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lemtuzumab with Rapid Steroid Taper in Simultaneous Kidney andancreas Transplantation: Comparison to Induction withntithymocyte Globulin

.S. Reddy, Y. Devarapalli, M. Mazur, K. Hamawi, H. Chakkera, A. Moss, K. Mekeel, D. Post,

. Heilman, and D. Mulligan

ABSTRACT

We compared our experience with alemtuzumab induction and rapid steroid taper (RST)in simultaneous kidney and pancreas transplantation (SKPT) with a historic control groupwho received rabbit antithymocyte globulin (r-ATG) induction with RST. 74 SKPTsperformed at our center between January 2005 to November 2008 who underwentimmunosuppression with RST in combination with r-ATG induction (n � 33; 1.5 mg/kg �4 for a total dose of 6 mg/kg) or alemtuzumab induction (n � 41; 30 mg single dose).Maintenance immunosuppression consisted of tacrolimus and mycophenolate mofetil.Steroids were discontinued after postoperative day 4. Recipient and transplant character-istics were similar between the 2 groups, with 82% of the r-ATG and 80% of thealemtuzumab group steroid free at 1 year. The rate of clinical acute rejection episodes was12% in the r-ATG group and 15% in the alemtuzumab group. The rates of cytomegalo-virus (CMV) infection, BK nephropathy, and graft survival were similar between the 2groups. There was no difference in mean serum creatinine, calculated GFR, or fastingblood sugar at 1 year between the 2 groups, whereas glycosylated hemoglobin (HbA1c) waslower at 1 year in the alemtuzumab (5.3 � 0.4) versus the r-ATG group (5.6 � 0.4; P �.0021). Induction with r-ATG or alemtuzumab with RST was safe and effective in SKPT.The incidences of acute rejection episodes, CMV infection, and BK nephropathy weresimilar. Mean HbA1C at 1 year was lower among the alemtuzumab group. Further

long-term follow-up is needed to confirm these results.

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nti–T-cell antibody induction, which has been shown todecrease the incidence of acute rejection episodes, is

urrently used in �80% of simultaneous kidney and pan-reas transplant (SKPT) recipients.1 The well known com-lications of long-term steroid use and the introduction ofotent immunosuppressive agents have led to renewed

nterest in steroid-sparing protocols. Corticosteroid avoid-nce or rapid steroid taper (RST) has become an increas-ngly common practice among kidney and kidney-pancreasransplantation cases. Our experience with RST using pro-ocol biopsies in the kidney transplant population showed ito be a safe and effective regimen with low incidence ofejection episodes.2 In January 2005, we expanded the usef the RST protocol in combination with rabbit antithymo-yte globulin (r-ATG) induction to patients receivingKPT. In January 2007, we started using induction with the

onoclonal anti-CD52 antibody alemtuzumab. Herein we k

041-1345/10/$–see front matteroi:10.1016/j.transproceed.2010.05.090

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ave reported our experience with RST in SKPT recipients,omparing 2 induction agents: alemtuzumab versus r-ATG.

ETHODS

e performed a retrospective review, with Institutional Reviewoard approval of 91 SKPTs performed between January 2005 andovember 2008. We excluded from this analysis 17 patients who

eceived transplants in the presence of donor-specific antibody or aositive cross-match with long-term steroid treatment. Among the4 SKPT recipients who received immunosuppression with RST, 33

From Transplant Center, Mayo Clinic Arizona, 5777 East Mayooulevard, Phoenix, Arizona.Address reprint requests to K. Sudhakar Reddy, MD, Consul-

ant, Transplant Center, Surgical Director, Kidney Pancreasransplant, Associate Professor of Surgery, Mayo Clinic Arizona,777 East Mayo Boulevard, Phoenix, AZ 85054. E-mail: reddy.

unam@mayo.edu

© 2010 by Elsevier Inc. All rights reserved.360 Park Avenue South, New York, NY 10010-1710

Transplantation Proceedings, 42, 2006–2008 (2010)

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ALEMTUZUB IN SIMULTANEOUS KIDNEY-PANCREAS TRANSPLANTATION 2007

nderwent induction treatment with r-ATG (1.5 mg/kg � 4 for aotal dose of 6 mg/kg) and 41 with alemtuzumab (30 mg singleose). Maintenance immunosuppression consisted of mycopheno-

ate mofetil (MMF; 1 g twice daily) and tacrolimus (target troughevels 10–15 ng/mL during the first month and 8–12 ng/mL during

onths 2–3 after transplantation, followed by 5–10 ng/mL after 3onths). All patients received 5 daily doses of steroids, startingith methylprednisolone 500 mg intravenously on the day of

ransplantation tapered to 30 mg of prednisone on day 4. Steroidsere discontinued after postoperative day 4. Protocol kidneyiopsies were performed at months 1, 4, and 12. All patients in the-ATG group and 75% of the alemtuzumab group had at least 1ear of follow-up (minimum follow-up of 6 months). All theransplantations were performed using systemic enteric drainage.he following oucome measures were compared between theroups, biopsy-proven clinical and subclinical acute rejection epi-odes, rate of cytomegalovirus (CMV) infection, BK nephropathy,idney and pancreas graft survival, and kidney and pancreasllograft function. Death with a functioning graft was considered toe a graft loss in calculating graft survival.

ESULTS

he mean age of the patients (r-ATG 45 � 13 y vslemtuzumab 47 � 12 y), rate of preemptive transplantsr-ATG 36% vs alemtuzumab 22%), incidence of type 2iabetes (r-ATG 9% vs alemtuzumab 17%), mean length oftay (r-ATG 7.8 � 3.2 d vs alemtuzumab 8.1 � 5.0 d), andercentage of patients steroid free at 1 year (r-ATG 82% vslemtuzumab 80%) were similar between the 2 groups.hree percent of the alemtuzumab group were retrans-lants, and all transplants in the r-ATG group were pri-ary. 97% of the r-ATG group and 92% of the alemtu-

umab group had a panel reactive antibody level of 0%. Theates of acute rejection episodes of kidney and/or pancreas,f CMV infection, of BK nephropathy, and graft survivalnd function in the 2 groups are presented in Table 1.

RST using r-ATG or alemtuzumab induction were asso-iated with excellent outcomes: similar rates of acute rejec-ion episodes, graft survival, CMV infection and BK ne-hropathy. The percentage of patients with a serumreatinine values above 1.5 at 1 year was numerically highern the alemtuzumab group (23% vs 12% in the r-ATGroup), but the difference was not significant. Whereas the

Table 1. Clinical Outcome Measures in A

Alemtuzumab

Clinical acute rejection (K or P) 15%Subclinical acute rejection 5%CMV infection 10%BK nephropathy 2%1-yr kidney graft survival 93%1-yr pancreas graft survival 88%Serum creatinine (mg/dL) 1.4 � 0% with serum creatinine �1.5 12%MDRD-GFR 61 � 2Fasting blood sugar (mg/dL) 93 � 1HbA1C 5.3 � 0

Abbreviations: CMV, cytomegalovirus; HbA1C, glycosylated hemoglobin; K, kidneltration rate; P, pancreas; r-ATG, rabbit antithymocyte globulin; RST, rapid steroid t

ean fasting blood sugar value was similar between the 2roups, the mean glycosylated hemoglobin (HbA1C) wasower in the alemtuzumab group (5.3 � 0.4 vs 5.6 � 0.4 inhe r-ATG group; P � .0021). However, we need furtherong-term follow-up to determine the significance of thisnding.

ISCUSSION

everal other studies have evaluated the use of alemtu-umab in SKPT (Table 2). Most work used either noteroids or RST and maintenance immunosuppression with

calcineurin inhibitor.3–9 Thai et al3 reported excellentraft survivals and an acceptable 30% acute rejection rate atyears using induction with a single-dose alemtuzumab and

acrolimus monotherapy; all patients received 2 g sol-medrol perioperatively. The rate of CMV infection wasignificantly lower among the alemtuzumab compared withthymoglobulin group in the study reported by Kaufman etl.4 However, in the study reported by Magliocca et al,5 theMV infection rate was higher among the alemtuzumabroup (2 doses of 30 mg intravenously) compared with aasiliximab group. Those authors have since altered theirrotocol to a single 30 mg instead of 2 doses of alemtu-umab. Pascual et al6 reported on a subgroup of theatients originally reported by Magliocca et al, showingcute antibody-mediated rejection (AMR) to be more commonhan acute cellular rejection (ACR) in both groups. Alemtu-umab prevented ACR better than basiliximab, whereas theMR rate was similar between the 2 groups. However, the

ate of AMR in unsensitized crossmatch-negative patients wasigher in that study compared with other published reports.In all of the above studies, alemtuzumab was given

ntravenously either as a single dose (30 mg) or as 2 doses30 mg each). Clatworthy et al reported subcutaneousdministration of alemtuzumab (2 doses) in SKPT recipi-nts producing lymphocyte depletion similar to that seen in

group of renal transplant patients who had receivedntravenous alemtuzumab.8 At our center, we initiallytarted using alemtuzumab in a single dose (30 mg) intra-enously and have since changed to a single dose (30 mg)ubcutaneously. The absolute lymphocyte counts, graft sur-

zumab Versus r-ATG Groups With RST

1) r-ATG (n � 33) P Value

12% NS6% NS

18% NS6% NS

97% NS94% NS

1.2 � 0.4 NS (.0559)23% NS

70 � 20 NS (.08)94 � 12 NS

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ival and acute rejection rates in patients receiving alemtu-umab subcutaneously were similar to those receiving in-ravenous alemtuzumab (data not shown). Gruessner et al9

valuated both calcineurin inhibitor– and steroid-free reg-mens using alemtuzumab induction and maintenance with

MF. The incidence of acute rejection episodes was sig-ificantly higher among the study group (41%) despite

ntense immunosuppression compared with the controlroup (9%) who received thymoglobulin induction, tacroli-us, and MMF.In summary, induction with r-ATG or alemtuzumab withST was safe and effective for SKPT. Both induction agentsere associated with acceptable short-term outcomes. The

ncidences of acute rejection episodes, CMV infections, andK nephropathy were similar between the 2 groups. MeanbA1C at 1 year was lower in the alemtuzumab group.urther long-term follow-up is needed to confirm theseesults.

EFERENCES

Table 2. Published Studies Evaluating the Use of Alemtuz

Author, Year GroupsMaintainance

AgentsNo.

Patie

ruessner et al,2005

Study: alemtuzumab MMF 21Control: r-ATG Tac, MMF 67

hai et al, 2006 Alemtuzumab Tac 30aufman, 2006 Study: alemtuzumab Tac, sirolimus 50

Control: r-ATG Tac, sirolimus 38latworthyet al, 2007

Alemtuzumab Tac, MMF 21

agliocca et al,2008

Study: alemtuzumab Tac, MMF, Pred 105

Control: basiliximab Tac, MMF, Pred 226uthusamyet al, 2008

Alemtuzumab Tac, MMF 83

ascual et al,2009

Study: alemtuzumab Tac, MMF, Pred 97

Control: basiliximab Tac, MMF, Pred 39

Abbreviations: ACR, acute cellular rejection; AMR, antibody-mediated rejecacrolimus.

1. White SA, Shaw JA, Sutherland DER: Pancreas transplanta-ion. Lancet 373:1808, 2009

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2. Heilman RL, Reddy KS, Mazur MJ, et al: Acute rejection riskn kidney transplant recipients on steroid-avoidance immunosup-ression receiving induction with either antithymocyte globulin orasiliximab. Transplant Proc 38:1307, 20063. Thai NL, Khna A, Tom K, et al: Alemtuzumab induction and

acrolimus montherapy in pancreas transplantation: one- and two-ear outcomes. Transplantation 82:1621, 2006

4. Kaufman DB, Leventhal JR, Gallon LG, Parker MA: Ale-tuzumab induction and prednisone-free maintatinance immuno-

herapy in simultaneous pancreas-kidney transplantation: compar-son with rabbit antithymocyte globulin—long-term results. Am Jransplant 6:331, 20065. Magliocca JF, Odorico JS, Pirsch JD, et al: A comparison of

lemtuzumab with basiliximab induction in simultaneous pancreas-idney transplantation. Am J Transplant 8:1702, 20086. Pascual J, Pirsch JD, Odorico JS, et al: Alemtuzumab induc-

ion and antibody-mediated kidney rejection after simultaneousancreas-kidney transplantation. Transplantation 87:125, 20097. Muthusamy ASR, Vaidya AC, Sinha S, et al: Alemtuzumab

nduction and steroid-free maintainance immunosuppression inancreas transplantation. Am J Transplant 8:2126, 20088. Clatworthy MR, Sivaprakasam R, Butler AJ, Watson CJ:

ubcutaneous administration of alemtuzumab in pancreas-kidneyransplantation. Transplantation 84:1563, 2007

9. Gruessner RWG, Kandaswamy R, Humar A, et al: Cal-ineurin inhibitor– and steroid-free immunosuppression in pancreas-

b in Simultaneous Kidney and Pancreas Transplantation

Follow-upKidney Graft

SurvivalPancreas

Graft Survival RejectionCMV

Infection

6 mo 81% 81% 41% 14%85% 79% 9% 5%

2 y 87% 87% 30% 13%3 y 91% 92% 8% 6%

86% 97% 5% 19%1 y 100% 95% 14% 5%

2 y 93% 92% 20% 29%

90% 85% 31% 16%1 y 94% 90% 22% 7%

2 y 91% 89% ACR 3%,AMR 14%

95% 82% ACR 13%,AMR 18%

MV, cytomegalovirus; MMF, mycophenolate mofetil; Pred, prednisone; Tac,

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idney and solitary pancreas transplantation. Transplantation 79:1184,005