Imapct of Clonal Hematopoiesis of Indeterminate Potential (CHIP) Associated Mutations and Risk of Comorbidities in Patients with Myelodysplastic Syndrome

Abstract Introduction: Comorbidities have a significant impact on the prognosis and survival of patients with myelodysplastic syndrome (MDS) (Naqvi et al, JCO. 2011). Recent studies have indicated the role of clonal hematopoiesis of indeterminate potential (CHIP) - associated mutations (TET2, ASXL1, DNMT3A and JAK2) and atherosclerotic cardiovascular disease (Ebert et al. NEJM. 2017). The objective of this study was to evaluate the association of these CHIP - associated mutations as well as TP53 mutations and comorbidities in patients with MDS. Methods: We conducted a retrospective study of 566 consecutive patients with MDS who presented to MD Anderson Cancer Center from August 2013 to December 2016. The Adult Comorbidity Evaluation-27 (ACE-27) scale, a validated 27-item comorbidity index for cancer patients was used to assess the severity of comorbid conditions. We used next-generation sequencing to detect the presence of CHIP mutations in the bone marrow samples. Data on demographics, international prognostic scoring system (IPSS) were collected. Wilcoxon's rank-sum test and chi-squared test were used to determine the association between genes and comorbidities. Results: Of the 566 patients included in this study, 66% were male, and 82% white; median age at presentation was 69 years (range: 22-93). A total of 350 (62%) patients had an IPSS of Intermediate-1 and low; complex karyotype was noted in 128 (23%) patients. The ACE-27 comorbidity scores were as follows: none, 101 (18%); mild, 214 (38%); moderate, 146 (26%); and severe, 105 (19%). Mutations in DNMT3A, ASXL1, TET2, JAK2 and TP53 were noted in 9%, 18%, 20%, 2% and 21% patients respectively. One hundred and seventy (30%) patients had no mutations. With respect to the cardiovascular system, patients harboring DNMT3A were noted to have a higher incidence of myocardial infarction than those without DNMT3A mutation (14% vs 6%; p= 0.03). As expected, patients with a JAK2 mutation had higher number of venous thromboembolic events (18% vs 4%; p= 0.013). TET2, ASXL1 and TP53 mutationshowever were not associated with increased cardiovascular events in our patients. TP53 mutations were highly associated with history of prior malignancy: solid tumors, 44% vs 21%; p= Conclusion: CHIP associated mutations namely DNMT3A was noted to be associated with higher number of cardiovascular events. Contrary to what is previously reported, we didn't find this association with TET2. TP53 mutations were highly prevalent in patients with therapy related MDS. Further work is ongoing studying the variant allele frequency of these mutations and impact on comorbidities. Disclosures Jabbour: Bristol-Myers Squibb: Consultancy. Daver: Karyopharm: Consultancy, Research Funding; Pfizer Inc.: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Incyte Corporation: Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Immunogen: Research Funding; Jazz: Consultancy; Kiromic: Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding. DiNardo: Daiichi-Sankyo: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Takahashi: Symbio Pharmaceuticals: Consultancy. Jain: Abbvie: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pemmaraju: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Cellectis: Research Funding; Stemline: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria, Research Funding. Kantarjian: Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Delta-Fly Pharma: Research Funding.