title: Mutations in histone modulators are associated with prolonged survival during azacitidine therapy.
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.
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Tobiasson
authors.affiliation: Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom.|Department of Haematological Medicine, King's College, London, United Kingdom.
authors.forename: Donal P
authors.initials: DP
authors.lastname: McLornan
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Karimi
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
authors.forename: Marios
authors.initials: M
authors.lastname: Dimitriou
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
authors.forename: Monika
authors.initials: M
authors.lastname: Jansson
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
authors.forename: Asmaa
authors.initials: A
authors.lastname: Ben Azenkoud
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Jädersten
authors.affiliation: Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
authors.forename: Greger
authors.initials: G
authors.lastname: Lindberg
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
authors.forename: Hani
authors.initials: H
authors.lastname: Abdulkadir
authors.affiliation: Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom.|Department of Haematological Medicine, King's College, London, United Kingdom.
authors.forename: Austin
authors.initials: A
authors.lastname: Kulasekararaj
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ungerstedt
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lennartsson
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Ekwall
authors.affiliation: Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom.|Department of Haematological Medicine, King's College, London, United Kingdom.
authors.forename: Ghulam J
authors.initials: GJ
authors.lastname: Mufti
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Hellström-Lindberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D001374:Azacitidine / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis*; D004252:DNA Mutational Analysis; D005260:Female; D006657:Histones / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D006657:Histones; D001374:Azacitidine
keywords: azacitidine; hypomethylating therapy; molecular marker; myelodysplastic syndrome; next-generation sequencing