Prognostic Impact of Concurrent DNMT3A, FLT3 and NPM1 Gene Mutations in Acute Myeloid Leukemia Patients

El-Rhman, Heba Allah Elsayed Abd; El-Meligui, Yomna M; Elalawi, Saffaa M

doi:10.1016/j.clml.2021.07.011

Cited by 10 publications

(9 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This new prognostic model clarifies the importance of DNMT3A R882 mutations and emphasizes the importance of triple‐mutated AML with duplicate FLT3 ‐ITD, NPM1 mutations, and DNMT3A mutations. In recent years, several large cohort studies have reported a poor prognosis in triple‐mutated AML 2,26–28 . Our study further supports these studies.…”

Section: Discussionsupporting

confidence: 91%

Mutational analysis of DNMT3A improves the prognostic stratification of patients with acute myeloid leukemia

et al. 2023

View full text Add to dashboard Cite

Nucleophosmin1 (NPM1) mutations are the most frequently detected gene mutations in acute myeloid leukemia (AML) and are considered a favorable prognostic factor. We retrospectively analyzed the prognosis of 605 Japanese patients with de novo AML, including 174 patients with NPM1‐mutated AML. Although patients with NPM1‐mutated AML showed a high remission rate, this was not a favorable prognostic factor for overall survival (OS); this is contrary to generally accepted guidelines. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNA methyltransferase 3A (DNMT3AR882 mutations) were a strong predicative factor indicating poor prognosis in all AML (p < 0.0001) and NPM1‐mutated AML cases (p = 0.0020). Furthermore, multivariate analysis of all AML cases showed that DNMT3AR882 mutations and the co‐occurrence of internal tandem duplication in FMS‐like tyrosine kinase 3 (FLT3‐ITD), NPM1 mutations, and DNMT3AR882 mutations (triple mutations) were independent factors predicting a poor prognosis related to OS, with NPM1 mutations being an independent factor for a favorable prognosis (hazard ratios: DNMT3AR882 mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3AR882 mutations and triple mutations on prognosis and according to the classification of NPM1‐mutated AML into three risk groups based on DNMT3AR882/FLT3‐ITD genotypes, we achieved the improved stratification of prognosis (p < 0.0001). We showed that DNMT3AR882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3AR882 mutations were excluded, NPM1 mutations were a favorable prognostic factor. This revealed that ethnological prognostic discrepancies in NPM1 mutations might be corrected through prognostic stratification based on the DNMT3A status.

show abstract

Section: Discussionsupporting

confidence: 91%

Mutational analysis of DNMT3A improves the prognostic stratification of patients with acute myeloid leukemia

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Further analysis revealed that the majority (96%) of these patients had mutations in the FLT3, NPM1, and additional genes, including DNMT3A and IDH1/2. In agreement with these findings, recent studies reported poor prognosis associated with concurrent mutations in the FLT3, NPM1, DNMT3A, and IDH1/2 genes [22][23][24]. To date, the ELN-2017 risk score only includes the co-occurrence of mutations in the NPM1 and FLT3 genes [9].…”

Section: Discussionsupporting

confidence: 59%

“…We expected that these patients had intermediate/adverse risk, but in fact, their outcome was better than that observed in the favorable group (Figure 4). Nevertheless, within this group, the outcome was worse for those patients with combined FLT3-ITD and DNMT3A mutations, reinforcing the view that the concurrent alteration of the two genes has a negative impact on prognosis [22][23][24].…”

Section: Discussionsupporting

confidence: 53%

Screening a Targeted Panel of Genes by Next-Generation Sequencing Improves Risk Stratification in Real World Patients with Acute Myeloid Leukemia

Matos¹,

Bernardo

Esteves³

et al. 2022

Cancers

View full text Add to dashboard Cite

Although mutation profiling of defined genes is recommended for classification of acute myeloid leukemia (AML) patients, screening of targeted gene panels using next-generation sequencing (NGS) is not always routinely used as standard of care. The objective of this study was to prospectively assess whether extended molecular monitoring using NGS adds clinical value for risk assessment in real-world AML patients. We analyzed a cohort of 268 newly diagnosed AML patients. We compared the prognostic stratification of our study population according to the European LeukemiaNet recommendations, before and after the incorporation of the extended mutational profile information obtained by NGS. Without access to NGS data, 63 patients (23%) failed to be stratified into risk groups. After NGS data, only 27 patients (10%) failed risk stratification. Another 33 patients were re-classified as adverse-risk patients once the NGS data was incorporated. In total, access to NGS data refined risk assessment for 62 patients (23%). We further compared clinical outcomes with prognostic stratification, and observed unexpected outcomes associated with FLT3 mutations. In conclusion, this study demonstrates the prognostic utility of screening AML patients for multiple gene mutations by NGS and underscores the need for further studies to refine the current risk classification criteria.

show abstract

“…However, patients with either NPM1 mutation alone or FLT3-ITD alone had longer OS. 73 Other co-mutations such as IDH1/2, CEBPA, and ASXL1 could affect the prognosis of AML patients. The prognostic analysis of isocitrate dehydrogenase (IDH1 and IDH2) mutations in newly diagnosed FLT3-ITD AML patients showed that double-mutated patients had higher white blood cell counts, increased peripheral and bone marrow blast percentages, a higher frequency of NPM1 mutations and a lower frequency of DNMT3A.…”

Section: Prognostic and Clinical Impact Of Flt3 Mutationsmentioning

confidence: 99%

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Tecik¹,

Adan²

2022

OTT

View full text Add to dashboard Cite

FMS-like tyrosine kinase 3 (FLT3) is mutated in approximately 30% of acute myeloid leukemia (AML) patients. The presence of FLT3-ITD (internal tandem duplication, 20–25%) mutation and, to a lesser extent, FLT3-TKD (tyrosine kinase domain, 5–10%) mutation is associated with poorer diagnosis and therapy response since the leukemic cells become hyperproliferative and resistant to apoptosis after continuous activation of FLT3 signaling. Targeting FLT3 has been the focus of many pre-clinical and clinical studies. Hence, many small-molecule FLT3 inhibitors (FLT3is) have been developed, some of which are approved such as midostaurin and gilteritinib to be used in different clinical settings, either in combination with chemotherapy or alone. However, many questions regarding the best treatment strategy remain to be answered. On the other hand, various FLT3-dependent and -independent resistance mechanisms could be evolved during FLT3i therapy which limit their clinical impact. Therefore, identifying molecular mechanisms of resistance and developing novel strategies to overcome this obstacle is a current interest in the field. In this review, recent studies of approved FLT3i and knowledge about major resistance mechanisms of clinically approved FLT3i’s will be discussed together with novel treatment approaches such as designing novel FLT3i and dual FLT3i and combination strategies including approved FLT3i plus small-molecule agents targeting altered molecules in the resistant cells to abrogate resistance. Moreover, how to choose an appropriate FLT3i for the patients will be summarized based on what is currently known from available clinical data. In addition, strategies beyond FLT3i’s including immunotherapeutics, small-molecule FLT3 degraders, and flavonoids will be summarized to highlight potential alternatives in FLT3-mutated AML therapy.

show abstract

Prognostic Impact of Concurrent DNMT3A, FLT3 and NPM1 Gene Mutations in Acute Myeloid Leukemia Patients

Cited by 10 publications

References 18 publications

Mutational analysis of DNMT3A improves the prognostic stratification of patients with acute myeloid leukemia

Mutational analysis of DNMT3A improves the prognostic stratification of patients with acute myeloid leukemia

Screening a Targeted Panel of Genes by Next-Generation Sequencing Improves Risk Stratification in Real World Patients with Acute Myeloid Leukemia

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Contact Info

Product

Resources

About