<i>NPM1</i> mutant variant allele frequency correlates with leukemia burden but does not provide prognostic information in <i>NPM1</i>‐mutated acute myeloid leukemia

Abbas, Hussein A.; Ravandi, Farhad; Loghavi, Sanam; Patel, Keyur P.; Borthakur, Gautam; Kadia, Tapan M.; Jabbour, Elias; Takahashi, Koichi; Cortes, Jorge; Issa, Ghayas C.; Konopleva, Marina; Kantarjian, Hagop M.

doi:10.1002/ajh.25454

Cited by 18 publications

(19 citation statements)

References 6 publications

(5 reference statements)

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“…There was no significant impact on CR rate and the impact on OS was of borderline significance. These results are similar to those presented by Rothenberg-Thurley et al (2018), who found that the NPM1 MUT allele burden was not an independent predictor of survival, whereas Abbas et al (2019) found no prognostic impact of the NPM1 MUT allele burden. In our cohort, the impact of the NPM1 MUT allele burden was only significant in those patients where their leukaemia co-expressed mutant NPM1 and a FLT3 ITD .…”

Section: Discussionsupporting

confidence: 91%

“…This data is discordant with that reported by Patel et al (), who found no relationship between NPM1 MUT allele levels and the presence of a FLT3 ITD . The reason for this major difference is not clear but it should be noted that only 14% of the FLT3 ITD ‐positive patients in our study received a FLT3 inhibitor compared to 57% and 78% in the studies reported by Patel et al () and Abbas et al () respectively.…”

Section: Discussioncontrasting

confidence: 64%

“…Furthermore, we found no greater benefit from consolidation with an allograft in first CR in those patients with higher as compared to lower NPM1 MUT allele burdens. Only 16% of our patients received an allograft in first CR compared to 41% in the Patel cohort, which may have contributed to this difference, but Abbas et al (2019) Overall survival stratified according to NPM1 mutant allele burden and the presence or absence of a FLT3 ITD . NPM1 high and low refer to mutant level above and below the median (43%).…”

Section: Discussionmentioning

confidence: 82%

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Analysis of the clinical impact of NPM1 mutant allele burden in a large cohort of younger adult patients with acute myeloid leukaemia

et al. 2019

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Summary Although an NPM1 mutation is generally considered to be a good prognostic marker in acute myeloid leukaemia, it has recently been suggested that a higher level of NPM1 mutant (NPM1MUT) alleles relative to wild‐type alleles is associated with poor clinical outcome. We therefore sought to confirm this finding in a larger study of 876 NPM1MUT cases entered into UK national trials. In univariate analysis, the higher NPM1MUT allele burden was associated with a lower complete remission (CR) rate, higher relapse rate and reduced overall survival, but this was largely attributable to the association of the higher NPM1MUT allele burden with other known poor risk factors, particularly the presence of a concomitant FLT3 internal tandem duplication. In multivariate analysis, there was no significant impact of the NPM1MUT allele burden on CR rates, and the impact on relapse and overall survival, whilst still significant, was greatly reduced. This impact was similar in patients who did or did not receive an allogeneic transplant in first CR. We conclude that the binary presence or absence of an NPM1 mutation, combined with minimal residual disease levels following induction therapy, should continue to be used in therapeutic management rather than stratification according to the NPM1MUT level.

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Section: Discussionsupporting

confidence: 91%

Section: Discussioncontrasting

confidence: 64%

Section: Discussionmentioning

confidence: 82%

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Analysis of the clinical impact of NPM1 mutant allele burden in a large cohort of younger adult patients with acute myeloid leukaemia

et al. 2019

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“…However, this NPM1 cohort included FLT3 ITD mutations, and NPM1 VAF was also correlated with elevated WBC. In contrast, Abbas et al showed that NPM1 allele frequency correlated with leukemia burden (and FLT3 ITD) but found no significant correlation with overall survival . Once again, context is important in NPM1 mutated AML, and associated mutations impact OS.…”

Section: Discussionmentioning

confidence: 93%

The combination of NPM1, DNMT3A, and IDH1/2 mutations leads to inferior overall survival in AML

et al. 2019

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Acute myeloid leukemia (AML) is a genetically heterogeneous disease with a clinical course predicted by recurrent cytogenetic abnormalities and/or gene mutations. The NPM1 insertion mutations define the largest distinct genetic subset, ∼30% of AML, and is considered a favorable risk marker if there is no (or low allelic ratio) FLT3 internal tandem duplication (FLT3 ITD) mutation. However, ∼40% of patients with mutated NPM1 without FLT3 ITD still relapse, and the factors that drive relapse are still not fully understood. We used a next‐generation sequencing panel to examine mutations at diagnosis; clearance of mutations after therapy, and gain/loss of mutations at relapse to prioritize mutations that contribute to relapse. Triple mutation of NPM1, DNMT3A and IDH1/2 showed a trend towards inferior overall survival in our discovery dataset, and was significantly associated with reduced OS in a large independent validation cohort. Analysis of relative variant allele frequencies suggests that early mutation and expansion of DNMT3A and IDH1/2 prior to acquisition of NPM1 mutation leads to increased risk of relapse. This subset of patients may benefit from allogeneic stem cell transplant or clinical trials with IDH inhibitors.

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“…They found that a higher NPM1 MUT VAF was significantly associated with reduced overall survival (OS) in both univariate and multivariate analysis (MVA), and they suggested that evaluation of the NPM1 MUT VAF may help guide subsequent management. However, in two other patient cohorts there was either no impact of NPM1 MUT VAF on outcome (Abbas et al , ) or the impact on outcome was seen only in univariate analysis and not MVA (Rothenberg‐Thurley et al , ). In our own large cohort study of 876 NPM1 MUT cases, we confirmed the Patel et al () study showing that the NPM1 MUT VAF had a major impact on event‐free survival and OS in univariate analysis ( P < 0·0001 for both), but we found that this was largely, although not entirely, attributable to an association with other known prognostic factors, particularly the white blood cell (WBC) count and the presence of a FLT3 ITD (Linch et al , ).…”

Section: Demographics Of the Total Cohort Of Dnmt3amut Patients Studiedmentioning

confidence: 99%

The clinical impact of mutant DNMT3A R882 variant allele frequency in acute myeloid leukaemia

et al. 2020

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NPM1 mutant variant allele frequency correlates with leukemia burden but does not provide prognostic information in NPM1‐mutated acute myeloid leukemia

Cited by 18 publications

References 6 publications

Analysis of the clinical impact of NPM1 mutant allele burden in a large cohort of younger adult patients with acute myeloid leukaemia

Analysis of the clinical impact of NPM1 mutant allele burden in a large cohort of younger adult patients with acute myeloid leukaemia

The combination of NPM1, DNMT3A, and IDH1/2 mutations leads to inferior overall survival in AML

The clinical impact of mutant DNMT3A R882 variant allele frequency in acute myeloid leukaemia

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