Quantitative detection of<i>IDH2</i>mutation for minimal residual disease monitoring in patients with acute myeloid leukemia and its comparison with mutations in<i>NPM1</i>gene

Ježíšková, Ivana; Rázga, Filip; Tošková, Martina; Dvořáková, Dana; Timilsina, Shira; Mayer, Jiřı́; Ráčil, Zdeněk

doi:10.3109/10428194.2012.727414

Cited by 12 publications

(10 citation statements)

References 15 publications

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“…The present study is the first to quantify IDH1/2 mutation levels in a large cohort of AML patients. Previous studies using Sanger sequencing, 23 qPCR, 24 or next-generation sequencing technology 25 suggested that the presence or the level of IDH1/2 mutations was correlated to disease status in most patients with AML, but the small number of IDH1/2 -mutated patients included in these studies precluded statistical analysis. Our study revealed that a positive IDH1/2 -VAF after induction chemotherapy was associated with a shorter disease-free survival.…”

Section: Discussionmentioning

confidence: 99%

Clinical relevance of IDH1/2 mutant allele burden during follow-up in acute myeloid leukemia. A study by the French ALFA group

Ferret¹,

Boissel

Hélevaut³

et al. 2018

Haematologica

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Assessment of minimal residual disease has emerged as a powerful prognostic factor in acute myeloid leukemia. In this study, we investigated the potential of IDH1/2 mutations as targets for minimal residual disease assessment in acute myeloid leukemia, since these mutations collectively occur in 15–20% of cases of acute myeloid leukemia and now represent druggable targets. We employed droplet digital polymerase chain reaction assays to quantify IDH1R132, IDH2R140, and IDH2R172 mutations on genomic DNA in 322 samples from 103 adult patients with primary IDH1/2 mutant acute myeloid leukemia and enrolled on Acute Leukemia French Association (ALFA) - 0701 or -0702 clinical trials. The median IDH1/2 mutant allele fraction in bone marrow samples was 42.3% (range, 8.2 – 49.9%) at diagnosis of acute myeloid leukemia, and below the detection limit of 0.2% (range, <0.2 – 39.3%) in complete remission after induction therapy. In univariate analysis, the presence of a normal karyotype, a NPM1 mutation, and an IDH1/2 mutant allele fraction <0.2% in bone marrow after induction therapy were statistically significant predictors of longer disease-free survival. In multivariate analysis, these three variables remained significantly predictive of disease-free survival. In 7/103 (7%) patients, IDH1/2 mutations persisted at high levels in complete remission, consistent with the presence of an IDH1/2 mutation in pre-leukemic hematopoietic stem cells. Five out of these seven patients subsequently relapsed or progressed toward myelodysplastic syndrome, suggesting that patients carrying the IDH1/2 mutation in a pre-leukemic clone may be at high risk of hematologic evolution.

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Section: Discussionmentioning

confidence: 99%

Clinical relevance of IDH1/2 mutant allele burden during follow-up in acute myeloid leukemia. A study by the French ALFA group

Ferret¹,

Boissel

Hélevaut³

et al. 2018

Haematologica

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“…Based upon the above-mentioned biological and clinical characteristics, especially their homogeneous mutation pattern in AML patients, NPM1 mutations may be considered an ideal leukemia-specific target for MRD detection [ 2 ]. Since the first application by Gorello et al of sensitive and specific RQ-PCR assays as a reliable system to quantitatively assess NPM1 -mutated gene copies [ 30 ], several studies have investigated the clinical implications of MRD monitoring in NPM1 -mutated AML undergoing intensive therapeutic approaches ( Table 1 ) [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ].…”

Section: Eln Recommendations For Mrd Assessmentmentioning

confidence: 99%

“…In this disappointing clinical setting, NPM1 -mutated MRD monitoring may potentially be useful for patients who obtain morphologic CR in order to define the best personalized post-remissional treatment approach and to early detect relapse [ 83 ]. However, although multiple series evaluating NPM1 -mutated MRD also enrolled some patients aged >60 years ( Table 1 ) [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 39 , 42 , 43 , 44 , 45 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 58 , 60 , 61 , 62 , 63 , 65 , 67 , 69 , 71 ], no study so far specifically focused on application and clinical significance of MRD monitoring in elderly patients with NPM1 -mutated AML. Since the most predictive timepoints and MRD thresholds appear to be highly variable even between cohorts of younger adult patients, they cannot be easily applied to elderly subjects with poor prognosis and future studies are needed to further address these underexplored issues [ 83 , 89 ].…”

Section: Mrd Assessment In Elderly Patients With Npm1 mentioning

confidence: 99%

Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives

Forghieri

Comoli

Marasca

et al. 2018

IJMS

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Acute myeloid leukemia (AML) with NPM1 gene mutations is currently recognized as a distinct entity, due to its unique biological and clinical features. We summarize here the results of published studies investigating the clinical application of minimal/measurable residual disease (MRD) in patients with NPM1-mutated AML, receiving either intensive chemotherapy or hematopoietic stem cell transplantation. Several clinical trials have so far demonstrated a significant independent prognostic impact of molecular MRD monitoring in NPM1-mutated AML and, accordingly, the Consensus Document from the European Leukemia Net MRD Working Party has recently recommended that NPM1-mutated AML patients have MRD assessment at informative clinical timepoints during treatment and follow-up. However, several controversies remain, mainly with regard to the most clinically significant timepoints and the MRD thresholds to be considered, but also with respect to the optimal source to be analyzed, namely bone marrow or peripheral blood samples, and the correlation of MRD with other known prognostic indicators. Moreover, we discuss potential advantages, as well as drawbacks, of newer molecular technologies such as digital droplet PCR and next-generation sequencing in comparison to conventional RQ-PCR to quantify NPM1-mutated MRD. In conclusion, further prospective clinical trials are warranted to standardize MRD monitoring strategies and to optimize MRD-guided therapeutic interventions in NPM1-mutated AML patients.

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“…Further enhancement of the sensitivity of our assay is possible through coupling with initial COLD-PCR amplification as already reported for IDH1 mutations detection [31], [32]. This would be of value if IDH1/2 mutational status is to be tested for detection of minimal residual disease [33]. Besides, our method is applicable not only to patients with myeloid malignancies but also to those with glial tumors or chondrosarcomas or cholangiocarcinomas as in its current format it covers all most frequent mutations.…”

Section: Discussionmentioning

confidence: 90%

Novel Multiplex Bead-Based Assay for Detection of IDH1 and IDH2 Mutations in Myeloid Malignancies

Shivarov

Ivanova²,

Hadjiev³

et al. 2013

PLoS ONE

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Isocitrate dehydrogenase 1 and 2 (IDH) mutations are frequently found in various cancer types such as gliomas, chondrosarcomas and myeloid malignancies. Their molecular detection has recently gained wide recognition in the diagnosis and prognosis of these neoplasms. For that purpose various molecular approaches have been used but a universally accepted method is still lacking. In this study we aimed to develop a novel bead-based liquid assay using Locked nucleic acids (LNA)-modified oligonucleotide probes for multiplexed detection of the most frequent IDH1 (p.R132C, p.R132G, p.R132H, p.R132L, p.R132S) and IDH2 (p.R140Q, p.R172K) mutations. The method includes four steps: 1) PCR amplification of the targeted fragments with biotinylated primers; 2) Direct hybridization to barcoded microbeads with specific LNA-modified oligonucleotide probes; 3) Incubation with phycoerythrin coupled streptavidin; 4) Acquisition of fluorescent intensities of each set of beads on a flow platform (LuminexCorp., USA). We tested the performance of the assay on both artificial plasmid constructs and on clinical samples from 114 patients with known or suspected myeloid malignancies. The method appeared to be superior to direct sequencing having a much higher sensitivity of 2.5% mutant alleles. Applying this method to patients' samples we identified a total of 9 mutations (one IDH1 p.R132C, seven IDH2 p.R140Q and one IDH2 p.R172K). In conclusion, this method could be successfully implemented in the diagnostic work-up for various tumors known to harbor IDH1/2 mutations (e.g. myeloid malignancies, gliomas, etc.). International initiatives are needed to validate the different existing methods for detection of IDH1/2 mutations in clinical settings.

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Quantitative detection ofIDH2mutation for minimal residual disease monitoring in patients with acute myeloid leukemia and its comparison with mutations inNPM1gene

Cited by 12 publications

References 15 publications

Clinical relevance of IDH1/2 mutant allele burden during follow-up in acute myeloid leukemia. A study by the French ALFA group

Clinical relevance of IDH1/2 mutant allele burden during follow-up in acute myeloid leukemia. A study by the French ALFA group

Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives

Novel Multiplex Bead-Based Assay for Detection of IDH1 and IDH2 Mutations in Myeloid Malignancies

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