé Dombret4 and Nicolas Duployez1,3
1CHU Lille, Laboratory of Hematology, Lille; 2Hospices Civils de Lyon, Lyon-Sud University Hospital, Department of Hematology, Lyon; 3Univ. Lille, CNRS, Inserm, CHU Lille, Institut de Recherche contre le Cancer de Lille, UMR9020 – UMR-S 1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille; 4AP-HP, Saint-Louis Hospital, Department of Hematology, Saint-Louis Research Institute, Université de Paris, Paris; 5Gustave Roussy Institute, Department of Hematology, Villejuif; 6Toulouse Cancer University Institute, Department of Hematology, Toulouse; 7CH Versailles, Department of Hematology, Le Chesnay; 8CHU Lille, Department of Clinic Hematology, Lille; 9Bordeaux Haut-Lévêque University Hospital, Department of Hematology, Pessac; 10CHU Limoges, Univ. Limoges, Department of Hematology, Limoges; 11AP-HP, Department of Hematology, Henri Mondor Hospital, Créteil and 12Curie Hospital, René Huguenin Hospital, Saint-Cloud, France
Correspondence: NICOLAS DUPLOYEZ nicolas.duployez@chru-lille.fr doi:10.3324/haematol.2020.260133 Received: May 20, 2020.
Accepted: November 16, 2020. Pre-published: December 10, 2020. Disclosures: no conflicts of interest to disclose.
Contributions: AL, ON, LF, EF, CPr and ND performed the molecular analyses; AL and ON designed the experiments; XT was the principal investigator of the ALFA-0702 trial; KCL ensured data management; XT, NB, SdB, ER, CR, JL, CB, AP, RI, PT, CPa, JV and HD provided samples and clinical data. AL and ND wrote the manuscript which was approved by all the authors.
Acknowledgments: the authors thank all Acute Leukemia French Association (ALFA) investigators and French Innovative Leukemia Organization (FILO) investigators who participated in the ALFA-0702 trial. The authors also thank Christophe Roumier and the tumor bank of Lille University Hospital (certification NF 96900-2014/65453-1) for handling, conditioning, and storing patients’ samples. The work of all clinical research assistants is also acknowledged here.
References
1. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447.
2. Paietta E. Minimal residual disease in acute myeloid leukemia: com- ing of age. Hematology Am Soc Hematol Educ Program. 2012;2012:35-42.
3.Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018;131(12):1275-1291.
4. Grimwade D, Jovanovic JV, Hills RK, et al. Prospective minimal resid- ual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol. 2009;27(22):3650-3658.
5. Jourdan E, Boissel N, Chevret S, et al. Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia. Blood. 2013;121(12):2213-2223.
6. Balsat M, Renneville A, Thomas X, et al. Postinduction minimal residual disease predicts outcome and benefit from allogeneic stem cell transplantation in acute myeloid leukemia with NPM1 mutation: a study by the Acute Leukemia French Association Group. J Clin Oncol. 2017;35(2):185-193.
7. Svec D, Tichopad A, Novosadova V, Pfaffl MW, Kubista M. How good is a PCR efficiency estimate: recommendations for precise and robust qPCR efficiency assessments. Biomol Detect Quantif. 2015; 3:9-16.
8. Falini B, Nicoletti I, Martelli MF, Mecucci C. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): bio- logic and clinical features. Blood. 2007;109(3):874-885.
9. Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352(3):254-266.
10. Alpermann T, Schnittger S, Eder C, et al. Molecular subtypes of NPM1 mutations have different clinical profiles, specific patterns of accompanying molecular mutations and varying outcomes in inter- mediate risk acute myeloid leukemia. Haematologica. 2016;101(2): e55-e58.
11. Gorello P, Cazzaniga G, Alberti F, et al. Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucle- ophosmin (NPM1) gene mutations. Leukemia. 2006;20(6):1103-1108.
12. Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374(5):422-433. 13. Thomas X, de Botton S, Chevret S, et al. Randomized phase II study
of clofarabine-based consolidation for younger adults with acute myeloid leukemia in first remission. J Clin Oncol. 2017;35(11):1223- 1230.
14. Koh Y, Park J, Bae E-K, et al. Non-A type nucleophosmin 1 gene mutation predicts poor clinical outcome in de novo adult acute myeloid leukemia: differential clinical importance of NPM1 muta- tion according to subtype. Int J Hematol. 2009;90(1):1-5.
15. Cilloni D, Petiti J, Rosso V, et al. Digital PCR in myeloid malignan- cies: ready to replace quantitative PCR? Int J Mol Sci. 2019; 20(9):2249.
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