Format

Send to

Choose Destination
Oncotarget. 2016 Apr 19;7(16):22103-15. doi: 10.18632/oncotarget.7899.

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

Author information

1
Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
2
Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom.
3
Department of Haematological Medicine, King's College, London, United Kingdom.
4
Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
5
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.

Abstract

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.

KEYWORDS:

azacitidine; hypomethylating therapy; molecular marker; myelodysplastic syndrome; next-generation sequencing

PMID:
26959885
PMCID:
PMC5008347
DOI:
10.18632/oncotarget.7899
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center