Feb. 01, 2020
The past two decades have witnessed a marked improvement in survival after heart transplantation; approximately 50% of recipients now survive over 13 years despite being older and having more comorbidities at the time of transplant compared with earlier transplant recipients.
Longer survival comes at a price — specifically, more years of exposure to immunosuppressive drugs and the potential associated risks. In the first year after transplant, death is most often due to acute rejection or infection. Although infection remains a significant cause of death after the first year, late deaths are most likely due to cardiac allograft vasculopathy (CAV) and malignancies.
Heart transplant recipients typically require more aggressive immunosuppressive regimens than do recipients of other solid organ transplants, and this intense immunosuppression is likely responsible for the increased incidence of CAV and malignancy seen in this population.
Two recent retrospective studies by the cardiac transplant group at Mayo Clinic in Rochester, Minnesota, have addressed the role of immunosuppressive agents — specifically, calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus, and mammalian target of rapamycin (mTOR) inhibitors such as sirolimus and everolimus — in the development of allograft vasculopathy and late malignancies in heart transplant recipients.
CNIs block the activity of calcineurin in T lymphocytes, decreasing the production of inflammatory cytokines, and have long been used in immunosuppressive regimens. Troublesome side effects include nephrotoxicity and hypertension. Sirolimus blocks signal transduction pathways in both B and T cells; this action is responsible for its immunosuppressive effect. Additionally, it impairs the proliferative response to cytokines and growth factors by vascular smooth muscle cells.
"Prior to 2006, most heart transplant patients at Mayo Clinic in Rochester, Minnesota, received induction therapy consisting of anti-thymocyte globulin (ATG), with a minority receiving muromonab CD-3 (OKT-3) during the first 5 years after transplant," says Sudhir S. Kushwaha, M.D., study author and past medical director of the heart transplantation program in the William J. von Liebig Center for Transplantation and Clinical Regeneration at Mayo Clinic in Rochester, Minnesota. "All patients also received maintenance immunosuppression that included a CNI, an anti-metabolite (azathioprine or mycophenolate mofetil) and tapering doses of prednisone. Conversion to sirolimus was prompted by deteriorating renal function attributed to the CNI, biopsy evidence of rejection or CNI intolerance."
After 2006, patients received rabbit ATG from transplant until tacrolimus was in the target range in addition to mycophenolate mofetil and steroids. After 6 months to allow for wound healing, stable patients without evidence of rejection were transitioned to sirolimus. If cardiac biopsy demonstrated rejection after the conversion process, a reduced dose of CNI was restarted and withdrawal attempted later.
Cardiac allograft vasculopathy
CAV is associated with both cell-mediated and humoral responses that result in immune-mediated endothelial damage, vascular inflammation, intimal smooth muscle proliferation and fibrosis.
The first study, published in the Journal of the American College of Cardiology in 2018, evaluated the incidence, progression and severity of CAV in patients receiving sirolimus for long-term immunosuppression compared with those receiving CNIs. A cohort of 402 patients who were transplanted between 1994 and 2005, were treated with a CNI alone (134 patients) or were converted to sirolimus (268 patients), and had undergone at least one intravascular ultrasound (IVUS) examination of their coronary arteries was reviewed. The primary endpoints included progression of CAV by IVUS volumetric assessment, all-cause mortality, CAV-related death and CAV-related events such as allograft failure. The demographic and clinical characteristics of the group were similar except for age; the sirolimus group was statistically older (54.2 ± 12.5 years versus 48.9 ± 14.5 years; p = 0.001).
At a mean follow-up of 8.9 years from transplant, all-cause mortality was lower in the sirolimus group compared with the CNI group, and incidence of fatal and nonfatal CAV-related events was also lower. Further analysis suggested better outcomes in patients with earlier (less than 2 years) conversion to sirolimus compared with later (longer than 2 years) conversion after transplant. The progression in plaque volume and the plaque index were both significantly mitigated in the sirolimus group compared with the CNI group. Conversion to sirolimus-based immunosuppression was associated with similar rates of rejection and without allograft deterioration.
The reduction in the mortality secondary to CAV-related disease did not fully account for the overall improved survival in transplant patients receiving sirolimus, prompting investigators to consider the role that sirolimus might play in the incidence of post-transplant malignancy.
The intensity and the duration of immunosuppression are associated with the risk of developing cancers, as well as recipient factors such as latent Epstein-Barr virus infection. One of the current challenges in the transplant field is reducing the risk of immunosuppression-related malignancies, while at the same time suppressing rejection of allografts.
In the second study, published in the Journal of the American College of Cardiology in 2019, 523 heart transplant patients were retrospectively evaluated; of these, 307 were converted to sirolimus and 216 remained on a CNI. Demographic and clinical characteristics were similar between the two groups, although the patients converted to sirolimus were on average slightly older (3.7 years); there was no difference in the rates of Epstein-Barr or cytomegalovirus viremia or the rates of rejection between the two groups. Those patients receiving ATG induction therapy were more likely to convert to sirolimus, while those receiving OKT-3 were more likely to remain on a CNI regimen (p < 0.0001). Mean follow-up was 10 years.
"Patients who converted to sirolimus had statistically significant lower overall rates of nonskin malignancies, post-transplant lymphoproliferative disease and recurrent nonmelanoma skin cancer," says Alfredo L. Clavell, M.D., one of the study authors and current medical director of cardiac transplantation in the William J. von Liebig Center for Transplantation and Clinical Regeneration at Mayo Clinic in Rochester, Minnesota. "Both the 10-year overall survival and the 10-year malignancy-free survival were statistically greater in the sirolimus group compared to the CNI-only group. There was no difference in the incidence of de novo nonmelanoma skin cancers, although the risk of recurrent skin cancer was significantly reduced in the sirolimus group."
The dose-dependent increase in associated cancers with CNIs has been attributed to increased levels of growth and angiogenic factors, effects not seen with mTOR inhibitors, and these factors are more likely to promote the development of malignant cells. The mTOR
inhibitors have anti-proliferative and anti-migratory effects on vascular smooth muscle cells, reduce extracellular matrix accumulation and fibrosis, and induce nitric oxide production, all resulting in positive remodeling of the vasculature. Thus, early conversion from a CNI-based regimen to sirolimus substitutes a stimulant to malignant transformation for one with a positive remodeling effect on the coronary vasculature, resulting in lower rates of CAV and malignancy.
For more information
Asleh R, et al. Long-term sirolimus for primary immunosuppression in heart transplant recipients. Journal of the American College of Cardiology. 2018;71:636.
Asleh R, et al. Incidence of malignancies in patients treated with sirolimus following heart transplantation. Journal of the American College of Cardiology. 2019;73:2676.