Pharmacogenetic (PGx) markers of cardiovascular side effects (CVSEs) in allogeneic hematopoietic cell transplant (HCT) patients receiving post-transplant cyclophosphamide (PTCy).

Abstract

6559 Background: PTCy is used to prevent graft versus host disease (GVHD) post-HCT. CVSEs can be observed with Cy. We previously showed 16% of PTCy-treated patients experienced CVSEs within 30 days post-HCT. PGx determinants of Cy metabolism have been explored, but data are lacking on the impact of PGx on PTCy-related CVSEs. This study aims to identify PGx markers of CVSE risk in adult patients undergoing HCT. Methods: This is a retrospective PGx study of patients who underwent HCT between January 2014 and July 2024. Germline DNA was extracted from buccal swabs, and genotyping was performed using the Illumina Global Diversity Array with Enhanced PGx. The analysis focused on 99 single nucleotide polymorphisms (SNPs) in 13 candidate genes involved in Cy metabolism: GSTM1, GSTA1, GSTP1, GSTT1, CYP3A5, CYP3A4, CYP2C9, CYP2C8, CYP2C19, CYP2A6, CYP2B6, ALDH1A1, and ALDH3A1. The primary endpoint was time to CVSE occurrence at 90 days, 180 days, and 5 years post-HCT, including acute or chronic ischemic heart disease, acute myocardial infarction, angina pectoris, atrial fibrillation or flutter, other arrhythmias, cardiomyopathy, heart failure, hypertensive heart disease, pericardial effusion, pericarditis, peripheral vascular disease, and pulmonary edema. Covariates included age, sex, ancestral variation, diabetes, dyslipidemia, hypertension, atherosclerosis, and CVSEs within 2 years prior to HCT. Using an additive genetic model, a Cox proportional hazards model was generated to evaluate the association between each SNP and time to CVSE, adjusting for covariates. A CVSE risk score was developed using the total number of risk alleles from statistically significant SNPs and tested for association with time to CVSE using a Cox proportional hazards model. Results: Of 86 evaluable patients, the median age was 60 (range 24-78), 78% were male, 77% White, and 20% Black; 54% received haploidentical and 24.4% matched related donor HCT. The incidence of CVSEs was 27% at 90 days post-HCT, 31% at 180 days, and 58% at 5 years. The table describes three SNPs significantly associated with time to CVSE (p<0.05). The CVSE risk score (n=19 for low risk, 0-1 risk alleles; n=49 for intermediate, 2-3 risk alleles; n=18 for high, 4-6 risk alleles) was significantly associated with time to CVSE (HR 2.30, 95% CI 1.43-3.71, p=0.0006). Conclusions: PTCy-related CVSEs were common post-HCT. Single nucleotide polymorphisms in CYP2A6, GSTT1, and ALDH1A1 may influence CVSE risk post-HCT. These findings require further validation in independent datasets and may be used to develop a clinicogenomic risk model for CVSE post-HCT. SNP Gene Risk allele frequency Hazard ratio (95% CI) p value rs1137115 CYP2A6 0.215 2.78 (1.48-5.23) 0.0015 rs1007888 GSTT1 0.494 1.78 (1.13-2.81) 0.0129 rs1330283 ALDH1A1 0.506 1.82 (1.06-3.12) 0.0301