Mutations in histone modulators are associated with prolonged survival during azacitidine therapy.

Tobiasson M, McLornan DP, Karimi M, Dimitriou M, Jansson M, Ben Azenkoud A, Jädersten M, Lindberg G, Abdulkadir H, Kulasekararaj A, Ungerstedt J, Lennartsson A, Ekwall K, Mufti GJ, Hellström-Lindberg E

Oncotarget 7 (16) 22103-22115 [2016-04-19; online 2016-03-10]

Early therapeutic decision-making is crucial in patients with higher-risk MDS. We evaluated the impact of clinical parameters and mutational profiles in 134 consecutive patients treated with azacitidine using a combined cohort from Karolinska University Hospital (n=89) and from King's College Hospital, London (n=45). While neither clinical parameters nor mutations had a significant impact on response rate, both karyotype and mutational profile were strongly associated with survival from the start of treatment. IPSS high-risk cytogenetics negatively impacted overall survival (median 20 vs 10 months; p<0.001), whereas mutations in histone modulators (ASXL1, EZH2) were associated with prolonged survival (22 vs 12 months, p=0.01). This positive association was present in both cohorts and remained highly significant in the multivariate cox model. Importantly, patients with mutations in histone modulators lacking high-risk cytogenetics showed a survival of 29 months compared to only 10 months in patients with the opposite pattern. While TP53 was negatively associated with survival, neither RUNX1-mutations nor the number of mutations appeared to influence survival in this cohort. We propose a model combining histone modulator mutational screening with cytogenetics in the clinical decision-making process for higher-risk MDS patients eligible for treatment with azacitidine.

NGI Stockholm (Genomics Applications) [Service]

NGI Stockholm (Genomics Production) [Service]

National Genomics Infrastructure [Service]

PubMed 26959885

DOI 10.18632/oncotarget.7899

Crossref 10.18632/oncotarget.7899

pii: 7899
pmc: PMC5008347