Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms

Traina, Fabı́ola; Visconte, Valeria; Elson, Paul; Tabarroki, Ali; Jankowska, Ania; Hasrouni, Edy; Sugimoto, Yuka; Szpurka, Hadrian; Makishima, Hideki; O’Keefe, Christine L.; Sekeres, Mikkael A.; Advani, Anjali S.; Kalaycio, Matt; Copelan, Edward A.; Saunthararajah, Yogen; Saad, Sara Teresinha Olalla; Maciejewski, Jaroslaw P.; Tiu, Ramon V.

doi:10.1038/leu.2013.269

Cited by 278 publications

(255 citation statements)

References 37 publications

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“…Mutations in the TET2, DNMT3A, TP53 genes were reported to be associated with a high probability of response to HMA [13,14,15]. At the same time, mutations in the EZH2 and TP53 genes are associated with a lower level of overall survival [11,13]. However these findings are not confirmed in the other studies [11,15].…”

Section: Discussioncontrasting

confidence: 55%

“…From the available data, it is known that the presence of a number of somatic mutations can affect the response rates to therapy and the level of overall survival [12]. Mutations in the TET2, DNMT3A, TP53 genes were reported to be associated with a high probability of response to HMA [13,14,15]. At the same time, mutations in the EZH2 and TP53 genes are associated with a lower level of overall survival [11,13].…”

Section: Discussionmentioning

confidence: 99%

“…In this study we summarized the results of 12 studies with whole exome/genome sequencing in MDS [10,11,[13][14][15][16][17][18][19][20][21][22].…”

Section: Discussionmentioning

confidence: 99%

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Meta-analysis of studies with genome sequencing in myelodysplastic syndrome treated with hypomethylating agents

Tsvetkov¹,

Epifanovskaya²,

Rudnitskaya³

et al. 2018

CTT

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SummaryMyelodysplastic syndrome represents a heterogenous group of clonal diseases affecting the hematopoietic stem cells underlied by different somatic gene mutations and/or altered epigenetic regulation induced by the disturbed microenvironment, as well as changes in the immune surveillance system. In many patients, the MDS is preceded by a period of non-clonal or clonal cytopenias of a non-clear significance that are determined by age-associated somatic mutations and increased leukemia risks resulting into a higher cellular proliferation, inefficient clonal growth, suppression of normal hematopoiesis, and, finally, into altered differentiation, thus causing accumulation of blast forms and a risk of evolving into acute leukemia. Substantial data on prevalence and impact of mutations on the prognosis in myelodysplastic syndrome was accessed by multiple groups however the results of several published studies are controversial. Thus we have performed an unconventional meta-analysis by accessing resulting confidence intervals both by statistical means and by creating pulled database with available individual patient data. 12 studies with 1238 patients were analyzed. The observed prevalence of mutations was the subject to significant variability (95%CI: ASXL1 13.6-29.8%; DNMT3A 7.3-12.9%; EZH2 2.4-7.0%; U2AF1 3.7-13.8%; TET2 14.2-32.5%; RUNX1 3.9-13.7%; TP53 4.7-15.2%; SRSF2 7.1-28.1%; RAS 2.2-15,1%; SF3B1 4.4-12.2%; CBL 0.1-8.9%; None, 8.0-23.3%; р<0.0001). The analysis of response to hypomethylating agents revealed improved response in patients with TP53 (95% CI 49-55%, p=0.0003), TET2(95% CI 49-52%, p=0.0001) and SRSF2 (95% CI 48-54%, p=0.0005) mutations; however the survival was worse in TP53 mutated patients (95% CI 44-49%, p=0.002) and better in SF3B1 mutated disease (95% CI 47-54%, p=0.01). The magnitude of difference was less than previously reported. The study confirmed the previous reports on the impact of TP53, TET2 and SF3B1 mutations on prognosis. Further studies on the potential prognostic markers are required, especially in patients with absence of conventional mutations.

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Section: Discussioncontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

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Meta-analysis of studies with genome sequencing in myelodysplastic syndrome treated with hypomethylating agents

Tsvetkov¹,

Epifanovskaya²,

Rudnitskaya³

et al. 2018

CTT

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“…There are conflicting reports on whether TET2 mutations results in DNA hypermethylation [53,54]. Nevertheless, TET2 mutations have been shown to predict response to DNMT inhibitor therapy in MDS [55,56]. The presence of an IDH1/2 mutation results in the production of 2-hydroxyglutarate that is structurally similar to a-ketoglutarate, and therefore, provides competitive inhibition to a-ketoglutarate-dependent enzymatic processes.…”

Section: Genetics (Cytogenetics Molecular Genetics and Epigenetics)mentioning

confidence: 99%

Myelodysplastic syndromes: Contemporary review and how we treat

2015

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Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for leukemic transformation. Diagnosis is currently based on the presence of peripheral blood cytopenias, peripheral blood and bone marrow dysplasia/blasts, and clonal cytogenetic abnormalities. With the advent of next generation sequencing, recurrent somatic mutations in genes involved in epigenetic regulation (TET2, ASXL1, EZH2, DNMT3A, IDH1/2), RNA splicing (SF3B1, SRSF2, U2AF1, ZRSR2), DNA damage response (TP53), transcriptional regulation (RUNX1, BCOR, ETV6) and signal transduction (CBL, NRAS, JAK2) have been identified in MDS. Conventional prognostication is by the revised International prognostic scoring system (IPSS-R) with additional adverse prognosis conferred by presence of ASXL1, EZH2, or TP53 mutations. Currently Food and Drug administration (FDA)-approved drugs for the treatment of MDS are not curative and their effect on survival is limited; they include the hypomethylating agents (HMA) azacitidine and decitabine and lenalidomide for MDS with isolated del(5q). To date, allogeneic stem cell transplant (ASCT) remains the only treatment option for possible cure. Given the current lack of drugs with convincing evidence of favorable effect on survival, we consider ASCT as the treatment of choice for most patients with symptomatic disease, and especially for those with high-risk disease. For nontransplant candidates, participation in clinical trials is preferred over conventional therapy. There is not one right way of treatment for patients who are not candidates for either ASCT or clinical trials and palliative drugs of choice depend on the clinical problem, such as symptomatic anemia (ESAs, danazol, HMA), thrombocytopenia (HMA), or neutropenia (myeloid growth factors). Conversely, there is no controlled evidence to support the use of iron chelating agents in MDS. Going forward, we believe it is time to incorporate mutation information in clinically derived prognostic models in MDS and encourage development of novel drugs with disease-modifying activity.

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“…Similar to the ara-C resistant cell line THP-1 (Ge et al, 2004), the AML cells had relatively high IC50 for this drug. Finally, decitabine is approved for treatment of high-risk MDS (Im et al, 2014) and may improve the complete remission rates in AML (Metzeler et al, 2012) and MDS patients (Traina et al, 2014) with DNMT3A mutations.…”

Section: Discussionmentioning

confidence: 99%

Genomic profiling and directed ex vivo drug analysis of an unclassifiable myelodysplastic/myeloproliferative neoplasm progressing into acute myeloid leukemia

Hyrenius-Wittsten

Sturesson

Bidgoli

et al. 2016

Genes Chromosomes & Cancer

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Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN‐U) are rare genetically heterogeneous hematologic diseases associated with older age and a poor prognosis. If the disease progresses into acute myeloid leukemia (AML), it is often refractory to treatment. To gain insight into genetic alterations associated with disease progression, whole exome sequencing and single nucleotide polymorphism arrays were used to characterize the bone marrow and blood samples from a 39‐year‐old woman at MDS/MPN‐U diagnosis and at AML progression, in which routine genetic diagnostics had not identified any genetic alterations. The data revealed the presence of a partial tandem duplication of the MLL gene as the only detectable copy number change and 11 non‐silent somatic mutations, including DNMT3A R882H and NRAS G13D. All somatic lesions were present both at initial MDS/MPN‐U diagnosis and at AML presentation at similar mutant allele frequencies. The patient has since had two extramedullary relapses and is at high risk of a future bone marrow relapse. A directed ex vivo drug sensitivity analysis showed that the patient's AML cells are sensitive to, for example, the MEK inhibitor trametinib and the proteasome inhibitor bortezomib, indicating that she may benefit from treatment with these drugs. © 2016 Wiley Periodicals, Inc.

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Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms

Cited by 278 publications

References 37 publications

Meta-analysis of studies with genome sequencing in myelodysplastic syndrome treated with hypomethylating agents

Meta-analysis of studies with genome sequencing in myelodysplastic syndrome treated with hypomethylating agents

Myelodysplastic syndromes: Contemporary review and how we treat

Genomic profiling and directed ex vivo drug analysis of an unclassifiable myelodysplastic/myeloproliferative neoplasm progressing into acute myeloid leukemia

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