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).

Copyright© Ferrata Storti Foundation.

Figures

Figure 1.

NPM1mut ratios at different checkpoints in patients who achieved complete remission. Black symbols indicate NPM1mut ratios at different checkpoints of patients who relapsed during follow-up, white symbols indicate NPM1mut ratios at different checkpoints of patients with ongoing remission. Gray symbols indicate NPM1mut ratios of patients who subsequently underwent allogeneic stem cell transplantation in first complete remission. Bars indicate median NPM1mut ratios at the specific checkpoint. NPM1mut: NPM1 mutation; RT - PCR: quantitative real-time polymerase chain reaction; CR: NPM1 mutation ratios of patients with ongoing complete remission; Tx in CR: NPM1 mutation ratios of patients who subsequently underwent allogeneic stem cell transplantation in first complete remission.

Figure 2.

Cumulative incidence of relapse (A and B) and overall survival (C and D) after induction therapy according to MRD status of NPM1mut ratios and NPM1mut kinetics. (A) and (C) NPM1mut ratios after induction therapy with a NPM1mut cut-off ratio of 0.01; (B) and (D) NPM1mut kinetics after induction therapy with a cut-off of -3 log. NPM1mut: NPM1 mutation.

Figure 3.

MRD assessment after induction and consolidation therapy in patients with paired samples. In total, 18 patients relapsed after consolidation therapy with a median time to relapse of 9.9 months. Nine patients were transplanted in first complete remission with a median time to allogeneic stem cell transplantation of 1.2 months and 17 patients had an ongoing remission with a median follow-up of 31.1 months after consolidation therapy. NPM1mut: NPM1 mutation; FU: follow-up period; CR: first complete remission; Tx: allogeneic stem cell transplantation in first complete remission.