Molecular Minimal Residual Disease in Acute Myeloid Leukemia

Jongen‐Lavrencic, Mojca; Grob, Tim; Hanekamp, Diana; Kavelaars, François G.; Hinai, Adil Al; Zeilemaker, Annelieke; Erpelinck-Verschueren, Claudia; Gradowska, Patrycja; Meijer, Rosa; Cloos, Jacqueline; Biemond, Bart J.; Graux, Carlos; Kooy, Marinus van Marwijk; Manz, Markus G.; Pabst, Thomas; Passweg, Jakob; Havelange, Violaine; Ossenkoppele, Gert J.; Sanders, Mathijs A.; Schuurhuis, Gerrit Jan; Löwenberg, Bob; Valk, Peter J.M.

doi:10.1056/nejmoa1716863

Cited by 609 publications

(634 citation statements)

References 30 publications

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“…20,21 However, DNMT3A, TET2, and ASXL1 mutations tend to persist in patients at CR after conventional intensive therapy. To the best of our knowledge, the impact of VAF for ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations has not been evaluated extensively previously.…”

Section: Discussionmentioning

confidence: 99%

Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia

Sasaki

Kanagal‐Shamanna

Montalban‐Bravo

et al. 2019

Cancer

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BACKGROUND:The impact of the allelic burden of ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations on survival remains unclear in patients with newly diagnosed acute myeloid leukemia (AML). METHODS: The authors assessed bone marrow aspirates from 421 patients with newly diagnosed AML using next-generation sequencing for ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations, defined as the presence of mutations in ASXL1, DNMT3A, JAK2, TET2, or TP53 with a minimum variant allele frequency (VAF) of 5%. RESULTS: A total of 71 patients (17%) had ASXL1 mutations, 104 patients (25%) had DNMT3A mutations, 16 patients (4%) had JAK2 mutations, 82 patients (20%) had TET2 mutations, and 86 patients (20%) had TP53 mutations. Among patients with each mutation, the median VAF of ASXL1 was 34.31% (range, 1.17%-58.62%), the median VAF of DNMT3A was 41.76% (range, 1.02%-91.66%), the median VAF of JAK2 was 46.70% (range, 10.4%-71.7%), the median VAF of TET2 was 42.78% (range, 2.26%-95.32%), and the median VAF of TP53 was 45.47% (range, 1.15%-93.74%). The composite complete response rate was 60%, and was 77% in patients with AML with and without ASXL1, DNMT3A, JAK2, TET2, or TP53 mutations, respectively (P = .006); the median overall survival was 11 months and 27 months, respectively (P < .001). Multivariate analysis identified age; an antecedent history of dysplasia; white blood cell count; adverse cytogenetic risk; previous treatment with an FLT3 inhibitor; and the VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations by next-generation sequencing as prognostic factors for overall survival. CONCLUSIONS: The VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations is associated with worse prognosis in patients with newly diagnosed AML. Cancer 2020;126:765-774.

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Section: Discussionmentioning

confidence: 99%

Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia

Sasaki

Kanagal‐Shamanna

Montalban‐Bravo

et al. 2019

Cancer

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“…Jongen-Lavrenic et al 42 studied a broader array of residual mutations in patients with AML in morphological remission via targeted NGS. In this study, while mutations isolated to the so-called ‘DTA’ genes (ie, D NMT3A , T ET2 and A SXL1 , which are relatively frequent in elderly individuals with CHIP) appeared to confer no obvious adverse outcomes upon follow-up, non-DTA mutations (which are found in biologically more advanced clones, eg, see figure 2) were associated with significantly higher rates of relapse and shorter survival.…”

Section: Ch In Other Contextsmentioning

confidence: 99%

Emerging patterns in clonal haematopoiesis

et al. 2019

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Clonal haematopoiesis (CH) is defined by the presence of acquired mutations and/or cytogenetic abnormalities in haematopoietic cells. By definition, these premalignant clones do not meet criteria for haematopoietic neoplasms listed in the Revised Fourth Edition of the WHO classification. CH is fairly common in elderly individuals and is associated with higher risks for haematological cancers, in particular myelodysplastic syndrome and acute myeloid leukaemia (AML), as well as cardiovascular events. Similar small clones have also been detected during follow-up in patients with AML in morphological remission, in individuals with aplastic anaemia, and in pre-chemotherapy blood samples from patients with other types of cancers. In each of these contexts, the presence of mutations carries different clinical implications, and sometimes demonstrates unique genetic profiles. Emerging research suggests that the number and identity of mutations, the size of the mutant clones and various other factors, including age, immune status and history of exogenous drugs/toxins, are important for disease biology and progression. This review focuses specifically on the subset of CH with gene mutations detected by sequencing, and includes discussions of nomenclature and molecular technologies that detect and quantify gene mutations.

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“…The Dutch group recently presented data showing that next generation sequencing (NGS) using a 54 gene panel could detect mutations in about 90% of AML cases, and that in about half of these, mutations persisted once patients entered CR at allelic frequencies ranging from 0.02% to 47% [4]. Persistent DNMT3A, TET2 or ASXL1 mutations were of no significance, but persistence of all other mutations was associated with an increased risk of disease recurrence.…”

Section: Impact Of Mrd By Disease Categorymentioning

confidence: 99%

“…Rates of relapse among 340 patients with AML based on persistence of MRD as detected by NGS and/or MFC [4]. …”

Section: Figurementioning

confidence: 99%

“…Both have individual strengths, and both have added to our prognostic prowess, but the variety of assays used has added to the difficulty of reaching firm recommendations about application to therapeutic decision making. Further complexity comes from recent studies demonstrating that next generation sequencing (NGS)-based assays provide yet additional prognostic information [4]. In addition to the assay employed, both the level of MRD and the kinetics of its rise, fall, or persistence are of prognostic importance.…”

Section: Introductionmentioning

confidence: 99%

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Hematopoietic cell transplantation as treatment of patients with acute myeloid leukemia with measurable residual disease after consolidation therapy

Appelbaum

2018

Best Practice & Research Clinical Haematology

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The persistence of measurable residual disease (MRD) following induction chemotherapy is the single most powerful prognostic factor available to clinicians treating patients with acute myeloid leukemia (AML). How to use this information to guide subsequent therapy is complex, and influenced by the category of AML being treated, the assays used to measure MRD, MRD levels and kinetics, and the spectrum of therapies available to the patient. In this literature-based review, each of these issues will be discussed, with a particular emphasis on the role of hematopoietic cell transplantation in the treatment of MRD-positive patients.

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Molecular Minimal Residual Disease in Acute Myeloid Leukemia

Cited by 609 publications

References 30 publications

Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia

Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia

Emerging patterns in clonal haematopoiesis

Hematopoietic cell transplantation as treatment of patients with acute myeloid leukemia with measurable residual disease after consolidation therapy

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