The proteasome inhibitor bortezomib (Velcade) failed to counteract late antibody-mediated rejection in kidney transplant patients, researchers reported from a small randomized trial.
In the placebo-controlled clinical study, overall graft survival at 2 years did not differ significantly between treatment arms and, in fact, numerically favored placebo (81% versus 96%; P=0.12). Patient survival also was no better with bortezomib than placebo (90% versus 100%, respectively; P=0.13), said Georg Böhmig, MD, of the Medical University of Vienna in Austria, and colleagues.
The trial’s primary endpoint, the change in estimated glomerular filtration rate (eGFR) over two years, was not significantly different between the treatment and placebo groups. The eGFR slope was -4.7 for the treatment group and -5.2 for placebo (difference 0.5; 95% CI -4.8 to 5.8; P=0.86), Böhmig and colleagues reported online in the Journal of the American Society of Nephrology.
The drug also had no apparent impact on donor-specific antibodies (DSA). Change in DSA at two years was not significantly different between the treatment and placebo groups, although substantial longitudinal variation of DSA in both groups made it difficult to detect a difference, the study authors reported.
Compounding the drug’s failure, overall adverse events were more common with bortezomib (91 versus 64) as were serious adverse events (10 versus 4). Bortezomib was associated with gastrointestinal toxicity, especially nausea and diarrhea. It was also associated with significantly higher grades of anemia, thrombocytopenia, and leukocytopenia, the study found.
“Our trial challenges the results of previous observational studies and argues against a beneficial effect of bortezomib as a treatment for late antibody-mediated rejection,” Böhmig and colleagues said. “The absence of an effect of bortezomib on DSA and disease activity is important because such effects would be expected, considering the known mechanism of action of the drug.”
Bortezomib, which is approved by the FDA for multiple myeloma and mantle cell lymphoma, promotes the apoptosis of plasma cells, they explained. However, “It is possible that the state of the plasma cells in late antibody-mediated rejection differs from that in other disease conditions in ways that render them less susceptible to the action of bortezomib,” they said.
The trial included 44 kidney transplant recipients diagnosed with late antibody-mediated rejection. They were randomized 1:1 to receive two cycles of either bortezomib or placebo at 3-month intervals in double-blinded fashion. Each treatment cycle consisted of bortezomib at 1.3 mg/m2, administered intravenously twice-weekly on days 1, 4, 8, and 11.
For antiviral prophylaxis, bortezomib-treated patients received oral valacyclovir at 500 mg/day for 3 weeks after initiation of each cycle. Patients in the control group received a 0.9% sodium chloride solution placebo, and instead of valacyclovir they received gelatin capsules filled with maltodextrin. Trial participants were followed for 24 months.
Despite the lack of efficacy reported in this trial, researchers should continue to explore the use of proteasome inhibitors to treat late antibody-mediated rejection of kidney transplants, Böhmig and colleagues said. “An interesting strategy to achieve a longer duration of inhibition and enhanced plasma cell depletion may be the use of new irreversible proteasome inhibitors, such as carfilzomib,” they said.
In addition, bortezomib may be more effective if combined with other agents or treatments, they suggested. “In this respect, the results of an ongoing trial designed to evaluate the effect of bortezomib as part of combinatorial treatment in late antibody-mediated rejection will be of interest,” they said. The Bortezomib in Rejection of Kidney Transplants (TRIBUTE) trial will assess the efficacy of bortezomib in combination with steroids, plasma exchange, and polyclonal intravenous immunoglobulins, according to clinicaltrials.gov.
Böhmig and colleagues noted some limitations to their trial, including using eGFR decline, the study’s main endpoint, as a surrogate of graft survival. However, “A study design to detect meaningful differences in survival rates would have necessitated a long-term multi-center trial including hundreds of patients. Even for our comparatively small trial, screening of more than 700 recipients was necessary for recruitment of less than 50 subjects eligible for the interventional part of the study,” they said.
The study was funded by the Austrian Science Fund and Sandoz GmbH, Austria.
No study authors reported relevant financial relationships.
F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner