Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from the TRANSFORM study

Abstract

TRANSFORM (TRANSplant eFficacy and safety Outcomes with an eveRolimus‐based regiMen) was a 24‐month, prospective, open‐label trial in 2037 de novo renal transplant recipients randomized (1:1) within 24 hours of transplantation to receive everolimus (EVR) with reduced‐exposure calcineurin inhibitor (EVR + rCNI) or mycophenolate with standard‐exposure CNI. Consistent with previously reported 12‐month findings, noninferiority of the EVR + rCNI regimen for the primary endpoint of treated biopsy‐proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR) <50 mL/min per 1.73 m2 was achieved at month 24 (47.9% vs 43.7%; difference = 4.2%; 95% confidence interval = −0.3, 8.7; P = .006). Mean eGFR was stable up to month 24 (52.6 vs 54.9 mL/min per 1.73 m2) in both arms. The incidence of de novo donor‐specific antibodies (dnDSA) was lower in the EVR + rCNI arm (12.3% vs 17.6%) among on‐treatment patients. Although discontinuation rates due to adverse events were higher with EVR + rCNI (27.2% vs 15.0%), rates of cytomegalovirus (2.8% vs 13.5%) and BK virus (5.8% vs 10.3%) infections were lower. Cytomegalovirus infection rates were significantly lower with EVR + rCNI even in the D+/R− high‐risk group (P < .0001). In conclusion, the EVR + rCNI regimen offers comparable efficacy and graft function with low tBPAR and dnDSA rates and significantly lower incidence of viral infections relative to standard‐of‐care up to 24 months. Clinicaltrials.gov number: NCT01950819.

Risks and benefits of everolimus

“…Thus, in summary, this trial together with the results of other recent data provides further evidence, that MPA/tacrolimus remains current standard of care in de‐novo renal allograft recipients, despite all the well known‐limitations of this combination therapy. Everolimus is a well‐proven second‐line treatment option in case of MPA intolerability, such as severe viral infections, which are difficult to treat.…”

“…Because of reimbursement issues in Brazil for the expensive valganciclovir prophylaxis, drug‐related side effects, and only 6% CMV high‐risk patients, the Sao Paolo group explored the option of a preemptive CMV treatment strategy with tight CMV monitoring together with the use of mTOR inhibitors . The observation of lower CMV infection rates under mTOR inhibitors compared with MPA dates back from early clinical trials and was confirmed in recent trials and meta‐analyzes .…”

“…Besides underimmunosuppression, typical drug‐related side effects (hyperlipidemia, stomatitis, edema, proteinuria, wound‐healing, and lymphoceles), remain a major concern in everolimus‐treated patients, leading to frequent discontinuations. All clinical trials and recent meta‐analyzes clearly demonstrate inferior tolerability of everolimus compared with MPA, as evidenced by higher discontinuation rates due to adverse events. Contrary to everolimus, MPA has a wide therapeutic range.…”

“…In contrast, everolimus‐associated side effects are more diverse and obviously more difficult to treat. Inexperience of the investigator and center differences may account for some of the observed differences, but 15 years after approval in Europe, even experienced investigators rather discontinue everolimus and switch to standard of care, than to manage the adverse event and continue everolimus, as evidenced by high discontinuation rates in recent large trials .…”

Interferon‐γ‐induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG‐CoA reductase

“…Previous reports have indicated that a switch from CNI to EVR (withdraw CNI) showed more frequent DSA appearance and increased risk of ABMR than the standard regimen (with CNI) [21‐23]. Results of a recent comparative study between ‘EVR with reduced‐exposure CNI (EVR + rCNI)’ and ‘mycophenolate with standard‐exposure CNI’ have demonstrated lowered incidence of de novo DSA and similar cellular rejection rate in the EVR + rCNI arm among on‐treatment patients [24]. Although EVR might have the potential to reduce DSA‐induced humoral rejection, we need to carefully assess the efficacy of EVR considering combined use of CNI.…”