Minimal Residual Disease Identified by NPM1 Mutation Is a Powerful Marker for Poorer Outcome in Standard-Risk AML


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The presence of minimal residual disease, as determined by quantitation of NPM1-mutated transcripts, provided powerful prognostic information independent of other risk factors.

Adam Ivey, MSc, and colleagues

In a study reported in The New England Journal of Medicine, Adam Ivey, MSc, from Guy’s Hospital, London, and colleagues found that a leukemia-specific marker consisting of mutation in the gene encoding nucleophosmin (NPM1) can be used to identify minimal residual disease in peripheral blood in standard-risk acute myeloid leukemia (AML), with minimal residual disease detected in this way being a strong prognostic factor for relapse and poorer survival.1

Study Details

In the study, a reverse-transcriptase quantitative polymerase chain reaction assay was used to detect minimal residual disease in 2,569 samples from 346 patients (development cohort) with NPM1-mutated AML who had received intensive treatment in the National Cancer Research Institute AML17 trial between April 2009 and June 2012. An additional group of 91 patients with NPM1 mutations who were enrolled in the AML17 study starting in June 2012 constituted a validation cohort. Median follow-up for survival was 40.5 months in the development cohort and 13.6 months in the validation cohort.

Prognostic Ability

The presence of NPM1-mutated transcripts as a marker for minimal residual disease status was highly prognostic for clinical outcomes. NPM1-mutated transcripts persisted in the peripheral blood of 15% of patients after their second chemotherapy cycle; risk of relapse after 3 years was 82% in these patients vs 30% in patients without NPM1-mutated transcripts (hazard ratio [HR] = 4.80, P < .001), and overall survival was 24% vs 75% (HR = 4.38, P < .001).

Predicting Outcome in Acute Myeloid Leukemia

  • Minimal residual disease defined as presence of NPM1-mutated transcripts was significantly prognostic for relapse and survival in patients with acute myeloid leukemia.
  • In patients in morphologic remission, rising levels of NPM1-mutated transcripts in prior samples predicted hematologic relapse.

On multivariate analysis, minimal residual disease was the only significant prognostic factor for relapse (HR = 5.09, P < .001) and death (HR = 4.84, P < .001). After adjustment for minimal residual disease status, no significant associations with survival were observed for FLT3 internal tandem duplication (ITD) mutations (P = 0.45), DNMT3A mutations (P = .93), or Medical Research Council risk group (P = .98). Overall, relapse rates were higher in minimal residual disease–positive patients among those without (76% vs 33%, P = .001) and with (92% vs 35%, P < .001) FLT3-ITD mutations and those without (100% vs 29%, P < .001) and with (76% vs 52%, P = .004) DNMT3A mutations.

In the validation cohort of 91 patients, minimal residual disease in peripheral blood after the second cycle of chemotherapy was associated with increased cumulative risk of relapse (70% vs 31%, P = .001) and poorer overall survival (40% vs 87%, P = .001).

Sequential Monitoring

Results of sequential monitoring of samples obtained after the end of consolidation treatment were available for 243 patients with NPM1 mutations in the development cohort. Among 53 patients with morphologic remission, rising levels of NPM1-mutated transcripts in prior samples predicted hematologic relapse (median increment of 0.7 log10 per month). Sequential monitoring of paired bone marrow and peripheral blood samples showed that the rate of detection of minimal residual disease was increased by marrow analysis and that time to relapse from identification of molecular positivity was numerically increased with detection in marrow vs blood (median, 133 vs 87 days, P = .65).

Mutations associated with preleukemic clones remained detectable during ongoing remission after chemotherapy, including in samples that were negative for NPM1 mutation. However, NPM1 mutations were identified in 69 of 70 patients at the time of relapse and thus provided a better marker of disease status.

The investigators concluded: “The presence of minimal residual disease, as determined by quantitation of NPM1-mutated transcripts, provided powerful prognostic information independent of other risk factors.” ■

Disclosure: The study was funded by Bloodwise and the National Institute for Health Research. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Ivey A, Hills RK, Simpson JV, et al: Assessment of minimal residual disease in standard-risk AML. N Engl J Med 374:422-433, 2016.


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