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

Abstract

Myelodysplastic 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.