Itzykson R, Kosmider O, Cluzeau T, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias

Service d'Hématologie Clinique Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris 13, Bobigny, France.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 10.43). 04/2011; 25(7):1147-52. DOI: 10.1038/leu.2011.71
Source: PubMed


The impact of ten-eleven-translocation 2 (TET2) mutations on response to azacitidine (AZA) in MDS has not been reported. We sequenced the TET2 gene in 86 MDS and acute myeloid leukemia (AML) with 20-30% blasts treated by AZA, that is disease categories wherein this drug is approved by Food and Drug Administration (FDA). Thirteen patients (15%) carried TET2 mutations. Patients with mutated and wild-type (WT) TET2 had mostly comparable pretreatment characteristics, except for lower hemoglobin, better cytogenetic risk and longer MDS duration before AZA in TET2 mutated patients (P=0.03, P=0.047 and P=0.048, respectively). The response rate (including hematological improvement) was 82% in MUT versus 45% in WT patients (P=0.007). Mutated TET2 (P=0.04) and favorable cytogenetic risk (intermediate risk: P=0.04, poor risk: P=0.048 compared with good risk) independently predicted a higher response rate. Response duration and overall survival were, however, comparable in the MUT and WT groups. In higher risk MDS and AML with low blast count, TET2 status may be a genetic predictor of response to AZA, independently of karyotype.

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    • "Potential links between gene mutations and the treatment responses to hypomethylating agents have been reported in a few small series. Itzykson et al. reported that patients with mutated TET2 and favorable cytogenetics had a higher response rate to azacitidine compared to patients with wild-type TET2 in myelodysplastic syndromes and low blast count AML [44]. Metzeler et al. reported a higher complete remission rate in AML patients with DNMT3A mutations treated with decitabine [45]. "
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    ABSTRACT: Minimally differentiated acute myeloid leukemia (AML-M0) is a rare subtype of AML with poor prognosis. Although genetic alterations are increasingly reported in AML, the gene mutations have not been comprehensively studied in AML-M0. We aimed to examine a wide spectrum of gene mutations in patients with AML-M0 to determine their clinical relevance. Twenty gene mutations including class I, class II, class III of epigenetic regulators (IDH1, IDH2, TET2, DNMT3A, MLL-PTD, ASXL1, and EZH2), and class IV (tumor suppressor genes) were analyzed in 67 patients with AML-M0. Mutational analysis was performed with polymerase chain reaction–based assays followed by direct sequencing. The most frequent gene mutations from our data were FLT3-ITD/FLT3-TKD (28.4%), followed by mutations in IDH1/IDH2 (28.8%), RUNX1 (23.9%), N-RAS/K-RAS (12.3%), TET2 (8.2%), DNMT3A (8.1%), MLL-PTD (7.8%), and ASXL1 (6.3%). Seventy-nine percent (53/67) of patients had at least one gene mutation. Class I genes (49.3%) were the most common mutated genes, which were mutually exclusive. Class III genes of epigenetic regulators were also frequent (43.9%). In multivariate analysis, old age [hazard ratio (HR) 1.029, 95% confidence interval (CI) 1.013-1.044, P = .001) was the independent adverse factor for overall survival, and RUNX1 mutation (HR 2.326, 95% CI 0.978-5.533, P = .056) had a trend toward inferior survival. In conclusion, our study showed a high frequency of FLT3, RUNX1, and IDH mutations in AML-M0, suggesting that these mutations played a role in the pathogenesis and served as potential therapeutic targets in this rare and unfavorable subtype of AML.
    Full-text · Article · Jun 2014 · Neoplasia (New York, N.Y.)
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    • "The efficacy and effectiveness of hypomethylating therapy in specific subsets of MDS patients and the presence of molecular mutations in genes relevant to methylation also justifies the efforts in genotyping large cohorts of patients with MDS receiving hypomethylating drugs for these specific molecular changes. Itzykson and colleagues showed that high-risk MDS patients carrying TET2 mutations have better response rate to 5-azacytidine without any improvement in OS [27]. We demonstrated in a cohort of 92 MDS patients that the presence of TET2 and DNMT3A mutations confers better response to both azacitidine and decitabine [28]. "
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    ABSTRACT: Myelodysplastic syndromes (MDS) are a group of clonal hematologic disorders characterized by inefficient hematopoiesis, hypercellular bone marrow, dysplasia of blood cells and cytopenias. Most patients are diagnosed in their late 60s to early 70s. MDS is a risk factor for the development of acute myeloid leukemia which can occur in 10-15% of patients with MDS. A variety of pathophysiologic mechanisms contributes to the genesis and persistence of MDS including immunologic, epigenetic, cytogenetic and genetic factors. The only potential curative option for MDS is hematopoietic cell transplantation which is suitable for only a few patients. Currently approved therapeutic options for MDS, including lenalidomide, decitabine, and 5-azacytidine, are targeted to improve transfusion requirements and quality of life. Moreover, 5-azacytidine has also been demonstrated to improve survival in some patients with higher risk MDS. New ways to predict which patients will better gain benefit from currently available therapeutic agents are the primary challenges in MDS. In the last 10 years, chromosome scanning and high throughput technologies (single nucleotide polymorphism array genotyping, comparative genomic hybridization, and whole genome/ exome sequencing) have tremendously increased our knowledge of MDS pathogenesis. Indeed, the molecular heterogeneity of MDS supports the idea of different therapeutic approaches which will take into account the diverse morphologic and clinical presentations of MDS patients rather than a restricted therapeutic strategy. This review will summarize the molecular abnormalities in key relevant components of the biology and pathogenesis of MDS and will provide an update on the clinical impact and therapeutic response in MDS patients.
    Full-text · Article · Apr 2014
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    • "Itzykson et al. investigated the effect of the ten-eleven translocation 2(TET2) gene mutations on AZA's efficacy in 86 MDS or low blast count AML patients and reported that the presence of a TET2 mutation predicted a higher response rate to AZA than the presence of wild-type TET2 did. However, response duration and survival were comparable between mutated and wild-type groups [7]. On the other hand, Voso et al. showed that TET2 mutations did not have impact on the response to AZA and there were no differences of duration of response and survival between mutated and wild-type groups [8]. "
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    ABSTRACT: Elderly patients with secondary acute myeloid leukemia (AML) following myelodysplastic syndrome (MDS) are often medically unfit for or resistant to chemotherapy, and their prognosis is dismal. In the present paper, we reported a case of secondary leukemia following MDS in an 80-year-old male patient who was deemed unfit for chemotherapy owing to his old age and poor physical condition. Despite a high tumor burden, treatment with AZA exerted a remarkable response, leading to an immediate cytoreduction in our case. Our results suggest that AZA can be an attractive therapeutic option for elderly MDS or AML patients, offering adequate efficacy and high tolerability.
    Full-text · Article · Mar 2014 · Case Reports in Medicine
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