Switch of the mutation type of the NPM1 gene in acute myeloid leukemia (AML): relapse or secondary AML?

Webersinke, Gerald; Kranewitter, Wolfgang; Deutschbauer, Sabine; Zach, Otto; Hasenschwandtner, Sonja; Wiesinger, K; Erdel, Martin; Marschon, Renate; Böhm, Alexandra; Tschurtschenthaler, G.

doi:10.1038/bcj.2014.42

Cited by 8 publications

(8 citation statements)

References 10 publications

(12 reference statements)

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“…The fact that we could identify and monitor rare NPM1 mutations using this technique validates our approach. There have been reports of switch of NPM1 mutations at relapse [16]. Although, we did not find any evidence of switch in the NPM1 mutation type either at post induction or post consolidation time points, an NGS based approach provides a definitive advantage over mutation specific testing in potentially detecting a NPM1 clonal switch.…”

Section: Discussioncontrasting

confidence: 65%

“…Diagnostic DNA was available in 81 patients. These samples were sequenced to characterize the mutation, ensure the stability of NPM1 mutation over post-induction (PI) and first post consolidation (PC) time points and ascertain whether there was any switch in the mutation type in the course of treatment [16]. We did not detect a clonal switch in our cohort.…”

Section: Resultsmentioning

confidence: 99%

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Clinical impact of measurable residual disease monitoring by ultradeep next generation sequencing in NPM1 mutated acute myeloid leukemia

et al. 2018

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Detection of measurable residual disease (MRD) by mutation specific techniques has prognostic relevance in NPM1 mutated AML (NPM1mut AML). However, the clinical utility of next generation sequencing (NGS) to detect MRD in AML remains unproven. We analysed the clinical significance of monitoring MRD using ultradeep NGS (NGS-MRD) and flow cytometry (FCM-MRD) in 137 samples obtained from 83 patients of NPM1mut AML at the end of induction (PI) and consolidation (PC). We could monitor 12 different types of NPM1 mutations at a sensitivity of 0.001% using NGS-MRD. We demonstrated a significant correlation between NGS-MRD and real time quantitative PCR (RQ-PCR). Based upon a one log reduction between PI and PC time points we could classify patients as NGS-MRD positive (<1log reduction) or negative (>1log reduction). NGS-MRD, FCM-MRD as well as DNMT3A mutations were predictive of inferior overall survival (OS) and relapse free survival (RFS). On a multivariate analysis NGS-MRD emerged as an independent, most important prognostic factor predictive of inferior OS (hazard ratio, 3.64; 95% confidence interval [CI] 1.58 to 8.37) and RFS (hazard ratio, 4.8; 95% CI:2.24 to 10.28). We establish that DNA based NPM1 NGS MRD is a highly useful test for prediction of relapse and survival in NPM1mut AML.

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Section: Discussioncontrasting

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Clinical impact of measurable residual disease monitoring by ultradeep next generation sequencing in NPM1 mutated acute myeloid leukemia

et al. 2018

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“…This is underlined by the identification of pre-leukemic clones of second AML that lack the primary AML pre-leukemic DNMT3A , TET2 , SRSF2 or RUNX1 mutations. 40,70 Nevertheless, most of these second-AML-initiating clones share the same early, pre-leukemic mutations as the primary AML clone, 40,65 and some even evolve similarly to the primary clone and acquire a different mutation in the same gene, 70,71 emphasizing the role of an environmental selective pressure (Figure 2).…”

Section: Clinical Implications and Future Challengesmentioning

confidence: 99%

Evolutionary trajectory of leukemic clones and its clinical implications

Tuval

Shlush

2019

Haematologica

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The ontogeny of acute myeloid leukemia is a multistep process. It is driven both by features of the malignant clone itself as well as by environmental pressures, making it a unique process in each individual. The technological advancements of recent years has increased our understanding about the different steps that take place at the genomic level. It is now clear that malignant clones evolve, expand and change even during what seem to be clinically healthy or “cured” periods. This opens a wide window for new therapeutic and monitoring opportunities. Moreover, prediction and even early prevention have become possible goals to be pursued. The aim of this review is to shed light upon recent observations in leukemia evolution and their clinical implications. We present a critical view of these concepts in order to assist clinicians when interpreting results of the ever growing myriad of genomic diagnostic tests. We wish to help clinicians incorporate genetic tests into their clinical assessment and enable them to provide genetic counseling to their patients.

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“…Indeed, we found that the universal and mutantspecific multiplex primer sets resulted in 0.093% positive partitions, indicating that counting was accurate irrespective of subtype (odds ratio, 1.002; 95% CI, 0.956e1.049; P Z 0.934) ( Figure 3B). Given the reported instances of clonal heterogeneity 23 and type switching 24 in selected AML cases and success with the multiplex target pool in Figure 3B, we next sought to determine the ability of the massively multiplex assay to quantify NPM1muts in the setting of clonal heterogeneity ( Figure 3C). To this end, plasmids harboring type A and/or type B NPM1muts were spiked into NPM1 wild-type GM12878 cDNA alone or combined as a 50:50 mixture of type A and type B (A:B) to target a total of approximately 350 NPM1mut/10 4 ABL1 copies in all cases.…”

Section: Other Rare Npm1mut Typesmentioning

confidence: 99%

“…Therefore, a substantial number of patients with NPM1mut AML would be ineligible for MRD assessment because they lack NPM1 sequence information and/or the availability of an appropriate test. Finally, although NPM1muts are generally stable over time, 20e22 there have been reports of intrapatient heterogeneity 23 and type switching, 24 both of which could result in false-negative determinations of MRD status in individual cases. Next-generation sequencingebased approaches can circumvent these challenges because they do not require prior sequence information for detection of NPM1muts in the context of MRD and have sensitivities that exceed flow cytometry.…”

mentioning

confidence: 99%

Minimal Residual Disease Monitoring of Acute Myeloid Leukemia by Massively Multiplex Digital PCR in Patients with NPM1 Mutations

Mencia-Trinchant

Alas

et al. 2017

The Journal of Molecular Diagnostics

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The presence of minimal residual disease (MRD) is widely recognized as a powerful predictor of therapeutic outcome in acute myeloid leukemia (AML), but methods of measurement and quantification of MRD in AML are not yet standardized in clinical practice. There is an urgent, unmet need for robust and sensitive assays that can be readily adopted as real-time tools for disease monitoring. NPM1 frameshift mutations are an established MRD marker present in half of patients with cytogenetically normal AML. However, detection is complicated by the existence of hundreds of potential frameshift insertions, clonal heterogeneity, and absence of sequence information when the NPM1 mutation is identified using capillary electrophoresis. Thus, some patients are ineligible for NPM1 MRD monitoring. Furthermore, a subset of patients with NPM1-mutated AML will have false-negative MRD results because of clonal evolution. To simplify and improve MRD testing for NPM1, we present a novel digital PCR technique composed of massively multiplex pools of insertion-specific primers that selectively detect mutated but not wild-type NPM1. By measuring reaction end points using digital PCR technology, the resulting single assay enables sensitive and specific quantification of most NPM1 exon 12 mutations in a manner that is robust to clonal heterogeneity, does not require NPM1 sequence information, and obviates the need for maintenance of hundreds of type-specific assays and associated plasmid standards.

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Switch of the mutation type of the NPM1 gene in acute myeloid leukemia (AML): relapse or secondary AML?

Cited by 8 publications

References 10 publications

Clinical impact of measurable residual disease monitoring by ultradeep next generation sequencing in NPM1 mutated acute myeloid leukemia

Clinical impact of measurable residual disease monitoring by ultradeep next generation sequencing in NPM1 mutated acute myeloid leukemia

Evolutionary trajectory of leukemic clones and its clinical implications

Minimal Residual Disease Monitoring of Acute Myeloid Leukemia by Massively Multiplex Digital PCR in Patients with NPM1 Mutations

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