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Test Catalog

Test ID: NPM1Q    
Nucleophosmin (NPM1) Mutation Analysis, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

As a prognostic indicator in patients with newly diagnosed acute myelogenous leukemia with normal karyotype and no FLT3 mutation and as a leukemia-specific marker of minimal residual disease

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

Both DNA and RNA are extracted. The assay is composed of 2 parts, a RNA-based, sensitive quantitative reverse transcription real-time polymerase chain reaction (RT-PCR) that detects and quantifies the most common altered NPM1 mRNA transcripts (A, B, D forms) in acute myeloid leukemia (AML), and a DNA-based qualitative NPM1 exon 12 variant screen by fragment analysis that detects essentially all altered forms reported in AML, including the rare non-A, B, D forms (with lower sensitivity at the DNA level).

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Acute myeloid leukemia (AML) is a genetically heterogeneous group of neoplasms. While cytogenetic aberrations detected at the time of diagnosis are the most used prognostic feature, approximately 50% of AML cases show a normal karyotype, which is considered an intermediate-risk feature. Within this group, FLT3 variants are considered indicators of poor prognosis. However, in the absence of a FLT3 variant, the presence of a nucleophosmin (NPM1) variant is associated with a more favorable prognosis. A NPM1 alteration is a common finding in de novo AML (25%-30% of cases) and consists of small insertion (typically 4 base pair) or insertion/deletion events involving exon 12. Three variants are highly recurrent, termed types A, B, and D and together account for approximately 90% of NPM1 alterations in de novo AML. Thus, in patients with newly diagnosed AML, those with normal karyotype, no FLT3 variant, and a NPM1 alteration are considered to have a better prognosis than patients in the same group with neoplasms lacking a NPM1 alteration. Furthermore, the presence of a NPM1 alteration serves as a sensitive marker for evaluating minimal disease and therapeutic response following treatment.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

The assay incorporates 2 parts: a qualitative screen for exon 12 nucleophosmin (NPM1) alterations, and a quantitative reverse transcription polymerase chain reaction (RT-PCR) to determine the copy number of NPM1 transcripts (relative to ABL1 reference mRNA). This strategy will allow for identification of the NPM1 alteration at diagnosis, as well as a high sensitivity method to monitor patients who are post-therapy for minimal residual disease (MRD). Results will therefore be interpreted with integration of the quantitative and qualitative test results in the context of NPM1 alteration type identified at the time of AML diagnosis if available. Because the quantitative RT-PCR component only reliably detects and quantifies the 3 most common variant types (A, B, D), there is a very small possibility that the qualitative assay may indicate the presence of NPM1 alteration, but the quantitative assay will be (falsely) negative. In patients with newly diagnosed acute myeloid leukemia, a normal karyotype, and no FLT3 variant, the presence of NPM1 alteration is an indicator of a more favorable prognosis. Similarly, following chemotherapy, the presence, relative quantity and trend of change of NPM1 mRNA transcript is associated with risk of disease relapse.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Because of the design of this assay, a very small number of NPM1 alterations at diagnosis may not be detected by the more targeted quantitative PCR component. In that setting, the qualitative part of the test can be used for limited minimal residual disease assessment, although the sensitivity is much lower (approximately 5% at the DNA level).

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Heath EM, Chan SM, Minden MD, Murphy T, Shlush LI, Schimmer AD: Biological and clinical consequences of NPM1 mutations in AML. Leukemia. 2017 Apr;31(4):798-807

2. Kronke J, Schlenck RF, Jensen KO, 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 Jul 1;29(19):2709-2716

3. Ivey A, Hills RK, Simpson MA, et al: Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016 Feb 4;374(5):422-433

4. Shayegi N, Kramer M, Bornhauser M, et al: The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML. Blood. 2013 Jul 4;122(1):83-92

Special Instructions Library of PDFs including pertinent information and forms related to the test