Alemtuzumab Induction in Renal Transplantation

Transcription

1 original article Induction in Renal Transplantation Michael J. Hanaway, M.D., E. Steve Woodle, M.D., Shamkant Mulgaonkar, M.D., V. Ram Peddi, M.D., Dixon B. Kaufman, M.D., Ph.D., M. Roy First, M.D., Richard Croy, M.A., and John Holman, M.D., for the INTAC Study Group* A BS TR AC T Background There are few comparisons of antibody induction therapy allowing early glucocorticoid withdrawal in renal-transplant recipients. The purpose of the present study was to compare induction therapy involving alemtuzumab with the most commonly used induction regimens in patient populations at either high immunologic risk or low immunologic risk. Methods In this prospective study, we randomly assigned patients to receive alemtuzumab or conventional induction therapy (basiliximab or rabbit antithymocyte globulin). Patients were stratified according to acute rejection risk, with a high risk defined by a repeat transplant, a peak or current value of panel-reactive antibodies of 20% or more, or black race. The 139 high-risk patients received alemtuzumab (one dose of 30 mg, in 70 patients) or rabbit antithymocyte globulin (a total of 6 mg per kilogram of body weight given over 4 days, in 69 patients). The 335 low-risk patients received alemtuzumab (one dose of 30 mg, in 164 patients) or basiliximab (a total of 40 mg over 4 days, in 171 patients). All patients received tacrolimus and mycophenolate mofetil and underwent a 5-day glucocorticoid taper in a regimen of early steroid withdrawal. The primary end point was biopsy-confirmed acute rejection at 6 months and 12 months. Patients were followed for 3 years for safety and efficacy end points. Results The rate of biopsy-confirmed acute rejection was significantly lower in the alemtuzumab group than in the conventional-therapy group at both 6 months (3% vs. 15%, P<01) and 12 months (5% vs. 17%, P<01). At 3 years, the rate of biopsyconfirmed acute rejection in low-risk patients was lower with alemtuzumab than with basiliximab (10% vs. 22%, P = 03), but among high-risk patients, no significant difference was seen between alemtuzumab and rabbit antithymocyte globulin (18% vs. 15%, P = 3). Adverse-event rates were similar among all four treatment groups. From the University of Alabama at Birmingham, Birmingham (M.J.H.); the University of Cincinnati College of Medicine, Cincinnati (E.S.W.); St. Barnabas Health System, West Orange, NJ (S.M.); California Pacific Medical Center, San Francisco (V.R.P.); the University of Wisconsin School of Medicine and Public Health, Madison (D.B.K.); and Astellas Pharma, Chicago (M.R.F., R.C., J.H.). Address reprint requests to Dr. Hanaway at Lyons Harrison Research Bldg., Rm. 728, rd Ave., South Birmingham, AL 35294, or at michael.hanaway@ccc.uab.edu. *Members of the Induction with Tacromilus (INTAC) study group are listed in the Supplementary Appendix, available at NEJM.org. Drs. Hanaway and Woodle contributed equally to this article. N Engl J Med 2011;364: Copyright 2011 Massachusetts Medical Society. Conclusions By the first year after, biopsy-confirmed acute rejection was less frequent with alemtuzumab than with conventional therapy. The apparent superiority of alemtuzumab with respect to early biopsy-confirmed acute rejection was restricted to patients at low risk for transplant rejection; among high-risk patients, alemtuzumab and rabbit antithymocyte globulin had similar efficacy. (Funded by Astellas Pharma Global Development; INTAC ClinicalTrials.gov number, NCT ) n engl j med 364;20 nejm.org may 19,

2 In the United States between 1998 and 2007, a total of 78% of renal-transplant recipients received antibody induction therapy. The most frequently used agents have been rabbit antithymocyte globulin (Thymoglobulin, Genzyme), a lymphocyte-depleting polyclonal antibody, and basiliximab (Simulect, Novartis Pharmaceuticals), a non lymphocyte-depleting monoclonal antibody targeting the interleukin-2 receptor. 1 More recently, alemtuzumab (Campath-1H, Berlex Laboratories), an anti-cd52 T-cell and B-cell depleting monoclonal antibody, has been used for induction in renal. 2-5 Although a number of trials of early glucocorticoid withdrawal and calcineurin-inhibitor minimization have been conducted in renal-transplant recipients over the past decade, it is not clear which induction agent is better A recently concluded 5-year multicenter trial of early glucocorticoid withdrawal showed a trend toward an increased risk of biopsy-confirmed acute rejection with anti interleukin-2 receptor antibody induction as compared with rabbit antithymocyte globulin. 11 However, other studies of early glucocorticoid withdrawal have not been adequately controlled for risk factors for acute rejection in the recipient (e.g., black race and repeat transplant) In this article, we describe a prospective, open-label, randomized, multicenter, controlled trial in which patients were randomly assigned to receive alemtuzumab or conventional induction therapy with either basiliximab or rabbit antithymocyte globulin. Me thods Study Design This study was sponsored by Astellas Pharma Global Development and was conducted at 30 centers (listed in the Supplementary Appendix, available with the full text of this article at NEJM.org). The study was conceived and designed by two academic and two industry authors. The manuscript was written by five academic and two industry authors, and all these authors made the decision to submit the manuscript for publication. The sponsor held the data, to which all authors had free access. Three academic and two industry authors analyzed the data. The trial was conducted in accordance with the protocol (available at NEJM.org). The study was approved by the institutional review board at each participating center; and written informed consent was provided by each participant before enrollment at each site. Enrollment Inclusion criteria were an age of 18 years or older and receipt of a live-donor or deceased-donor kidney. Exclusion criteria were kidneys from expandedcriteria donors, kidneys from donors without a heartbeat, kidneys with ischemic times exceeding 36 hours, positive cytotoxic or flow-cytometric cross-matches, and kidneys from HLA-identical live donors. Detailed inclusion and exclusion criteria are presented in the Supplementary Appendix. Study Objective and Hypotheses The objective of the study was to compare the safety and efficacy of the induction agent alemtuzumab with the safety and efficacy of basiliximab and rabbit antithymocyte globulin in adult renal-transplant recipients treated with tacrolimus and mycophenolate mofetil and also undergoing rapid glucocorticoid withdrawal. We hypothesized that alemtuzumab would be associated with superior prevention of biopsy-confirmed acute rejection at 6 months and at 1 year, as compared with conventionalinduction therapy, as part of a regimen of early glucocorticoid withdrawal. Sample-size determination was based on an evaluation of the ability to detect the superiority (or inferiority) of alemtuz umab induction therapy as compared with conventional induction therapy with respect to the primary end point of biopsy-confirmed acute rejection at 6 months and 12 months. The study was designed to continue beyond the 12-month primary end point to 3 years, in order to assess the longer-term safety and efficacy of the treatment regimens. Outcomes All outcomes were monitored at 6, 12, 24, and 36 months. The primary efficacy end point was the rate of biopsy-confirmed acute rejection (defined as Banff grade I) at 6 months and 12 months. (Banff criteria are standard pathological criteria for rejection diagnosis and grading.) Secondary end points included measures of rejection, efficacy, patient and graft survival, graft function, infection, cancer, and metabolic measures. A complete list of secondary outcomes is presented in the Supplementary Appendix. Intervention Induction Therapy Patients were randomly assigned to receive either alemtuzumab or conventional induction therapy and were stratified at each center according to immunologic risk, with a high risk of transplant 1910 n engl j med 364;20 nejm.org may 19, 2011

3 Induction in Renal Transplantation rejection defined by a repeat transplant, a peak or current value of panel-reactive antibodies of 20% or more, or black race (see the Supplementary Appendix). Patients assigned to alemtuzumab received a single intravenous dose of 30 mg at the time of. Low-risk patients assigned to conventional therapy received basiliximab: a total of two intravenous doses, 20 mg each, one at the time of and one on day 3, day 4, or day 5. High-risk patients assigned to conventional therapy received rabbit antithymocyte globulin in four intravenous doses of 1.5 mg per kilogram of body weight each, given on day 0, day 1, and day 2, as well as either day 3 or day 4. Maintenance Immunosuppression All patients received tacrolimus, mycophenolate mofetil, and 1 g or less of prednisolone (or equivalent glucocorticoid) over a period of 5 days. Oral tacrolimus was initiated within 48 hours after, or when clinically indicated in patients with delayed graft function, at a dose of 0.10 to 0 mg per kilogram per day in two divided doses, with a target whole-blood trough level of 7 to 14 ng per milliliter for the first 90 days after and 4 to 12 ng per milliliter after 90 days. Mycophenolate mofetil (CellCept, Roche Pharmaceuticals) was administered orally or intravenously daily at a dose of 2 g per day. Mycophenolic acid (Myfortic, Novartis Pharmaceuticals), given orally at a dose of 1440 mg per day, could be substituted for mycophenolate mofetil. Glucocorticoids were discontinued by day 5 after, before discharge from the hospital. The dose of mycophenolate mofetil or mycophenolic acid could be adjusted by the investigator on the basis of assessments of adverse events or efficacy. Prophylaxis against infection with cytomegalovirus, Pneumocystis carinii, fungi, or bacteria and treatment for acute rejection were administered per institutional protocol. Study visits occurred at baseline; at days 1, 7, and 14; and at months 1, 2, 3, 6, 12, 24, and 36. Interim Analysis The data and safety monitoring board met at 6, 12, and 36 months to perform interim safety and efficacy analyses (see the Supplementary Appendix). No formal stopping rules were given in the board s charter. Statistical Analysis Assuming a difference of 9 to 11 percentage points in the rate of biopsy-confirmed acute rejection and a two-sided type I error rate of 5%, we calculated that a total sample of 500 patients would be needed to provide 85% power to detect a significant difference between patients receiving alemtuzumab and patients receiving conventional therapy at months 6 and 12. Analyses were performed on data from study patients who received at least one dose of tacrolimus and one dose of induction therapy. The primary end point was analyzed at 6 and 12 months with the use of Kaplan Meier estimates, with censoring on the last day of tacrolimus use and comparison of the differences between treatment groups on the basis of large-sample normal approximation by means of Greenwood s formula error. After an interim analysis by the data and safety monitoring board, the type I error rate for a significant difference was adjusted to 5 on the basis of the Lan DeMets method 15 with the use of an O Brian Fleming boundary, and the 95.3% confidence interval for the difference between treatment groups was computed. A significant difference was considered to be present only if the difference was significant at both time points (6 and 12 months). All other tests of significance were two-sided, with a significance level of 5. Data on secondary end points survival of patients and grafts, freedom from treated rejection (in patients not undergoing biopsy), and failure-ofefficacy measures (biopsy-confirmed acute rejection, death, or graft loss) were analyzed by means of methods similar to those used for the primary end point. Doses of tacrolimus and mycophenolate mofetil were compared with the use of Wilcoxon s rank-sum test, and trough levels of the drugs were compared with the use of Student s t-test. Mean changes from baseline values for serum creatinine and lymphocyte counts were compared across the four treatment groups by means of analysis of covariance. Adverse-event rates were compared with the use of Fisher s exact test. All tests were two-sided, with a P value of 5 considered to indicate statistical significance. No imputations were made for missing data. Six- and 12-month analyses were repeated at 36 months, with all two-sided tests at a 5 significance level. R esult s Study Patients Enrollment began in May 2005 and ended in February A total of 501 patients were enrolled; 251 n engl j med 364;20 nejm.org may 19,

4 were randomly assigned to receive alemtuzumab, and 250 to receive conventional therapy (Fig. 1). A total of 474 patients were found to be eligible for the study and underwent risk stratification. In all, there were 139 high-risk recipients, 70 of whom received alemtuzumab and 69 of whom received rabbit antithymocyte globulin. There were 335 lowrisk recipients, 164 of whom received alemtuzumab and 171 of whom received basiliximab. Baseline characteristics of the study patients and the kidney donors are given in Table 1. No significant differences were seen between the treatment groups with regard to age, sex, race or ethnic group, numbers of HLA mismatches, panelreactive antibody values, repeat transplants, coldischemia times, delayed graft function, or donor type. The alemtuzumab group had a larger percentage of male donors than the conventionaltherapy group (P = 4). Primary End Point The rate of biopsy-confirmed acute rejection was significantly lower among patients receiving alemtuzumab than among those receiving conventional therapy, at both 6 months (3% vs. 15%, P<01) and 12 months (5% vs. 17%, P<01) after (Fig. 2). Maintenance Immunosuppression Minor differences were found between the alemtuzumab group and the conventional-therapy group in the trough levels of tacrolimus, doses of mycophenolate mofetil or mycophenolic acid, and serum creatinine levels over the 3-year study period (Fig. D in the Supplementary Appendix). Details on dosing and levels of maintenance immunosuppressive agents are provided in the Supplementary Appendix. Secondary End Points The rate of biopsy-confirmed acute rejection at 36 months was lower with alemtuzumab than with conventional therapy (13% vs. 20%, P = 3). Low-Risk Patients Among low-risk patients, the rate of biopsy-confirmed acute rejection was lower with alemtuzumab than with basiliximab at 6 months (2% vs. 18%, P<01), 12 months (3% vs. 20%, P<01), and 36 months (10% vs. 22%, P = 03) (Fig. 2). At 36 months, alemtuzumab and basiliximab were associated with similar rates of severe rejection (Banff grade >IIB) (1% vs. 4%, P = 0) and rejection requiring antibody therapy (7% vs. 12%, P = 0.11). High-Risk Patients Among high-risk patients, no significant differences were seen in the rates of biopsy-confirmed acute rejection between patients receiving alemtuzumab and patients receiving rabbit antithymocyte globulin at 6 months (6% and 9%, respectively; P = 9), 12 months (10% and 13%, respectively; P = 0.53), and 36 months (18% and 15%, respectively; P = 3) (Fig. 2). In addition, there were no significant differences between patients receiving alemtuzumab and patients receiving rabbit antithymocyte globulin in the rates of severe rejection (0% and 3%, respectively; P = 0.15) or rejection for which the patient received antibody therapy (12% and 11%, respectively; P = 0.94) at 36 months. Late Biopsy-Confirmed Acute Rejection Rates of late biopsy-confirmed acute rejection (i.e., rejection occurring between 12 and 36 months after in patients who did not have biopsy-confirmed acute rejection within the first 12 months) were 8% with alemtuzumab as compared with 3% with conventional therapy (P = 3). Rates of late biopsy-confirmed acute rejection among low-risk patients were 8% in the alemtuzumab group and 3% in the basi - lix imab group (P = 0.12). Rates of late biopsyconfirmed acute rejection among high-risk patients were 10% in the alemtuzumab group and 2% in the rabbit-antithymocyte-globulin group (P = 0.13). Survival of Patients Three-year Kaplan Meier actuarial estimates of survival among the study patients were 96% with alemtuzumab and 96% with conventional therapy (P = 0.38) (Fig. 2). Among the low-risk patients, the estimates were 95% with alemtuzumab and 98% with basiliximab (P = 0.19). Among the highrisk patients, the estimates were 99% with alemtuzumab and 91% with rabbit antithymocyte globulin (P = 7) (Fig. 2). Graft Survival Three-year Kaplan Meier actuarial estimates of graft survival were 93% with alemtuzumab and 90% with conventional therapy (P = 0.97) (Fig. 2). After censoring of data on deaths, the estimated rates of graft survival were 95% with alemtuzumab and 93% with conventional therapy (P = 0.38). Among the low-risk patients, the estimates were 93% with alemtuzumab and 92% with basiliximab 1912 n engl j med 364;20 nejm.org may 19, 2011

5 Induction in Renal Transplantation 501 Renal-transplant recipients underwent randomization 180 Low-risk recipients were assigned to receive basiliximab 175 Low-risk recipients were assigned to receive alemtuzumab 70 High-risk recipients were assigned to receive rabbit antithymocyte globulin 76 High-risk recipients were assigned to receive alemtuzumab 9 Were excluded 2 Did not undergo owing to donor 4 Did not undergo owing to recipient 1 Died 2 Did not meet inclusion criteria 11 Were excluded 2 Did not undergo owing to donor 7 Did not undergo owing to recipient 2 Had early graft loss owing to technical 1 Was excluded 1 Did not undergo owing to recipient 6 Were excluded 4 Did not undergo owing to donor 2 Did not undergo owing to recipient 171 Were included in primary analysis 164 Were included in primary analysis 69 Were included in primary analysis 70 Were included in primary analysis 31 Withdrew 7 Had adverse event 2 Withdrew consent 2 Did not comply with protocol 9 Had graft loss 8 Had other reason 3 Were lost to follow-up 30 Withdrew 11 Had adverse event 4 Withdrew consent 4 Did not comply with protocol 4 Had graft loss 1 Had other reason 6 Were lost to follow-up 21 Withdrew 7 Had adverse event 3 Withdrew consent 6 Had graft loss 2 Had other reason 3 Were lost to follow-up 19 Withdrew 2 Had adverse event 4 Withdrew consent 1 Did not comply with protocol 6 Had graft loss 4 Had other reason 2 Were lost to follow-up 140 Completed 3-yr study 134 Completed 3-yr study 48 Completed 3-yr study 51 Completed 3-yr study Figure 1. Randomization, Treatment, and Follow-up of the Study Patients. High-risk patients were defined as patients at high risk for graft rejection because of a repeat transplant, a peak or current value for panel-reactive antibodies of 20% or more, or black race. (P = 0.74) (Fig. 2). After censoring of data on deaths, the estimated rates of graft survival among low-risk patients were 97% with alemtuzumab and 94% with basiliximab (P = 0.17). Among the high-risk patients, the estimates were 91% with alemtuzumab and 84% with rabbit antithymocyte globulin (P = 0.32) (Fig. 2). After censoring of data on deaths, the estimated rates of graft survival among highrisk patients were 91% with alemtuzumab and 91% with rabbit antithymocyte globulin (P = 8). Efficacy Efficacy was assessed as a composite of freedom from biopsy-confirmed acute rejection, death, or graft loss at 3 years. Among low-risk patients, the rate of efficacy at 3 years was 85% with alemtuzumab as compared with 76% with basiliximab (P = 4) (Fig. 2). Among high-risk patients, the rate of efficacy at 3 years was 76% with alem tuzumab and 70% with rabbit antithymocyte globulin (P = 2) (Fig. 2). Serum creatinine levels did not differ significantly between the two treatment groups within the high-risk or low-risk subgroups (Fig. D in the Supplementary Appendix). Lymphocyte Count Among low-risk patients, the mean total lymphocyte count was significantly lower in the alemtuz- n engl j med 364;20 nejm.org may 19,

6 Table 1. Baseline Characteristics of Renal-Transplant Recipients and Donors, According to Risk and Treatment Group.* Characteristic All Patients High-Risk Subgroup Low-Risk Subgroup (N = 234) Conventional Therapy (N = 240) P Value (N = 70) Rabbit Antithymocyte Globulin (N = 69) P Value (N = 164) Basiliximab (N = 171) P Value Recipients Sex no. (%) Male 152 (65) 152 (63) 37 (53) 39 (57) 115 (70) 113 (66) Female 82 (35) 88 (37) 33 (47) 30 (43) 49 (30) 58 (34) Race % White Black Other Age yr Mean 48.0± ± ± ±1 49.4± ±13.6 Range Previous receipt of transplant no. (%) 16 (7) 13 (5) (20) 10 (14) (1) 3 (2) 9 Type of donor no. (%) Living, related 85 (36) 89 (37) 21 (30) 15 (22) 64 (39) 74 (43) Living, unrelated 52 (22) 59 (25) 7 (10) 11 (16) 45 (27) 48 (28) Deceased 97 (41) 92 (38) 42 (60) 43 (62) 55 (34) 49 (29) HLA mismatch no. (%) (7) 19 (8) 2 (3) 5 (7) 15 (9) 14 (8) 1 7 (3) 16 (7) 1 (1) 4 (6) 6 (4) 12 (7) 2 29 (12) 29 (12) 6 (9) 10 (14) 23 (14) 19 (11) (77) 176 (73) 61 (87) 50 (72) 120 (73) 126 (74) Panel-reactive antibody at baseline Mean % 5.8± ± ± ± ± ±2.8 Median (range) % 0 (0 85) 0 (0 98) 0 (0 85) 0 (0 98) 0 (0 75) 0 (0 28) 20% no. (%) 28 (12) 21 (9) 5 23 (33) 20 (29) (3) 1 (1) 4 Cold-ischemia time hr Mean 8.5± ± ±1 13.1±1 7.1± ±8.7 Range 0 38 <1 36 <1 31 < <1 36 Delayed graft function no. (%) 19 (8) 21 (9) 0 7 (10) 9 (13) (8) 12 (7) n engl j med 364;20 nejm.org may 19, 2011

7 Induction in Renal Transplantation Donors Sex no. (%) Male 123 (53) 104 (43) 41 (59) 34 (49) 82 (50) 70 (41) Female 111 (47) 136 (57) 29 (41) 35 (51) 82 (50) 101 (59) Age yr Mean 37.6± ± ± ± ± ±12.4 Range Cytomegalovirus serologic status Donor positive, recipient negative no. (%) 62 (26) 57 (24) (23) 17 (25) 3 46 (28) 40 (23) 0.55 * Plus minus values are means ±SD. P values were calculated with the use of a chi-square test for discrete variables and one-way analysis of variance for continuous variables. Race was provided by the investigators. Panel-reactive antibody values at baseline were the highest levels within the 6-month period before or at the time of ; data were available for 197 patients in the alemtuzumab group and 198 in the conventional-therapy group. For cold-ischemia time, data were available for 223 patients in the alemtuzumab group and 228 in the conventional-therapy group. umab group than in the basiliximab group at all time points (Fig. 2). Among high-risk patients, the use of lymphocyte-depleting antibodies (alemtuzumab and rabbit antithymocyte globulin) in both treatment groups resulted in a low mean total lymphocyte count within the first week after to less than 10% of the baseline value (Fig. 2). Adverse Events Table 2 lists the adverse events and serious adverse events reported in the study patients. The incidence of serious adverse events related to cancer was higher in the alemtuzumab group than in the conventional-therapy group (P = 3). However, the overall rate of adverse events related to cancer was similar in the two treatment groups. Low-Risk Patients Among low-risk patients, the rate of infectious adverse events that were serious was slightly lower with basiliximab than with alemtuzumab (22% vs. 35%, P = 2). However, the rates of all infectious adverse events did not differ significantly between these two groups. The 3-year rates of cytomegalovirus and BK virus infections, cancer, and B-cell lymphoma (post- lymphoproliferative disorders) were similar among the treatment groups. High-Risk Patients Among high-risk patients, the rate of all infectious adverse events was slightly higher with rabbit antithymocyte globulin than with alemtuzumab (81% vs. 60%, P = 09). However, the rates of serious infectious adverse events were similar between these two groups. The 3-year rates of cytomegalovirus and BK virus infections, urinary tract infections, pneumonia, or B-cell lymphoma (post lymphoproliferative disorders), and cancer were similar among the treatment groups. Post Hoc Analyses of c4d+ biopsy specimens Antibody-mediated rejection was not a prespecified end point, and we did not collect donor-specific antibody data, nor did we perform a central review of kidney-biopsy specimens. We reviewed biopsy reports by local pathologists to obtain data on the incidence of C4d+ staining. Among all study patients, C4d+ staining was reported for 8 of 226 patients (4%) receiving alemtuzumab and 2 of 238 patients (1%) receiving conventional therapy (P = 6). Among low-risk patients, C4d+ staining n engl j med 364;20 nejm.org may 19,

8 A BCAR 6 mo Conventional 12 mo 36 mo Months % of Patients with BCAR Conventional therapy P Value <01 <01 3 B BCAR, According to Risk of Graft Rejection High Risk Rabbit antithymocyte globulin Low Risk Basiliximab C Efficacy Failure High Risk Rabbit antithymocyte globulin Low Risk Basiliximab D Survival of Patients and Grafts High Risk, survival of patients Rabbit antithymocyte globulin, survival of patients, graft survival Rabbit antithymocyte globulin, graft survival Low Risk, survival of patients Basiliximab, survival of patients, graft survival Basiliximab, graft survival E Mean Lymphocyte Count Count (cells/mm 3 ) Rabbit antithymocyte globulin High Risk Count (cells/mm 3 ) Low Risk P<5 Basiliximab n engl j med 364;20 nejm.org may 19, 2011

9 Induction in Renal Transplantation Figure 2 (facing page). Kaplan Meier Estimates of Freedom from Biopsy-Confirmed Acute Rejection (BCAR), Failure of Efficacy, Survival of Patients and Grafts, and Lymphocyte Counts. Panel A shows the proportions of study patients remaining free from BCAR according to overall treatment group. Panels B through E show data according to both treatment group and risk of graft rejection, with a high risk defined by a repeat transplant, a peak or current value for panel-reactive antibodies of 20% or more, or black race. Panel B shows data for freedom from BCAR, Panel C data for freedom from failure of efficacy (defined as BCAR, death, or graft loss), Panel D data for survival of patients and grafts, and Panel E mean lymphocyte counts. In Panel E, means for low-risk patients were significantly different (P<5) at all time points except day 0. The x-axis units in Panel E are not to scale; the I bars indicate standard deviations. was reported for 5 of 164 patients (3%) receiving alemtuzumab and 2 of 171 patients (1%) receiving basiliximab (P = 7). Among high-risk patients, C4d+ staining was reported for 3 of 67 patients (4%) receiving alemtuzumab and no patients receiving rabbit antithymocyte globulin (P = 5). Since we did not systematically collect data on C4d+ staining, our statistical comparisons should be considered exploratory. Discussion Studies have shown that early withdrawal of glucocorticoids results in excellent long-term outcomes in kidney-transplant recipients. 4,8,9,11 Antibody induction therapy is generally considered important for achieving optimal results with early glucocorticoid withdrawal. 13 Our trial indicates that alemtuzumab was more effective in preventing biopsy-confirmed acute rejection than conventional induction therapy and was as effective as rabbit antithymocyte globulin in high-risk transplant recipients. The primary end point was tested with the use of two control therapies: rabbit antithymocyte globulin induction in patients at high risk for graft rejection and basiliximab in low-risk patients. These agents were chosen because they are the most frequently used induction agents in the United States for these two groups of patients. The graft-rejection rate among patients who received alemtuzumab was dramatically lower than the rate among those who received basiliximab, an interleukin-2 receptor antibody, and alemtuzumab was not associated with an increased risk of infection. The degree of lymphocyte depletion was not correlated with the rate of adverse events. Furthermore, the treatment groups did not differ significantly with respect to specific types of bacterial infections (urinary tract infections, pneumonia, and bacteremia) or opportunistic viral infections (cytomegalovirus and BK virus infections). Incidences of B-cell lymphoma (post- lymphoproliferative disorders) and other cancers were also similar between the alemtuzumab groups and the conventionaltherapy groups. A previously published, singlecenter comparison of alemtuzumab induction and basiliximab induction in patients undergoing early glucocorticoid withdrawal also showed no significant differences in infection rates. 4 The differences in rejection rates that we found among the groups did not result in significant differences in the survival of patients or allografts. The higher rejection rates and greater severity of rejection seen with basiliximab induction as compared with alemtuzumab induction were not associated with poorer outcomes. Although it is possible that the higher frequency of early rejection associated with basiliximab does not compromise long-term graft survival, rejection is historically viewed as a strong predictor of allograft failure. 16,17 A comparative study of rabbit antithymocyte globulin and basiliximab showed that the rate of rejection was higher with basiliximab than with rabbit antithymocyte globulin but that the higher rate was not associated with a lower 1-year rate of graft survival. 18 However, 5-year results of the same study showed an increased rate of graft loss, after censoring of data on deaths, among patients receiving basiliximab. 19 Previous studies of the efficacy of alemtuzumab induction in patients undergoing renal have had contradictory results (see the Supplementary Appendix). Although some studies have shown excellent results with alemtuzumab, 2-5 others have shown that alemtuzumab may be associated with increased rates of acute rejection or antibody-mediated rejection or decreased rates of graft survival after censoring of data on deaths Though a review of Scientific Registry of Transplant Recipient data suggested that alemtuzumab was associated with reduced renal-allograft survival as compared with anti interleukin-2 receptor antibody induction, this association was not significant in the multivariate analysis. 20 One study showed a 21.2% rate of antibody-mediated rejection with alemtuzumab, but 121 of the 613 patients did not receive calcineurin-inhibitor therapy, and failure to provide such therapy is known to increase n engl j med 364;20 nejm.org may 19,

10 Table 2. Selected Serious Adverse Events and Adverse Events from 0 to 3 Years after Transplantation, According to Risk and Treatment Group.* Event All Patients High-Risk Subgroup Low-Risk Subgroup Alemtu zumab (N = 234) Conventional Therapy (N = 240) P Value Alemtu zumab (N = 70) Rabbit Antithymocyte Globulin (N = 69) P Value Alemtu zumab (N = 164) no. of patients (%) no. of patients (%) no. of patients (%) Basiliximab (N = 171) P Value Serious adverse events Any 124 (53) 121 (50) 6 33 (47) 40 (58) 4 91 (55) 81 (47) 0.16 Cardiovascular event 17 (7) 25 (10) 6 2 (3) 8 (12) 6 15 (9) 17 (10) 5 Infection 76 (32) 61 (25) (27) 23 (33) 6 57 (35) 38 (22) 2 Cancer 11 (5) 3 (1) 3 4 (6) (4) 3 (2) 1 Renal dysfunction 23 (10) 27 (11) 6 6 (9) 3 (4) 9 17 (10) 24 (14) 0.32 Diabetes-related event 7 (3) 9 (4) 0 2 (3) 3 (4) 8 5 (3) 6 (4) 0 Gastrointestinal event 16 (7) 27 (11) (9) 5 (7) 0 10 (6) 22 (13) 4 Hematologic event 16 (7) 14 (6) (7) 3 16 (10) 9 (5) 0.15 Adverse events White-cell count <3000/mm (57) 84 (35) <01 44 (63) 34 (49) (54) 50 (29) <01 Platelet count <50,000/mm 3 2 (1) 1 (<1) (1) 9 2 (1) 0 4 GCSF use 24 (10) 19 (8) 3 8 (11) 6 (9) (10) 13 (8) 0.56 Infection Any 171 (73) 179 (75) (60) 56 (81) (79) 123 (72) 0.17 CMV 30 (13) 22 (9) 4 8 (11) 8 (12) 0 22 (13) 13 (8) 0.11 BK virus 26 (11) 24 (10) (10) 10 (14) 5 19 (12) 14 (8) 0.36 EBV 0 4 (2) (1) (2) 5 Herpes simplex 6 (3) 4 (2) (1) (3) 4 (2) 0.75 Herpes zoster 11 (5) 8 (3) 9 2 (3) 2 (3) 0 9 (5) 6 (4) 4 Candida Noninvasive 4 (2) 5 (2) 0 1 (1) 3 (4) (2) 2 (1) 8 Invasive 4 (2) 7 (3) (3) 5 4 (2) 5 (3) 0 Cancer Any 18 (8) 13 (5) (7) 1 (1) 1 13 (8) 12 (7) 4 B-cell lymphoma 1 (<1) (<1) 0 9 Skin cancer 9 (4) 11 (5) 2 2 (3) 1 (1) 0 7 (4) 10 (6) 2 Other cancer 8 (3) 2 (<1) 6 3 (4) (3) 2 (1) 7 * CMV denotes cytomegalovirus, EBV Epstein Barr virus, and GCSF granulocyte colony-stimulating factor. P values of less than 5 were considered to indicate statistical significance. The P values were calculated with the use of Fisher s exact test (two-tailed). One patient in this category had malignant melanoma and prostate cancer. One patient in this category had bladder cancer and basal-cell cancer n engl j med 364;20 nejm.org may 19, 2011

11 Induction in Renal Transplantation the risk of rejection. 23 Antibody-mediated rejection was not an end point in our study, and alloantibody formation was not assessed. However, a post hoc review of local biopsy reports did not show a significantly increased rate of C4d+ staining of the samples from patients receiving alemtuzumab. In addition, post hoc analysis of rates of late acute rejection (rejection between 12 and 36 months after ) in our study revealed a trend toward higher rates with alemtuz umab than with conventional-induction therapy. Future studies should evaluate antibody-mediated rejection, late rejection, and development of donor-specific HLA antibody in patients receiving alemtuzumab. The low rates of biopsy-confirmed acute rejection in this study may have been due, in part, to the exclusion of patients who received kidneys from expanded-criteria donors, donors without a heartbeat, and standard-criteria donor kidneys with prolonged cold-ischemia times. Kidneys from such donors are at increased risk for delayed graft function, which may be associated with an increased risk of acute rejection. The predominance of living-donor transplants may also have contributed to the low rates of biopsy-confirmed acute rejection. However, donor characteristics were similar among all treatment groups. In conclusion, our results indicate that alemtuzumab induction with early glucocorticoid withdrawal is superior to conventional immunosuppression in preventing biopsy-confirmed acute rejection in the first year after. This benefit was primarily realized in recipients at low immunologic risk. Supported by Astellas Pharma Global Development. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. 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