See the current standings! | NephMadness.com for backstory | #NephMadness on Twitter
Dr. Prosek’s clinical interests include the CardioRenal Syndrome where he is working with his cardiology colleagues to define the role of ultrafiltration in acute decompensated heart failure, and the budding field of OncoNephrology, where he holds a clinic devoted to managing the toxicities of targeted chemotherapies such as VEGF-inhibitors and tyrosine kinase inhibitors.
Belatacept was put on the map in the 2010 BENEFIT trial, and efforts to define its role in transplantation are quickly ramping up. Belatacept is a CTLA-4 inhibitor, blocking the costimulatory pathways for T-cell activation. This is a welcome development, and its importance is best understood in the historical context of transplant immunosuppression. The role (and subsequent doses) of glucocorticoids has certainly diminished over the decades as additional medications for maintenance immunosuppression have been developed. Although there is disagreement on whether steroids should be stopped altogether (KDIGO Guidelines) or maintained at low doses, it’s clear that the toxicities related to exposure to higher doses over long periods of time have been greatly reduced. This has been accomplished mostly on the back of calcineurin inhibitors. While these drugs have a narrower side effect profile than steroids, they have one particularly unfortunate consequence, if not painfully ironic – chronic allograft nephropathy or calcineurin inhibitor toxicity.
Belatacept is being developed as a potential replacement for calcineurin inhibitors, and early studies have shown promise in this regard. The aforementioned BENEFIT trial compared two dosing regimens of belatacept versus cyclosporine. Although more acute rejection was seen in the belatacept arms, GFRs were significantly higher with the experimental treatment. This study follow up has now reached five years with the belatacept arm benefiting from almost 25% higher GFR compared to the cyclosporine arm (77.2±22.7 with belatacept and 59.3 ±15.3 with CSA at 60 months). BENEFIT-EXT explored the “expanded criteria” donor population, a group perhaps even more sensitive to the risks of calcineurin inhibition. At twelve months graft survival was similar, but the belatacept group reached fewer “renal impairment endpoints” and benefited from an additional 4-7 mL/min of clearance.
The success of these two phase III trials have led to a proliferation of further trials which are ongoing. These investigations are wide-ranging including efforts to use belatacept in steroid-free protocols, kidney-pancreas transplantation, liver transplantation, and in renal recipients with delayed graft function.
What is holding belatacept back is cost, necessity of intravenous administration, but perhaps most concerning is a background rate of malignancy. In the 5 year follow-up of BENEFIT, there were 3 cases of PTLD with belatacept and one with CSA. Other cancers seemed to be more common with belatacept:
- 3 cases of PTLD with belatacept versus 1 with CSA
- 9 cases of non melanoma skin cancers versus 2 with CSA
- 1 Kaposi sarcoma versus none with CSA
- 1 prostate cancer versus none
- 2 breast cancers versus none
- 1 malignant melanoma versus none
Two cases of progressive multifocal leukoencephalopathy with belatacept have also occurred, the patients were taking higher doses at more frequent dosing intervals than recommended. See this page for a nice summary of the some of the safety issues. As the existing and forthcoming studies progress, we will more precisely quantify the incidence of these potentially devastating complications – only then will we truly know if we’ve reached the new age of transplant maintenance therapies.