Alemtuzumab (Campath-1H) in Kidney Transplantation

G. Ciancio.;* G. W. Burke III

Am J Transplant.  2008;8(1):15-20.  ©2008 Blackwell Publishing
Posted 03/17/2008

Abstract and Introduction

Abstract

Kidney transplantation has become the treatment of choice for both the quality of life and survival in patients with end-stage renal disease (ESRD). However, the immunosuppressive regimen which allows optimal kidney transplant outcome remains elusive. One of the more promising induction agents, Alemtuzumab, was introduced to kidney transplantation by Calne in the late 1990s with low dose cyclosporine A monotherapy, with the hope of establishing ‘prope' or near tolerance. Subsequent pilot studies with Alemtuzumab alone or monotherapy (DSG, Rapa) demonstrated high rates of acute rejection (AR) along with occasional humoral components that lead to abandoning the concept of Alemtuzumab as a ‘magic bullet' to achieve tolerance, prope or otherwise. A number of programs (including our own) has since modified maintenance immunosuppression using low dose tacrolimus, and shown acceptable rates of AR, with relatively low incidence of viral infection and lymphoproliferative disorders along with cost benefit. However, there are only three prospective, randomized studies which are small with one year or less follow-up, and most published series utilize historical control groups with relatively short follow-up. As extrapolation from short-term data is far from secure, long-term, prospective, randomized studies with Alemtuzumab will be necessary to determine the optimal immunosuppressive regimen.

Introduction

Progress in the development of immunosuppressive regimens has reduced the incidence and severity of acute rejection (AR) after renal transplantation. This has resulted in improved short-term (primarily 1 year) outcomes,[1–3] but with less marked effects on long-term graft survival.[4] This is due in part to the nephrotoxicity of calcineurin inhibitors (CNIs),[5] the alloimmune component of transplant glomerulopathy,[6] and other less well-defined processes.[7] Regimens that can yield similar short-term results but with less long-term deterioration[8,9] continue to be sought, perhaps even eventually allowing the development of immunologic tolerance.[10,11]

New biologic agents such as (chimeric or humanized) monoclonal antibodies with longer half-lives have been introduced as induction therapy.[2] The resulting prolonged biologic effect may allow lower dosages of (nephrotoxic) CNIs, both short- and long-term, and perhaps lower doses or avoidance of corticosteroids. One such agent is Alemtuzumab, a humanized CD52-specific complement fixing (cytotoxic-lymphodepleting) IgG1 monoclonal antibody first introduced in hemato-oncology by Waldmann and Hale,[12] then in renal transplantation by Calne.[13] The human CD52 antigen is found in variable concentrations on all peripheral blood mononuclear cells. Alemtuzumab profoundly depletes T cells from peripheral blood for several months with effects, albeit less marked, on B cells, natural killer cells, and monocytes, (in descending order) and with the least effect on CD34+ (immature) hematopoetic stem cells. (see review 14).

Alemtuzumab is currently not indicated for organ transplantation and thus patients should be informed of its off-label use and its evolving experimental nature.

Alemtuzumab in Kidney Transplantation

Early experience

The Cambridge group performed the first series of human deceased donor renal transplants using Alemtuzumab induction therapy as prophylaxis against rejection in combination with low dose cyclosporine monotherapy.[13] The pilot trial ( Table 1 ) of 31 patients utilized two doses of Alemtuzumab, 20 mg each, given on the day of the transplant and the following day. Cyclosporine monotherapy was used posttransplant with trough levels in the range of 100–150 ng/mL. There were six episodes of steroid-responsive rejection with one case of an almost acellular vasculitic rejection also treated with steroids. With 5-year follow-up,[15] the incidence of AR which had been lower initially in the Alemtuzumab treated group,[13] equaled that of the control group (contemporaneous kidney transplant recipients all but five of whom were treated with triple maintenance therapy without induction) and was approximately 30% due to an increase in late (1–3 years post kidney transplant) episodes of AR. Furthermore, the serum creatinine was the same in both groups at 5 years, despite the hope that the lower cyclosporine A concentration in Alemtuzumab recipients would translate to reduced nephrotoxicity. Importantly, the Alemtuzumab patients on cyclosporine A monotherapy were ‘no more tolerant than patients on triple therapy' as judged by graft survival and incidence of AR.[13]

QU: Is Alemtuzumab tolerogenic?

Alemtuzumab alone: Kirk et al.[16] were the first to use Alemtuzumab in a pilot trial designed to test the need for maintenance immunosuppression in the context of multiple doses of Alemtuzumab. Seven nonsensitized recipients of living donor kidneys received Alemtuzumab without additional immunosuppression. Alemtuzumab was administered at 0.3 mg/kg per dose. Six patients received three doses in the peritransplant period: four on days –5, –3 and –1 and two on days –3, –1 and +2. One received four doses on days –1, +1, +3 and +5.[11,13] Profound peripheral lymphocyte and monocyte depletion occurred. Nonetheless, all patients developed rejection episodes within the first month that were characterized by monocytic (not lymphocytic) infiltrates with only rare T cells in the peripheral blood or allograft. Most were reversed with steroid therapy although one required OKT3 as well. Sirolimus maintenance therapy was then initiated. There were no late rejections.

Of note, one patient developed auto immune thyroid disease 3 years after transplant/Alemtuzumab induction while receiving sirolimus monotherapy.[17] Autoimmunity has also previously been reported in multiple sclerosis patients treated with Alemtuzumab.[18] Although Alemtuzumab was used in higher doses and without subsequent immunosuppression in this report,[17] the possibility of autoimmune phenomena including thyroiditis associated with Alemtuzumab, should be recognized.

Alemtuzumab with short-term deoxyspergualin monotherapy: This same group[19] investigated whether Alemtuzumab and deoxyspergualin (DSG) monotherapy would induce tolerance in humans. Five recipients of live donor kidneys were treated perioperatively with Alemtuzumab and DSG in a pilot trial and followed postoperatively without maintenance immunosuppression. Alemtuzumab was used for peripheral and nodal T-cell depletion; DSG was chosen for[1] the demonstration of tolerance when added to a T-cell depletion model in nonhuman primates[20] and for its inhibitory effect on monocyte/macrophage activation.[21] Despite profound T-cell depletion and DSG dosing, all patients developed reversible rejection that was similar in timing, histology and transcriptional profile to that seen in patients treated with Alemtuzumab alone.[16]

Answer: No.

QU: Is Alemtuzumab effective with non-CNI maintenance therapy?

Sirolimus monotherapy: At the University of Wisconsin,[22] 29 patients received two doses of 20 mg each of Alemtuzumab on day 0 and day 1. Twenty-four (living donor) recipients then received maintenance sirolimus therapy. Thirty percent in this pilot study experienced significant rejection episodes, usually between 2–3 weeks postoperatively, which were typically of a humoral rather than cellular nature. Some were difficult to control, requiring a combination of plasmapheresis, cytomegalovirus (CMV) IGm thymoglobulin, rituximab, steroid bolus, mycophenolate mofetil (MMF) and tacrolimus. Using a modification in the protocol, the initial dose of Alemtuzumab was given the day before transplantation followed by a dose of thymoglobulin 1.5 mg/kg on day 1 (patients 26–29). A 2-week course of steroids was also added. Nevertheless, of five patients, three experienced AR.

At 3-years, the pilot study included a 46% rate of rejection (humoral and/or cellular). Seven (54%) of these were humoral, treated with the regimen described.[23] However, graft and patient survival of 96% and 100%, respectively, were achieved. Fifty percent of the patients were maintained on monotherapy without serious infections and there were no malignancies. Because of the high incidence of early rejection, however, a brief course of a CNI was recommended.[23]

Rapa/MMF; no CNI: Flechner et al.[24] in a pilot study of 22 patients (14 living donor; 8 deceased donors) used Alemtuzumab (30 mg, day 0 and 1) induction with mycophenolate mofetil (500 mg b.i.d.) and sirolimus (concentration controlled 8–12 mg/mL) maintenance in order to avoid CNI and steroids. With a mean follow-up of 15.9 months, patient survival was (21/22) 96% and graft survival (19/22) 87%. However, AR occurred in 8 (36.3%-two humoral). Of 19 surviving grafts, 18 (95%) remain steroid and 15 (79%) CNI free. Overall infection rates were low, but two patients developed severe acute respiratory distress syndrome (ARDS) at month 3 and 7, respectively, resulting in mortality in one and graft loss in the other. No cancer or posttransplant lymphoproliferative disease (PTLD) was observed. The higher than expected rate of AR, leucopenia and possible pulmonary toxicity raised concerns regarding the efficacy and safety of this protocol.

Serial Alemtuzumab/MMF; no CNI/steroids: Gruessner et al.[25] reported a nonrandomized study of 75 pancreas–kidney and solitary pancreas recipients who received alemtuzumab (4 doses for induction and up 12 doses within the first year) and mycophenolate mofetil (≥2 g/day) monotherapy. Alemtuzumab, 30 mg IV, was given intraoperatively as well as for maintenance dosing. The maximum number of Alemtuzumab doses was limited to 10 within the first year. In a 6-month follow-up, the results were compared with a historical group of 266 consecutive pancreas recipients using thymoglobulin induction and tacrolimus maintenance. Pancreas allograft survival at 6 months in the Alemtuzumab for SPK recipients was 81% (vs. 79%; p ≥ 0.66); for PAK recipients, 91% (vs. 85%; p ≥ 0.59); and for PTA recipients, 71% (vs. 84%; p ≥ 0.07). The incidence of a first (reversible) rejection episode at 6 months in the Alemtuzumab versus control group for SPK recipients was 41% (vs. 9%; p ≥ 0.0003); for PAK recipients, 14% (vs. 10%; p ≥ 0.89); and for PTA recipients, 19% (vs. 26%; p ≥ 0.36). Based on 6-month data, the combination of alemtuzumab and MMF was associated with a high rejection rate (in SPK recipients), but good (graft and native) kidney function; it eliminated undesired CNI and steroid-related side effects. Longer follow-up is necessary to evaluate both efficacy and safety.

Answer: No

Is Alemtuzumab effective with CNI maintenance therapy?

University of Wisconsin: After their initial experience with Alemtuzumab and sirolimus monotherapy, the Wisconsin group[26] reported a single center retrospective study comparing patients who received two doses of Alemtuzumab at the time of renal transplant in combination with a low dose of steroids (10 mg methylprednisolone per day), mycophenolate mofetil and either tacrolimus or cyc1osporine (n = 126) with those who received either an anti-CD25 antibody (n = 799), thymoglobulin (n = 160) or other antibody treatment (n = 156). The choice of induction antibody was made by the operating surgeon based on ‘perceived efficacy, side effect profile and cost'.[20] The latter three groups were in combination with a CNI, mycophenolate mofetil and higher dose steroids. The Alemtuzumab group overall experienced less rejection than the other three groups: Alemtuzumab ~22%, anti-CD25 ~30% and thymoglobulin ~32% (from figure 2 in Ref. 20) (p = 0.037). The follow-up in the Alemtuzumab group was 12 months versus 4–6 years for the other groups. A subgroup with delayed graft function, treated with Alemtuzumab, experienced less rejection and improved graft survival statistically p = 0.0096 and 0.0119, respectively, than the control groups. The rate of AR in the Alemtuzumab DGF group (n = 23) was 14%, anti-CD25 (n = 127) was 38% and in the thymoglobulin group (n = 41) 42% (figure 2 in Ref. 20). However, the follow-up was limited to 200 days for Alemtuzumab recipients with DGF (figure 2 in Ref. 20). There was no difference in infection or malignancies among the four groups. Further follow-up will be necessary to assess outcome in the Alemtuzumab group.

University of Pittsburgh: Reports from the University of Pittsburgh[27] suggested lymphoid depletion with Alemtuzumab before rather than after kidney transplantation would reduce the anticipated donor-specific response and allow avoidance of high-dose steroids and multiple maintenance immunosuppressive agents. Three groups were retrospectively compared: historical controls with no pretreatment (n = 152), thymoglobulin (5 mg/kg) pretreatment group (n = 101) and Alemtuzumab (30 mg) pretreatment group (n = 90). Patient and graft survival were not significantly different in either of the depleted groups versus the historical controls. However, there were markedly different incidences and times to AR. In the thymoglobulin-pretreated patients, the onset was earlier and the incidence higher (40% at 6 months, ~50% at 1 year (figure 2 in Ref. 27) (p < 0.001) than in either the Alemtuzumab or historical controls. The incidence of rejection during the first 6 months after Alemtuzumab pretreatment was 1%, however, by 12 months the AR rate increased to 20% (figure 2 in Ref. 27). Of note, 3-year graft survival in the thymoglobulin group, which experienced the high rate of AR, was 70% compared to ~80% in the historical control group (figure 1 in Ref. 27).

Spaced weaning of tacrolimus was attempted in 91 (90.1%) of the 101 recipients of the thymoglobulin pretreatment group. In 45% of these patients, daily maintenance therapy was resumed because of AR. In view of the high rate of AR and worse graft survival observed with space weaning after thymoglobulin pretherapy, spaced weaning was delayed for 1 year before being attempted in 83 (91.2%) of the 90 patients of the Alemtuzumab pretreatment group. With follow-up of 12–18 months, 62 (74%) of the 84 Alemtuzumab-treated patients were on spaced weaning, 14% on daily monotherapy, with only 12% receiving more than a single agent. However, further follow-up of graft survival and change in creatinine is necessary to evaluate the safety and efficacy of Alemtuzumab in this trial.

More recently this group has reported results in an LRD kidney transplant protocol with Alemtuzumab and spaced weaning of tacrolimus monotherapy.[28] The 1-year actuarial patient and graft survival was 98.6% and 98.1%, respectively. With larger numbers and better use of immunologic monitoring, the 1-year AR episodes were 6.8%. They report no CMV or other infection, no DGF and PT DM rate of.5%.[28] However, longer follow-up will be critical to assess the effectiveness of this approach.

The University of Miami: The Miami experience with Alemtuzumab began with a pilot study in an attempt to (1) reduce both early and long-term CNI nephrotoxicity, and (2) eliminate steroids. Alemtuzumab (two doses, 30 mg each) was used as induction therapy in 44 de novo renal allograft recipients.[29] Maintenance Tacrolimus trough levels were 5–7 ng/mL; with reduced MMF dosage (500 mg twice daily). With a median follow-up of 9 (range 1–19) months, patient and graft survival were both 100%. Biopsy-proven AR was diagnosed in four patients (9%). Four patients (9%) developed infections that required hospitalization. Thirty-eight (86%) remained off long-term corticosteroid therapy. In our experience, the combination of Alemtuzumab, low dose tacrolimus and mycophenolate mofetil, and avoidance of maintenance corticosteroid use was safe and effective for kidney transplant recipients.

Later reports and our own experience, however, suggested that a higher incidence of biopsy-demonstrated AR may exist in the African–American and Hispanic subgroups treated with Alemtuzumab.[30] This remains controversial because others, in a small, prospective randomized study, showed equivalence in AR rates at 1 year comparing Alemtuzumab to thymoglobulin in an immunologically high-risk group that included African–Americans and Hispanics.[31] Of note, the second randomized prospective study comparing Alemtuzumab with CyA (low dose) monotherapy (n = 20) to triple immunosuppression (CyA, azathioprine and steroids) without induction (n = 10) also reported equivalence.[32] However, the study was small with only 6-month follow-up, and the AR rate was already relatively high: 25% (Alemtuzumab) versus 20% (standard immunosuppression).

Answer: Yes, but longer follow-up and randomized studies are necessary to draw meaningful conclusions.

QU: Is Alemtuzumab better than other induction agents?

Alemtuzumab versus thymoglobulin versus daclizumab: Our group[33] subsequently designed the first randomized prospective trial using three different antibody induction agents in 90 first renal transplant recipients from deceased donors: thymoglobulin, Alemtuzumab and daclizumab. Maintenance immunosuppression included tacrolimus and mycophenolate in all three arms, and methylprednisolone in the thymoglobulin and daclizumab groups. The targeted trough level of tacrolimus was between 8 and 10 ng/mL for thymoglobulin and daclizumab groups, with a targeted mycophenolate dose of 1 gm twice daily. In the alemtuzumab treated arm, target tacrolimus trough level was lower 4–7 ng/mL (to reduce long-term nephrotoxicity,) with 500 mg twice daily doses of mycophenolate and no steroids. AR rates at 1 year were equivalent, that is 5/30 in all three groups (~16.6%). In the alemtuzumab group, there was slightly lower GFR at 1 month, but no difference at 1 year.

In the Alemtuzumab group, 80% remained steroid-free at 1 year, with lower tacrolimus trough levels and mycophenolate dosing. There were no differences in other adverse events. No direct comparison among these three arms is possible, because the maintenance regimens are different.[33] However, the efficacy of Alemtuzumab appears similar to that of the other two agents in this small, prospective randomized study. Further follow-up is in progress.

Alemtuzumab versus basiliximab: A nonrandomized, retrospective, sequential study comparing outcomes in kidney transplant recipients induced either with Alemtuzumab (n = 123) or basiliximab (n = 155) with a prednisone-free maintenance protocol using tacrolimus and mycophenolate mofetil was reported from Northwestern.[34] Mean follow-up was 33 ± 23 months (range 30–42 months) for Alemtuzumab and 47 ± 10 months (range 31–65 months) for the basiliximab group, and ~2/3 were living donors.[33]

The 1-year actual patient and death censored kidney transplant survival rates, Alemtuzumab versus basiliximab, were 96.8% versus 99.4%, and 99.2% and 99.4%, respectively (p = n.s.). Although the rate of AR was lower in the Alemtuzumab group for the first 3 months, by 12 months, the rate of AR for both groups was equivalent (Alemtuzumab 14.9%; basiliximab 13.5%). There was no difference in creatinine concentration at 1 year and minimal change over 36 months. CMV occurred in 21% (Alemtuzumab) and 19% (basiliximab) in the zero negative recipients, and in both groups PTLD occurred in two patients. The Northwestern team has also demonstrated reduced cost associated with alemtuzumab induction.[35]

Answer: It is possible to achieve excellent short-term (1 year) results with Alemtuzumab. However, comparison studies suffer from lack of (1) long-term follow-up and (2) randomized, prospective controlled trials. The best induction protocol for the long-term remains to be defined.

Alemtuzumab for the Treatment of Acute Rejection in Renal Transplant Patients

There are anecdotal reports describing the use of Alemtuzumab in the treatment of AR.[36] There are no prospective studies. There appears to be a higher risk of infection in patients treated with Alemtuzumab for AR.[37]

Alemtuzumab: acute humoral rejection (AHR) in renal transplant recipients

In kidney transplant patients who received Alemtuzumab induction, AHR appeared to occur with higher frequency, requiring an aggressive combination of plasmapheresis and intravenous immunoglobulin, in addition to steroid therapy.[19,22,24] One case of AHR with an almost acellular vasculitic rejection that was treated with steroids was reported in Calne's original study.[13] It should be noted that plasma cells do not express the CD52 epitope in detectable concentrations and that memory T (and perhaps B lymphocytes) may also be somewhat more refractory to Alemtuzumab.[38] Kirk et al.[16] reported no AHR, but a high incidence of reversible AR with monocytic predominance in the biopsy infiltrates. Notably, chemokine transcript levels in these biopsies were consistently high, suggesting the facilitation of infiltrating cells.[19] All were responsive to treatment followed by maintenance with steroids or sirolimus or both. Hill et al.[39] reported an early severe AHR (C4d+) resulting in renal allograft loss in a recipient treated with Alemtuzumab induction therapy, cyclosporine A, mycophenolate mofetil and steroids. This patient developed donor specific anti-class I antibody. The presence of antidonor MHC antibodies or B cell crossmatch pretransplantation is not detailed.[39] It is clear that Alemtuzumab induction, even with additional immunosuppressive agents does not prevent AHR in renal allograft recipients.

Alemtuzumab/Tregs

Our group[33] reported significantly more leucopenia with Alemtuzumab than thymoglobulin or daclizumab, but a greater percentage of T regulatory cells as assessed by number of Fox-P3 mRNA copies, by flow cytometry and semiquantitative PCR analysis. This was in the context of low dose mycophenolate mofetil and low dose/level tacrolimus maintenance immunosuppression. However, Noris et al.[40] using cyclosporine A as the CNI, not tacrolimus, did not identify Tregs. In this study, Treg phenotype and function was monitored during immune reconstitution in 21 renal transplant recipients treated with Alemtuzumab and MMF who received sirolimus or cyclosporine as maintenance therapy. Three patients, one on sirolimus and two on cyclosporine, experienced an AR episode that responded to steroid therapy. In sirolimus treated patients, hyporesponsiveness demonstrated in vitro was reversed by Treg depletion. T cells from cyclosporine treated patients were anergic. Thus, in their study CD4+CD25 high Treg expansion in renal transplant patients, appeared to occur with sirolimus but not CyA maintenance immunosuppression. Translating this observation into a real clinical benefit,[41] because sirolimus protocols without CNI have shown higher rates of AR, remains a challenge for the future.

Conclusion

The use of Alemtuzumab as induction therapy in kidney transplantation, has evolved over the past decade, typical of many novel therapeutic agents, from the initial response of enthusiasm, to a realization that it is not a panacea. The learning curve has been through tolerance, prope tolerance, mono/dual agent maintenance therapies to current protocols, generally embracing low dose CNIs and steroid sparing successfully. There are suggestions that Alemtuzumab is particularly effective in delayed graft function, and that there are important cost savings with its use.

However, preventing AHR will be critically important. It may be necessary to avoid the use of Alemtuzumab in those patients with B-cell positive crossmatches and/or antidonor antibody. If the current experience showing low rates of AR, with correspondingly low rates of viral infections, lymphoproliferative disorders and posttransplant diabetes at 1 year, can be validated in randomized, prospective, long-term protocols, then Alemtuzumab will assume an important role in kidney transplantation induction therapy.


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Table 1. Published Effects of Alemtuzumab


Table 1: Published Effects of Alemtuzumab

 



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Acknowledgements

The authors would like to express their appreciation to Ms. Maruja Chavez for her perspicacious, prescient and perceptive perseverance in the preparation of this paper.

Reprint Address

Corresponding author: *Gaetano Ciancio, gciancio@med.miami.edu


G. Ciancio.* and G. W. Burke III, Department of Surgery, Division of Transplantation, University of Miami Miller School of Medicine, Miami, FL