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Keywords:

  • Alemtuzumab;
  • antithymocyte globulin;
  • renal allograft rejection;
  • steroid resistant

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References
  9. Supporting Information

Steroid-resistant renal allograft rejections are commonly treated with rabbit antithymocyte globulin (RATG), but alemtuzumab could be an effective, safe and more convenient alternative. Adult patients with steroid-resistant renal allograft rejection treated with alemtuzumab (15–30 mg s.c. on 2 subsequent days) from 2008 to 2012 (n = 11) were compared to patients treated with RATG (2.5-4.0 mg/kg bodyweight i.v. for 10–14 days; n = 20). We assessed treatment-failure (graft loss, lack of improvement of graft function or need for additional anti-rejection treatment), infections during the first 3 months after treatment and infusion-related side effects. In both groups, the median time-interval between rejection and transplantation was 2 weeks, and approximately 75% of rejections were classified as Banff-IIA or higher. Three alemtuzumab-treated patients (27%) experienced treatment failure, compared to eight RATG treated patients (40%, p = 0.70). There was no difference in the incidence of infections. There were mild infusion-related side-effects in three alemtuzumab-treated patients (27%), and more severe infusion-related side effects in 17 RATG-treated patients (85%, p = 0.013). Drug related costs of alemtuzumab-treatment were lower than of RATG-treatment (€1050 vs. €2024; p < 0.01). Alemtuzumab might be an effective therapy for steroid-resistant renal allograft rejections. In contrast to RATG, alemtuzumab is nearly devoid of infusion-related side-effects. These data warrant a prospective trial.


Abbreviations
ATG,

antithymocyte globulin

CMV,

cytomegalovirus

MMF,

mycophenolate mofetil.

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References
  9. Supporting Information

The first-line treatment of established acute cellular allograft rejection is high-dose steroids. When treatment with steroids fails or a rejection quickly recurs, treatment with anti-T cell antibodies is often the next step. Most experience is based on the use of antithymocyte globulin (ATG) and Muromonab-CD3 [1]. However, Muromonab-CD3 is no longer available and currently, steroid-resistant acute rejections are therefore mostly treated with a 10–14 days course of ATG [2, 3]. Although efficacious, this treatment has several drawbacks. First, ATG should be administered intravenously using a central venous catheter, high flow vein or arteriovenous fistula to prevent phlebitis. Second, the administration is associated with severe infusion-related side effects like fever, chills, headache, dyspnea, myalgia and hypotension [4]. This limits its tolerability, especially in older individuals or those with significant cardiopulmonary comorbidity.

Alemtuzumab is a depleting, humanized monoclonal antibody, directed specifically to the CD52 molecule, which is expressed on T cells and several other lymphoid and myeloid cell types [5]. Alemtuzumab is currently registered for the treatment of chronic lymphatic leukemia but data on the safety and efficacy of treatment of acute rejection after organ transplantation are scarce. Several studies reported the results in small groups of patients, merely demonstrating that recurrent or steroid-resistant rejection can be reversed with alemtuzumab [6-10]. Randomized trials comparing alemtuzumab with other T cell-depleting agents for the treatment of acute rejection have not been performed. In early trials with alemtuzumab as induction therapy, intravenous administration was frequently accompanied by infusion reactions. In more recent trials, in which alemtuzumab was given subcutaneously, infusion-related side effects were rare or not reported [11, 12].

We hypothesized that alemtuzumab might be preferred over ATG for steroid-resistant rejection after renal transplantation. We analyzed our first experience with alemtuzumab in this setting, and compared this with results obtained in a historical cohort of patients treated with ATG.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References
  9. Supporting Information

All renal allograft recipients treated with alemtuzumab for steroid-resistant rejection since 2008 were identified in three academic centers in the Netherlands. Subsequently, a control group was composed, consisting of patients that were treated with ATG for steroid-resistant acute rejection. For each alemtuzumab-treated patient, we selected the two ATG-treated patients in the same center of whom the transplantation date was most closely preceding and following that of the alemtuzumab-treated patient.

Next, we excluded patients who never had a functioning graft (defined as urine production post transplantation with a drop in serum creatinine without requirement of dialysis) before the onset of antibody therapy, or in whom there was no biopsy confirming the presence of acute cellular rejection. In addition, patients who already had received any anti-T cell antibodies after the current transplantation (as induction therapy or treatment of prior rejection episode) were excluded.

Consequently, none of the analyzed patients had received induction therapy with a depleting anti-T cell agent. Some patients received basiliximab as induction therapy, and another part of the patients participated in an ongoing double blind randomized trial, comparing rituximab with placebo as induction therapy. Maintenance immunosuppression consisted of the combination of a calcineurin inhibitor, an antiproliferative agent, and steroids in all patients. In case of graft dysfunction without obvious pre- or postrenal cause, a graft biopsy was performed. Pathologic examination of the biopsy tissue included C4d staining in all cases and rejections were classified according to Banff'97 criteria [13]. When a graft biopsy was not possible (e.g. because of the use of anticoagulant therapy) and the suspicion of rejection was strong, anti-rejection therapy was started without prior graft biopsy. Donor-specific anti-HLA antibodies were not routinely measured. First-line anti-rejection treatment consisted of methylprednisolone, with doses varying between 500 and 1000 mg during 3–6 days. When there was no successful response to steroids, or graft function deteriorated during or shortly after steroid therapy, the rejection episode was considered steroid resistant. In part of the cases a (re)biopsy was performed to confirm the persistence of rejection. Alemtuzumab (Campath-1H Genzyme Europe BV, Naarden, The Netherlands) was given in 15–30 mg doses subcutaneously at 2 subsequent days. ATG (Thymoglobulin®, Genzyme) was administered in a dosage of 2.5–4.0 mg/kg bodyweight intravenously for 10–14 days, with adjustments based on lymphocyte or CD4+ T cell counts. In both groups patients were treated with antihistamines, steroids and acetaminophen before antibody therapy.

We assessed the rate of treatment-failure and infections during the first 3 months after the start of treatment with anti-T cell antibodies, and recorded all malignancies during follow-up. Treatment failure was defined as graft loss, the need for additional anti-rejection therapy or lack of improvement of graft function (defined as the absence of a drop in serum creatinine of 25% or more at any time within a 3 month interval after start of treatment). Furthermore, we analyzed the incidence of infusion-related side effects and the drug-related costs of both antibody treatments.

We performed overall group comparisons using a chi-square test or Fisher-exact test (if counts per group were below five). For continuous variables we used either an unpaired t-test (normally distributed data) or a Wilcoxon test (not-normally distributed data). All statistical tests were two-sided and p < 0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References
  9. Supporting Information

From January 2008 to April 2012, we identified 14 patients treated with alemtuzumab and 28 patients treated with ATG. Of the 14 alemtuzumab-treated patients, two were treated earlier with other anti-T cell antibodies (muromonab-CD3 and ATG, respectively) after the current transplantation, and one was still on dialysis at start of antibody treatment. Therefore, 11 alemtuzumab-treated patients were included in the analysis. In five patients in the control group, no biopsy was performed to confirm the presence of rejection, and in one case there was only borderline rejection. Moreover, one patient had received ATG as induction therapy, and one was still on dialysis at start of antibody treatment. As a result, 20 ATG-treated patients were analyzed.

In the majority of alemtuzumab-treated patients, the use of other anti-T cell antibodies was considered to be unattractive for the following reasons: treatment with ATG after a previous transplantation (n = 4), positive test for antirabbit IgG antibodies (n = 2), fluid overload (n = 1) and recent cardiac ischemia (n = 1). In three cases, alemtuzumab was chosen without specific contra-indication for other anti-T cell antibodies.

Baseline characteristics of alemtuzumab- and ATG-treated patients are stated in Table 1. The number of HLA mismatches was lower in the alemtuzumab-treated patients. However, 55% of the alemtuzumab-treated patients underwent a retransplant compared to only 5% of the ATG-treated patients (p < 0.01). The majority of rejections in each group were classified as Banff IIA. The median time interval between transplantation and antibody treatment of rejection was 42 days in the alemtuzumab group (range 4–752) and 22 days in ATG-treated patients (range 6––849; p = 0.73). Additional Supporting Information on individual patients may be found in Tables S1 and S2 of the online version of this article.

Table 1. Baseline characteristics of patients treated with alemtuzumab or ATG
 Alemtuzumab (n = 11)ATG (n = 20)p-Value
Recipient age, years (median, range)49 (19–72)48 (24–66)0.93
Sex–no. (%)  0.48
 Male5 (45)12 (60) 
 Female6 (55)8 (40) 
Cause of end stage renal disease–no. (%)  0.32
 Glomerulonephritis6 (55)6 (30) 
 Polycystic kidney disease2 (18)3 (15) 
 Diabetic nephropathy0 (0)2 (10) 
 Hypertension1 (9)1 (5) 
 Other2 (18)8 (40) 
Rank order of transplantation–no. (%)  <0.01
 First5 (45)19 (95) 
 Second or more6 (55)1 (5) 
Peak value of panel reactive antibodies% (median, range)10 (0–83)0 (0–92)0.077
HLA A, B, and DR mismatches – no. (median, range)2 (1–5)5 (1–6)0.029
Donor age, years (median, range)51 (10–74)53 (36–66)0.89
Type of donor–no. (%)  0.32
 Donation after brain death5 (45)4 (20) 
 Donation after cardiac death1 (9)2 (10) 
 Living5 (45)14 (70) 

Three alemtuzumab-treated patients (27%) experienced treatment failure, compared with eight ATG-treated patients (40%; p = 0.70), see Tables 2 and 3. Serum creatinine 3 months after start of antibody treatment was comparable between both groups (182 ± 84 vs. 187 ± 101 μmol/L; p = 0.89). The median number of infections per patient within 3 months after treatment was one in alemtuzumab-treated patients (range 0–6) and two in ATG-treated patients (range 0–6; p = 0.81). A cytomegalovirus (CMV) primary infection or reactivation occurred in four alemtuzumab-treated patients, compared to five among ATG-treated patients (36% vs. 25%, p = 0.68). During follow-up, two ATG-treated patients developed a malignancy (one lymphoma at 35 months and one squamous-cell carcinoma at 30 months after treatment). In both groups, one patient died; the alemtuzumab-treated patient died of Cryptococcus sepsis 50 days after initiation of treatment, and the ATG-treated patient died 3 days after initiation of ATG-treatment because of cardiac arrest. This patient had a severe lactic acidosis and possibly anaphylaxis, which was considered to be related to ATG treatment.

Table 2. Outcome in alemtuzumab-treated patients
 Lowest serum creatininePre-treatmentThree months post-Efficacy within 3 months after treatment
 post transplantationserum creatininetreatment serum Lack of improvementNeed for further
ID(μmol/L)(μmol/L)creatinine (μmol/L)Graft lossof graft functionanti-rejection treatment
1584781247NoNoNo
286128Patient diedYesYesNo
3331332200NoNoNo
49413287NoNoNo
5603658165NoNoNo
6527776NoNoNo
7523889255NoNoNo
896486350NoNoNo
996138131NoYesNo
1097131140NoYesNo
11110166171NoNoNo
Table 3. Outcome in ATG-treated patients
 Lowest serum creatininePre treatmentThree monthsEfficacy within three months after treatment
 post transplantationcreatininepost treatment Lack of improvementNeed for further anti-
ID(μmol/L)(μmol/L)creatinine (μmol/L)Graft lossof graft functionrejection treatment
12246345108NoNoNo
13325896148NoNoNo
14468562158NoNoNo
15123350121NoNoNo
16171278102NoNoNo
17286468217NoNoNo
18112490181NoNoYes
1916416495NoNoNo
20120126130NoYesNo
21214306141NoNoNo
22105350413NoYesNo
23118285Patient diedYes (patient died)NoNo
24119158100NoNoNo
25153164141NoNoNo
26484602220NoNoNo
27245485264NoNoYes
28611608290NoNoNo
29168224238NoYesNo
30152219516YesYesNo
3194301201NoNoYes

One or more infusion-related side effects occurred in three alemtuzumab-treated patients (27%). One patient developed malaise, dyspnea, myalgia and tachycardia, whereas the other two had either a local hematoma or a mild rash. In comparison, all but three ATG-treated patients experienced one or more infusion-related side effects such as hypotension, fever, chills, nausea, malaise and thrombocytopenia (85%; p = 0.013). The median drug-related costs of alemtuzumab treatment were €1050 (range €525–€1050), whereas the median drug-related costs of ATG treatment were €2024 (range €855–€3875; p < 0.01).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References
  9. Supporting Information

In this retrospective analysis, alemtuzumab appeared to be similarly effective as ATG in the treatment of steroid-resistant renal allograft rejection. The incidence of infections was low and not different from that seen after ATG therapy. Importantly, treatment with alemtuzumab was associated with fewer infusion-related side effects that were also considerably milder.

These results have to be interpreted with caution however, because of the nonrandomized and small nature of this study. Of note, there were some differences between both groups. There were more retransplanted patients in the alemtuzumab group, which could partly be explained by the fact that in a number of cases alemtuzumab was used to avoid repeated ATG treatment after prior use for an earlier graft. In general, retransplanted patients may be more sensitized and therefore more difficult to treat. However, despite the larger number of retransplants in the alemtuzumab group, the outcome was similar to that in the ATG-treated patients. Moreover, we noticed that within both groups there was considerable variation in the interval between transplantation and rejection. No difference in effectiveness of alemtuzumab was found in early versus late (defined as occurring more than 6 months posttransplant) rejections (data not shown), but the small numbers in these subgroups preclude firm conclusions.

The incidence of infections was similar in both groups, including the incidence of primary CMV infection of reactivation. However, our follow-up period was relatively short, especially considering the long-lasting T cell-depletion that can be observed after alemtuzumab treatment [14]. The majority of literature data concern the use of alemtuzumab as induction therapy. In this regard, it is of interest that one of the trials on induction therapy with alemtuzumab showed less acute rejections but an increased incidence of CMV disease [15]. This was not confirmed in a larger cohort of 547 patients [16]. However, the latter study showed that the incidence of opportunistic infections was increased when patients received alemtuzumab for the treatment of allograft rejection compared with those who received alemtuzumab as induction therapy (21 vs. 4.5%; p <0.01). In a noncomparative study with 40 patients treated with alemtuzumab for steroid-resistant or severe rejection, a total of 14 patients (35%) had infectious complications, of whom two (5%) died [9]. In a recent article reporting long-term follow-up data, the Cambridge group also found an excess of early infection-related death in alemtuzumab-treated patients [10].

Aside from these concerns, our data show great advantages of the use of alemtuzumab, namely the significantly lower incidence of infusion-related side effects, the possibility to administer alemtuzumab subcutaneously and lower costs. This renders alemtuzumab a valuable alternative for ATG to treat acute rejection, especially in frail patients. We think that a randomized prospective trial to compare these two treatments is warranted.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References
  9. Supporting Information

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. No financial support was received for this study.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References
  9. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References
  9. Supporting Information
FilenameFormatSizeDescription
ajt4328-sup-0001-TableS1.docx33K

Table S1: Individual patient data on immunosuppression, graft histology and timing of rejections in alemtuzumab-treated patients

Table S2: Individual patient data on immunosuppression, graft histology and timing of rejections in ATG-treated patients

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