Mutations in the DNA Methylation Pathway and Number of Driver Mutations Predict Response to Azacitidine in Myelodysplastic Syndromes
Overview
Authors
Affiliations
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 [OR]: 0.56, 95% confidence interval [CI]: 0.33-0.94; p=0.028), and a positive association was found for having ≥1 mutation in a DNA methylation-related gene: (OR: 4.76, 95%CI: 1.31-17.27; p=0.017). Mutations in (hazard ratio [HR]: 3.88; 95%CI: 1.94-7.75) and (HR: 2.50; 95%CI: 1.23-5.09) 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: and 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 mutations, and low number of total mutations are associated with a better response to azacitidine.
Response to Azacytidine in a Patient With Refractory Peripheral T-cell Lymphoma With TET2 Mutation.
Le M, Al-Moussally F, Carilli A Cureus. 2024; 16(7):e65416.
PMID: 39184618 PMC: 11344967. DOI: 10.7759/cureus.65416.
Nannya Y, Tobiasson M, Sato S, Bernard E, Ohtake S, Takeda J Blood Adv. 2023; 7(14):3624-3636.
PMID: 36989067 PMC: 10365941. DOI: 10.1182/bloodadvances.2022009564.
Urabe A, Chi S, Minami Y Int J Mol Sci. 2023; 24(4).
PMID: 36835136 PMC: 9961620. DOI: 10.3390/ijms24043727.
Zhang X, Hsi E, Crane G, Cheng Y EJHaem. 2023; 4(1):236-240.
PMID: 36819168 PMC: 9928664. DOI: 10.1002/jha2.617.
Biallelic TET2 mutations confer sensitivity to 5'-azacitidine in acute myeloid leukemia.
Stolzel F, Fordham S, Nandana D, Lin W, Blair H, Elstob C JCI Insight. 2022; 8(2).
PMID: 36480300 PMC: 9977313. DOI: 10.1172/jci.insight.150368.