Landscape of TP53 Abnormalities and Their Clinical Relevance in Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia

• Published in: Blood 2018-11, Vol.132 (Supplement 1), p.2791-2791
• Main Authors: Montalban-Bravo, Guillermo, Benton, Christopher B., Kanagal-Shamanna, Rashmi, Sasaki, Koji, Assi, Rita, Kadia, Tapan M., Ravandi, Farhad, Ganan-Gomez, Irene, Cortes, Jorge E., Daver, Naval G., Takahashi, Koichi, DiNardo, Courtney D., Jabbour, Elias J., Borthakur, Gautam, Pemmaraju, Naveen, Konopleva, Marina Y., Pierce, Sherry A., Bueso-Ramos, Carlos E., Kornblau, Steven M., Patel, Keyur, Colla, Simona, Kantarjian, Hagop M., Andreeff, Michael, Garcia-Manero, Guillermo
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-99-119706

INTRODUCTION: Mutations in TP53 can be detected in up to 16-19% patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). TP53 mutations confer adverse prognosis irrespective of currently available therapies. The clinical impact of the type, clonality and number of TP53 abnormalities is unclear. Preclinical data suggests some TP53 mutations may be associated with additional transactivation activity and increased oncogenicity. METHODS: We evaluated 1401 patients with previously untreated AML or MDS treated at The University of Texas MD Anderson Cancer Center from 2012 to 2016. Sequencing data was obtained by use of a 28 or 53-gene targeted PCR-based next generation sequencing platform. The following mutations in TP53 where defined as GOF based on available in vitro data: R172H, R175H, R270H, G245S, R248W, G248Q and R273H. Response was defined following 2003 IWG criteria for patients with AML and 2006 revised IWG criteria for patients with MDS. Generalized linear models were used to study the association of overall response (OR), complete response (CR) and risk factors. Kaplan-Meier produce limit method was used to estimate the median overall survival (OS). RESULTS: A total of 593 (42%) patients had MDS and 808 (56%) had AML. In a total of 984 (70%) patients, data on therapy with sufficient follow up and response evaluation was available, with 494 (35%) patients receiving therapy with hypomethylating agents (HMAs) and 373 (27%) with chemotherapy regimens. Among evaluated MDS pts, based on the Revised-IPSS prognostic model, 62 (11%) had very-low risk, 149 (25%) had low, 121 (20%) intermediate, 109 (18%) high and 152 (26%) very-high risk. A total of 167 (28%) pts with MDS and 223 (26%) pts with AML had complex karyotype. A total of 405 mutations in TP53 were detected among 151 (26%) and 161 (20%) patients with MDS and AML, respectively. Mutations included 332 (82%) missense, 26 (6%) nonsense, 34 (8%) frameshift insertions or deletions and 13 (3%) splice-site mutations. The most prevalent mutation was R273H (MDS: n=10, AML: n=9) followed by R248W (MDS: n=8, AML: n=8), Y220C (MDS: n=7, AML: n=8) and R175H (MDS: n=7, AML: n=6). Median variant allele frequency (VAF) of TP53 mutations was 39% (range 1-94). Among patients with TP53-mutant disease: 1 TP53 mutation was identified in 105 (70%) and 126 (78%) MDS and AML pts respectively, 2 in 44 (29%) and 34 (21%) and 3 in 2 (1%) and 1 (1%) respectively. The median difference in VAF among detectabl