Alemtuzumab Induction and Prednisone-Free Maintenance Immunotherapy in Kidney Transplantation: Comparison with Basiliximab Induction—Long-Term Results

Authors


  • Presented at the 2005 American Transplant Congress, May 2005. Seattle, WA.

*Corresponding author: Dixon B. Kaufman, d-kaufman2@northwestern.edu

Abstract

This study examined alemtuzumab (anti-CD 52, Campath-1H) and basiliximab (anti-CD 25, Simulect) as induction immunosuppression in kidney transplantation.

We used a single-center, nonrandomized, retrospective, sequential study design to evaluate outcomes in kidney transplant recipients given either alemtuzumab (n = 123) or basiliximab (n = 155) induction in combination with a prednisone-free maintenance protocol using tacrolimus and mycophenolate mofetil. Kaplan–Meier analyses of long-term patient and graft survivals and rejection rates were determined according to induction agent, donor source and recipient ethnicity. Secondary endpoints included the quality of renal allograft function and the etiology of infectious complications.

Overall long-term patient and graft survival rates did not significantly differ between patients treated with alemtuzumab and basiliximab. A lower rate of early (<3 months) rejection was observed in the alemtuzumab (4.1%) versus the basiliximab (11.6%) group, but the rates for both groups were equivalent at 1 year. Patient and kidney survival and rejection rates were nearly identical between Caucasians and African Americans that received alemtuzumab. Quality of renal function and incidence of infectious complications were similar in the two groups.

Alemtuzumab induction therapy was similar in efficacy to basiliximab in a prednisone-free maintenance immunosuppressive protocol for an ethnically diverse population of kidney transplant recipients.

Introduction

Antibody induction therapy has been examined as a means to permit elimination of chronic exposure to corticosteroids in kidney transplant recipients. Most published reports have presented small, single-center pilot studies limited to a single induction strategy. Further, most patient cohorts are low-immunological risk transplant recipients. Very few reports have presented long-term results, especially in high-risk recipients (1) such as African Americans (2). No studies have focused on the importance of the choice of class of induction monoclonal antibodies used in steroid-avoidance protocols.

Alemtuzumab (Campath-1H®, ILEX Oncology, Inc., San Antonio, TX) is an attractive induction agent to consider in steroid-avoidance protocols because of its powerful immune-cell depleting activity. Alemtuzumab is a humanized monoclonal antibody (IgG1) that reacts with the CD52 cell-surface antigen densely expressed on T- and B-cells, eosinophils and some populations of monocytes, macrophages and dendritic cells (3). Calne et al. (4) were the first to report evidence of the utility of alemtuzumab to facilitate steroid-free immunosuppression in kidney transplantation. They initiated a pilot study in 1997 with two 20-mg doses of alemtuzumab as induction therapy in conjunction with cyclosporine (Sandimmune®, Novartis, Basil, Switzerland) monotherapy. Excellent long-term patient and graft survival with low rejection and infection rates helped establish the feasibility of using alemtuzumab in this manner and led to the concept of “prope tolerance.”

More recently, Kirk et al. (5) and Knechtle et al. (6) independently reported on a double-dose alemtuzumab induction strategy in conjunction with calcineurin-inhibitor- and steroid-free maintenance that depended on sirolimus (Rapamune®, Wyeth Pharmaceuticals, Philadelphia, PA) monotherapy. This protocol was applied to relatively low-immunological risk Caucasian recipients of kidneys from living donors. Excellent short-term patient and graft survival rates and renal allograft function were achieved. Unfortunately, high rejection rates limited consideration about applying this immunosuppressive approach more broadly and called into question the tolerogenic potential of alemtuzumab.

These studies suggest that the choice of maintenance agents used in conjunction with alemtuzumab may have important implications on the efficacy of this agent with respect to rejection risk. In fact, two studies initiated after this protocol was introduced described the use of double-dose alemtuzumab in steroid-containing (7) and prednisone-free (7) protocols, both based on a more conventional approach that used a calcineurin inhibitor and mycophenolate mofetil (CellCept®, Roche, Nutley, NJ) (MMF) maintenance therapy. One of these studies (7) demonstrated less rejection and improved graft survival in patients with delayed graft function; the other (8) demonstrated short-term feasibility in very low-risk recipients.

In this study, 123 adult kidney transplant recipients received a single dose (30 mg) of alemtuzumab induction therapy in conjunction with tacrolimus (Prograf®, Fujisawa Pharmaceuticals, Deerfield, IL) and MMF in a prednisone-free protocol. The patients were followed up for a minimum of 30 months; outcomes were compared to those of a previous consecutive historical group of patients who received basiliximab (Simulect®, Novartis, East Hanover, NJ) rather than alemtuzumab. Long-term patient and graft survival rates were determined and survival results were also analyzed according to donor source and recipient ethnicity. In addition, analyses of intensity of exposure to maintenance therapy, rejection rates, infection rates and quality of renal function were conducted. The results indicated that induction with either single-dose alemtuzumab or basiliximab in combination with tacrolimus and MMF facilitated a prednisone-free protocol in kidney transplantation. Long-term patient and graft survival rates across an ethnically diverse kidney transplant recipient population were equivalent for alemtuzumab- and basiliximab-treated recipients. Alemtuzumab allowed reduced exposure to tacrolimus and MMF, providing better prophylaxis against early rejection episodes without an increase in infectious complications and without compromising long-term renal function.

Materials and Methods

Study design

This was a single-center, retrospective, non-randomized, sequential study of a prednisone-free immunosuppression protocol for kidney transplant recipients who received tacrolimus and MMF maintenance therapy in conjunction with either alemtuzumab or basiliximab induction. The two recipient cohorts were treated sequentially. All patients were entered in a consecutive manner according to the particular induction therapy received.

The alemtuzumab treatment group (n = 123) included recipients of kidneys from deceased and living donors and did not exclude anyone based on ethnic background. Transplants were performed during the year from October 2, 2001 through September 29, 2002. The minimum follow-up time was 2.5 years post-transplant, with a mean ± SD of 33 ± 2.3 months (range 30–42 months). The basiliximab-treated group (n = 155) was also inclusive with respect to donor source and ethnicity and included patients who received their transplants during the year from September 23, 1998 through September 9, 2001. The mean ± SD follow-up for recipients receiving basiliximab was 47.0 ± 10.1 months (range 31–65 months).

Demographics

Recipient (Table 1) and donor (Table 2) demographics were stratified according to the induction agent received. The recipient demographic features of age, gender, race, duration and type of dialysis, donor source, HLA mismatch in the deceased-donor group and cytomegalovirus (CMV) status of the respective groups are remarkably similar except for the relatively higher proportion of recipients of grafts from living donors in the alemtuzumab group (75%, 94/123) than in the basiliximab group (63%, 97/155). Within the living donor category, there were similar proportions of living unrelated donors in the alemtuzumab group (25%, 31/123) and the basiliximab group (18%, 28/155). The donor demographics of age, gender, race and cold ischemia time were also similar in the two treatment groups.

Table 1.  Demographics of renal transplant recipients

Characteristic
Basiliximab
(n = 155)
Alemtuzumab
(n = 123)
Age43.7 ± 12.9 years46.3 ± 13.3 years
Range14–67 years18–77 years
Gender (M:F)92 (59%):62 (41%)70 (57%):53 (43%)
Race
 Caucasian93 (60%)76 (61%)
 African American30 (19%)28 (23%)
 Hispanic19 (12%)13 (11%)
Dialysis duration pre-transplant25.2 ± 25.8 months22.2 ± 23.0 months
Dialysis modality pre-transplant
 Hemodialysis97 (62%)82 (67%)
 Peritoneal dialysis31 (20%)23 (19%)
 None27 (18%)18 (14%)
Donor source
 Deceased58 (37%)31 (25%)
 AB mismatch2.5 ± 2.62.6 ± 2.7
 DR mismatch1.3 ± 1.31.3 ± 1.3
 Living related69 (45%)63 (50%)
 Living unrelated28 (18%)31 (25%)
CMV status
 D+/R−32 (21%)19 (16%)
 D+/R+54 (35%)53 (43%)
 D−/R+29 (19%)26 (21%)
 D−/R−38 (25%)25 (20%)
Table 2.  Demographics of renal organ donors

Characteristic
Basiliximab
(n = 155)
Alemtuzumab
(n = 123)
Age36.7 ± 12.8 years36.7 ± 11.4 years
Range9–69 years10–63 years
Gender (M:F)80 (52%):75 (48%)60 (49%):63 (51%)
Race
 Caucasian105 (68%)83 (67%)
 African American25 (16%)23 (19%)
 Hispanic15 (10%)12 (10%)
 Other10 (6%)5 (4%)
CIT of kidney23.1 ± 7.3 h21.8 ± 9.3 h

Immunosuppression and medical therapeutics

Maintenance immunosuppression for patients in both groups included a 3-day course of intravenous corticosteroids: methylprednisolone, 500 mg in the operating room, 250 mg on post-transplant day 1 and 125 mg on post-transplant day 2. Oral prednisone was not used. Recipients also received tacrolimus adjusted to achieve 12-h blood concentrations of approximately 6–8 ng/mL by immunoassay (IMX®, Abbott Labs, IL). The MMF target dose was 1.5–2.0 g/day in the alemtuzumab-treated recipients and 2.5–3.0 g/day in the basiliximab treatment group. Immunosuppressive drug levels or doses were studied over a 3-year period. Most recipients received prophylactic ganciclovir or valganciclovir for 3 months post-transplant; the exceptions were recipients with negative CMV serologic status who received grafts from donors with a CMV-negative serologic status. Bactrim® was used for pneumocystis prophylaxis except in patients with sulfa allergies, who were given dapsone or aerosolized pentamadine. For fungal prophylaxis, patients were given oral clotrimazole or Nystatin® for 3 months post-transplant.

Statistical analyses

We determined actuarial patient and graft survival rates, death-censored graft survival rates, the cumulative incidence of biopsy-proven acute rejection episodes, parameters of renal function (mean serum creatinine levels) and infectious complications. Actuarial patient and graft survival rates were calculated beginning at the time of transplantation. Kidney graft failure was defined as removal or loss of function requiring return to dialysis. Actuarial survival estimates were calculated using Kaplan–Meier life-table analysis (9) and the series was followed through 3/26/05. The Cox–Mantel test was used to compare differences in rejection rates. Data are presented as means ± SD. All statistical tests were two-tailed; p < 0.05 was considered significant.

Results

Demographics

All patients (n = 278) who received renal transplants from deceased or living donors beginning in September 1998 were managed using a prednisone-free, tacrolimus/MMF-based maintenance immunosuppressive protocol in combination with two different induction agents, alemtuzumab (n = 123) or basiliximab (n = 155). The 123 patients who received alemtuzumab were all treated a year earlier, between September 1998 and September 2001 and all received the same induction therapy. Thus, two sequential transplant eras were defined according to the type of induction therapy received. There were no significant differences in the demographic characteristics of the two recipient cohorts (Table 1). Specifically, the groups had comparable numbers of African Americans (alemtuzumab, 23%; basiliximab, 19%) and comparable numbers of recipients of kidneys from deceased donors (alemtuzumab, 25%; basiliximab, 37%). Donor and recipient CMV status was also comparable in the two groups. There were no significant differences in other recipient or donor demographic characteristics of the two cohorts (Table 2).

Maintenance immunosuppression

All patients were managed with a prednisone-free maintenance regimen of tacrolimus and MMF. Over a 3-year follow-up period, less than 7% of recipients in each induction treatment group required chronic prednisone therapy. Recipients in the alemtuzumab induction group received significantly less exposure to both tacrolimus and MMF as measured at 1, 6, 12, 24 and 36 months post-transplant (Table 3). At 1 and 2 years post-transplant, the mean 12-h trough concentration of tacrolimus and dose of MMF were both 25% higher in patients treated with basiliximab than in those treated with alemtuzumab.

Table 3.  Maintenance immunosuppression dosing of MMF and 12-h trough concentrations of tacrolimus in kidney transplant recipients receiving prednisone-free maintenance immunosuppression and either basiliximab or alemtuzumab induction
Time (months)
post-transplant
Basiliximab
(n = 155)
Alemtuzumab
(n = 123)

p-Value
Agent
 MMF (g/day)
  12664 ± 5081638 ± 4180.0001
  62097 ± 6931521 ± 5560.0001
  122063 ± 6891656 ± 3860.0001
  241996 ± 6941564 ± 3850.0017
  361962 ± 6741556 ± 2830.0001
 Tacrolimus (ng/mL)
  110.7 ± 4.18.1 ± 2.90.001
  67.6 ± 4.46.3 ± 2.50.02
  127.2 ± 2.86.4 ± 2.20.033
  247.4 ± 2.85.9 ± 2.00.004
  367.2 ± 3.36.3 ± 1.9ns

Patient and graft survival

The overall 1-year patient and graft survival rates were similar for the two treatment groups (Figure 1). The 1-year actual patient survival rates for recipients who received alemtuzumab and basiliximab were 96.8% and 99.4%, respectively (p = ns). The 1-year actual death-censored graft survival rates for recipients that received alemtuzumab and basiliximab were 99.2% and 99.4%, respectively (p = ns).

Figure 1.

(A) Patient survival, (B) kidney allograft functional survival rates and (C) cumulative rejection-free rates in renal transplant recipients given prednisone-free maintenance immunosuppression with tacrolimus and MMF and induction therapy with either basiliximab (n = 155), or alemtuzumab (n = 123). The results were not statistically significantly different in any outcomes (Cox–Mantel test).

Overall long-term patient survival rates were similar between both treatment groups as well (Figure 1). Over a 3-year post-transplant time period, there were five deaths in the alemtuzumab group and two deaths in the basiliximab group (Table 4). Three of the deaths in the alemtuzumab group were not transplant-related and were due to tracheal collapse immediately post-extubation following surgery, cardiac death and intracerebral hemorrhage. Overall long-term graft survival also did not differ significantly between the two groups (Figure 1). Specifically, there were 10 graft losses (exclusive of death) in the alemtuzumab group and 7 graft losses in the basilixamab group during the 3 years of follow-up (Table 4).

Table 4.  Etiology of death or kidney graft loss according to induction therapy

Group
Death/graft
loss
Time
post-transplant
Donor
type

Diagnosis
  1. LD = living donor; DD = deceased donor; CAN = chronic allograft nephropathy.

AlemtuzumabDeathDay 0LDRespiratory arrest
Death5 monthsDDSepsis
Death5 monthsLDCardiac arrest
Death8 monthsLDIntracranial bleed
Death22 monthsLDSepsis
Graft loss9.5 monthsLDArterial thrombosis
Graft loss14 monthsDDCAN
Graft loss14 monthsDDBK polyoma
Graft loss16 monthsLDTorsion
Graft loss23 monthsLDRecurrent disease
Graft loss23.5 monthsDDRecurrent disease
Graft loss24 monthsLDCortical necrosis
Graft loss26.5 monthsLDCAN
Graft loss33.5 monthsLDCAN
Graft loss33.5 monthsLDRejection
BasiliximabDeath11 monthsDDSepsis
Death35 monthsLDHeart failure
Graft loss7 monthsDDSepsis
Graft loss17 monthsDDRejection
Graft loss18.5 monthsDDCAN
Graft loss21 monthsLDRejection
Graft loss21.5 monthsDDRejection
Graft loss33 monthsLDCAN
Graft loss35 monthsDDRejection

Patient and graft survival rates were also analyzed according to donor source (Figure 2). The 1-year actual patient survival rates among alemtuzumab- and basiliximab-treated recipients of kidneys from deceased donors were 96.8% and 98.3%, respectively (p = ns); the rates among recipients of kidneys from living donors were 96.7% and 100%, respectively (p = ns). The actual 1-year graft survival rates among alemtuzumab- and basiliximab-treated recipients of transplants from deceased donors were 100% and 98.3%, respectively (p = ns), while those among recipients of transplants from living donors were 98.9% and 100%, respectively (p = ns). Further comparison of patients who received their kidneys from deceased donors and those who received transplants from living donors showed that there was no significant difference with respect to either long-term patient survival (Figure 2A and 2D) or long-term kidney graft survival rates (Figure 2B and 2E). The results were also analyzed according to living related and unrelated status. No significant differences in outcomes were observed.

Figure 2.

Patient survival, kidney allograft functional survival rates and cumulative rejection-free rates in recipients of either deceased- (A, B, C) or living-donor (D, E, F) renal transplant recipients given prednisone-free maintenance immunosuppression with tacrolimus and MMF and induction therapy with either basiliximab or alemtuzumab. Statistical analyses using Cox–Mantel test.

The causes of kidney graft losses in the alemtuzumab- and basiliximab-treated groups according to donor source are shown in Table 4. Most of the graft losses in both treatment groups were secondary to immunological or infectious transplant complications. Two graft losses in the alemtuzumab-treated recipients of grafts from living donors were technical in nature, including ischemic necrosis by vascular pedicle torsion and late arterial thrombosis.

Rejection

The overall rejection rates were similar in the two treatment groups (Figure 1C). The 12-month actual rejection rates for recipients that received alemtuzumab and basiliximab were 14.9% and 13.5%, respectively (p = ns). There were 19 recipients in the alemtuzumab group and 21 in the basilixamab group that had a rejection episode within that time frame (Table 5).

Table 5.  Characterization of kidney graft rejection according to induction therapy

Induction
Transplant
date
Donor
source

Gender

Ethnicity
Time
post-transplant (days)
Banff
grade

Treatment
  1. LRD = living related donor; LURD = living unrelated donor; DD = deceased donor; AA = African American; CAN = chronic allograft nephropathy.

Alemtuzumab8/16/02LRDMCaucasian101bThymoglobulin
4/25/02LRDMCaucasian121aSteroids
4/16/02LRDFCaucasian531aSteroids, OKT3
6/7/02LRDFCaucasian631bOKT3
10/25/01LURDFCaucasian721aSteroids
2/15/02LURDMCaucasian971bOKT3
5/17/02LURDFCaucasian1141aSteroids
9/27/02LURDFPacific Islander1142bOKT3, Thymoglobulin, PP
3/28/02LRDMAsian1181aSteroids
11/6/01LURDFCaucasian1362aOKT3
6/13/02LRDMCaucasian1371bThymoglobulin
10/23/01LURDFCaucasian1531bOKT3, Thymoglobulin
8/4/02DDMAA1572aOKT3
3/22/02LURDFAA1681bThymoglobulin
9/17/02DDFCaucasian2062aThymoglobulin/OKT3
7/3/02DDMHispanic2091bOKT3
9/7/02DDMCaucasian2131aThymoglobulin
8/15/02DDMCaucasian2431bThymoglobulin
5/9/02LURDMCaucasian2831bOKT3
Basiliximab02/01/01LRDFAA32aOKT3
01/06/99LRDMHispanic42bOKT3
03/29/01LRDFCaucasian42aOKT3
03/03/00LRDMCaucasian51bOKT3
09/29/98LRDMCaucasian61bSteroids
12/08/98LRDFCaucasian61bOKT3
12/22/99LRDMCaucasian71bOKT3
11/17/00DDFCaucasian71bOKT3
09/30/99LURDMArmenian72aOKT3
05/03/01LRDFCaucasian81bOKT3
02/15/00DDMCaucasian102aOKT3
12/03/98LRDMHispanic111bOKT3
12/01/00LRDFCaucasian121aSteroids
12/21/99LRDMCaucasian161aSteroids
09/14/99DDFCaucasian271aSteroids
11/20/99DDFAA682aThymoglobulin
11/30/99DDMCaucasian791bOKT3
10/24/99DDFCaucasian862aOKT3
09/15/99DDMAA1961aSteroids
05/29/01DDFCaucasian2241bOKT3
07/01/01DDMCaucasian2911bOKT3

The severity of rejection was assessed using Banff criteria. There was a trend toward less severity of rejection in the alemtuzumab group, in which the proportion of rejection episodes of grade Banff 1a or 1b was 77% (10/13); the corresponding proportion in the basiliximab group was 61% (11/18). Treatment of rejection was based on severity, with steroids used for Banff 1a and antibody used for any rejection of greater severity. There was one case of vascular rejection requiring plasmapheresis (day 114), but no episodes of early humoral or macrophage-mediated rejection or hemolytic uremic syndrome such as those described in the series using sirolimus monotherapy (10,11).

The kinetics of rejection was also very different. The mean ± SD days (median day) of rejection in the alemtuzumab group was 148 ± 82 (153 days) and, in the basiliximab treatment group, 51 ± 83 (10 days). Within 90 days of transplant there were 5 recipients (4% incidence) in the alemtuzumab treatment group with rejection episodes and 18 recipients (12% incidence) in the basiliximab treatment group.

The analyses of rejection were also stratified according to donor source (Figure 2C and 2F). For recipients of kidneys from deceased donors, the 12-month actual rejection rates for recipients that received alemtuzumab and basiliximab were 16.7% and 15.5%, respectively (p = ns). The mean ± SD days (median day) of rejection in the alemtuzumab and basiliximab treatment groups were 226 ± 43 (213 days) and 110 ± 102 (79 days), respectively. Within 90 days of transplant, there were 0 recipients in the alemtuzumab treatment group that had a rejection episode and 6 recipients (10.3% incidence) in the basiliximab treatment group.

For recipients of kidneys from living donors, the 12-month actual rejection rates for recipients that received alemtuzumab and basiliximab were 14.3% and 12.4%, respectively (p = ns). In both the alemtuzumab and basiliximab treatment groups, the mean ± SD day of rejection occurred significantly earlier than it did in the deceased-donor group. The mean ± SD days (median days) of rejection in the alemtuzumab and basiliximab treatment groups were 66 ± 53 (58 days) and 7 ± 4 (6 days), respectively. Within 90 days of transplant four recipients (5.5% incidence) in the alemtuzumab treatment group and 12 recipients (12.4% incidence) in the basiliximab treatment group had a rejection episode.

Patient and graft survival and rejection according to ethnicity

Patient and graft survival in the alemtuzumab treatment group were also analyzed after stratification by ethnicity (Figure 3). Alemtuzumab-treated Caucasian and African American recipients demonstrated statistically equivalent patient and graft survival rates (Figure 3). The 1-year actual patient survival rates among alemtuzumab-treated Caucasian and African American recipients were 96.1% and 96.4%, respectively (Figure 3A, p = 0.90) and the 1-year actual graft survival rates (death-censored) in Caucasian and African American recipients were 98.6% and 100%, respectively (Figure 3B, p = 0.58). Rejection rates in the alemtuzumab group were also analyzed according to ethnicity. Figure 3C shows no difference in the incidence of rejection among Caucasian and African American recipients.

Figure 3.

Patient survival, kidney allograft functional survival rates and cumulative rejection-free rates in African American and Caucasian recipients receiving prednisone-free maintenance immunosuppression with tacrolimus and MMF and induction therapy with alemtuzumab (A, B, C). The results were not statistically significantly different in any outcome (Cox–Mantel test).

Quality of renal function

Serum creatinine values were compared between the two treatment groups at 1, 6, 12, 24 and 36 months post-transplant. Quality of renal allograft function according to serum creatinine values were similar throughout the 3-year follow-up period (Table 6).

Table 6.  Serum creatinine values in kidney transplant recipients receiving prednisone-free maintenance immunosuppression and either alemtuzumab or basiliximab induction
Time
post-transplant
(month)


Alemtuzumab


Basiliximab


p-Value
08.14 ± 3.209.01 ± 3.72 
11.51 ± 0.751.54 ± 0.49ns
61.38 ± 0.561.39 ± 0.55ns
121.42 ± 0.591.36 ± 0.48ns
241.41 ± 0.521.45 ± 0.68ns
361.52 ± 0.721.42 ± 0.65ns

Infectious complications and malignancy

The significant infectious complications and malignancies that occurred within 3 years of transplantation are listed in Table 7. The overall incidence and etiology of infectious disease were very similar in both induction treatment groups. CMV occurred in 4% and 5% of recipients in the alemtuzumab and basiliximab groups, respectively. The incidence of CMV in recipients that were not previously exposed to CMV that received organs from donors with positive CMV serology in the alemtuzumab and basiliximab groups were 21% and 19%, respectively. The incidence of malignancy was also similar in the two induction groups. Two recipients in each group acquired post-transplant lymphoproliferative disease (PTLD).

Table 7.  Major infectious disease or malignancy within 3 years of kidney transplantation in recipients receiving prednisone-free maintenance immunosuppression and either alemtuzumab or basiliximab induction
AlemtuzumabBasiliximab
Cytomegalovirus × 5Cytomegalovirus × 8
Varicella-Zoster virus × 3Herpes simplex virus × 4
MycobacteriumVaricella-Zoster virus
BK nephritisBK nephritis
Enterococcus bacteremiaHistoplasmosis
Candida pneumonitisPyelonephritis × 2
Bacterial septic deathKlebsiella bacteremia
 Bacterial septic death
 Psoas abscess
 Infected liver cyst
PTLD × 2PTLD × 2
Adenocarinoma (unknown primary)Carcinoid (pulmonary)
Breast carcinomaEndometrial carcinoma

Discussion

The emphasis of this retrospective, single-center study was on comparing the long-term results of a prednisone-free immunosuppression protocol that included the use of different agents, basiliximab or alemtuzumab, for induction therapy, but maintenance immunosuppression with the same agents, tacrolimus and MMF. Initiated in September 1998, the study included transplant recipients from two distinct periods as defined by the induction agent received, basiliximab before October 2001 and alemtuzumab thereafter. Because of its early starting date, the study contains some interesting elements. Notably, it describes a long-term view of results, especially in the basiliximab cohort. Also with respect to the use of alemtuzumab induction, this study is not only the first to apply alemtuzumab induction as a single dose, but the first to use it in combination with both tacrolimus and MMF. Moreover, the protocol using either basiliximab or alemtuzumab was broadly applied to an ethnically diverse group of kidney transplant patients who received grafts from either deceased or living donors.

The beneficial effects of steroid-free immune suppression are well known. Excellent long-term results can be achieved when patients receive adequate induction therapy (1,2,4,10–14). Matas et al. (10) recently reported the long-term results of the use of rabbit anti-lymphocyte globulin followed by a calcineurin inhibitor and MMF or sirolimus in a series of 477 patients. In their study, initiated in October 1999, there was a 90% graft survival rate at 4 years and an 86% acute rejection-free rate. Importantly, many side effects associated with chronic steroid exposure were reduced in the prednisone-free group, including a significant reduction in CMV disease. Diminished CMV risk in association with prednisone-free protocols has also been observed in pancreas (15) and liver (16) transplant recipients.

In this series, both basiliximab and alemtuzumab induction facilitated a prednisone-free maintenance protocol that was associated with very satisfactory long-term patient and graft survival rates. Further, it was possible to maintain the prednisone-free immunosuppression regimen in both groups. There was very little difference in the overall 3-year patient and graft survival rates in the two induction treatment groups. In the alemtuzumab group there was greater than 99% graft survival (death-censored) at 1 year, with rejection rates under 15%. Excellent results were noted in recipients of transplants from deceased donors (100% at 1 year), including African American recipients. When analyzed according to donor source, the basiliximab group showed a trend toward a better long-term graft survival rate. However, we consider the differences in outcomes to be small within the context of immune-mediated etiology since the cause of graft loss in the living-donor group treated with alemtuzumab included two late vascular complications, arterial thrombosis and vascular pedicle torsion.

Overall rejection rates and the severity of rejection episodes were also similar in the basiliximab- and alemtuzumab-treated groups and were not influenced by either donor source or recipient ethnicity. However, a difference in outcome with respect to the timing of rejection was consistently observed. We observed a relatively high incidence (72% (13/18) of rejections) of very early (within 2 weeks of transplant) rejection episodes in the basiliximab treatment group. Eleven of the 13 basiliximab-treated recipients with very early rejection required antibody therapy for treatment. The association between early rejection in recipients treated with basiliximab and a prednisone-free maintenance protocol has been previously reported (3,4). The higher rate of early rejection noted in the basiliximab group compared to the alemtuzumab group could be interpreted as a relative failure of rejection prophylaxis of this induction strategy when used in a steroid-free maintenance environment despite relatively higher exposure to both tacrolimus and MMF in the former.

Therefore, the mechanisms of action of the two classes of induction agents, IL-2 receptor blockade or lymphocyte depletion, have important implications for the efficacy of a prednisone-free immunosuppressive strategy. Several studies show that the risk of early rejection is increased in recipients on a steroid-avoidance protocol when anti-CD25 agents are used as induction agents (10–12). The rejection risk associated with anti-CD25 blockade may also be relatively higher compared to recipients that receive steroid-free immunosuppression in conjunction with a T-cell depleting induction agent such as anti-lymphocyte globulin (13,14).

In fact, the observation of a relatively high incidence of early rejection was our motivation to switch to alemtuzumab. In this study we observed that alemtuzumab provided improved prophylaxis against early rejection even when exposure to tacrolimus and MMF was significantly less during that early time period. The profound early reduction in peripheral lymphocyte counts induced by alemtuzumab likely accounts for its potent prophylaxis against early acute rejection episodes when it is combined with a calcineurin inhibitor, even at relatively low trough concentrations. Early and aggressive rejection episodes involving histologic changes consistent with components of humoral immunity and/or hemolytic uremic syndrome in association with a paucity of T-lymphocyte infiltration, but laden with macrophages, have been described in the initial reports on the use of alemtuzumab in steroid-free and calcineurin-inhibitor-free protocols (5,6). That was not our observation in this series of alemtuzumab/tacrolimus/MMF-treated recipients. Moreover, the cyclosporine-based steroid-free protocol with alemtuzumab induction reported by Calne et al. (4) was not associated with rejection episodes of that character. The differences in the timing and character of rejection described in these four reports (including this one) may relate to the use of calcineurin inhibitors. Kirk et al. (5) reported on an in vitro system to characterize the sensitivity to calcineurin inhibitors and insensitivity to sirolimus of the repopulating lymphocytes in patients treated with alemtuzumab.

An important issue related to the timing of acute rejection episodes concerns the obligation of the transplant hospital to assume the financial risk of treating transplant-related complications. Rejection therapies and hospitalizations occurring within the global period of care (usually 30–90 days post-transplant) as defined in managed care contracts with commercial payors of transplant networks must be covered by the negotiated case rate for the initial transplant episode. Therefore, one must consider how the choice of induction therapy may affect financial risk as well as medical quality issues. A rejection episode that occurs at 20 days rather than at 120 days post-transplant may not have a major effect on the medical well-being of the recipient. However, there may be a significant negative financial impact to the health-care provider if rejection occurs within the global period of managed care when this prednisone-free maintenance immunosuppressive protocol is combined with basiliximab rather than alemtuzumab.

Although the maintenance agents were identical in the two induction groups, differences in exposure to these agents may also explain the outcomes. Patients treated with alemtuzumab were given significantly less MMF than those treated with basiliximab at all time points analyzed over the 3-year follow-up period, as well as significantly less tacrolimus at all time points analyzed over a 2-year period. The reason less maintenance immunosuppression was given was because of concern about over-immunosuppression with alemtuzumab induction. Unexpectedly, a higher rate of later rejection (3–6 months) occurred in the alemtuzumab group perhaps reflecting inadequate maintenance immunosuppression exposure when lymphocyte repopulation would be anticipated. Thus, this protocol requires vigilant monitoring during the post-transplant period, possibly including the use of mycophenolic acid (MPA) monitoring (17). This may also explain why we did not observe an increased incidence of infectious complications including CMV infection or an increase in the rate of PTLD in these patients.

The firmness of the conclusions that can be drawn from this study is mainly limited by the study design. A single-center, nonrandomized, retrospective, sequential design study was used. Although there were no significant differences in the demographic characteristics of the patient groups, the basiliximab-treated patients were studied a year earlier. To ensure meaningful comparisons, we stratified our analysis for high-risk groups, including African Americans and cadaveric donors and demonstrated no significant reduction in graft survival, patient survival or the incidence of acute rejection in either treatment group. The study design of a prospective, randomized trial would need to be implemented to validate the findings in this and other reports (18). That appears to be the next logical step.

Despite the study limitations, it appears that alemtuzumab induction is effective in facilitating a long-term prednisone-free maintenance protocol for a broad population of kidney transplant recipients. Alemtuzumab may also offer some advantages compared to alternative induction agents in the context of a steroid-free maintenance regimen. First, in contrast to other T-cell depleting agents, a complete course of alemtuzumab may be given as a single, peripherally administered dose in the operating room at the time of transplantation. Second, unlike the IL-2R antagonists, alemtuzumab induction has a lymphocyte depleting effect that is proving to be a more effective means of prophylaxis against early acute rejection than is IL-2R antagonist induction. Third, less exposure to the maintenance agents, tacrolimus and MMF, may be required, at least in the short term. However, alemtuzumab appeared to be associated with an increased risk of delayed acute rejection episodes, so that patients may require increased monitoring by, for example, measurement of MPA levels, or perhaps an empiric intensification of immunosuppression after the recovery of recipient lymphodepletion. In conclusion, alemtuzumab induction followed by prednisone-free maintenance therapy using tacrolimus and MMF provided a practical immunosuppression protocol after renal transplantation in an ethnically diverse group of kidney transplant recipients who received their grafts from deceased or living donors.

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