Efficacy of azacitidine is independent of molecular and clinical characteristics - an analysis of 128 patients with myelodysplastic syndromes or acute myeloid leukemia and a review of the literature

Abstract

Azacitidine is the first drug to demonstrate a survival benefit for patients with MDS. However, only half of patients respond and almost all patients eventually relapse. Limited and conflicting data are available on predictive factors influencing response. We analyzed 128 patients from two institutions with MDS or AML treated with azacitidine to identify prognostic indicators. Genetic mutations in ASXL1, RUNX1, DNMT3A, IDH1, IDH2, TET2, TP53, NRAS, KRAS, FLT3, KMT2A-PTD, EZH2, SF3B1, and SRSF2 were assessed by next-generation sequencing.With a median follow up of 5.6 years median survival was 1.3 years with a response rate of 49%. The only variable with significant influence on response was del(20q). All 6 patients responded (p = 0.012) but survival was not improved. No other clinical, cytogenetic or molecular marker for response or survival was identified. Interestingly, patients from poor-risk groups as high-risk cytogenetics (55%), t-MDS/AML (54%), TP53 mutated (48%) or relapsed after chemotherapy (60%) showed a high response rate. Factors associated with shorter survival were low platelets, AML vs. MDS, therapy-related disease, TP53 and KMT2A-PTD. In multivariate analysis anemia, platelets, FLT3-ITD, and therapy-related disease remained in the model. Poor-risk factors such as del(7q)/-7, complex karyotype, ASXL1, RUNX1, EZH2, and TP53 did not show an independent impact. Thus, no clear biomarker for response and survival can be identified. Although a number of publications on predictive markers for response to AZA exist, results are inconsistent and improved response rates did not translate to improved survival. Here, we provide a comprehensive overview comparing the studies published to date.

The evolving role of next generation sequencing in myelodysplastic syndromes

“…At present, there is not enough data to support that mutation status can predict response to DNMTIs. While some studies found correlations between TET2 mutations and improved response and DNMT3A mutations and poor response, further studies have not supported these associations (Traina et al , ; Bejar & Steensma, ; Jung et al , ; Kuendgen et al , ) . Somatic mutation status may, however, predict duration of response to therapy.…”

“…Mutations in SF3B1 are present in approximately 20% of MDS cases. There are well‐established associations between SF3B1 mutations and MDS subtypes: MDS with ring sideroblasts and single or multi‐lineage dysplasia (MDS‐RS‐SLD, MDS‐RS‐MLD, respectively; Malcovati et al , ) and the related MDS/myeloproliferative neoplasm (MPN) overlap disease, MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN‐RS‐T)(Savona et al , ; Kuendgen et al , ). SF3B1 mutations are commonly found in the presence of MDS with ring sideroblasts and overlap considerably with del 5q (Papaemmanuil et al , ; Yoshida et al , ; Visconte et al , ; Malcovati et al , ).…”

Anthracycline-related cardiotoxicity in older patients with acute myeloid leukemia: a Young SIOG review paper

“…101 Furthermore, certain high-risk subgroups may benefit from HMA such as those with TP53 mutations, or complex karyotypes. [102][103][104] A head-to-head comparison between decitabine and "317" as the preferred induction strategy for older patients is currently being tested in the InDACtion trial. 105 The BCL-2 inhibitor venetoclax in combination with HMA 106 or low-dose cytarabine 107 has shown promising results.…”

Logic of Epigenetics and Investigation of Potential Gene Regions

“…In this regard, such diseases have emerged in new therapeutic targets. Chemical agents such as 5-azacytidine and 5-aza-2′-deoxycytidine, which inhibit methylation by binding to and inhibiting DNMT enzyme, are now being tested in phase II-III studies [35][36][37][38]. Furthermore, use of oligonucleotides that bind to promoter regions at specific gene level and perform gene inhibition is seen as approaches that may contribute to cancer treatments [39][40][41].…”