Highlights of the World Transplant Congress 2006

2006年7月22－27日

美国麻萨诸塞州波士顿

July 22 - 27, 2006, Boston, Massachusetts
Alemtuzumab: A New Player in Induction Therapy in Renal Transplantation
Ron Shapiro, MD
Introduction
The field of transplantation has benefitted enormously from the increased number of new agents that have become available over the past 12 years. Among these, a number of antibodies, depleting and nondepleting, have been introduced into clinical practice, and the use of antibody induction therapy has substantially increased over the past decade. In the last 3 years, one of these preparations, alemtuzumab, a humanized anti-CD52 monoclonal antibody, has been utilized by a growing number of programs, although it accounts for only 7% of antibody use in the United States. A number of presentations at this World Transplant Congress focused on the results associated with alemtuzumab induction. In contrast to earlier, more optimistic reports from previous meetings and publications, a few single-center studies and registry reviews were rather more pessimistic. There were also several single-center reports and a single-center and a multicenter randomized trial that reported favorable outcomes. Highlights from these presentations are used in an attempt to explain these somewhat disparate findings.

Alemtuzumab: Cause for Optimism?
Two studies of the innovative combination of alemtuzumab, rituximab, and intravenous immunoglobulin were reported. In the first by Vo and colleagues,[1] 30 sensitized patients underwent living-donor or deceased-donor renal transplantation. Of particular interest was the use of subcutaneous vs intravenous (IV) alemtuzumab, in 2 x 15 mg (0.5 mL) doses in the buttocks or thighs; no diminution of lymphocyte depletion or immunosuppressive efficacy was noted, and tolerability was excellent. Maintenance immunosuppression was with tacrolimus (TAC), mycophenolate mofetil (MMF), and corticosteroids. One-year patient and graft survival rates were 100% and 97%, respectively. The incidence of acute humoral rejection was 17%, and the incidence of acute cellular rejection was 10%. Cytomegalovirus (CMV) infection occurred in 3% and BK viremia (BKV) occurred in 17% of patients, although BKV nephropathy was not observed in any patients. Leflunomide, intravenous immunoglobulin (IVIG), and reduction in immunosuppression were used to treat BKV infection. In general, the authors were quite pleased with the successful outcomes and the low rate of infectious complications in this difficult-to-manage group of patients.

Another report describing the use of alemtuzumab in sensitized patients was presented by Leventhal and colleagues.[2] Eleven living-donor transplant recipients with positive crossmatches, with a titer of 1:256 or less, were treated with rituximab 1-2 weeks prior to transplantation and started on TAC and MMF. Plasmapheresis and IVIG were used to achieve a negative crossmatch, or failing that, an 8-fold reduction in the antibody titer. Alemtuzumab 30 mg IV was administered in the operating room, and TAC, MMF, and steroids were continued after transplantation. At 20 months of follow-up, patient and graft survival rates were 100% and 91%, respectively; the only graft loss was due to recurrent disease. One late acute rejection episode and 2 subclinical acute rejection episodes were noted, but no acute humoral rejection was observed. Neither posttransplant lymphoproliferative disease (PTLD) nor BKV was observed, and the mean serum creatinine (SCr) concentration was < 2.0 mg/dL. The results with this small but challenging subgroup of approximately 1000 patients treated at Northwestern who received alemtuzumab were quite favorable.

A single-center report on the use of alemtuzumab and TAC monotherapy in 64 patients was presented by Chan and colleagues.[3] Also described for the purposes of comparison were 106 immediately preceding cases who received daclizumab, TAC, MMF, and 1 week of steroids. The alemtuzumab-treated patients had 1-year patient and graft survival rates of 100% and 95.3%, respectively, and an acute rejection rate of 3.1%. The historical control patients had a similarly good outcome at 1 year, with 97% patient and 94% graft survival rates, and an acute rejection incidence of 14.2%. Infectious complications were less frequent in the alemtuzumab-treated patients, 27.2% vs 44.3%. The cost savings in the alemtuzumab group averaged $11,000/patient. The authors were pleased with these results and plan to initiate a randomized trial of alemtuzumab.

Light and colleagues[4] presented data on 195 patients (of whom 76 [39%] were African-Americans), who received 1 (n = 115 [59%]) or 2 (n = 80 [41%]) doses of alemtuzumab, along with tacrolimus and MMF, and no steroids. Patient and graft survival rates at 1 year were 100% and 94%, respectively. The authors noted an increase in BKV viruria (up to 27%) with no BKV nephropathy. The incidence of acute rejection was 30% in the BKV group, and was thought to be associated with a reduction in immunosuppression in response to the BKV. The incidence of acute rejection in the patients who did not develop BKV was 7.7%. There was a higher incidence of BKV in patients who received 2 doses of alemtuzumab (65%), and the authors noted in the discussion that they were discontinuing the practice of giving 2 doses.

Patients on a regimen that allowed steroid avoidance and eventual calcineurin inhibitor withdrawal had a low incidence of rejection and good renal function, according to Zilvetti and colleagues.[5] Thirty patients received 2 doses of IV alemtuzumab 30 mg, with MMF 500 mg twice daily for 12 months and TAC for the first 6 months, followed by sirolimus (eventual sirolimus monotherapy). Patient and graft survival rates were 93%, and 1 patient was withdrawn from the regimen for a possible drug reaction. The incidence of acute rejection was 10%, and PTLD occurred in 3%. The mean SCr concentration was 1.5 mg/dL.

At 23 months of follow-up, patient and graft survival rates were 92% and 89%, respectively (death-censored graft survival was 97%) in 75 patients treated with a regimen of alemtuzumab induction and TAC monotherapy, with early (at 2 months) steroid withdrawal, according to Potdar and colleagues.[6] The mean SCr concentration was 1.4 mg/dL and the incidence of acute rejection was 13%. The incidence of infectious complications was 10%. Ninety-two percent of the patients with functioning kidneys were being maintained on TAC monotherapy, leading the authors to be enthusiastic about this regimen.

Medium-term outcomes in 280 unselected adults receiving alemtuzumab preconditioning with TAC monotherapy (with subsequent spaced weaning of TAC) were reported by Shapiro and colleagues.[7] One- and 2-year patient survival rates were 97% and 95%, and 1- and 2-year graft survival rates were 94% and 89%, respectively. The preweaning incidence of acute rejection was 8%, and the incidence of steroid-resistant rejection was 2%. The mean SCr concentration at 1 and 2 years was 1.5 mg/dL and 1.6 mg/dL, respectively. Spaced weaning was attempted in 80% of the patients at a mean of 8 months posttransplantation, and was associated with a 26% incidence of postweaning rejection (10% steroid resistant). Weaning was abandoned in other patients when they developed donor-specific antibody, and they were returned to once-daily TAC monotherapy, with subsequent elimination of the donor-specific antibody in some cases. At most recent follow-up, 55% of the patients were on spaced weaning, including 19% who were on every other day, 31% who were on thrice-weekly, 4% who were on twice-weekly, and 1% who were on once-weekly TAC monotherapy. The incidence of CMV disea