Prognostic impact of CSF3R mutations in favorable risk childhood acute myeloid leukemia.
Ontology highlight
ABSTRACT:
SUBMITTER: Tarlock K
PROVIDER: S-EPMC7193184 | biostudies-literature | 2020 Apr
REPOSITORIES: biostudies-literature
Publications
Prognostic impact of CSF3R mutations in favorable risk childhood acute myeloid leukemia.
Tarlock Katherine K Alonzo Todd T Wang Yi-Cheng YC Gerbing Robert B RB Ries Rhonda E RE Hylkema Tiffany T Smith Jenny L JL Maxson Julia E JE Meshinchi Soheil S
Blood 20200401 18
Similar Datasets
Project description:Studies on the clinical significance of Nucleophosmin (NPM1) mutations in pediatric AML in a large cohort are lacking. Moreover, the prognosis of patients with co-occurring NPM1 and FLT3/ITD mutations is controversial. Here, we analyzed the impact of NPM1 mutations on prognoses of 869 pediatric AML patients from the TAGET dataset. The frequency of NPM1 mutations was 7.6%. NPM1 mutations were significantly associated with older age (P < 0.001), normal cytogenetics (P < 0.001), FLT3/ITD mutations (P < 0.001), and high complete remission induction rates (P < 0.05). Overall, NPM1-mutated patients had a significantly better 5-year EFS (P = 0.001) and OS (P = 0.016) compared to NPM1 wild-type patients, and this favorable impact was maintained even in the presence of FLT3/ITD mutations. Stem cell transplantation had no significant effect on the survival of patients with both NPM1 and FLT3/ITD mutations. Multivariate analysis revealed that NPM1 mutations were independent predictors of better outcome in terms of EFS (P = 0.004) and OS (P = 0.012). Our findings showed that NPM1 mutations confer an independent favorable prognostic impact in pediatric AML despite of FLT3/ITD mutations. In addition, pediatric AML patients with both NPM1 and FLT3/ITD mutations appear to have favorable prognoses and may not need hematopoietic stem cell transplantations.
| S-EPMC6949268 | biostudies-literature
Project description: Not available
| S-EPMC10544281 | biostudies-literature
Project description:BackgroundInterleukin-7 receptor (IL7R) mutation has been demonstrated to be an adverse prognostic factor in acute lymphoblastic leukemia (ALL) patients. However, the effects of the IL7R mutation on acute myeloid leukemia (AML) have rarely been reported. Here, we investigated IL7R mutations and their effects on AML patients.MethodsA total of 346 newly diagnosed AML patients from January 2017 to July 2020 at Nanfang Hospital were analyzed in this study. A genomic panel of 167 gene targets was detected by next-generation sequencing.ResultsAmong 346 patients, 33 (9.5%) AML patients carried IL7R mutations. With a median follow-up of 50.7 months (95% confidence interval (CI) 17.3-62.2), the 5-year overall survival (OS) rates were 51.5% (95% CI 37.0%-71.0%) and 72.2% (95% CI 67.4%-77.3%; p = 0.008), the 5-year event-free survival (EFS) rates were 36.1% (95% CI 23.2%-57.1%) and 58.1% (95% CI 52.9%-63.8%; p = 0.005), the 5-year non-relapse mortality (NRM) were 21.4% (95% CI 8.5%-38.2%) and 6.2% (95% CI 3.7%-9.5%; p = 0.004) in the IL7R mutant (IL7R MUT ) group and non-IL7R mutant (IL7R WT ) group, respectively. There is no significant difference in the disease-free survival (75.1% vs 73.5%, p = 0.885) and cumulative incidence of relapse (25.7% vs 25.2%, p = 0.933) between IL7R MUT and IL7R WT group. Furthermore, patients who underwent hematopoietic stem cell transplantation (HSCT) still had more adverse outcomes in the IL7R MUT group than in the IL7R WT group (5-year OS: 61.9% vs 85.3%, p = 0.003). In the TET2 (p = 0.013) and DNA methyltransferase 3A (DNMT3A; p = 0.046) mutation subgroups, the presence of IL7R mutations was associated with worse OS than in AML patients without IL7R mutations.ConclusionOur study demonstrated that the IL7R mutation is associated with an inferior prognosis for AML patients. Patients with IL7R mutations have higher NRM, shorter OS, and EFS than patients without IL7R mutations, even patients who have undergone HSCT. Future larger and multicentric prospective studies will be explored.
| S-EPMC11439168 | biostudies-literature
Project description:Internal tandem duplication of the fms-like tyrosine kinase-3 gene (FLT3-ITD) and nucleophosmin-1 (NPM1) mutations have prognostic importance in acute myeloid leukemia (AML) patients with intermediate-risk karyotype at diagnosis, but less is known about their utility to predict outcomes at relapse. We retrospectively analysed outcomes of 70 patients with relapsed, intermediate-risk karyotype AML who received a uniform reinduction regimen, with respect to FLT3-ITD and NPM1 mutation status and first complete remission (CR1) duration. CR1 duration, but not molecular status, was significantly correlated with CR2 rate. On univariate analysis, patients with mutated FLT3-ITD (FLT3+) had significantly worse overall survival (OS) compared with those with neither an NPM1 nor FLT3-ITD mutation (NPM1-/FLT3-). On multivariate analysis, shorter CR1 duration was significantly correlated with inferior OS at relapse (P<0.0001), while FLT3 and NPM1 mutation status and age were not significantly correlated with OS. Patients who subsequently underwent allogeneic stem cell transplant (alloSCT) had a superior OS regardless of CR1 duration, but outcomes were better in patients with CR1 duration>12 months. In intermediate-risk karyotype AML patients receiving reinduction, CR1 duration remains the most important predictor of OS at relapse; FLT3-ITD and NPM1 status are not independent predictors of survival.
| S-EPMC3674456 | biostudies-other
Project description: Not available
| S-EPMC3148921 | biostudies-literature
Project description:Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. The interaction between these distinct classes of mutations occurs at the level of myeloid lineage enhancers where mutant CEBPA prevents activation of a subset of differentiation associated enhancers. To confirm this enhancer-dependent mechanism, we demonstrate that CEBPA mutations must occur as the initial event in AML initiation. This improved mechanistic understanding will facilitate therapeutic development targeting the intersection of oncogene cooperativity.
| S-EPMC6884457 | biostudies-literature
Project description:Acute myeloid leukemia (AML) is a biologically complex and molecularly and clinically heterogeneous disease, and its incidence increases with age. Cytogenetics and mutation testing remain important prognostic tools for treatment after induction therapy. The post-induction treatment is dependent on risk stratification. Despite rapid advances in determination of gene mutations involved in the pathophysiology and biology of AML, and the rapid development of new drugs, treatment improvements changed slowly over the past 30 years, with the majority of patients eventually experiencing relapse and dying of their disease. Allogenic hematopoietic stem cell transplantation remains the best chance of cure for patients with intermediate- or high-risk disease. This review gives an overview about advances in prognostic markers and novel treatment options for AML, focusing on new prognostic and probably therapeutic mutations, and novel drug therapies such as tyrosine kinase inhibitors.
| S-EPMC5070622 | biostudies-literature
Project description:Activating mutations in the gene encoding for receptor of colony stimulating factor 3 (CSF3R) are drivers of pathogenesis in chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). We describe a patient with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) and three unique CSF3R truncating mutations which are predicted to be activating. After a slow early response to induction chemotherapy, dasatinib was added based on data from in vitro experiments demonstrating that dasatinib effectively targets key downstream kinases in CSF3R-mutated CNL/aCML. The patient subsequently achieved complete remission with minimal residual disease negativity that has been durable.
| S-EPMC7305335 | biostudies-literature
Project description:BackgroundDNA methyltransferase 3A (DNMT3A) mutation was recently introduced as a prognostic indicator in normal karyotype (NK) AML and we evaluated the incidence and prognostic impact of DNMT3A mutations in Korean NK AML patients.MethodsTotal 67 NK AML patients diagnosed during the recent 10 years were enrolled. DNMT3A mutations were analyzed by direct sequencing and categorized into nonsynonymous variations (NSV), deleterious mutations (DM), and R882 mutation based on in silico analysis results. Clinical features and prognosis were compared with respect to DNMT3A mutation status.ResultsThree novel (I158M, K219V, and E177V) and two known (R736H and R882H) NSVs were identified and the latter three were predicted as DMs. DNMT3A NSVs, DMs, and R882 mutation were identified in 14.9%-17.9%, 10.3%-10.4%, and 7.5% of patients, respectively. DNMT3A mutations were frequently detected in FLT3 ITD mutated patients (P=0.054, 0.071, and 0.071 in NSV, DMs, and R882 mutation, resp.) but did not affect clinical features and prognosis significantly.ConclusionsIncidences of DNMT3A NSVs, DMs, and R882 mutation are 14.9%-17.9%, 10.3%-10.4%, and 7.5%, respectively, in Korean NK AML patients. DNMT3A mutations are associated with FLT3 ITD mutations but do not affect clinical outcome significantly in Korean NK AML patients.
| S-EPMC4306257 | biostudies-literature
Project description:Isocitrate dehydrogenase 1 (IDH1) gene aberrations have recently been reported in acute myeloid leukemia (AML). To evaluate the prognostic significance of IDH1 mutations in AML, we performed a meta-analysis. Fifteen studies covering a total of 8121 subjects were included in this analysis. The frequency of IDH1 R132 mutations were 4.4-9.3% for AML patients and 10.9-16.0% for cytogenetically normal (CN)-AML patients. The IDH1 mutations were associated with NPM1 mutations in 6 studies and normal cytogenetics in 5 studies. AML patients with IDH1 mutations had inferior overall survival compared to patients without the mutations (hazard ratio 1.17, 95% CI: 1.02-1.36). Additionally, in CN-AML patients, IDH1 mutations were associated with a lower complete remission rate (risk ratio 1.30, 95% CI: 1.04-1.63). Although the available literature is limited to observational studies, these results may justify the risk-adapted therapeutic strategies for AML according to the IDH1 status.
| S-EPMC3512179 | biostudies-other