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Alemtuzumab (Campath-1H): A Systematic Review in Organ Transplantation

Morris, Peter J.1; Russell, Neil K.1,2

doi: 10.1097/01.tp.0000219235.97036.9c
Editorials and Perspectives: Overview

Alemtuzumab (Campath-1H) is a powerful antilymphocyte antibody that produces profound and long-lasting lymphopenia. It is being used with increasing frequency for induction in organ transplantation, with the aim of allowing steroid-free and/or calcineurin-free/sparing maintenance immunosuppressive protocols. Despite a considerable experience with this agent, mostly in kidney transplantation, there are only two relatively small randomized controlled trials available, and therefore the level of evidence for its role in transplantation is limited. Nevertheless, it does appear that the incidence of acute rejection is low after induction with alemtuzumab, perhaps if used with a calcineurin inhibitor, and that steroid-free and calcineurin-sparing protocols are possible. Although there is a profound and long-lasting T cell lymphopenia after administration of alemtuzumab, there is no apparent increase in infection, posttransplantation lymphoproliferative disease, or other side effects, other than perhaps autoimmune disease. Whether alemtuzumab is more effective than Thymoglobulin or anti–interleukin 2 receptor antibodies cannot be answered at this time. However from a cost aspect, the use of alemtuzumab for induction compares more than favorably with other lymphocyte-depleting agents. Alemtuzumab is an attractive agent for induction in organ transplantation, but there is a need for more and larger randomized trials with long-term follow-up before its true role can be established, particularly with respect to safety.

1 Centre for Evidence in Transplantation, Royal College of Surgeons of England and London School of Hygiene & Tropical Medicine, University of London, London, UK.

2 Department of Surgery, Cambridge University, Cambridge, UK.

Address for correspondence: Peter J. Morris, A.C., F.R.S., F.R.C.S., The Royal College of Surgeons of England, 35-43 Lincoln's Inn Fields, London WC2A 3PE, UK.

E-mail: pmorris@rcseng.ac.uk

Received 27 February 2006. Accepted 6 March 2006.

Alemtuzumab (Campath-1H; Berlex, Montville, NJ) is a humanized rat monoclonal antibody (rat immunoglobulin [Ig] G2b) directed against the CD52 antigen, which is expressed on all blood mononuclear cells and also on cells lining the male reproductive tract. It is a powerful cytolytic agent and has been used therapeutically in bone marrow transplantation, several autoimmune diseases, and organ transplantation. Although it was first used in organ transplantation in 1998 to prevent rejection and is being used with increasing frequency as induction therapy in many institutions, there is a paucity of good quality evidence that would allow its role in organ transplantation to be established.

For the purposes of this review, we systematically searched the literature with use of Medline, Embase, and the Cochrane Library as well as hand-searching conference proceedings for relevant abstracts published before March 2006. Herein we will briefly discuss the development of the Campath antibodies and the mechanism of action of alemtuzumab, and we will review in some detail the clinical data that are available. Although quite extensive, this is mostly in the form of retrospective reports of noncontrolled studies in the prevention and treatment of rejection across the whole spectrum of organ transplantation, with most of the data arising from the use of alemtuzumab in kidney transplantation. There are only two randomized controlled trials of alemtuzumab in the literature, and only 50 patients in total received this new agent in these trials. Attention is also given to adverse events, especially infection, in view of the profound and long-lasting lymphopenia produced by alemtuzumab.

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THE CAMPATH ANTIBODIES AND ALEMTUZUMAB

The first Campath antibodies were created from rat hybridomas in an attempt to produce antibodies that would lyse lymphocytes in the presence of a human complement (1). All these antibodies were directed against the same antigen, now known as the CD52 antigen. The first antibody was a rat IgM antibody (Campath-1M) that resulted in only a transient lymphopenia in patients with lymphocyte cancer, in contrast to an IgG antibody (Campath-1G), which was an IgG2b antibody produced as a switch variant of IgG2a (2). This antibody was profoundly lytic in the presence of human complement but also produced lysis by antibody dependent cellular cytotoxicity. Finally, to prevent the development of rat globulin antibody responses in patients, the rat antibody was humanized, the first such successful humanization of a clinically used monoclonal antibody (3). Alemtuzumab and Campath-1G have very similar lytic activities, but alemtuzumab has gradually replaced Campath-1G in clinical practice in the past 10 years. In addition, in two studies of Campath antibodies used to treat rejection, 15 of 17 patients given the rat antibody Campath-1G exhibited a rat antiglobulin response, in contrast to zero of 12 patients given the humanized antibody alemtuzumab (4). No antiidiotype antibodies were detected, but it should be noted that repeat courses of the antibody were not given and that the patients were all receiving concurrent immunosuppression. In contrast, three of four patients with rheumatoid arthritis who received a repeat course of the antibody in the absence of other immunosuppression developed an antiidiotype response (5).

The CD52 antigen is expressed on T and B lymphocytes, monocytes, macrophages, and eosinophils, as well as on the lining of the male reproductive tract. Its function is currently unknown (2). It is a short glycoprotein consisting of a sequence of only 12 amino acids. It is attached to the outer layer of the cell membrane by a glycosyl phosphatidylinositol lipid anchor. The CD52 antigen is one of the most abundant antigens on the surface of lymphocytes, accounting for approximately 5% of the surface antigens. This probably explains in part the profound and long-lasting lymphopenia produced after the administration of one or two doses of the antibody; these depressed lymphocyte levels may take months to years to return to normal levels. For example, two doses of alemtuzumab, 40 mg in total, given over 2 days in patients with a kidney transplant produce profound lymphopenia. Although B lymphocyte counts return to normal levels within 3–12 months, CD4+ and CD8+ lymphocyte counts remain significantly depressed for as long as 3 years (6).

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ALEMTUZUMAB IN ORGAN TRANSPLANTATION

Alemtuzumab has been used as induction therapy in human solid organ transplants since 1998. It has also been used for maintenance therapy and the treatment of acute rejection in solid organ transplantations.

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Induction Therapy

Kidney

Alemtuzumab was first used as an induction agent by Calne et al. (7) in 1998 in 13 renal transplant recipients who received low-dose cyclosporine alone as maintenance therapy. At the time of publication, patient and graft survival rates were 100% and there were two episodes of acute rejection, with a follow-up of 6–12 months. Azathioprine and prednisolone were added to one patient's immunosuppressive regimen as a result of rejection. Watson et al. (8) recently published the 5-year results of the initial series along with the findings in another 20 patients who were subsequently entered in this pilot trial (total of 33 patients). They found no significant difference in graft or patient survival or acute rejection rates in a retrospective contemporaneously controlled comparison with the findings in 66 patients who underwent kidney transplantation in the same unit at the same time and were treated with triple therapy (cyclosporine, azathioprine, and prednisolone). However, seven patients in the control group were in a highly sensitized condition and received induction therapy with thymoglobulin. Indeed, there is an impression that the patients in the control group were at higher risk and had not been selected for induction with alemtuzumab. Of interest was the observation that two patients in the alemtuzumab group developed autoimmune disease, which we will discuss later.

Vathsala et al. (9) recently published the results of a randomized controlled trial of alemtuzumab, albeit a small trial. This trial, involving three institutions, compared alemtuzumab induction and low-dose cyclosporine maintenance with triple therapy with cyclosporine, azathioprine, and steroids. Thirty patients were included in the trial, 20 of whom were randomized to the alemtuzumab group and 10 of whom were randomized to the standard therapy group (ie, a two-to-one ratio). After 6 months, the acute rejection rate, graft and patient survival, and renal function were all comparable between the two groups. The acute rejection rates were 25% and 20% in the alemtuzumab group and standard group, respectively. Fifteen of the 20 patients in the alemtuzumab group received no treatment with steroids. Of interest was the observation that 27 infectious complications occurred in the alemtuzumab group (n=20), compared with seven in the control group (n=10).

The only other randomized trial to date is that reported by Ciancio et al (10). This was a well planned three-arm trial with 30 patients in each arm in which induction with Thymoglobulin, alemtuzumab, and daclizumab were compared. All patients received maintenance immunosuppression with tacrolimus, mycophenolate mofetil (MMF), and steroids, but the alemtuzumab group received half the dose of tacrolimus and no steroids after the first week. In this interval report with a median follow-up of 15 months, there was no difference in patient or graft survival, acute rejection rates, or renal function, nor was there any differences in infections or incidence of diabetes or hyperlipidemia. However, 80% of the alemtuzumab group remained steroid-free. Of particular interest in this study was the documentation of T regulatory cells that appeared in a higher proportion of the patients in the alemtuzumab arm, an observation which we will discuss later.

A number of nonrandomized retrospective studies with large patient numbers have been reported in which alemtuzumab was compared with other induction therapies in renal transplant recipients. Knechtle et al. (11) compared induction with alemtuzumab (n=126) to historical control groups treated with anti-CD25 antibody (basiliximab; n=799), Thymoglobulin (n=160), and other induction therapy, such as OKT3 or antithymocyte globulin (n=156). For maintenance immunosuppression, all groups received a calcineurin inhibitor and MMF. Prednisone was used in all groups except the group that received alemtuzumab.

There was a marginal reduction in the incidence of biopsy-proven acute rejection (P=.037) and a better graft survival (P=.0159) in the alemtuzumab group. Also, when looking at the subgroup of patients who experienced delayed graft function, there was significantly less acute rejection (P=.0096) and a significant improvement in graft survival (P=.0119) in the alemtuzumab group. There was no significant difference in patient survival. The same group of investigators also looked at the incidence of infection and malignancy, which showed no significant difference between groups. However, a current analysis of this data with a 3-year follow-up has shown no difference in rejection rate, and graft survival was now in fact better in the anti-CD25 receptor antibody induction group than in the other two groups. There were also more viral and fungal infections in the Thymoglobulin and alemtuzumab groups (S.J. Knechtle, M.D., March 2006, oral presentation and personal communication).

Before this study, Knechtle et al. (12) performed a pilot study with alemtuzumab induction and sirolimus monotherapy in 29 patients. However, as a result of a high incidence of early humoral rejection, the protocol was changed for the last few patients to include Thymoglobulin and a rapidly tapering dose of steroids. Twenty-nine patients were enrolled in the study. Thirteen patients had an acute rejection, of which six were humoral as determined by deposition of the C4d complement component on immunohistologic analysis (13). The 3-year results show graft and patient survival rates of 96% and 100%, respectively.

Shapiro et al. (14) compared alemtuzumab induction (n=90) versus historic control patients treated with Thymoglobulin induction (n=101) and a non–induction therapy group (n=152). In the control group without induction therapy, the maintenance immunosuppression was tacrolimus, prednisolone, and usually a third agent (MMF or sirolimus). Both induction therapy groups received tacrolimus only postoperatively. After 3–4 months, spaced weaning of the tacrolimus was attempted in the induction therapy groups. There was no significant difference in overall graft or patient survival, but when looking at the subgroup of living-donor grafts, graft survival was significantly better for alemtuzumab and Thymoglobulin compared with the control group without induction therapy (P=.037). The acute rejection rate was similar in the alemtuzumab and control groups, which was better than that in the Thymoglobulin group.

Kaufman et al. (15) recently published 3-year follow-up data on a nonrandomized retrospective study that compared alemtuzumab (n=123) and basiliximab (n=155) induction therapy combined with a steroid-free maintenance protocol of tacrolimus and MMF. They found no significant difference in acute rejection rate, graft survival, or patient survival between the two groups at 3 years. Renal function was also similar between the two groups throughout the study time.

Ciancio et al. (16) had previously carried out a prospective nonrandomized pilot trial in 44 patients who underwent renal transplantation with alemtuzumab induction followed by low-dose tacrolimus and MMF maintenance immunosuppression. Patient and graft survival rates were 100% and biopsy-proven rejection was diagnosed in four patients. Follow-up ranged from 1 to 19 months, and 38 of the 44 patients did not receive steroids. The promising results from this study no doubt led to the aforementioned prospective randomized trial undertaken by the same group.

In another pilot study of alemtuzumab induction with MMF and sirolimus in a relatively low-risk group of patients (17), there were eight acute rejections (36%) with leukopenia and possible pulmonary toxicity, leading the authors to suggest that initial use of a calcineurin inhibitor might be necessary with alemtuzumab induction. This experience is similar to that reported by Knechtle et al. (12).

A recent report of 196 living donor transplants in which all kidneys were retrieved by laparoscopic nephrectomy describes induction with alemtuzumab (n=166) or Thymoglobulin (n=24) (18). All patients underwent maintenance therapy with tacrolimus monotherapy and then underwent spaced weaning of tacrolimus. Neither details of how the relatively small number of patients was selected to receive Thymoglobulin nor any details of the living donors (e.g. living related or unrelated) were given. The results are excellent, with a very low rejection rate in the alemtuzumab group (8.4%) and patient and graft survival rates of 99% and 98%, respectively, with a mean follow-up of 401 days. Eighty-four percent of patients were receiving daily monotherapy or spaced-dose monotherapy, confirming the early efficacy of alemtuzumab. However, the conclusion that alemtuzumab is superior to Thymoglobulin hardly seems justified.

Interestingly, Tan et al. (19) also reported the use of alemtuzumab in three HIV-positive recipients of living-donor renal transplants with follow-up ranging from 5 to 10 months. They reported that viral loads remained undetectable and that CD4 counts were slowly recovering.

In an attempt to induce donor allograft tolerance, alemtuzumab was used as induction therapy alone with no maintenance therapy by Kirk and colleagues (20). They treated seven nonsensitized recipients of living-donor transplant kidneys perioperatively with alemtuzumab only. All seven patients developed early rejection within the first month, requiring initiation of maintenance immunosuppression. All rejection episodes were reversed. More recently, the same authors (21) treated a further five recipients of a living-donor kidney with alemtuzumab and a brief course of deoxyspergualin, which was added to the treatment regimen with the aim of preventing the early macrophage and monocyte infiltration observed in the patients treated earlier. However, all patients exhibited a reversible rejection similar to the aforementioned group and rejection was preceded by or associated with marked increases in several chemokine transcripts. Therefore, used in this protocol, alemtuzumab was, perhaps not surprisingly, unable to produce tolerance.

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Pancreas and kidney

Gruessner et al. (22) performed a prospective, nonrandomized, observational cohort study to compare alemtuzumab-treated patients with a historical control group (n=266) in which Thymoglobulin was used for induction and tacrolimus was administered for maintenance therapy. Seventy-five recipients of pancreas/kidney and solitary pancreas transplants received alemtuzumab as induction therapy and as many as 12 doses in the first year as maintenance therapy, along with MMF alone. This is an interesting report in that alemtuzumab was given in four 30-mg doses over the first 42 days together with one dose of Thymoglobulin on day 4 to delete any CD52 cells. Alemtuzumab was then given at any time the total lymphocyte count was greater than 200/mm3, including treatment for acute rejection, for a maximum of 12 doses.

The two study groups were subdivided into simultaneous pancreas and kidney, pancreas after kidney, and pancreas-alone transplants. With a minimum follow-up of 6 months, there was no significant difference in patient and graft survival rates between the two groups or between the subgroups. No grafts were lost from rejection during the first 6 months. The incidence of acute rejection was not significantly different in the pancreas after kidney and pancreas-alone subgroups but was significantly higher in the alemtuzumab-treated simultaneous pancreas/kidney group compared with the Thymoglobulin-treated simultaneous pancreas/kidney transplant group (P=.0003). In view of the fact that alemtuzumab was used for maintenance immunosuppression in this trial, it is important to note that the investigators found no increase in infection compared with the control group and there were no instances of posttransplantation lymphoproliferative disease. This study (22) was designed as a pilot study and patients are now being entered into a randomized trial comparing the alemtuzumab protocol with the investigators' previous standard immunosuppression regimen of Thymoglobulin induction with tacrolimus/MMF maintenance.

Another more recent retrospective study by Kaufman et al. (23) comparing alemtuzumab (single dose of 30 mg) and Thymoglobulin in patients who were also receiving simultaneous pancreas and kidney transplants showed excellent 3-year graft and patient survival rates with no difference between groups with respect to acute rejection. The only difference was that the incidence of viral infections was significantly lower in the alemtuzumab group. The authors also commented on the much lower cost of induction with alemtuzumab compared with Thymoglobulin.

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Liver

Tryphonopoulos et al. (24) compared 77 liver transplant recipients treated with alemtuzumab induction and low-dose tacrolimus maintenance immunosuppression between 2001 and 2004 with 50 similar liver transplant recipients treated with conventional tacrolimus and steroid immunosuppression in a nonrandomized study.

There was no significant difference in patient and graft survival between the two groups, but there was a significant reduction in acute rejection in the alemtuzumab group compared with the control group (P=0.009).

Marcos et al. (25), in another retrospective study, examined alemtuzumab induction and tacrolimus maintenance immunosuppression with spaced weaning of tacrolimus in liver transplant recipients compared with conventional tacrolimus and steroids without lymphoid depletion. However, in contrast to the report from Tryphonopoulos and colleagues (24), they included patients with hepatitis C virus (HCV) in the study (25). Seventy-six liver transplant recipients (38 HCV-negative, 38 HCV-positive) who were treated with alemtuzumab induction therapy and tacrolimus maintenance therapy were compared with 84 contemporaneous liver transplant recipients (58 HCV-negative, 26 HCV-positive). There was no significant overall difference in acute rejection or graft or patient survival between the two groups, even though the results at 1 year depended on the HCV status of the recipients. The results were poor in both groups who were HCV-positive, and the authors suggest that viral replication may occur more readily in the patients given alemtuzumab induction and do not believe it should be used in HCV-positive patients.

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Intestinal and multivisceral

Tzakis and colleagues (26) examined the use of alemtuzumab induction in intestinal and multivisceral transplants in a series of reports in recent years. Twenty-two patients who received 26 grafts (14 intestinal, 11 multivisceral, one liver/intestinal) were treated with alemtuzumab induction and tacrolimus maintenance immunosuppression. Five patients died within the first month from pulmonary embolus (n=1), intraabdominal bleeding (n=1), graft pancreatitis (n=2), or sepsis (n=1), and of the 17 patients who were followed for more than 2 months, there were eight episodes of acute rejection and six episodes of suspected rejection. There were four other deaths 2–16 months after transplantation. Two were caused by severe rejection, one was caused by opiate overdose, and one was caused by a complication from closure of an ileostomy. Of the remaining 13 patients, all were reported to have functioning grafts and be receiving enteral nutrition. Compared with their previous experience, the results with alemtuzumab indicate similar patient and graft survival, but with a reduced incidence and severity of acute rejection.

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Lung

McCurry et al. (27), in a nonrandomized retrospective study, compared 48 patients who underwent lung transplantation with Thymoglobulin (n=38) or alemtuzumab (n=10) induction therapy and tacrolimus maintenance therapy versus a historical cohort of 28 patients who underwent lung transplantation with daclizumab induction and tacrolimus, azathioprine, and steroid maintenance immunosuppression therapy. There was no significant difference in patient or graft survival among the three groups, with patient and graft survival rates greater than 90% at 6 months. However, there was a significant reduction in acute rejection in the alemtuzumab group compared with the Thymoglobulin group (P=.03) and the daclizumab group (P=.05). There was no significant difference in pulmonary function between the two groups. In passing, the authors mentioned three patients given a combined heart/lung transplant and one with a heart transplant with alemtuzumab induction before transplantation who were free of rejection with Tacrolimus therapy.

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Composite tissue allografts

Abdominal wall transplants can be useful in patients undergoing intestinal or multivisceral transplantation, as closure of the abdominal wall after such procedures can be incredibly difficult. Levi et al. (28) performed abdominal wall transplantation in eight patients after intestinal (n=4) or multivisceral transplantation (n=4). Alemtuzumab was used for induction therapy in all but one patient. There were two deaths, and in the six patients who survived, five of the abdominal wall grafts were reported to be intact and viable, each in a patient who had received induction therapy with alemtuzumab. One graft failed because of infarction and the patient's abdomen closed by secondary intention.

We are aware of no studies of the use of alemtuzumab induction in other composite tissue allografts, but it has been used successfully to treat rejection in a case of steroid- and antithymocyte globulin–resistant rejection in a case of bilateral forearm transplantation (29).

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Pediatric transplantation

There is limited evidence of the use of alemtuzumab in pediatric transplantation cases. Bartosh et al. (30) described four high-risk pediatric kidney transplantation procedures in which alemtuzumab was used for induction and MMF, a calcineurin inhibitor, and steroids were used for maintenance therapy. There were three cases of acute rejection, but no grafts were lost to rejection, nor were there any deaths. However, recurrence of focal segmental glomerular sclerosis occurred in one patient.

Kato et al. (31) performed a retrospective review of medical records of all pediatric intestinal and multivisceral transplants that took place at their institution between 1994 and 2004. The study included 17 pediatric patients who received alemtuzumab induction and tacrolimus maintenance with no steroids and showed that patient survival in the alemtuzumab group was significantly worse than that in patients treated with daclizumab (n=40) over the same time period (P=.0004). However, the authors thought this could have been a result of patient selection bias but did propose that alemtuzumab appeared to be less well tolerated than daclizumab in children. Obviously, the role of alemtuzumab in children will have to wait to be defined until its safety and efficacy are firmly established in adults, other than in special situations.

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Treatment of Rejection

Although alemtuzumab is most commonly used as an induction agent, its first use in solid organ transplantation was as a treatment for acute rejection. In 1995, Friend et al. (32) published results of 12 renal transplant recipients with biopsy-proven rejection who were treated with alemtuzumab. All 12 rejection episodes were reversed, but there was an unacceptable rate of severe infection. Basu et al. (33) reported a series of 40 renal transplant recipients who had an episode of acute rejection that was steroid-resistant or was graded as Banff 1B or worse. All 40 patients had undergone induction with a lymphocyte-deleting agent other than alemtuzumab. Patients were given one dose of alemtuzumab (30 mg) and rejection was reversed in 25 of the 40 cases. The authors noted a high rate of serious infection. Alemtuzumab has also been used in five renal transplant recipients to treat rejection that was refractory to steroids and Thymoglobulin or OKT3, with reversal reported in four patients (34). Alemtuzumab was also used to successfully treat refractory rejection in a lung transplant recipient (35) and in one case of bilateral hand transplantation (29).

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Pathology of Acute Rejection

Acute rejection does occur in renal transplant recipients who undergo induction therapy with Alemtuzumab, albeit with a low incidence, despite the profound lymphocyte depletion. However, the histologic pattern may be different than that seen with conventional immunosuppression in that it is often characterized by a monocyte infiltration that coincides with the return of monocytes to the peripheral blood and the production of chemokines (20, 21, 36), and/or with the deposition of the complement component C4d, characteristic of a humoral rejection (12, 17, 36). Indeed, Knechtle et al. (12) suggested that the use of alemtuzumab induction with sirolimus maintenance therapy alone may lead to a higher incidence of humoral rejection. In this study (12), five of eight rejection episodes were associated with biopsy-proven humoral rejection. However, in the trial by Kaufman et al. (15) of tacrolimus and MMF, there were no episodes of acute rejection that were humoral in origin or macrophage-mediated. In a number of other studies, no histologic details were given other than a statement that rejection was graded based on Banff criteria. This suggests that, in the presence of a calcineurin inhibitor after induction with alemtuzumab, humoral rejection is uncommon

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Comparison Versus Other Induction Agents

Prevention of acute rejection

Although lymphocyte depletion as induction therapy in organ transplantation has been used for many years with use of a variety of monoclonal and polyclonal antibodies, none have produced the profound and long-lasting lymphopenia seen after one or two doses of alemtuzumab. Most of the comparisons reported involve the use of historical controls in which Thymoglobulin (6, 8, 12, 16) or an anti–interleukin 2 receptor antibody (6, 16, 9) was used for induction. The results are mixed, although, in general, they tend to suggest that the incidence of acute rejection might be lower in the presence of alemtuzumab induction. However, in the one randomized trial reported to date in which comparisons were made among alemtuzumab, basiliximab, and Thymoglobulin in a three-arm trial, there was no difference in acute rejection rates or graft survival. Therefore, at this moment in time, there is no sound evidence that induction with alemtuzumab is superior in terms of prevention of rejection than Thymoglobulin or an anti–interleukin 2 receptor antibody.

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Sparing of steroids and calcineurin inhibitors

Because of the long-lasting lymphopenia, especially of B and T lymphocytes, produced by alemtuzumab, it had been hoped that its use might facilitate the development of steroid-free regimens and calcineurin-sparing or calcineurin-free regimens to avoid the long-term complications of these agents, particularly nephrotoxicity in the case of the latter. Most of the studies reported have used alemtuzumab induction with a steroid- and calcineurin inhibitor–free protocol (12, 22), a steroid-free and calcineurin-reduced protocol (8, 9, 14, 24–27), or a steroid-free protocol (15, 37).

As of yet, none of the retrospective studies of calcineurin inhibitor–free or -reduced immunosuppression and alemtuzumab induction in renal transplantation have been able to show any significant improvements in renal function compared with conventional therapies. This may be a reflection of the limited follow-up in these studies.

The longest follow-up is reported by Watson et al. (8), who reported that, after 5 years, there was no significant difference in renal function in the alemtuzumab group that received reduced cyclosporine as maintenance immunosuppression, despite the fact that the patients in this group received significantly less cyclosporine than the control group for the first 2 years after transplantation.

Shapiro et al. (14) showed that alemtuzumab induction allowed them to achieve spaced weaning of tacrolimus to every other day or less in 74% of patients, but at 1-year follow-up, there was no significant difference in renal function. Gruessner et al. (22), who employed a steroid- and calcineurin inhibitor–free protocol, did not see a significant difference in renal function in their series of combined kidney/pancreas transplants, but follow-up was short. Conversely, improved renal function was observed in liver transplant recipients treated with alemtuzumab induction and low-dose tacrolimus monotherapy (24).

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Role in tolerance induction

An initial expectation was that the profound lymphopenia produced by alemtuzumab might allow a degree of tolerance to be established in organ transplantation, and indeed the title of an early report by Calne and colleagues (7) included the phrase “Prope tolerance.” Certainly, this led to the exploration of studies of steroid-free and calcineurin-sparing protocols to show that this was feasible, but of course no trials have attempted to reproduce the same regimen with use of more conventional induction protocols. However, two recent studies are of considerable interest. The first is the three-arm randomized trial (10) in which T regulatory cells (as defined by the percentage of CD4+, CD25+ cells) was shown to be higher in the arm of patients who received induction therapy with alemtuzumab and maintenance with reduced-dose tacrolimus. In addition, there was an increased copy number of the transcription factor Fox-P3, a marker of regulatory T cells (10, 38). In the second study, Bloom et al. (6) were able to demonstrate that alemtuzumab induction in combination with sirolimus did result in a degree of donor-specific hyporesponsiveness as demonstrated with several in vitro tests. These are all very early data, but they are encouraging. Nevertheless, another recent study notes patients in whom profound lymphopenia was produced with alemtuzumab or Thymoglobulin exhibited T cells with a phenotype compatible with that of effector cytotoxic memory T cells (39). In addition, there was no evidence of the development of a T cell–regulatory population.

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Complications

Cytokine storm

As with all antibody treatments, there is an initial reaction with alemtuzumab. However, it is relatively modest and suppressed with an intravenous bolus injection of 1 g of methylprednisolone before administration of the antibody.

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Infection

Despite the profound and long-lasting CD4 T cell depletion for 2–3 years produced by one or two doses of alemtuzumab, there has been a surprising lack of serious infection in nearly all studies reported. Silveira and colleagues (40) examined a cohort of 449 consecutive transplant recipients who received alemtuzumab to determine the incidence of bloodstream infections, which might be expected to have an increased incidence in patients in a CD4-depleted state, as seen in patients with AIDS, for example. No increased risk was noted. Similarly, a low incidence of infection was noted in another small study in comparison with a historical control group (41), and indeed this has been a feature of all the reports described earlier.

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Autoimmune disease

An interesting observation made in the long-term study of Watson et al. (8) was the occurrence of an autoimmune disorder in two patients who had received alemtuzumab, one with autoimmune hypothyroidism and one with autoimmune hemolytic anemia. This is relevant bearing in mind that, of 27 patients with multiple sclerosis treated with alemtuzumab, nine developed autoimmune hyperthyroidism (42). So far, this has not been noted in reports of alemtuzumab use in organ transplantation. If this is borne out with further experience, could it be related to the earlier recovery of B cell levels and/or an alteration in the balance of autoimmune regulatory cells in patients treated with alemtuzumab?

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Cost

The cost of alemtuzumab compares favorably with that of other antilymphocyte agents, particularly bearing in mind that one or two doses of 20 or 30 mg are sufficient to produce long-lasting lymphopenia. For example, in the UK, a 30-mg in 1-mL vial of alemtuzumab costs £275, basiliximab 10 mg in a vial costs £758, daclizumab 25 mg in a 5-mL vial costs £223, and Thymoglobulin 25 mg in a 5-mL vial costs £123. Therefore, a typical course of alemtuzumab costs £550, whereas a course of basiliximab (two doses of 20 mg) costs £3,016, a course of daclizumab (5 doses of 1 mg/kg) costs £3,345, and a course of Thymoglobulin (seven doses of 1 mg/kg) costs £2,583. Therefore, there is a significant cost advantage to induction therapy with alemtuzumab that which will differ depending on the dose regimen of the other antilymphocytic agents used.

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CONCLUSION

Alemtuzumab is an extremely interesting antilymphocyte agent that produces a profound and long-lasting lymphopenia, especially of T lymphocytes. Its use in organ transplantation results in a low incidence of rejection, and indeed it is able to reverse steroid-resistant acute rejection, but probably with an unacceptable risk of infection, which has not been a feature of its use for induction therapy. Although most experience had been in kidney transplantation, alemtuzumab has also been used in other forms of organ transplantation with similar results. It may also allow the use of protocols that avoid the use of steroids and allow the use of lower doses of calcineurin inhibitors. Attempts to avoid a calcineurin inhibitor have been associated with acute rejection, often of a humoral nature, and it is probably necessary to include a calcineurin inhibitor in the initial induction therapy to prevent this. There is no clinical evidence that a degree of tolerance is produced with this agent, but interestingly, there are some early data that suggest the presence of regulatory T cells after induction therapy with alemtuzumab. Only two relatively small randomized trials have been reported to date, and there is no evidence in these reports, nor in general from the retrospective studies, that alemtuzumab is superior to Thymoglobulin or anti–interleukin2 receptor antibodies as an induction agent. Therefore, there is a need for large, prospective randomized trials of alemtuzumab therapy for induction, and long-term follow-up of all patients is essential in view of the long-term T cell depletion associated with the use of this agent.

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ACKNOWLEDGMENT

The authors thank Leticia Barcena for her help in formulating a search strategy for this systematic review.

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Keywords:

Alemtuzumab; Campath; Monoclonal antibodies; Rejection

© 2006 Lippincott Williams & Wilkins, Inc.