<scp>IDH</scp>1 and <scp>IDH</scp>2 mutations confer an adverse effect in patients with acute myeloid leukemia lacking the <scp>NPM</scp>1 mutation

Yamaguchi, Shoichiro; Iwanaga, Eisaku; Tokunaga, Kenji; Nanri, Tomoko; Shimomura, Taizo; Suzushima, Hitoshi; Mitsuya, Hiroaki; Asou, Norio

doi:10.1111/ejh.12271

Cited by 42 publications

(34 citation statements)

References 39 publications

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“…Previous studies of IDH1 mutations on outcome after IC have reported either no impact on or an increased rate of disease recurrence. [37][38][39] Therefore, our data demonstrating a reduced risk of relapse after allo-SCT in patients with an IDH1 mutation raise the possibility that the genetic factors determining outcome after IC may differ from those determining relapse after allo-SCT.…”

Section: Discussionmentioning

confidence: 77%

Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia

et al. 2016

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Key Points• We identify genes prognostic of disease relapse in patients allografted for AML.• Mutational profiles often change at relapse postallograft, which may have implications for the design of posttransplant interventions.Disease relapse is the major cause of treatment failure after allogeneic stem cell transplantation (allo-SCT) in acute myeloid leukemia (AML). To identify AML-associated genes prognostic of AML relapse post-allo-SCT, we resequenced 35 genes in 113 adults at diagnosis, 49 of whom relapsed. Two hundred sixty-two mutations were detected in 102/113 (90%) patients.An increased risk of relapse was observed in patients with mutations in WT1 (P 5 .018), DNMT3A (P 5 .045), FLT3 ITD (P 5 .071), and TP53 (P 5 .06), whereas mutations in IDH1were associated with a reduced risk of disease relapse (P 5 .018). In 29 patients, we additionally compared mutational profiles in bone marrow at diagnosis and relapse to study changes in clonal structure at relapse. In 13/29 patients, mutational profiles altered at relapse. In 9 patients, mutations present at relapse were not detected at diagnosis. In 15 patients, additional available pre-allo-SCT samples demonstrated that mutations identified posttransplant but not at diagnosis were detectable immediately prior to transplant in 2 of 15 patients. Taken together, these observations, if confirmed in larger studies, have the potential to inform the design of novel strategies to reduce posttransplant relapse highlighting the potential importance of post-allo-SCT interventions with a broad antitumor specificity in contrast to targeted therapies based on mutational profile at diagnosis.

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Section: Discussionmentioning

confidence: 77%

Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia

et al. 2016

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“…In addition, in the aspect of FAB classification, patients with M1 harbored higher percentage of IDH mutations (6,17,18,24,25,29,30,39,42), whereas in cases with M4, lower percentage was observed (17,24,29,47). Besides, the frequency of IDH mutations was higher in cases with normal karyotype in 9 studies (6, 16-18, 24, 25, 29, 30, 39, 40, 42, 48).…”

Section: Study Characteristicsmentioning

confidence: 91%

“…As shown in Supplementary Table S1, IDH gene aberrations were closely associated with elderly patients in 12 studies (16, 18, 25, 26, 30, 32, 33, 38, 41-43, 47, 48) and with higher platelet count in 9 studies (16,18,26,27,29,36,38,42,43). In addition, in the aspect of FAB classification, patients with M1 harbored higher percentage of IDH mutations (6,17,18,24,25,29,30,39,42), whereas in cases with M4, lower percentage was observed (17,24,29,47).…”

Section: Study Characteristicsmentioning

confidence: 93%

Correlation Between Isocitrate Dehydrogenase Gene Aberrations and Prognosis of Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis

et al. 2017

Clinical Cancer Research

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Purpose: Whether isocitrate dehydrogenase (IDH) gene aberrations affected prognosis of patients with acute myeloid leukemia (AML) was controversial. Here, we conducted a meta-analysis to evaluate their prognostic value.Experimental Design: PubMed, Embase, Cochrane, and Chinese databases were searched to identify studies exploring how IDH gene aberrations affected AML outcome. Pooled HRs and relative risks (RR) were calculated, along with 95% confidence intervals (CI).Results: Thirty-three reports were included.

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“…The aggregate frequency of these two mutations in AML is relatively high, approximately 15-20% of all patients with AML and 25-30% of patients with CN-AML harboring either IDH1or IDH2mutations respectively [27]. Different studies have reported the IDH1/2 mutational status in AML patients and a statistically significant co-occurrence with NPM1 and CEBPA mutations [137]. In the two consecutive studies correlations IDH1/2 mutations with outcome in AML, except for the IDH1/2 mutation enrichment in the NPM mutant group, it was reported that patients with the IDH-R140 mutation had an improved OS and decreased response rates.…”

Section: Idh1/2 Mutationsmentioning

confidence: 99%

“…However it has been observed that IDH-mutant AMLs have a unique methylation profile characterized by global promoter hypermethylation, which provides these cases reasonable candidates for demethylation therapies [141]. Recent finding suggested that allogeneic HSCT may improve OS in younger patients with IDH mutations [137]. However, patient numbers who underwent allogeneic HSCT were small; the efficacy of allogeneic HSCT should be verified in large cohort of patients with IDH mutations…”

Section: Idh1/2 Therapeutic Implicationmentioning

confidence: 99%

Distinct Gene Mutations, their Prognostic Relevance and Molecularly Targeted Therapies in Acute Myeloid Leukemia (AML)

Tayyab¹

2014

J Cancer Sci Ther

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Acquired genetic alterations which include balanced and unbalanced chromosome aberrations and submicroscopic gene mutations and changes in gene expression strongly influenced by pretreatment clinical features and prognosis of adults patients with acute myeloid leukemia (AML). Cytogenetic profiling separate AML patients into three broad prognostic groups: favorable, intermediate and adverse. The cytogenetic risk classifications vary to some extent for younger adult patients and for those aged 60 years or older. In many cases, patients with specific cytogenetic rearrangement such as those with a normal karyotype or those with either RUNX1-RUNX1T1 or CBFB-MYH11 feature of core-binding factor (CBF) can be further subdivided into prognostic categories depend on the presence or absence of specific gene mutations or changes in gene expression. Advancement in the understanding of cancer genetic and discovery of recurrent mutations in AML provide opportunity to develop targeted therapies and improve the clinical outcome. The identified gene mutations, mainly targetable lesions are gain of function mutations of JAK2 and cKIT and FLT3 in APL have been associated with clinical features and/ or outcome of patients with these AML subtypes. These data emphasize the significance of genetic testing for common translocations for diagnosis, prognosis and increasingly targeted therapy in acute leukemia. Notably, these several molecular genetic alterations constitute a variety of diverse new targets for salvage therapies. These approaches intend to develop targeted treatment concepts that depend on interference with molecular genetics or epigenetic mechanisms. This report provides an overview on characteristic gene mutations, discuss their biological functions and Prognostic significance, which serve as basis for selected therapy approaches now or might represent options for such approaches in the future and expected to have a role in treating AML subtypes with characteristic molecular alterations.

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IDH1 and IDH2 mutations confer an adverse effect in patients with acute myeloid leukemia lacking the NPM1 mutation

Cited by 42 publications

References 39 publications

Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia

Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia

Correlation Between Isocitrate Dehydrogenase Gene Aberrations and Prognosis of Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis

Distinct Gene Mutations, their Prognostic Relevance and Molecularly Targeted Therapies in Acute Myeloid Leukemia (AML)

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