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

// Magnus Tobiasson 1 , Donal P. McLornan 2, 3 , Mohsen Karimi 1 , Marios Dimitriou 1 , Monika Jansson 1 , Asmaa Ben Azenkoud 1 , Martin Jadersten 1 , Greger Lindberg 4 , Hani Abdulkadir 1 , Austin Kulasekararaj 2, 3 , Johanna Ungerstedt 1 , Andreas Lennartsson 5 , Karl Ekwall 5 , Ghulam J. Mufti 2, 3 , Eva Hellstrom-Lindberg 1 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 Correspondence to: Magnus Tobiasson, e-mail: magnus.tobiasson@ki.se Eva Hellstrom-Lindberg, e-mail: eva.hellstrom-lindberg@ki.se Keywords: myelodysplastic syndrome, azacitidine, hypomethylating therapy, next-generation sequencing, molecular marker Received: December 13, 2015      Accepted: February 21, 2016      Published: March 3, 2016 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.