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Chromosomal Abnormalities and Prognosis in NPM1-Mutant AML


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In a study reported in the Journal of Clinical Oncology, Angenendt et al found that adverse-risk cytogenetics were associated with significantly poorer outcomes vs normal karyotype among patients with acute myeloid leukemia (AML) with a nucleophosmin 1 (NPM1) mutation.

As stated by the investigators, NPM1 mutations are associated with favorable prognosis when an internal tandem duplication in the fms-related tyrosine kinase 3 gene (FLT3) is absent (FLT3-ITD–neg) or present at low allelic ratio (FLT3-ITD–low). The investigators sought to determine whether this favorable prognosis is affected by presence of abnormal karyotypes.

Study Details

The study included intensively treated patients with NPM1-mutant/FLT3-ITD­­–neg/low AML prospectively enrolled in registry databases from nine international study groups or treatment centers.

Key Findings

Among 2,426 patients with NPM1-mutant/FLT3-ITD–neg/low AML, 2,000 (82.4%) had normal and 426 (17.6%) had abnormal karyotypes, including 329 (13.6%) with intermediate-risk and 83 (3.4%) with adverse-risk chromosomal abnormalities.

KEY POINTS

  • Complete remission rates were 87.7% with normal karyotypes, 86.0% with intermediate-risk abnormalities, and 66.3% for adverse-risk abnormalities.
  • Overall survival at 5 years was 52.4%, 44.8%, and 19.5%, respectively.

Complete remission rates were 87.7% with normal karyotypes, 86.0% with intermediate-risk abnormalities, and 66.3% for adverse-risk abnormalities (P < .001). Overall survival at 5 years was 52.4%, 44.8%, and 19.5%, respectively (P < .001). Event-free survival at 5 years was 40.6%, 36.0%, and 18.1% (P < .001). Cumulative incidence of relapse at 5 years was 43.6%, 44.2%, and 51.9% (P = .0012).

The associations of poorer outcome with adverse-risk cytogenetics remained significant (P < .001 for all outcomes) on multivariate analysis adjusting for clinicopathologic risk factors.

Among patients with adverse-risk chromosomal aberrations, no differences were found between NPM1 wild-type vs mutant status for overall survival (hazard ratio [HR] = 0.96,  P = .77), event-free survival (HR = 1.07, P = .68), or cumulative incidence of relapse (HR = 0.89, P = .53).

The investigators concluded, “Karyotype abnormalities are significantly associated with outcome in NPM1[-mutant]/FLT3-ITD–neg/low AML. When adverse-risk cytogenetics are present, patients with [an] NPM1 [mutation] share the same unfavorable prognosis as patients with NPM1 wild-type [disease] and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in NPM1[-mutant]/FLT3-ITD–neg/low AML.”

Linus Angenendt, MD, of the Department of Medicine, University Hospital Münster, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Innovative Medical Research Fund of the University of Münster Medical School, German Research Foundation, French government, Ministry of Health of the Czech Republic, National Health and Medical Research Council of Australia, and others. For full disclosures of the study authors, visit jco.ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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