Sirolimus Therapy and Risk of Late Cellular Rejection in Heart Transplant Patients with Cardiac Allograft Vasculopathy

PURPOSE Traditionally, heart transplant (HT) patients with cardiac allograft vasculopathy (CAV) are treated with a combination of calcineurin inhibitor (CNI) and sirolimus (SRL). Recent data suggest outcomes in patients with CAV may be improved by treatment with SRL and mycophenolate mofetil (MMF), without CNI. However, this CNI free regimen for HT patients with renal dysfunction resulted in more rejection. Here we evaluated the relationship between risk of rejection and SRL use in CAV. METHODS This is a single center, retrospective study of HT patients with CAV, transplanted between 6/2003 - 10/2018. From 357 HT patients, 39 with CAV treated with SRL were identified. Rejection included ISHLT grading ≥ 1R/1B requiring therapy. Incidence of post SRL conversion rejection was analyzed for 2 groups: SRL/CNI and SRL/MMF. RESULTS Of 39 patients identified, 11 received SRL/MMF and 28 received SRL/CNI. Six of 11 patients in the SRL/MMF group developed cellular rejection after transition to SRL, compared to 3 of 28 in the SRL/CNI group (55% vs 11%, p = 0.004; Fig. 1). Four of 6 patients on SRL/MMF who developed post SRL transition rejection, had a history of previous rejection. However, those who did not experience late rejection also had no history of early rejections (66% vs 0%, p=0.045). The average level of SRL was 10.5 ng/ml +/- 1.1 in the group with post SRL rejection and 7.6 ng/mL +/- 1.9 in the group without (p = 0.01). The average dose of MMF was 1834 +/- 376 mg daily in the group with post SRL rejection and 2000 +/- 0 mg daily in the group without (p = 0.78). CONCLUSION In HT patients with CAV treated with CNI free regimen, despite therapeutic levels of SRL, there is a significant increase in the risk of cellular rejection not seen in those on SRL/CNI. In those on SRL/MMF therapy who experienced post SRL rejection, there was a higher incidence of pre-conversion rejection. Reduced dose CNI/SRL immunosuppression regimens need to be considered in CAV patients, especially those with a history of previous rejection.