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

Mutations in Histone Modulators Are Associated With Prolonged Survival During Azacitidine Therapy

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Free PMC article

Mutations in Histone Modulators Are Associated With Prolonged Survival During Azacitidine Therapy

Magnus Tobiasson et al. Oncotarget. .
Free PMC article

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.

Conflict of interest statement

CONFLICTS OF INTERESTGhulam Mufti: has received research funding from Celgene and been part of their advisory board.Eva Hellström-Lindberg: has received research grant from Celgene for the national MDS registry.Martin Jädersten: has recieved honoraria for lectures for Celgene.Austin Kulasekararaj: has recieved honoraria for advisory board and lectures for Celgene.

Figures

Figure 1
Figure 1. Survival curves using Kaplan-Meier estimation
Figure 2
Figure 2. Forest plot indicating hazard ratio including confidence interval for all pre-treatment variables
The hazard ratios were retrieved using cox univariate regression models for each variable analyzed separately. Abbreviations: IPSS International prognostic score system, ANC absolute neutrophil count, HR hazard ratio, CI confidence interval.
Figure 3
Figure 3. Kaplan-Meier estimated survival stratified for the two dominant predictors in the cox regression model: Adverse cytogenetics and histone modulator mutations
Abbreviations: HM histone modulator mutation.

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References

    1. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20:2429–40. - PubMed
    1. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223–32. - PMC - PubMed
    1. Grovdal M, Karimi M, Tobiasson M, Reinius L, Jansson M, Ekwall K, Ungerstedt J, Kere J, Greco D, Hellstrom-Lindberg E. Azacitidine induces profound genome-wide hypomethylation in primary myelodysplastic bone marrow cultures but may also reduce histone acetylation. Leukemia. 2014;28:411–3. - PubMed
    1. Shen L, Kantarjian H, Guo Y, Lin E, Shan J, Huang X, Berry D, Ahmed S, Zhu W, Pierce S, Kondo Y, Oki Y, Jelinek J, et al. DNA Methylation Predicts Survival and Response to Therapy in Patients With Myelodysplastic Syndromes. 2010 2010-02-01. - PMC - PubMed
    1. Sohlberg E, Pfefferle A, Andersson S, Baumann BC, Hellstrom-Lindberg E, Malmberg KJ. Imprint of 5-azacytidine on the natural killer cell repertoire during systemic treatment for high-risk myelodysplastic syndrome. Oncotarget. 2015;6:34178–90. doi: 10.18632/oncotarget.6213. - DOI - PMC - PubMed

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