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Malignancy With Sirolimus Post–Cardiac Transplantation
Study Questions:
Does immunosuppression using sirolimus post–cardiac transplantation decrease risk of malignancy post-transplant?
Methods:
A total of 523 patients, at a single center, who underwent heart transplantation (HT) between January 1994 and December 2016 were analyzed retrospectively. These patients were either treated with a calcineurin inhibitor (CNI, n = 216) or converted to sirolimus (SRL, n = 307 with no concomitant use of calcineurin inhibitor). All patients received induction therapy with antithymocyte globulin (ATG) and some received muromonab-CD3 (OKT3) in the first 5 years of the study. All patients received maintenance therapy with a CNI (tacrolimus or cyclosporine), mycophenolate or azathioprine, and prednisone. In 2006, a new protocol was introduced where patients were routinely converted from CNI to SRL if they were stable on a medical regimen and had no evidence of rejection. SRL levels were targeted towards 10-14 ng/ml, while the CNI was titrated off; 307 patients were converted to therapy with SRL at a median of 1.1 years post-HT. The main outcomes were: incidence of de novo malignancies (excluding nonmelanoma cancers [NMSCs]), post-transplantation lymphoproliferative disorders (PTLDs), and first and subsequent NMSC.
Results:
Of the 307 HT recipients converted to SRL, they were found to be slightly older by 3.7 years, more likely to receive dual organ heart and liver transplantation (SRL: 8.5% vs. CNI: 4.6%), receive ATG therapy more frequently (SRL: 79% vs. CNI: 63.4%), and OKT3 less frequently (SRL: 21.2% vs. CNI: 42.1%) than patients beings treated with CNI therapy. The rates of cytomegalovirus and Epstein-Barr virus infection were similar between the SRL and CNI groups at baseline. There was a significant difference in rates of acute cellular, antibody-mediated rejection or hemodynamically significant rejection between the two groups. Overall de novo malignancies (non-NMSC) occurred in 31% of CNI patients and in 13% of SRL patients at 10 years post-HT (unadjusted hazard ration [HR], 0.36; 95% confidence interval [CI], 0.20-0.65 for SRL compared with CNI; p < 0.001). The incidence of PTLD was significantly lower in the SRL group (unadjusted HR, 0.14; 95% CI, 0.03-0.59; p = 0.009). The incidence of NMSC post-HT was similar in the SRL group and CNI groups (adjusted HR, 0.92; 95% CI, 0.66-1.28; p = 0.62). However, conversion to SRL was associated with a significantly decreased risk of subsequent primary occurrences of NMSC compared with CNI therapy (adjusted HR, 044; 95% CI, 0.28-0.69; p < 0.001). Late survival post-HT was decreased in patients who developed non-NMSC, PTLD, or non-PTLD compared with patients who did not develop malignancies. NMSC had so significant effect on survival.
Conclusions:
In HT patients who had complete conversion to SRL-based immunosuppression therapy, there is evidence of reduced incidence of de novo NMSC malignancies, PTLDs, and lower subsequent primary occurrences of NMSC; thus, providing some late survival benefit.
Perspective:
This study, over a 10-year period, provided favorable strong evidence for HT recipients being treated with SRL therapy and the risk of development of de novo malignancies. The main limitation of SRL use remains drug intolerance due to gastrointestinal symptoms, mouth ulcers, and peripheral edema. Randomized clinical trials are still needed to address survival benefit with ideal immunosuppression therapies in HT recipients.
Clinical Topics: Cardiac Surgery, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Novel Agents, Acute Heart Failure, Heart Transplant
Keywords: Antilymphocyte Serum, Azathioprine, Calcineurin, Cyclosporine, Cytomegalovirus, Epstein-Barr Virus Infections, Graft Rejection, Heart Failure, Heart Transplantation, Immunosuppression, Immunosuppressive Agents, Liver Transplantation, Lymphoproliferative Disorders, Muromonab-CD3, Neoplasms, Prednisone, Secondary Prevention, Sirolimus, Tacrolimus
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