title: Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse.
abstract: Monitoring minimal residual disease is an important way to identify patients with acute myeloid leukemia at high risk of relapse. In this study we investigated the prognostic potential of minimal residual disease monitoring by quantitative real-time polymerase chain reaction analysis of NPM1 mutations in patients treated in the AMLCG 1999, 2004 and 2008 trials. Minimal residual disease was monitored - in aplasia, after induction therapy, after consolidation therapy, and during follow-up - in 588 samples from 158 patients positive for NPM1 mutations A, B and D (with a sensitivity of 10(-6)). One hundred and twenty-seven patients (80.4%) achieved complete remission after induction therapy and, of these, 56 patients (44.1%) relapsed. At each checkpoint, minimal residual disease cut-offs were calculated. After induction therapy a cut-off NPM1 mutation ratio of 0.01 was associated with a high hazard ratio of 4.26 and the highest sensitivity of 76% for the prediction of relapse. This was reflected in a cumulative incidence of relapse after 2 years of 77.8% for patients with ratios above the cut-off versus 26.4% for those with ratios below the cut-off. In the favorable subgroup according to European LeukemiaNet, the cut-off after induction therapy also separated the cohort into two prognostic groups with a cumulative incidence of relapse of 76% versus 6% after 2 years. Our data demonstrate that in addition to pre-therapeutic factors, the course of minimal residual disease in an individual is an important prognostic factor and could be included in clinical trials for the guidance of post-remission therapy. The trials from which data were obtained were registered at www.clinicaltrials.gov (#NCT01382147, #NCT00266136) and at the European Leukemia Trial Registry (#LN_AMLINT2004_230).
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Munich, Germany max.hubmann@med.uni-muenchen.de.
authors.forename: Max
authors.initials: M
authors.lastname: Hubmann
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Köhnke
authors.affiliation: Institute of Medical Informatics, Biometry and Epidemiology (IBE), Faculty of Medicine, Ludwig Maximilian University of Munich, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Hoster
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Munich, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Munich, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Dufour
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Munich, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Zellmeier
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Fiegl
authors.affiliation: Department of Hematology and Oncology, Barmherzige Brüder Hospital, Regensburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Braess
authors.affiliation: Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Bohlander
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Munich, Germany Clinical Cooperation Group Immunotherapy, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Munich, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Subklewe
authors.affiliation: Institute of Biostatistics and Clinical Research, University of Muenster, Germany.
authors.forename: Maria-Cristina
authors.initials: MC
authors.lastname: Sauerland
authors.affiliation: Department of Medicine A, Hematology and Oncology, University of Muenster, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: Department of Medicine A, Hematology and Oncology, University of Muenster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Büchner
authors.affiliation: German Society of Hematology and Oncology, Berlin, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wörmann
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Munich, Germany Clinical Cooperation Group Leukemia, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Munich, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Spiekermann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D060828:Induction Chemotherapy / Q000379:methods*; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods*; D012008:Recurrence; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate / Q000639:trends; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin