Alemtuzumab and tolerance: the university of wisconsin experience

Abstract

H istorically, the transplantation program at the University of Wisconsin, Madison, WI, has used induction agents followed by steroid-based maintenance therapy in solid organ transplantation. Nonhuman primate experiments showed the usefulness of an antibody that could effectively deplete 2 to 3 logs of lymphocytes from the recipient at the time of renal transplantation.1 Experience in humans has accumulated with virtually all of the commonly used antibodies including Minnesota antilymphocyte globulin, OKT3 (muromonab-CD3), Thymoglobulin (rabbit antithymocyte globulin; SangStat Medical Corporation, Fremont, CA), Simulect (basiliximab; Novartis AG, Basel, Switzerland), Zenapax (daclizumab; Hoffmann-La Roche Inc, Nutley, NJ), and, most recently, alemtuzumab (CAMPATH 1H; ILEXTM Oncology, Inc [ILEX], San Antonio, TX). Our protocol is modified on the basis of results and clinical experience in one of the largest renal transplant programs in the United States. Because of the published results observed in renal transplant recipients treated with alemtuzumab as an induction agent followed by cyclosporine maintenance therapy,2,3 physicians at Wisconsin designed an immunosuppressive protocol in which 29 low-risk patients were treated with alemtuzumab 20 mg intravenously and methylprednisolone 500 mg intravenously on days 0 and 1 and maintenance therapy with rapamycin (sirolimus) 2 mg/d orally starting on day 1 (Fig 1). Rapamycin was substituted for cyclosporine because it predisposes alloreactive cells to apoptosis whereas cyclosporine inhibits their apoptosis and because rapamycin is antifibrogenic and is not nephrotoxic. The dose of rapamycin was adjusted to achieve target levels in blood of 8 to 12 ng/dL.4 Eight of the 29 patients (28%) experienced a rejection episode, with all but 2 occurring within 30 days after transplantation, and most of which (5/8) were shown histologically to include humoral responses. These 5 patients had evidence of C4d deposition in the peritubular capillaries. Results from flow cytometry studies performed retrospectively on patients who experienced rejection episodes confirmed that the episodes were humoral responses directed at major histocompatibility complex class I antigen, but these responses were not because of pretransplant recipient sensitization. Treatment of rejection with steroids, Thymoglobulin, plasmapheresis, and rituximab was well tolerated, indicating that the treatment regimen did not induce overimmunosuppression. Interestingly, the occurrence of early rejection was clustered around younger patients, with 7 of 13 patients younger than 45 years experiencing rejection compared with 1 of 16 patients older than 45 years. To date, no incidents of biopsy-proven chronic rejection have been detected. Other notable complications included 2 operations for lymphoceles and 1 case of hepatotoxicity with anemia, all of which were considered as secondary effects of the rapamycin therapy. There were no systemic or opportunistic infections. The treatment regimen was modified as a result of the unexpected increased incidence of aggressive humoral rejection and because flow cytometry results showed that patients who experienced these rejection episodes had CD52-negative cells in the blood within 1 month after transplantation. Physicians theorized that CD52-negative cells may be involved in the rejection process. Therefore Thymoglobulin was added to the treatment to target the CD52-negative cells, and steroids were included to deter nonspecific activation of the immune response (Table 1). Five patients were treated with the modified treatment regimen of alemtuzumab 20 mg intravenously on days 1 and 0 followed by Thymoglobulin 1.5 mg/kg on day 1, maintenance therapy with sirolimus 2 mg/d starting on day 1, and steroid therapy 500 mg starting on day 1 tapered to 30 mg and discontinued on day 14. Three of the patients have From the Division of Organ Transplantation, University of Wisconsin, Madison, WI. Address reprint requests to Stuart Knechtle, MD, Division of Organ Transplantation, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792-7375. © 2003 Elsevier Inc. All rights reserved. 0955-470X/03/1704-0000$30.00/0 doi:10.1016/S0955-470X(03)00079-X