Mutational and Clinical Characteristics Associated with Atherosclerotic Disease Burden in the MDS Canada Database: A Single-Center Analysis of CT Coronary Artery Calcium Scores

Introduction: Myelodysplastic syndromes (MDS) are a genetically/mutationally heterogenous group of myeloid cancers associated with bone marrow failure/cytopenias and with a predisposition towards progression to acute myeloid leukemia (AML). Cardiovascular disease is a major cause of mortality and morbidity in patients with MDS. Preclinical and clinical evidence increasingly support a mechanistic association between MDS and the precursor clonal hematopoiesis of indeterminate potential (CHIP) with atherosclerotic and coronary artery disease. In this ongoing analysis of the MDS-Canada database, we aim to determine clinical and mutational characteristics of patients with MDS associated with atherosclerotic disease burden (assessed by cardiac CT) at a single center. Methods: We included adults with a diagnosis of MDS, chronic myelomonocytic patients and low blast (20-29%) AML; patients with atypical CML, MDS/MPN with ring sideroblasts and thrombocytosis or MDS-MPN-unclassifiable were excluded. Banked bone marrow DNA/RNA samples are being used for NGS analysis. Cardiovascular risk factors (including hypertension, dyslipidemia, physical inactivity, family history, smoking history), history of established cardiovascular disease (including coronary artery disease, cardiomyopathy/heart failure and arrhythmias), medications (including antihypertensives, lipid-lowering medications, antiplatelet agents) and laboratory parameters (including lipid profiles and CRP) are being captured prospectively in the MDS-CVD study. Coronary artery calcium score assessment using CT Coronary angiogram, 2D echocardiogram and detailed lipid assessment is offered to consenting patients without an established history of CVD. Results: Coronary artery calcium score assessment has been performed in 21 patients to date. Median age of these patients was 78 (range: 53-87); 43% were female. Median IPSS-R of these patients was 2.0 and 62% were classified into “good” IPSS-R risk cytogenetics. MDS with ring sideroblasts (24%), MDS with multilineage dysplasia (14%) and MDS with excess blasts (14%) comprised the majority of WHO classifications; an additional 14% had CMML. 47% of patients were current or former smokers, 47% of patients were taking lipid-lowering medications, 29% were taking either beta-blockers or calcium channel blockers and 9.5% were taking antiplatelet agents. Mean systolic/diastolic blood pressure at time of enrollment was 133.4 (SD: 21.3) / 73.0 (SD: 9.8) mm Hg. Cardiovascular risk based on clinical and laboratory parameters was estimated using the Framingham and sex-stratified Reynold's risk scores in eligible patients (i.e. under 80 years of age): the median estimated risk of cardiovascular events over 10 years was 11.0% (range: 2.1%-18.7%) using the Framingham and 11.8% (range: 1.9%-27.0%) using the Reynold's risk scores respectively. Median coronary artery calcium score was 333 (range: 0-1947); 33% of patients had no to mild disease (CT Calcium score 0-100), 24% of patients had moderate disease (CT Calcium score 100-400) and 43% of patients had severe disease (CT Calcium score ≥ 400). Patients with severe disease were referred to cardiologists for additional investigations including stress tests and cardiovascular risk factor optimization including initiation of statins. Of those in the MDS-Canada database with CT Calcium score data, 11 patients additionally had NGS completed (with ongoing assessment for the remaining patients). Genes involved in DNA methylation (including TET2 [27%], DNMT3A [18%] and IDH2 [9%]) and RNA splicing (including SF3B1 [27%] and SRSF2 [18%]) were the most frequently mutated to date with a median of 2.5 mutations (range: 1-6) per patient. Conclusion: 43% of MDS patients without a history of CVD were found to have high coronary calcium scores indicative of potentially high atherosclerotic burden. NGS analysis and CT Coronary calcium scores are ongoing for 100 planned patients enrolled in a single-center of the MDS-CAN study. The mutational analysis of those with pre-existing overt CVD will be compared to those with occult disease or no disease. Analysis of baseline clinical characteristics and mutational analysis may inform features of MDS associated with a higher burden of atherosclerotic/coronary artery disease for early screening and intervention.

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