Abstract
Recent studies have reported that measurable residual disease (MRD) analysis using NPM1 mutations helps determine whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated in acute myeloid leukemia (AML) patients. However, the optimal timing and cutoff value for measuring MRD using genomic DNA remain undetermined. This study aimed to investigate the optimal timing and cutoff value to ascertain the value of NPM1 mutation in MRD assessment. NPM1-mutated MRD was quantified by real-time polymerase chain reaction of bone marrow samples from 56 patients with NPM1-positive AML who achieved hematological remission. The area under the receiver-operating characteristic curve was greatest when MRD was assessed after two courses of post-remission therapy with a cutoff value of 0.010% (specificity, 68.4%; sensitivity, 87.0%). Patients whose MRD was below the cutoff value throughout the course of treatment had significantly better overall survival and relapse-free survival rates. Of the 33 patients who did not undergo transplantation during the first remission, all of the 11 who were never MRD-negative at any point experienced a relapse. Evaluating MRD with a cutoff value of 0.010% after two courses of post-remission therapy helps predict prognosis and determine the indication for allo-HSCT.
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References
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47.
Miyawaki S, Emi N, Mitani K, Oyashiki K, Kitamura K, Morishita T, et al. Clinical course of the disease and the level of WT1 mRNA in 191 patients with acute myeloid leukemia (AML): joint research by 23 institutions in Japan. Rinsho Ketsueki. 2005;46(12):1279–87.
Miyawaki S, Hatsumi N, Tamaki T, Naoe T, Ozawa K, Kitamura K, et al. Prognostic potential of detection of WT1 mRNA level in peripheral blood in adult acute myeloid leukemia. Leuk Lymphoma. 2010;51(10):1855–61.
Gao MG, Ruan GR, Chang YJ, Liu YR, Qin YZ, Jiang Q, et al. The predictive value of minimal residual disease when facing the inconsistent results detected by real-time quantitative PCR and flow cytometry in NPM1-mutated acute myeloid leukemia. Ann Hematol. 2020;99(1):73–82.
Abdelhamid E, Preudhomme C, Helevaut N, Nibourel O, Gardin C, Rousselot P, et al. Minimal residual disease monitoring based on FLT3 internal tandem duplication in adult acute myeloid leukemia. Leuk Res. 2012;36:316–23.
Gaidzik VI, Weber D, Paschka P, Kaumanns A, Krieger S, Corbacioglu A, et al. DNMT3A mutant transcript levels persist in remission and do not predict outcome in patients with acute myeloid leukemia. Leukemia. 2018;32(1):30–7.
Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352:254–66.
Thiede C, Koch S, Creutzig E, Steudel C, Illmer T, Schaich M, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006;107:4011–20.
Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374(5):422–33.
Shayegi N, Kramer M, Bornhäuser M, Schaich M, Schetelig J, Platzbecker U, et al. The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML. Blood. 2013;122:83–92.
Hubmann M, Köhnke T, Hoster E, Schneider S, Dufour A, Zellmeier E, et al. Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse. Haematologica. 2014;99:1317–25.
Krönke J, Schlenk RF, Jensen KO, Tschürtz F, Corbacioglu A, Gaidzik VI, et al. Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group. J Clin Oncol. 2011;29:2709–16.
Forghieri F, Comoli P, Marasca R, Potenza L, Luppi M. Minimal/measurable residual disease monitoring in NPM1-mutated acute myeloid leukemia: a clinical viewpoint and perspectives. Int J Mol Sci. 2018;19:3492.
Patkar N, Kodgule R, Kakirde C, Raval G, Bhanshe P, Joshi S, et al. Clinical impact of measurable residual disease monitoring by ultradeep next generation sequencing in NPM1 mutated acute myeloid leukemia. Oncotarget. 2018;9:36613–24.
Höllein A, Meggendorfer M, Dicker F, Jeromin S, Nadarajah N, Kern W, et al. NPM1 mutated AML can relapse with wild-type NPM1: persistent clonal hematopoiesis can drive relapse. Blood Adv. 2018;2(22):3118–25.
Bacher U, Porret N, Joncourt R, Sanz J, Aliu N, Wiedemann G, et al. Pitfalls in the molecular follow up of NPM1 mutant acute myeloid leukemia. Haematologica. 2018;103(10):e486–8.
Kapp-Schwoerer S, Weber D, Corbacioglu A, Gaidzik VI, Paschka P, Krönke J, et al. Impact of gemtuzumab ozogamicin on MRD and relapse risk in patients with NPM1-mutated AML: results from the AMLSG 09–09 trial. Blood. 2020;136(26):3041–50.
Chou WC, Tang JL, Wu SJ, Tsay W, Yao M, Huang SY, et al. Clinical implications of minimal residual disease monitoring by quantitative polymerase chain reaction in acute myeloid leukemia patients bearing nucleophosmin (NPM1) mutations. Leukemia. 2007;21:998–1004.
Kurosawa S, Yamaguchi H, Yamaguchi T, Fukunaga K, Yui S, Wakita S, et al. Decision analysis of postremission therapy in cytogenetically intermediate-risk acute myeloid leukemia: the impact of FLT3 internal tandem duplication, nucleophosmin, and CCAAT/enhancer binding protein alpha. Biol Blood Marrow Transplant. 2016;22:1125–32.
Sakaguchi M, Yamaguchi H, Najima Y, Usuki K, Ueki T, Oh I, et al. Prognostic impact of low allelic ratio FLT3-ITD and NPM1 mutation in acute myeloid leukemia. Blood Adv. 2018;2(20):2744–54.
Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454–64.
Schnittger S, Bacher U, Kern W, Alpermann T, Haferlach C, Haferlach T. Prognostic impact of FLT3-ITD load in NPM1 mutated acute myeloid leukemia. Leukemia. 2011;25(8):1297–304.
Wakita S, Yamaguchi H, Omori I, Terada K, Ueda T, Manabe E, et al. Mutations of the epigenetics-modifying gene (DNMT3a, TET2, IDH1/2) at diagnosis may induce FLT3-ITD at relapse in de novo acute myeloid leukemia. Leukemia. 2013;27(5):1044–52.
Miyawaki S, Sakamaki H, Ohtake S, Emi N, Yagasaki F, Mitani K, et al. A randomized, postremission comparison of four courses of standard-dose consolidation therapy without maintenance therapy versus three courses of standard-dose consolidation with maintenance therapy in adults with acute myeloid leukemia. Cancer. 2005;12:2726–34.
Wakita S, Yamaguchi H, Ueki T, Usuki K, Kurosawa S, Kobayashi Y, et al. Complex molecular genetic abnormalities involving three or more genetic mutations are important prognostic factors for acute myeloid leukemia. Leukemia. 2016;30(3):545–54.
Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.
Gorello P, Cazzaniga G, Alberti F, Dell’Oro MG, Gottardi E, Specchia G, et al. Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations. Leukemia. 2006;20(6):1103–8.
Pettersson L, Johansson Alm S, Almstedt A, Chen Y, Orrsjö G, Shah-Barkhordar G, et al. Comparison of RNA- and DNA-based methods for measurable residual disease analysis in NPM1-mutated acute myeloid leukemia. Int J Lab Hematol. 2021;43(4):664–74.
Schuurhuis Gerrit J, Heuser M, Freeman S, Béné MC, Buccisano F, Cloos J, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD working party. Blood. 2018;131(12):1275–91.
Yuan XQ, Peng L, Zeng WJ, Jiang BY, Li GC, Chen XP. DNMT3A R882 mutations predict q poor prognosis in AML: a meta-analysis from 4474 patients. Medicine. 2016;95(18):e3519.
Patel SS, Kuo FC, Gibson CJ, Steensma DP, Soiffer RJ, Alyea EP 3rd, et al. High NPM1-mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML. Blood. 2018;131:2816–25.
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We would like to thank Editage (www.editage.com) for English language editing. We are also indebted to the inpatient nursing teams and support staff for the excellent care they provided to our patients and their families.
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Marumo, A., Wakita, S., Morita, K. et al. NPM1-mutation-based measurable residual disease assessment after completion of two courses of post-remission therapy is a valuable clinical predictor of the prognosis of acute myeloid leukemia. Int J Hematol 116, 199–214 (2022). https://doi.org/10.1007/s12185-022-03328-6
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DOI: https://doi.org/10.1007/s12185-022-03328-6