Characteristics, Predictors, and Outcomes of Early mTOR Inhibitor Use After Heart Transplantation: Insights From the UNOS Database

Abstract

Background The clinical characteristics of mTOR (mammalian target of rapamycin) inhibitors use in heart transplant recipients and their outcomes have not been well described. Methods and Results We compared patients who received mTOR inhibitors within the first 2 years after heart transplantation to patients who did not by inquiring the United Network for Organ Sharing (UNOS) database between 2010 and 2018. The primary end point was all‐cause mortality with retransplantation as a competing event. Rejection, malignancy, hospitalization for infection, and renal transplantation were secondary end points. There were 1619 (9%) and 15 686 (81%) mTOR inhibitors+ and mTOR inhibitors− patients, respectively. Body mass index, induction, cardiac allograft vasculopathy, calculated panel reactive antibody, and fewer days in 1A status were independently associated with mTOR inhibitors+ status. Over a follow‐up of 10.4 years, there was no difference in all‐cause mortality after adjusting for donor and recipient characteristics (adjusted subdistribution hazard ratio, 1.03 [0.90–1.19]; P =0.66). mTOR inhibitors+ were independently associated with increased risk for rejection (odds ratio [OR], 1.43 [1.11–1.83]; P =0.005) and basal skin cancer (OR, 1.35 [1.19–1.51]; P =0.012) but not for infection or renal transplantation. Conclusions mTOR inhibitors are used in <10% patients in the first 2 years after heart transplantation and are noninferior to contemporary immunosuppression regimens in terms of all‐cause mortality, infection, malignancy, or renal transplantation. They are associated with risk for rejection.

Primary prophylaxis with mTOR inhibitor enhances T cell effector function and prevents heart transplant rejection during talimogene laherparepvec therapy of squamous cell carcinoma

“…These reinvigorated T cells can potentially lead to improved anti-tumor efficacy of T-VEC and potentially other type of cancer immunotherapies. In addition to previously reported benefits from studies that have suggested lower risk of certain malignancies, lower mortality, fewer cardiac allograft vasculopathy-related events, and lower risk of renal dysfunction with the use of mTORi 70 , this dual benefit of mTORi may hold significant promise in the context of cancer immunotherapy for SOT recipients. By unraveling the underlying mechanisms involved in T cell exhaustion, differentiation, and response to immunotherapy, we can better optimize treatment strategies and potentially improve patient outcomes.…”

Tumorigenic role of tacrolimus through mTORC1/C2 activation in post-transplant renal cell carcinomas

“…However, it may be important to assess the mTOR activity of tumour cells before initiating mTOR inhibitor therapy. Although rapalogs are generally used to reduce the risk of tumours after transplantation [ 52 , 53 ], there is a new study from 2022 questioning the effectiveness of early conversion to mTOR inhibitor-based IS regimens in reducing tumour incidence [ 54 ].…”

Adult and late adolescent complications of pediatric solid organ transplantation

“…mTOR inhibitors have been proposed as an alternative immunosuppressive agent to decrease the onset or progression of CAV, but a recent retrospective review of showed increased rates of rejection and CAV in children treated with mTOR inhibitors, though the authors did not feel the association with CAV was likely to be causal. 23 Statin medications have been shown to slow the development of CAV in adult patients, and studies in pediatric heart recipients demonstrate safety and efficacy in lowering total cholesterol, triglyceride, and LDL levels. Data on the effectiveness of statins to delay CAV in pediatric heart patients are mixed.…”

“…The causes of CAV are poorly understood but likely include some combination of immune mechanisms (e.g., antibody‐mediated rejection) in addition to traditional nonimmune cardiac risk factors, including dyslipidemia, hypertension, diabetes, and obesity. mTOR inhibitors have been proposed as an alternative immunosuppressive agent to decrease the onset or progression of CAV, but a recent retrospective review of showed increased rates of rejection and CAV in children treated with mTOR inhibitors, though the authors did not feel the association with CAV was likely to be causal 23 . Statin medications have been shown to slow the development of CAV in adult patients, and studies in pediatric heart recipients demonstrate safety and efficacy in lowering total cholesterol, triglyceride, and LDL levels.…”