Alemtuzumab Induction and Steroid-Free Maintenance Immunosuppression in Pancreas Transplantation

Transcription

1 American Journal of Transplantation 2008; 8: Wiley Periodicals Inc. C 2008 The Authors Journal compilation C 2008 The American Society of Transplantation and the American Society of Transplant Surgeons doi: /j x Alemtuzumab Induction and Steroid-Free Maintenance Immunosuppression in Pancreas Transplantation A. S. R. Muthusamy a,a.c.vaidya a, S. Sinha a, D. Roy a,d.e.elker a andp.j.friend a,b, a Department of Transplant Surgery, Oxford Transplant Centre, Churchill Hospital, Oxford, UK b Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, UK Corresponding author: Peter J. Friend, peter.friend@nds.ox.ac.uk Paper presented at the American Transplant Congress, May San Francisco, CA. Alemtuzumab is a humanized anti-cd52 antibody that depletes lymphocytes and has been increasingly used as induction agent in transplantation. The impact of alemtuzumab induction immunosuppression in pancreas transplantation was evaluated, with particular reference to steroid avoidance in maintenance. A total of 100 patients who received 102 pancreas transplants (83 simultaneous kidney pancreas [SPK], 15 pancreas after kidney transplantation [PAK] and 4 pancreas transplant alone [PTA]) were included. All patients received two doses of 30-mg alemtuzumab i.v. with tacrolimus (trough level 8 12 ng/ml) and mycophenolate mofetil (MMF,1g/day) with no maintenance steroids. This analysis included 62 male and 38 female recipients, with mean (±SD) age of 42 (±7.6) years. Median follow-up was 17 months (range 8 41 months). One-year patient, pancreas and kidney graft survival (actuarial) was 97%, 89% and 94%, respectively. Overall incidence of rejection was 25%. Side effects of alemtuzumab administration included thrombocytopenia (14%), pulmonary edema (2%) and rash (1%). Twenty-five percent required reoperations (12% for bleeding). Infectious complications included Cytomegalovirus (CMV,6.8%) BK viruria (3.8%), fungal infections (4%), primary varicella (1%) and posttransplant lymphoproliferative disorders (PTLD,1%). Eighty-three percent did not require any steroids posttransplant. These results indicate that alemtuzumab is safe and enables pancreas transplantation to be carried out without maintenance steroids in 83% of cases and acceptable rejection rate. Key words: Alemtuzumab, immunosuppression, pancreas transplantation, steroid avoidance Received 22 December 2007, revised 23 June 2008 and accepted for publication 02 July 2008 Introduction Alemtuzumab is a humanized anti-cd52 monoclonal antibody that is licensed for treatment of chronic lymphocytic leukemia and has found increasing use in organ transplantation (1). The CD52 antigen, whose function is unknown, is expressed on all mononuclear cells as well as the male reproductive tract. Alemtuzumab functions by causing cytolysis of CD52-positive cells, and has the ability to cause rapid and profound lymphocyte depletion involving T and B cells, natural killer cells and monocytes, with slow reconstitution of different subpopulations (2,3). It has also found unlicensed use in various disorders of immune response, including rheumatoid arthritis (4), multiple sclerosis (5) and graft-versus-host disease (6). The majority of the clinical experience with alemtuzumab has been primarily with renal transplantation, where it was used initially to treat graft rejection by Friend et al. (7) and subsequently as an induction agent by Calne et al. in 1998 (8). Subsequently, alemtuzumab has found increasing popularity as an induction agent for kidney as well as kidney pancreas transplantation (9). The use of alemtuzumab as an induction agent in kidney and kidney pancreas transplantation has demonstrated its ability to allow low-dose maintenance immunosuppression with acceptable risk of early rejection despite steroid-free (10,11) and steroid and calcineurin inhibitor-free (12) maintenance immunosuppression regimens. Alemtuzumab is easy to administer, has a long-lasting effect and is cost effective (11). In this study, we present our results with the use of alemtuzumab induction to obtain a steroid-free maintenance regimen in kidney pancreas and pancreas transplantation. Alemtuzumab was chosen as the induction agent, due to its powerful lytic properties, and due to its successful use in a steroid and calcineurin inhibitor-free immunosuppression regimen for kidney transplantation (13) at our centre. Alemtuzumab also offered opportunity to avoid steroids in the maintenance regime due to its well-known deleterious effects (14) and also the possibility of reducing the incidence of graft loss due to rejection. We also had the benefit of long-term experience with the use of alemtuzumab in clinical transplantation (7,8,13,15,16). Materials and Methods This was a single-center retrospective analysis of all patients who underwent pancreas transplantation, either as simultaneous kidney pancreas 2126

2 Alemtuzumab Induction in Pancreas Transplants (SPK), pancreas after kidney transplantation (PAK) or pancreas transplant alone (PTA) using alemtuzumab induction from July 2004 to April This included retransplants, as well as highly sensitized patients. All pancreas grafts were implanted intraperitoneally with enteric exocrine drainage and systemic venous drainage. The transplant ureteroneocystostomy was routinely stented. The endpoints of the study were patient and graft survival, steroid avoidance, rejection episodes and incidence of complications. Pancreas graft failure was defined as requirement of exogenous insulin to maintain euglycemia, and kidney graft failure was defined as requirement of regular dialysis. Immunosuppression protocol All patients received methylprednisolone (Solu-medrol R, Pharmacia, Surrey, UK) 500 mg intravenously (i.v.) before perfusion of the pancreas graft, followed by a further 250 mg i.v. if a kidney graft was implanted simultaneously. Induction immunosuppression consisted of two doses of alemtuzumab 30 mg (Campath R, Genzyme, Oxford, UK), given i.v., the first dose within 6 h of reperfusion of the pancreas graft, followed by the second dose of alemtuzumab 30 mg i.v., 24 h after the first dose. Both doses of alemtuzumab were preceded by bolus doses of methyl prednisolone 250 mg i.v. No other steroids were given routinely after the transplant. Maintenance immunosuppression consisted of tacrolimus (Prograf R, Astellas Pharma Ltd, UK) 0.05 mg/kg/day PO from day 1 and mycophenolate mofetil (MMF) (Cellcept R, Roche Ltd, UK) 500 mg b.d. PO. Target trough levels of tacrolimus were between 8 and 12 ng/ml, and this was maintained throughout the life of the transplant. No routine empirical reduction in tacrolimus dosing was performed in the face of delayed graft function, unless a renal graft biopsy was obtained. The dosage of mycophenolate was adjusted according to the absolute neutrophil count; the daily dose was reduced to 500 mg if the neutrophil count was less than /L, and stopped if this fell below cells /L. Infection prophylaxis All patients received oral Nystatin (Nystan R, Bristol-Myers Squibb, Uxbridge, UK) U q.d.s. PO for 1 month, Co-trimoxazole (Septrin R, Glaxo Smithkline, Uxbridge, UK) 480 mg OD for 6 months and cytomegalovirus (CMV) prophylaxis for 3 months, depending upon donor and recipient serology. CMV-negative recipients receiving CMV-positive organs received valganciclovir (Valcyte R, Roche Ltd, Welwyn Garden City, UK) whereas CMV-positive recipients received valaciclovir (Valtrex R, Glaxo Smithkline) regardless of the CMV status of the donor. CMV donor- and recipient-negative transplants did not receive prophylaxis. All at-risk patients (donor or recipient CMV positive) were monitored by weekly CMV antigenemia testing. All SPK recipients underwent routine urine cytology screening for BK virus (17); PAK and PTA recipients were tested if they had evidence of renal dysfunction (i.e. increase of creatinine >15% from baseline). Anticoagulation protocol All patients underwent thromboelastography-directed anticoagulation for at least 6 weeks posttransplant beginning preoperatively with a combination of aspirin, heparin and Dextran40 TM, with the aim of maintaining the coagulation index between 3 and+3. The rationale and the details of this protocol are described elsewhere (18). Graft monitoring All patients were reviewed routinely at the Oxford Transplant Centre, and had fasting C-peptide, amylase, C-reactive protein and glucose level checked during each visit. All patients with a pancreas graft underwent a standard oral glucose tolerance test every 3 months, as well as during episodes of graft dysfunction. Diagnosis and management of acute rejection The renal graft was used as the marker of rejection in the SPK group and identified by increase in the serum creatinine. Renal graft biopsy was obtained whenever possible. However, if there was no safe percutaneous access to the (intraperitoneal) renal graft or if the patient was anticoagulated, biopsy was contraindicated and treatment was administered on clinical grounds. Similarly, patients suspected to have isolated pancreatic rejection were treated on clinical suspicion. The diagnosis of rejection was confirmed retrospectively by a positive response to increased immunosuppression. All episodes were treated with three doses of methylprednisolone (Solu-medrol R ) along with an increase in baseline immunosuppression either increasing the dose of tacrolimus or myphenolate or the introduction of steroids into the maintenance immunosuppression. All patients had a favorable response to the steroid pulse, and did not require any further antirejection therapy with antibodies. Results A total of 100 patients who underwent 102 transplants were included in this analysis. The study included 62 male and 38 female recipients, with 91 Caucasian, 5 Asian and 4 of Afro Caribbean ethnicity. The mean (±SD) recipient age was 42 (±7.6) years, and BMI 24.7 ± 3.9 kg/m 2.Of the 102 transplants, 83 were SPK, 15 PAK and 4 PTA. All except two grafts were obtained from donors after brain death (DBD); two grafts were obtained from donors after cardiac death (DCD). Mean donor age was 33 years (range 5 62 years). The pancreas grafts had a median cold ischemia time of 11.5 h (range 5 18 h). The median HLA mismatch was 4. Median follow-up was 17 months (range 8 41 months), with complete capture of mortality and major morbidity events in all patients. Median hospital stay following transplant was 15 days (range 8 88 days). Patient and graft survival The 1-year actuarial patient, pancreas and kidney graft survival was 97%, 89% and 94%, respectively (Figure 1). There were three deaths, all in the SPK group. Deathcensored 1-year overall pancreas graft survival was 92%, and the kidney graft survival was 98%. Actuarial 1-year pancreas graft survival in SPK, PAK and PTA was 90%, 80% and 100%, respectively (Figure 2). One patient was found dead at home on day 32, following a presumed cardiac dysrhythmia- there were no conclusive autopsy findings. One patient died on day 180 as a result of a fatal complication of a percutaneous liver biopsy. Both these deaths occurred with functioning grafts. The third patient died 60 days posttransplant due to multiorgan failure secondary to abdominal sepsis. Six patients presented with failed pancreases at 3,10,11,13,18 and19 months posttransplant and had angiographic appearances suggestive of chronic rejection (19). Three of these were PAK transplants, two SPK; one patient had a pancreas retransplant. Two grafts were lost to severe pancreatitis (day 7, day 14). One graft developed complete venous thrombosis by day 3 due to inadvertent narrowing of the splenic vein. One graft was removed immediately after reperfusion due to poor perfusion of the graft. One SPK patient lost both grafts due American Journal of Transplantation 2008; 8:

3 Muthusamy et al. were treated and 2% of pancreas grafts (n = 2) were lost due to presumed rejection (based on angiographic appearances after graft failure). In the PAK group, 27% of patients (n = 4) were treated for rejection and 20% of grafts (n = 3) failed due to presumed rejection (angiographic appearances). None of the patients in the PTA group received antirejection therapy and no grafts were lost. Figure 1: Actuarial graft and patient survival following alemtuzumab induction and steroid-free maintenance immunosuppression. Effects of alemtuzumab administration Alemtuzumab produced a profound lymphopenia, with lymphocyte counts returning to pretransplant levels by the end of the first year post-transplant. No case of absolute neutropenia (absolute neutrophil count <1000/mL blood) was encountered. One patient developed a rash and two developed acute pulmonary edema that was attributed to the drug. Fourteen percent of patients developed a transient thrombocytopenia (platelet count <100). Fifteen patients received only one dose of alemtuzumab; this was due to low platelet counts and concern over bleeding (11 patients), pulmonary edema (two cases) elderly patient (one case) and previous alemtuzumab exposure (one case). Infections and other complications The overall incidence of CMV antigenemia was 6.8% (seven patients), occurring mainly in the SPK group and exclusively in the high-risk group (positive donor to negative recipient). All patients responded to intravenous ganciclovir therapy and have functioning grafts. Figure 2: Actuarial pancreas graft survival by type in alemtuzumab induction and steroid-free maintenance immunosuppression. to poor compliance. One renal graft was lost to venous thrombosis. Graft function All patients had normal glycemic control and had normal glycated hemoglobin level by 3 months posttransplant (5.2 ± 0.6%), and had fasting C-peptide levels of 0.8 ± 0.5 nmol/l at 12 months posttransplant. SPK patients had 1-year creatinine of 130 ± 42.1 lmol/l (estimated creatinine clearance by Cockgraft Gault formula 66.8 ± 18.1 ml/min). Eighteen percent of patients (n = 15) receiving SPK had delayed graft function of the kidney, defined by any dialysis requirement posttransplant. All patients with successful transplants demonstrated normal glucose tolerance on 3-monthly glucose tolerance tests (data not shown). Two patients (n = 2) had delayed graft function of the pancreas, defined by requirement for exogenous insulin after 72-h posttransplantation. Rejection The incidence of treated rejection episodes in the entire series was 25.4%. In the SPK group, 22% patients (n = 18) All patients with SPK were followed up routinely by our BKV screening protocol (17), which involves routine urine cytology for decoy cells. Positive urine cytology (defined by >10 decoy cells/high-power field) triggered a quantitative PCR estimation of BKV viral load in plasma (>1000 copies/ml = significant). Additional urine cytology for BKV was performed in the face of renal graft dysfunction (>15% increase in serum creatinine) in all groups (SPK, PAK and PTA) to rule out underlying BK nephropathy. Renal allograft biopsy was performed if it was considered safe (some patients were on systemic anticoagulation). Management of BK nephropathy included controlled withdrawal of immunosuppression with close monitoring of plasma BK viral load and urine cytology. The incidence of BK nephropathy (defined by presence of renal graft dysfunction and significant BK viruria with >10 decoy cells per high-power field and positive plasma PCR for BKV) was 3.8%, all occurring in SPK patients. All patients have renal grafts with good and stable function. There were two cases of herpes one patient developed primary varicella infection, was treated with ganciclovir and recovered with no complications; the second patient had herpes zoster treated with valaciclovir and recovered. Four patients developed fungal infections treated successfully with systemic antifungal therapy. One SPK recipient developed an EBV+, CD20+ large B-cell lymphoma 9 months 2128 American Journal of Transplantation 2008; 8:

4 Alemtuzumab Induction in Pancreas Transplants Reoperations Bleeding was the most common cause for reoperation, occurring in 12% of all patients, mostly within 48-h posttransplant and usually in patients with thrombocytopenia; no specific bleeding was located in most of these cases. Patients who required in excess of three units of blood to maintain their hemoglobin in the immediate postoperative period were reexplored. Figure 3: Percentage of recipients requiring maintenance steroids after pancreas transplantation using alemtuzumab. following transplant; this has responded to immunosuppression reduction. Maintenance immunosuppression and steroid avoidance Eighty-four patients (83.4%) did not require any steroids postoperatively. Sixteen patients were treated with steroids (Figure 3), most commonly as an addition to baseline immunosuppression following treatment for acute rejection where increase in the doses of tacrolimus or mycophenolate was contraindicated due to concerns about toxicity. The average mycophenolate dose and the tacrolimus trough levels at various time points posttransplant are shown in Figure 4. Sixteen patients had mycophenolate temporarily withdrawn for varying duration during the first year, owing to low neutrophil count (< /L). There were two cases of graft venous thrombosis, one occurring in the pancreas graft and the other in a renal graft. The pancreas graft thrombosis was due to a technical problem, due to inadvertent narrowing of the splenic vein. There were five major wound complications; three cases of severe graft pancreatitis requiring reoperation and two cases of bowel obstruction posttransplant requiring surgical intervention. There was one case of graft duodenal leak requiring graft pancreatectomy. Reoperations were required in 25% (n = 26) of patients. Readmissions Forty-three patients required 51 readmission episodes into hospital for the reasons shown in Table 1, most commonly for glycemic control during treatment of rejection episodes with methyl prednisolone. Urinary tract infections were typically early posttransplant and associated with indwelling ureteric stents in the kidney transplant. All abdominal collections presenting after discharge from hospital were managed either through percutaneous drainage or conservatively. Postural hypotension was managed by intravenous supplementary fluids along with the introduction of fludrocortisone and midodrine (20). One patient developed femoral vein thrombosis 4 months posttransplant, 4 weeks after withdrawal of warfarin therapy for profound hypercoagulability demonstrated on thromboelastography (anticoagulation protocol). Warfarin was recommenced for a period of 6 months and then withdrawn, with no recurrence. No underlying hypercoagulable state was identified. Figure 4: Average MMF dose (mg/day) and Tacrolimus trough level posttransplant: Alemtuzumab induction in pancreas transplantation. American Journal of Transplantation 2008; 8:

5 Muthusamy et al. Table 1: Indication for readmission following alemtuzumab induction in pancreas transplantation Rejection 15 Urinary tract infection 8 Abdominal collection 6 CMV infection 4 Postural hypotension 4 Pharyngitis 4 Bowel obstruction 3 Pancreatitis 2 Calf vein thrombosis 1 Others 5 Discussion This retrospective analysis of a steroid-free maintenance immunosuppression regimen suggests that alemtuzumab is a safe induction agent in pancreas transplantation. Avoiding steroids in maintenance immunosuppression in the pancreas transplant recipient is attractive due to the wellknown deleterious effects of steroids on wound healing (particularly enteric anastomotic leakage) as well as induction of insulin resistance. Also, steroid avoidance has been shown to reduce the incidence of CMV infection in pancreas transplantation (21). The initial bolus of corticosteroids given at the time of reperfusion is to ameliorate the ischemia-reperfusion injury, and also to reduce the systemic effects of cytokine release following alemtuzumab administration. In the recent months, we have switched to subcutaneous administration of alemtuzumab (avoiding the necessity of giving additional corticosteroids) that has reduced the total amount of steroids used by a third of the previously used cumulative dose. Of interest, the low rate of duodenal leak (1%) could be related to the avoidance of maintenance steroids and its adverse effects on wound healing. The overall incidence of treated episodes of acute rejection (25%) was comparable to results in some other studies using alemtuzumab induction in pancreas transplantation (22,23), but higher than others (11). However, the reported incidence in this series is likely to be a significant overestimate, as these episodes were not biopsy proven. We do not practice percutaneous biopsy of these intraperitoneal pancreas grafts due to the risk of complications (24 26), particularly as all our patients receive systemic anticoagulation. The higher incidence of delayed graft function of the kidney (18%) in the SPK group despite relatively short cold ischemia (12 h) is likely to be related to the use of expanded criteria donors (i.e. donors over 45 years of age) who represented 18% of the donors. Of interest, the incidence of delayed graft function of the pancreas was much lower (2%). In line with other reported series (27), the incidence of graft loss due to (presumed) immunological causes was higher in the PAK group. This assumption was based on graft angiographic appearances and hence, could be an overestimate. We assume that this risk of immunological loss is due to lack of effective pancreas graft surveillance. The overall PAK graft survival (80%) however is comparable to Organ Procurement and Transplantation Network (OPTN) data (as of January 2008). There is a significant diversity in both the dose and the frequency of alemtuzumab administration as an induction immunosuppressant among various groups (9,11,28). Our induction protocol was based upon the experience with the use of alemtuzumab in kidney transplantation (3,13). The experience of the senior author has been with the use of two doses (8). Also, the vial size of alemtuzumab is 30 mg. Hence, after prolonged discussions with various investigators in other institutions, the two-dose, 30 mg per dose regimen (although arbitrary) was adopted. Various studies have reported the use of alemtuzumab as a part of a steroid-free regimen, but some have reported higher incidence of infectious complications (29,30), autoimmune diseases and delayed acute rejection (31). Our cohort of patients did not show a higher incidence of infectious complications; the incidence of CMV infection, was exclusively in the high-risk group (positive donor to negative recipient), and the incidence is lower than reported literature (30). We have not experienced any cases of autoimmune disease as yet. There was a 14% incidence of thrombocytopenia following the first dose of alemtuzumab, which has been reported to occur rarely with its use outside transplantation (32). Although the mean total white cell count of these patients was significantly lower than the patients receiving other antibody induction, the lower dose of maintenance MMF dose (1000 mg/day), the dynamic modulation of the MMF dose based on neutrophil count and pre-emptive withdrawal of MMF in patients with low neutrophil count (< /L), has avoided the risk of absolute neutropenia in our patients, and none of the patients in our series required augmentation with granulocyte-colony stimulating factor (G-CSF) to manage neutropenia. One patient who developed a posttransplant lymphoproliferative disease was at high risk of developing Epstein-Barr virus (EBV) infection, being an EBV-negative recipient of donor-ebv positive grafts. Our results support the findings by other groups that alemtuzumab is a safe and effective induction agent with acceptable complication rates. It allows a steroid-free maintenance immunosuppression in the majority of cases a particular advantage following pancreas transplantation. Although the mean follow-up in this series is relatively short, other groups have not reported any major increase in complications after the first year following pancreas transplantation. Long-term follow-up data of this cohort would be of interest American Journal of Transplantation 2008; 8:

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