Prognostic significance of NPM1 mutations in acute myeloid leukemia: A meta-analysis

Abstract

Nucleophosmin 1 (NPM1) mutations have been identified in a substantial number of patients with acute myeloid leukemia (AML). Favorable outcomes in AML cases with NPM1 mutations have been previously reported. However, widely differing survival estimates have been indicated. Therefore, a meta-analysis of nine studies including a total of 4509 subjects was performed. The frequency of NPM1 mutations was found to be 6.45-56.08%. NPM1-mutation type (NPM1-mt) patients had >2-fold higher odds of achieving complete remission compared with NPM1-wild-type (NPM1-wt). The summary hazard ratio (HR) of NPM1-mt/NPM1-wt for disease-free survival (DFS) and OS was 0.67 and 0.63, respectively. In conclusion, these findings suggest that the NPM1 mutation has a favorable effect on the outcome for AML. The present meta-analysis was based on data abstracted from observational studies. However, the results obtained may justify the risk-adapted therapeutic strategies for AML according to the NPM1 status.

Nucleophosmin: from structure and function to disease development

“…Further, NPM1 deregulation or mutation will suppress the ability of that cell to respond to apoptotic stimuli, allowing for the tolerance of the genetic instability. Consistent with a role in genetic instability and specifically the repair of double-strand DNA breaks we see that AML patients with a mutated NPM1 have a >2 fold higher odds of achieving complete remission as compared to patients with a wild type NPM1 [108]. NPM1 in cancer is most strikingly highlighted in acute myeloid leukemia where approximately 30 % of patients will have a mutation or fusion event implicating NPM1.…”

Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group

“…More intriguing, however, is the paradoxical cooperative favorable effect on NPM1 conferred by FLT3-TKD, a phenomenon not observed between FLT3-ITD and NPM1 (Figure 1). 5 One may surmise, based on the similar response rates observed between FLT3-TKD 1 NPM1 1 and NPM1 1 -only mutation cohorts, that favorable effects are likely due to durable CRs effected by chemotherapy on an inherently biologically indolent disease. As alluded above, FLT3-ITD and FLT3-TKD mutants show distinct gain-of-function phenotypes with distinct differences in signaling properties and gene expression patterns.…”

“…9 Patients with FLT3-ITD and NPM1 mutations have improved response rates and disease-free and OS compared with those who only have the FLT3-ITD mutation, although outcomes are inferior to NPM1-only-mutated AML. 5 In a previous study, Bacher et al 10 showed that, in contrast to the prognostic impact of FLT3-ITD on NPM1, FLT3-TKD has an additional favorable impact on outcomes in NPM1-mutated AML, suggesting a cooperative positive effect. This favorable effect of FLT3-TKD-NPM1 on OS compared with the overall AML population was recently confirmed by Pappaemanuil et al 11 However, case numbers in this particular group in the Bacher et al 10 study were few.…”

“…4 The favorable prognosis conferred by NPM1 mutations was most recently confirmed in a meta-analysis, which demonstrated NPM1 mutations to be associated with higher complete remission (CR) rates and prolonged disease-free and overall survival (OS). 5 In regards to FMS-like tyrosine kinase 3 (FLT3), the more common internal tandem duplication (ITD) is associated with short remission durations and high relapse rates after conventional induction therapy, 6 whereas the less frequent tyrosine kinase domain (TKD) mutations are of unclear prognostic relevance. The incidence of ITD and TKD mutations in FLT3-mutated AML vary slightly according to age, clinical risk groups, and cytogenetic profile.…”

Considerations and challenges for patients with refractory and relapsed acute myeloid leukaemia

“…Similarly, studies of patients with relapsed AML have shown that FLT3-ITD is a significant negative predictor of survival following relapse [18,39,40]. Mutation of the nucleophosmin 1 (NPM1) gene, found in around 30% of AML, has been associated with better clinical outcomes (higher CR rates and longer DFS and OS) in patients with newly diagnosed AML, particularly in the absence of FLT3-ITD [41]. However, in patients with relapsed AML, NPM1 status was not consistently a significant predictor of CR2 or OS [18,40,42].…”