Abstract
Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce proliferation of lymphoid cells; thus, their use for immunosuppression after heart transplantation (HT) may reduce post-transplant lymphoproliferative disorder (PTLD) risk. This study sought to investigate whether the sirolimus (SRL)-based immunosuppression regimen is associated with a decreased risk of PTLD compared with the calcineurin inhibitor (CNI)-based regimen in HT recipients. We retrospectively analyzed 590 patients who received HTs at two large institutions between 1 June 1988 and 31 December 2014. Cox proportional-hazard modeling was used to examine the association between type of primary immunosuppression and PTLD after adjustment for potential confounders, including Epstein–Barr virus (EBV) status, type of induction therapy, and rejection. Conversion from CNI to SRL as primary immunosuppression occurred in 249 patients (42.2%). During a median follow-up of 6.3 years, 30 patients developed PTLD (5.1%). In a univariate analysis, EBV mismatch was strongly associated with increased risk of PTLD (HR 10.0, 95% CI: 3.8–26.6; p < 0.001), and conversion to SRL was found to be protective against development of PTLD (HR 0.19, 95% CI: 0.04–0.80; p = 0.02). In a multivariable model and after adjusting for EBV mismatch, conversion to SRL remained protective against risk of PTLD compared with continued CNI use (HR 0.12, 95% CI: 0.03–0.55; p = 0.006). In conclusion, SRL-based immunosuppression is associated with lower incidence of PTLD after HT. These findings provide evidence of a benefit from conversion to SRL as maintenance therapy for mitigating the risk of PTLD, particularly among patients at high PTLD risk.
Highlights
Post-transplant lymphoproliferative disorder (PTLD) presents a group of heterogeneous diseases characterized by uncontrolled lymphoid cell proliferation as a consequence of immunosuppression after solid organ and hematopoietic stem cell transplantation [1,2].post-transplant lymphoproliferative disorder (PTLD) can clinically vary from benign lymphoid hyperplasia to aggressive anaplastic or diffuse large B-cell lymphomas
This study was designed to investigate whether conversion to SRL-based immunosuppression affects the incidence of PTLD following heart transplantation (HT) in a large double-center HT population
The salient findings of our study are that substitution of calcineurin inhibitor (CNI) by SRL as primary immunosuppression is associated with a substantial decrease in risk of PTLD independent of other known risk factors, including Epstein–Barr virus (EBV) mismatch and type of induction therapy post-HT
Summary
Post-transplant lymphoproliferative disorder (PTLD) presents a group of heterogeneous diseases characterized by uncontrolled lymphoid cell proliferation as a consequence of immunosuppression after solid organ and hematopoietic stem cell transplantation [1,2]. PTLD can clinically vary from benign lymphoid hyperplasia to aggressive anaplastic or diffuse large B-cell lymphomas. T-cell immunity, with the incidence of non-Hodgkin lymphoma being 25- to 100-fold higher in transplant recipients as compared to matched subjects from the general population [3]. The incidence of PTLD is typically higher after transplantation of solid organs that require high-intensity immunosuppressive agents, such as in lung and heart transplantation (HT) [1,4]. Among HT recipients, substitution of calcineurin inhibitor (CNI) with SRL as primary immunosuppression has been shown to attenuate cardiac allograft vasculopathy (CAV) and improve clinical outcomes [7,8]
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