Association of weight loss with risk of myelodysplastic syndromes (MDS) in adults with obesity: Insights from the SPLENDID cohort.

person Rahul Mishra Department of Hematology and Medical Oncology, Taussig cancer institute, Cleveland Clinic, Cleveland, OH info_outline Rahul Mishra, Rickesha Wilson, Chao Tu, Alex Milinovich, Hetty E Carraway, Jame Abraham, Ali Aminian, Abhay Singh

Authors person Rahul Mishra Department of Hematology and Medical Oncology, Taussig cancer institute, Cleveland Clinic, Cleveland, OH info_outline Rahul Mishra, Rickesha Wilson, Chao Tu, Alex Milinovich, Hetty E Carraway, Jame Abraham, Ali Aminian, Abhay Singh Organizations Department of Hematology and Medical Oncology, Taussig cancer institute, Cleveland Clinic, Cleveland, OH, Bariatric and Metabolic Institute, Department of General Surgery, Cleveland Clinic, Cleveland, OH, Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH Abstract Disclosures Research Funding No funding received None. Background: MDS arises from pre-existing somatic mutations or clonal hematopoiesis (CH). A normal body mass index (BMI) is strongly associated with a lower prevalence of CH. We hypothesized that intentional weight loss (IWL) might be associated with lower incidence of MDS and studied this in the context of bariatric surgery (BSx) among adults with obesity. Methods: In the SPLENDID (Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death) matched cohort study, adults with BMI ≥35Kg/m 2 who had BSx (ages 18-80) during 2004-2017 were included. Each patient (pt) who underwent BSx was matched with propensity score by the nearest-neighbor method to five pts who did not undergo BSx for their obesity, resulting in a total of 30318 pts. MDS diagnosis was made using contemporary WHO criteria and myeloid sequencing mutation data were analyzed. Multivariable cox regression analysis estimated time to MDS as the primary endpoint. Results: 5053 adults with obesity had BSx while 25265 adults underwent nonsurgical (NS) care. Median age and BMI were 46 years (y) and 45kg/m 2 . The majority were females (77%); and had white (73%) race. Follow-up was over 17y period with median (IQR) of 6.1 (3.8-8.9)y for the entire cohort. BSx-group had 19.2% greater WL at 10-y [mean between-group difference: 24.8 (95% CI, 24.6-25.1) kg]. One patient (male) in the BSx-group vs twenty-four patients (twelve females) in the NS-group developed MDS (incidence rate: 0.03 vs 0.14, per 1000 person-years). A fully adjusted hazard ratio was 0.14 (95%CI 0.02-1.14), which did not reach conventional level of statistical significance (p = 0.066) due to small number of events. A third of MDS pts had high-risk disease per IPSS-R prognostic score (7/20 evaluable pts). 10 (of 11 NS MDS pts with available NGS data) pts had ≥1 nonsynonymous mutations and most pts (6/11) harbored multiple [Median (IQR): 2 (1-3)] high-risk mutations despite a younger median age of the cohort. Conclusions: In this large cohort of adults with obesity, we observed a lower incidence of MDS after IWL achieved with BSx. Higher prevalence of high-risk-MDS mutations in a relatively young NS-cohort with obesity warrants further investigation of effects of IWL on clonal evolution, its clinical relevance, and role of screening in halting progression of CH to MDS via early detection and targeted intervention. Bariatric Surgery (N = 5053) Non-surgical (N = 25265) Standardized mean difference, % Baseline characteristics Age year, median (IQR) 46.0 (37.0 to 55.0) 46.0 (34.0 to 57.0) 4.2 Age year at MDS diagnosis 65 65 (59.0-67.0) NA Females (%) 3884 (76.9) 19 514 (77.2) 0.9 Body mass index kg/m 2 , median (IQR) 45.5 (41.0-51.6) 45.1 (40.7-50.1) 13.0 Length of follow up, median (IQR) yrs 5.8 (3.4-8.8) 6.1 (3.9-8.9) 7.7 Incidence of MDS (per 1000 person-yrs) 0.03 0.14 Adjusted HR (95%CI), p-value: 0.14 (0.02, 1.14), 0.066