Mutational and Clonal Landscape of Acute Myeloid Leukemia with Myelodysplastic Related Changes
Authors: Montalban Bravo Guillermo , Kanagal-Shamanna Rashmi , Benton Christopher B. , Colla Simona , Ganan-Gomez Irene , Sasaki Koji , Ravandi Farhad , Kadia Tapan M. , Cortes Jorge E. , Daver Naval G. , Takahashi Koichi , DiNardo Courtney D. , Jabbour Elias J. , Borthakur Gautam , Naqvi Kiran , Konopleva Marina Y. , Pierce Sherry A. , Bueso-Ramos Carlos E. , Patel Keyur , Kantarjian Hagop M. , Garcia-Manero Guillermo 
Published: October 2019

Abstract
INTRODUCTION: Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is a subtype of AML within the WHO classification system defined by morphologic, cytogenetic and clinical features. Although cytogenetic abnormalities define this group, there is little knowledge on the mutational landscape and clonal architecture of this heterogeneous group of leukemias.
METHODS: We evaluated all patients (pts) with AML-MRC diagnosed and treated at The University of Texas MD Anderson Cancer Center from April 2017 to May 2018. All patients underwent conventional metaphase karyotyping. Somatic mutation analysis was done by use of an 81-gene targeted amplicon-based next generation sequencing (NGS) platform using whole bone marrow mononuclear cells. Previously described somatic mutations registered at the Catalogue of Somatic Mutations in Cancer (COSMIC) and other databases, as well as literature were considered as potential drivers. Variant allele frequency (VAF) estimates were used to evaluate clonal variant relationships. In mutations with likely loss of heterozygosity (VAF >60%), VAFs were adjusted according to zygosity. Clonal relationships were tested using Pearson goodness-of-fit tests with heterogeneity being defined in pts with goodness-of-fit p values <0.05. Mutations with significantly higher VAF in pts with p<0.05 where defined as dominant and those with significantly lower VAF as minor.
RESULTS: A total of 95 pts with AML-MRC were included. Median age at diagnosis was 70 years (range 28-84). Diagnosis of AML-MRC was based on MDS-defining cytogenetic abnormalities in 30 (32%) patients, presence of >50% dysplasia in at least 2 lineages in 21 (22%) pts and due to history of prior myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN) in 44 (46%) pts. Among pts with a prior history of MDS or MDS/MPN, 23 (52%) had received therapy with hypomethylating agents, 1 (2%) with lenalidomide and 3 (7%) with ruxolitinib. Median bone marrow blast percentage on aspirate was 33% (range 1-94%). A total of 55 (58%) pts had complex karyotype, with 19 (20%) having monosomy 5 or del(5q), 14 (15%) having monosomy 7 or del(7q) and 18 (19%) having both. A total of 260 mutations were identified among 90 pts. The most frequently mutated gene was TP53, present in 43% of pts, followed by ASXL1, NRAS, DNMT3A, SRSF2, TET2 and U2AF1, all present in >10% pts (Figure A). The median number of detectable mutations was 2 (range 0-8) with 21 (22%) pts having 1 mutation, 28 (30%) 2, 15 (16%) 3, 9 (10%) 4, 7 (7%) 5, 6 (6%) 6, 1 (1%) 7 and 3 (3%) 8 mutations. Mutations in TP53 were more commonly observed in pts in whom the diagnosis of AML-MRC was due to cytogenetic abnormalities (p=0.001). In addition, mutations in RUNX1 were more commonly observed in pts with a known prior history of MDS (p=0.038). Mutations in ASXL1 were significantly associated with NRAS (r=0.338, p=0.01), SETBP1 (r=0.471, p<0.001), STAG2 (r=0.54, p<0.001) and SRSF2 (r=0.337, p=0.001) mutations. A significant association was found between STAG2 and U2AF1 mutations (r=0.438, p<0.001). Variant allele frequencies of identified mutations in genes found to be mutated in at least 4 pts are shown in Figure B. Clonal relationships were studied among pts with 2 or more detectable mutations (n=69). Among these, 44 pts (64%) were found to have clonal heterogeneity with presence of multiple clones. Clonal dominance of identified mutations is shown in Figure C. Mutations in ASXL1, BCOR, IDH1, SF3B1, SRSF2, TP53 and U2AF1 tended to appear in dominant clones while mutations In IKZF1, JAK2, KRAS, NRAS and PTPN11 were more commonly observed within minor clones.
CONCLUSION: AML-MRC is a heterogeneous sub-type of AML with diverse mutational abnormalities. Further characterization of molecular abnormalities and their clonal context may define distinct subgroups within this WHO entity.
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Disclosures
Colla: Abbvie: Research Funding. Sasaki:Otsuka Pharmaceutical: Honoraria. Ravandi:Amgen: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Orsenix: Honoraria; Abbvie: Research Funding; Sunesis: Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Sunesis: Honoraria; Macrogenix: Honoraria, Research Funding; Jazz: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding. Kadia:Novartis: Consultancy; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy; Abbvie: Consultancy; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; BMS: Research Funding; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Novartis: Consultancy; Takeda: Consultancy; Celgene: Research Funding. Cortes:novartis: Research Funding. Daver:Kiromic: Research Funding; Pfizer: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Daiichi-Sankyo: Research Funding; ImmunoGen: Consultancy; Incyte: Consultancy; ARIAD: Research Funding; Alexion: Consultancy; Novartis: Research Funding; Sunesis: Consultancy; Karyopharm: Research Funding; Otsuka: Consultancy; Sunesis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. DiNardo:Medimmune: Honoraria; Abbvie: Honoraria; Karyopharm: Honoraria; Agios: Consultancy; Celgene: Honoraria; Bayer: Honoraria. Jabbour:novartis: Research Funding. Konopleva:Stemline Therapeutics: Research Funding; cellectis: Research Funding; Immunogen: Research Funding; abbvie: Research Funding.