Conversion from calcineurin inhibitors to mTOR inhibitors as primary immunosuppressive drugs in pediatric heart transplantation

Abstract

There are only a few reports of successful use of mammalian target of rapamycin (mTORI) as primary immunosuppression in pediatric heart transplantation. Compared to calcineurin inhibitors, mTORI have less side effects, especially nephrotoxicity, infections, and malignancies. A retrospective study was conducted at our institution of all 170 heart transplants from 1995 to 2015. Nineteen patients were switched from tacrolimus (n=15) or cyclosporin (n=4) to everolimus (n=4) or sirolimus (n=15) due to nephrotoxicity (n=5), malignancy (n=8), EBV viremia/reactive plasmacytic changes (n=5), and immune hemolytic anemia (n=1). We monitored for rejection, infection, BUN, creatinine, hyperlipidemia, EBV and CMV copies, CBC, cardiac allograft vasculopathy (CAV), and death. Target trough levels of sirolimus and everolimus were 4-10. Four treatment failures included debilitating rash, bone marrow suppression, recurrent rejection, and renal transplantation. There were no deaths. One patient had recurrent rejection episodes, and tacrolimus was reinitiated. One patient with preexisting CAV underwent heart retransplantation. One patient, who was treated for PTLD, transformed to CD30+ Hodgkins disease, and was treated with brentuximab. There were three acute rejection episodes. Median creatinine preswitch was higher 0.82 than postswitch 0.78 (P=.016). Median eGFR was lower preswitch, 75.6, than postswitch, 91.2 (P=.0004). These results indicate that conversion to mTORI as primary immunosuppression may be safely accomplished in some pediatric heart transplant patients.

Long‐term experience using CNI‐free immunosuppression in selected paediatric heart transplant recipients

“…Short-term improvement of renal function was observed by some other authors. 4,[19][20][21] The biggest cohort (n = 35) with the longest follow-up besides our study was investigated by Sierra et al, 2017. 19 In their retrospective analysis, a significant improvement of renal function up to 5 years after discontinuation of CNI with no increased risk of rejection (which was defined as ISHLT grade 2R or higher or AMR) was showed which is supported by our data as we came to the same results in our patient cohort.…”

“…Short-term improvement of CNI-induced nephropathy in paediatric patients, as described in our patient cohort, has been observed by other authors. 4,[19][20][21] Long-term follow-up data on renal function showed a significantly increased eGFR after 5 years of CNI-free immunosuppression. 19 Our data and the results of previous studies suggest some reversibility of CNI-induced nephrotoxicity in paediatric heart transplant recipients, even when CNI discontinuation is initiated late after transplantation.…”

“…Similar or slightly higher rejection rates have been described by other authors in paediatric patients. 4,[19][20][21] No patients required re-conversion to CNI-based immunosuppression.…”

“…One patient developed PTLD relapse, but the overall PTLD recurrence risk was lower after immunosuppression conversion. 20 Due to the limited data, it remains inconclusive whether mTORi-containing regimens have beneficial effects on new onset PTLD or reduce PTLD recurrence in high-risk paediatric heart transplant recipients, as described for adult recipients. 15 However, our data suggest that these patients might substantially benefit from a CNI-free immunosuppressive regimen.…”

“…17,18 Limited single-centre studies indicate that conversion to mTORis in combination with MMF may be a safe maintenance therapy without loss of efficacy and stabilisation of renal function in selected patients. 4,14,[19][20][21][22] However, an increased risk of acute rejection (21% vs. 6.8%) was reported in a randomised controlled trial of adult heart transplant patients receiving CNI-free immunosuppression vs. a CNIreduced regimen. 23 Therefore, this study aimed to evaluate the longterm therapeutic efficacy and safety of CNI-free immunosuppression in selected paediatric patients in terms of survival, graft function, renal function, development of malignancies and progression of CAV.…”