Are somatic mutations predictive of response to erythropoiesis stimulating agents in lower risk myelodysplastic syndromes?

Kosmider, Olivier; Passet, Marie; Santini, Valeria; Platzbecker, Uwe; Andrieu, Valérie; Zini, Gina; Beyne‐Rauzy, Odile; Guerci, Agnès; Masala, Erico; Balleari, Enrico; Bulycheva, Ekaterina; Dreyfus, François; Fenaux, Pierre; Fontenay, Michaëla; Park, S.

doi:10.3324/haematol.2016.142695

Cited by 42 publications

(35 citation statements)

References 14 publications

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“…The inclusion of molecular markers in prognostic scores for MDS, together with other clinical and genetic data, is likely to lead to a better prediction of patient outcomes in the near future. Previous studies have assessed the role of candidate gene mutations in the context of MDS therapy, including response to erythropoietic stimulating agents [24], to hypomethylating agents [1,12,13,17,22,23,25,26], or in the bone marrow transplantation setting [27][28][29]. In the present study, no clinical characteristic was associated with overall response to azacitidine, and the same was true for any single mutated gene.…”

Section: Discussionmentioning

confidence: 39%

Mutations in DNA Methylation Pathway and Number of Driver Mutations Predict Response to Azacitidine in Myelodysplastic Syndromes

Cedena¹,

Rapado²,

Santos‐Lozano³

et al. 2017

Leukemia Research

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We evaluated the association of mutations in 34 candidate genes and response to azacitidine in 84 patients with myelodysplastic syndrome (MDS), with 217 somatic mutations identified by next-generation sequencing. Most patients (93%) had ≥1 mutation (mean=2.6/patient). The overall response rate to azacitidine was 42%. No clinical characteristic was associated with response to azacitidine. However, total number of mutations/patient was negatively associated with overall drug response (odds ratio .09) were associated with shorter overall survival. Meta-analysis of 6 studies plus present data (n=815 patients) allowed assessment of the association of drug response with mutations in 9 candidate genes: ASXL1, CBL, EZH2, SF3B1, SRSF2, TET2, DNMT3A, IDH1/2 and TP53. TET2 mutations predicted a more favorable drug response compared with 'wild-type' peers (pooled OR: 1.67, 95%CI: 1.14-2.44; p=0.01). In conclusion, mutations in the DNA methylation pathway, especially TET2 mutations, and low number of total mutations are associated with a better response to azacitidine. www.impactjournals.com/oncotarget/[

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Section: Discussionmentioning

confidence: 39%

Mutations in DNA Methylation Pathway and Number of Driver Mutations Predict Response to Azacitidine in Myelodysplastic Syndromes

Cedena¹,

Rapado²,

Santos‐Lozano³

et al. 2017

Leukemia Research

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“…13,28 During treatment with ESAs, MDS lower-risk patients did not experience an increase of thrombotic events compared with nontreated patients, 29 quite different to what was observed for other hematologic neoplasias. It is therefore not necessary to establish any antithrombotic therapy, unless in the presence of thrombophilia.…”

Section: Treatment Of Anemiamentioning

confidence: 98%

“…Recurrent individual somatic mutations (SF3B1, TET2, ASXL1, and DNMT3A) evaluated in a selected group of anemic lower-risk MDS had no impact on response to ESAs, nor had the size of the mutated clones, 28 whereas the presence of .2 mutations was confirmed to be predictive of shorter survival. 13,28 During treatment with ESAs, MDS lower-risk patients did not experience an increase of thrombotic events compared with nontreated patients, 29 quite different to what was observed for other hematologic neoplasias.…”

Section: Treatment Of Anemiamentioning

confidence: 99%

Treatment of low-risk myelodysplastic syndromes

Santini

2016

Hematology

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The majority of myelodysplastic syndrome (MDS) patients belong to the International Prognostic Scoring System (IPSS) and IPSS-revised (IPSS-R) lower-risk categories. Their precise diagnostics and prognostic stratification is often a challenge, but may ensure the optimization of therapy. The availability of diverse treatment options has significantly improved the quality of life and survival of this group of patients. Anemia is the most relevant cytopenia in terms of frequency and symptoms in lower-risk MDS, and may be treated successfully with erythropoietic stimulating agents, provided a careful selection is performed on the basis of IPSS-R, endogenous erythropoietin levels, and transfusion independence. Doses and duration of therapy of erythropoietic-stimulating agents (ESAs) are critical to determine efficacy. In case a patient fails ESA treatment, the available options may include lenalidomide (approved for del5q positive cases), hypomethylating agents, and a rather large number of experimental agents, whose clinical trials should be offered to a larger number of MDS patients. The choice for second-line treatment must take into account biologic, cytogenetic, and molecular-identified characteristics of individual patients, as well as frailty and comorbidities. Other cytopenias are less frequently presenting as isolated. Specific therapy for thrombocytopenia has been proposed in experimental clinical trials with thrombomimetic agents that have shown good efficacy, but raised some safety concern. Although neutropenia is targeted symptomatically with growth factor supportive care, the immunosuppressive treatments are indicated mainly for pancytopenic, hypoplastic lower-risk MDS; they are not widely used because of their toxicity, despite the fact that they may induce responses. Finally, hematopoietic stem cell transplant is the curative option also for lower-risk MDS and timing should be carefully evaluated, balancing toxicity and the possibility of survival advantage. Finally, even when considered suitable for lower-risk MDS, transplant application is limited to the rarer fit and younger MDS patient.

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“…Early initiation of treatment is associated with higher response rates and longer duration of response. Response rates of up to 64.5% have been described in patients with no or a low transfusion burden, serum EPO levels below 500 IU L −1 and those receiving high doses of EPO . An NGS study of 79 lower‐risk MDS patients treated with EPO showed 74% erythroid haematological improvement (HI‐E) in 51 patients with ≤2 mutations versus 46% in 28 patients with >2 mutations ( P = 0.01) .…”

Section: Treatment Of Lower‐risk Mdsmentioning

confidence: 99%