Comprehensive molecular landscape in patients older than 80 years old diagnosed with acute myeloid leukemia: A study of the French Hauts‐de‐France AML observatory

Renaud, Loïc; Nibourel, Olivier; Marceau-Renaut, Alice; Gruson, Bérengère; Cambier, Nathalie; Lionne‐Huyghe, Pauline; Choufi, Bachra; Rodriguez, Céline; Frimat, Cécile; Plantier, Isabelle; Stalnikiewicz, Laure; Bemba, Maxime; Berthon, Céline; Marolleau, Jean‐Pierre; Quesnel, Bruno; Preudhomme, Claude; Duployez, Nicolas

doi:10.1002/ajh.25328

Cited by 6 publications

(13 citation statements)

References 10 publications

(7 reference statements)

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“…In line with these findings, Heiblig et al showed that in older AML patients IDH2 mutations seem to confer a more favourable outcome compared to IDH1 mutations (overall survival at three years 76% compared to 54%, respectively) [ 53 ]. Renaud et al reported similar findings in a group of French AML patients older than 80 years, showing in these patients a 10% frequency of IDH1 and 16% of IDH2 mutations [ 54 ]. In adult AML patients, IDH1 and IDH2 mutations are usually mutually exclusive with TET2 mutations; however, in older AML patients, it is more frequent to observe an IDH/TET2 co-mutation pattern [ 54 ].…”

Section: Idh Mutations In Amlsupporting

confidence: 53%

“…Renaud et al reported similar findings in a group of French AML patients older than 80 years, showing in these patients a 10% frequency of IDH1 and 16% of IDH2 mutations [ 54 ]. In adult AML patients, IDH1 and IDH2 mutations are usually mutually exclusive with TET2 mutations; however, in older AML patients, it is more frequent to observe an IDH/TET2 co-mutation pattern [ 54 ]. Standard treatments of older AML patients are based on conventional care regimens (reduced-intensity chemotherapy) or on hypomethylating agents, such as azacytidine.…”

Section: Idh Mutations In Amlsupporting

confidence: 53%

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Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes and in Acute Myeloid Leukemias

Testa

Castelli

2020

Cancers

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Acute myeloid leukemia (AML) is a heterogeneous disease generated by the acquisition of multiple genetic and epigenetic aberrations which impair the proliferation and differentiation of hematopoietic progenitors and precursors. In the last years, there has been a dramatic improvement in the understanding of the molecular alterations driving cellular signaling and biochemical changes determining the survival advantage, stimulation of proliferation, and impairment of cellular differentiation of leukemic cells. These molecular alterations influence clinical outcomes and provide potential targets for drug development. Among these alterations, an important role is played by two mutant enzymes of the citric acid cycle, isocitrate dehydrogenase (IDH), IDH1 and IDH2, occurring in about 20% of AMLs, which leads to the production of an oncogenic metabolite R-2-hydroxy-glutarate (R-2-HG); this causes a DNA hypermethylation and an inhibition of hematopoietic stem cell differentiation. IDH mutations differentially affect prognosis of AML patients following the location of the mutation and other co-occurring genomic abnormalities. Recently, the development of novel therapies based on the specific targeting of mutant IDH may contribute to new effective treatments of these patients. In this review, we will provide a detailed analysis of the biological, clinical, and therapeutic implications of IDH mutations.

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Section: Idh Mutations In Amlsupporting

confidence: 53%

Section: Idh Mutations In Amlsupporting

confidence: 53%

Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes and in Acute Myeloid Leukemias

Testa

Castelli

2020

Cancers

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“…For FLT3-ITD, no significant difference could be observed. Comparing data from the present study with those from the recently published study by Renaud et al [29] revealed similar mutation frequencies, with the possible exception of FLT3-ITD ( Figure 2). ASXL1 mutations, typically associated with secondary AML [32], appeared equally rare ( 6%) in both older and younger patients (data not shown).…”

Section: The Mutational Profile In the Elderly Display Distinct Featuressupporting

confidence: 87%

“…The mutation frequencies were retrieved from their publication [28]. For comparison with a cohort of elderly patients the recently published data by Renaud et al was used [29]. By using a panel of 36 genes, they characterized the mutational spectrum in AML patients older than 80 years (mean 83 years), including 17 with NPM1 mutation selected for this comparison [29].…”

Section: Comparative Studiesmentioning

confidence: 99%

Mutational spectrum of de novo NPM1-mutated acute myeloid leukemia patients older than 75 years

Pettersson

Holmgren

Juliusson

et al. 2021

Leukemia & Lymphoma

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AML with mutated NPM1 occurs in all age groups. Yet, the mutational pattern is not extensively studied in the very old, which may hamper appropriate risk assessment. Herein we examined 22 cases of NPM1-mutated de novo AML in patients older than 75, with a median age of 84. All diagnostic samples were sequenced aiming for coverage of the most relevant AML-associated mutations. For comparison with younger patients, we used already published data on several cohorts. A total of 76 mutations including 50 different variants were identified in 16 recurrently mutated AML genes. Compared with younger patients, a significant enrichment of TET2 and SRSF2 was observed, together with a reduced frequency of DNMT3A mutations. Our results indicate that the mutational pattern may be different in the very old as compared to younger patients with NPM1-mutated AML. HIGHLIGHTS The mutational spectrum of NPM1-mutated AML in patients above 75 years displays distinct features. A significant enrichment of TET2 and SRSF2 mutations together with a reduced frequency of DNMT3A mutations was observed in the elderly. NPM1 mutation is a secondary event in the development of AML in the very old.

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“…Around 22%-33% of AML cases present with DNMT3A mutations. 14,[47][48][49] One of the vital findings pertaining to DNMT3A in AML is the identification of DNMT3A missense mutations that affect the encoding of arginine R882 (codon CGC), causing loss of methylation activity of DNMT3A. 50 R882 mutation occurred in 13.2% (n = 37/281) of AML patients, and other types of mutations encompassing DNMT3A were found in 25 AML patients (8.9%).…”

Section: Dnmt3a In Amlmentioning

confidence: 99%

Oncogenic Roles and Inhibitors of DNMT1, DNMT3A, and DNMT3B in Acute Myeloid Leukaemia

2019

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Epigenetic alteration has been proposed to give rise to numerous classic hallmarks of cancer. Impaired DNA methylation plays a central role in the onset and progression of several types of malignancies, and DNA methylation is mediated by DNA methyltransferases (DNMTs) consisting of DNMT1, DNMT3A, and DNMT3B. DNMTs are frequently implicated in the pathogenesis and aggressiveness of acute myeloid leukaemia (AML) patients. In this review, we describe and discuss the oncogenic roles of DNMT1, DNMT3A, and DNMT3B in AML. The clinical response predictive roles of DNMTs in clinical trials utilising hypomethylating agents (azacitidine and decitabine) in AML patients are presented. Novel hypomethylating agent (guadecitabine) and experimental DNMT inhibitors in AML are also discussed. In summary, hypermethylation of tumour suppressors mediated by DNMT1 or DNMT3B contributes to the progression and severity of AML (except MLL-AF9 and inv(16)(p13;q22) AML for DNMT3B), while mutation affecting DNMT3A represents an early genetic lesion in the pathogenesis of AML. In clinical trials of AML patients, expression of DNMTs is downregulated by hypomethylating agents while the clinical response predictive roles of DNMT biomarkers remain unresolved. Finally, nucleoside hypomethylating agents have continued to show enhanced responses in clinical trials of AML patients, and novel non-nucleoside DNMT inhibitors have demonstrated cytotoxicity against AML cells in pre-clinical settings.

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Comprehensive molecular landscape in patients older than 80 years old diagnosed with acute myeloid leukemia: A study of the French Hauts‐de‐France AML observatory

Cited by 6 publications

References 10 publications

Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes and in Acute Myeloid Leukemias

Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes and in Acute Myeloid Leukemias

Mutational spectrum of de novo NPM1-mutated acute myeloid leukemia patients older than 75 years

Oncogenic Roles and Inhibitors of DNMT1, DNMT3A, and DNMT3B in Acute Myeloid Leukaemia

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