Mutations in histone modulators are associated with prolonged survival during azacitidine therapy
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Magnus Tobiasson1, Donal P. McLornan2,3, Mohsen Karimi1, Marios Dimitriou1, Monika Jansson1, Asmaa Ben Azenkoud1, Martin Jädersten1, Greger Lindberg4, Hani Abdulkadir1, Austin Kulasekararaj2,3, Johanna Ungerstedt1, Andreas Lennartsson5, Karl Ekwall5, Ghulam J. Mufti2,3, Eva Hellström-Lindberg1
1Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden
2Department of Haematological Medicine, King’s College Hospital NHS Foundation Trust, London, United Kingdom
3Department of Haematological Medicine, King’s College, London, United Kingdom
4Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden
5Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
Magnus Tobiasson, e-mail: [email protected]
Eva Hellström-Lindberg, e-mail: [email protected]
Keywords: myelodysplastic syndrome, azacitidine, hypomethylating therapy, next-generation sequencing, molecular marker
Received: December 13, 2015 Accepted: February 21, 2016 Published: March 3, 2016
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.
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