Retrospective Nested Case Control Study of the Impact of Immunosuppression on Post Transplant Malignancy among Adult Heart Transplant Patients

Abstract

Purpose Post-transplant malignancy is diagnosed in approximately 18% of heart transplant (HTx) recipients and is a leading long-term cause of death among these patients. The association between exposure to rabbit anti-thymocyte globulin (rATG), a polyclonal depleting antibody used for its immunomodulatory activity, and incidence of malignancy in HTx is unclear. Methods This is a single-center, retrospective chart review of all HTx recipients who received rATG induction between October 1, 2008 and December 31, 2015. ICD-9 codes were used to identify HTx patients who were diagnosed with any malignancy post-transplant (cases). A nested, case-control study design was used to determine the relative risk of rATG exposure with the incidence of malignancy post-transplant. Cancer cases were matched to controls in a 1:2 method based on age, sex, Epstein Barr Virus donor/recipient status, and year of transplant. Secondary analyses amongst 1:2 matches examined the impact of maintenance immunosuppression exposure on cancer risk using a weighted equation composed of the drug dose, duration, and trough values when applicable. Results Of the 126 patients included in the study, 25 developed malignancy. These 25 patient cases were matched to 50 control patients. The primary endpoint was to evaluate the association of rATG on the risk of malignancy. The median cumulative rATG dose in milligrams (mg) between groups was 365mg in cases and 465mg in controls (OR 0.94, 95% CI 0.79 - 1.11, p=0.46). The cumulative dose of rATG in mg/kg was 4.7 mg/kg in cases vs. 5.7 mg/kg in controls (OR 0.96, 95% CI 0.82 - 1.12, p=0.59). By both univariate and multivariate analyses, there were no statistically significant differences in malignancyassociated with the usage of or quantified exposure to tacrolimus, sirolimus, cyclosporine, or mycophenolate mofetil, although sirolimus showed anti-oncotic trends. Conclusion The results of this study demonstrate current rATG dosing strategies may not singularly be associated with malignancy development as previous dosing strategies suggested. Additional investigations are needed to explore the multiple factors associated with post-transplant malignancy as well as the possible modulating effect of sirolimus.