Bortezomib Shows Promise as Antirejection Therapy


Bortezomib Shows Promise as Antirejection Therapy

www.medpagetoday.com/Surgery/Transplantation/12281

CINCINNATI, Dec. 29 — Kidney transplant recipients experiencing refractory acute rejection saw a quick and durable resolution after a short course of bortezomib (Velcade), investigators here said.
Action Points  <!— –>

  • Explain to patients that a drug used to treat a type of blood-related cancer showed potential as a means to treat or prevent rejection after kidney transplantation.
  • Note that the study involved only six patients.
  • Note also that bortezomib is not approved for use as antirejection therapy.

The treatment effectively quelled eight episodes of antibody-mediated rejection and concomitant acute cellular rejection in six patients, E. Steve Woodle, M.D., of the University of Cincinnati, and colleagues reported in the Dec. 27 issue of Transplantation.The drug achieved marked and prolonged reductions in donor-specific antihuman leukocyte antigen antibody levels and improved allograft function.

“Bortezomib represents the first effective antihumoral therapy with activity in humans that targets plasma cells,” the authors concluded.

A lack of direct activity against the mature plasma cell — the major antibody-producing cell — limits the effectiveness of current antihumoral therapies, including plasmapheresis, intravenous immune globulin, and polyclonal antilymphocyte antibodies.

The proteosome inhibitor bortezomib has pleiotropoic immune modulating effects, including preclinical activity against nontransformed plasma cells.

That activity, combined with dissatisfaction with standard therapies for antibody-mediated rejection, led the authors to evaluate bortezomib as treatment or prophylaxis for cell-mediated allograft rejection.

The six patients included in the study had episodes of acute rejection as defined by at least a 20% increase from baseline in serum creatinine plus histologic evidence of acute rejection by Banff criteria.

Baseline serum creatinine was defined as the mean of five consecutive measurements that immediately preceded acute rejection.

Initial rejection episodes occurred from 25 to 2,774 days after transplantation. In all cases, bortezomib was initiated after failure of a trial of one or more standard antirejection therapies.

Two patients had a second rejection episode. In one case, the initial episode occurred on posttransplant day 223 and the second on day 452. In the second case, the initial rejection episode occurred on posttransplant day 25 and the second on day 245. Recurrent episodes were treated immediately with bortezomib.

Each rejection episode was treated with a single course of bortezomib at labeled dosing.

In all cases, the immunodominant donor-specific antihuman antibody declined by more than 50% within 14 days of treatment and remained suppressed for as long as 14 months.

Every patient had one or more additional donor-specific antihuman antibodies, which declined with treatment to undetectable levels.

Principal bortezomib-related toxicities were gastrointestinal effects, thrombocytopenia, and paresthesias, all of which were transient.

The observation of recurrent rejection episodes in two patients “argues for more aggressive therapeutic approaches,” the authors said. “One such approach was used with bortezomib therapy in the third patient in this report, where bortezomib therapy was used concomitantly with additional agents.”

Additionally, antihuman antibody levels rebounded in some patients. The observation requires longer follow-up to determine the clinical significance, the authors said.

However, they noted, clinical experience with bortezomib in multiple myeloma has suggested that administration of multiple cycles of therapy might be a reasonable approach to enhance the drug’s activity.

The authors reported no potential conflicts of interest.