ORIGINAL ARTICLE

Alemtuzumab Induction in Non-Hepatitis CPositive Liver Transplant RecipientsJosh Levitsky,1,2 Kavitha Thudi,1 Michael G. Ison,1,3 Edward Wang,1,4 and Michael Abecassis11Comprehensive Transplant Center, 2Division of Hepatology, Department of Medicine, 3Division ofInfectious Diseases, Department of Medicine, and 4Division of Biostatistics and Epidemiology, Departmentof Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL

Limited data exist for the use of alemtuzumab (AL) induction in liver transplantation (LT) recipients. We compared the out-comes of hepatitis C virus–negative LT recipients who received AL induction followed by tacrolimus and mycophenolatemofetil without steroids to cohort who received no AL induction, tacrolimus, and a steroid taper. Fifty-five AL-induced recipi-ents were compared to 85 non–AL-induced recipients with similar characteristics. Two-year patient survival (80% versus88.2%, P ¼ 0.0665) and graft survival (76.4% versus 82.4%, P ¼ 0.1792) were not significantly different between the ALand non-AL groups, respectively. Other outcomes, including acute rejection (20% versus 30.3%), renal dysfunction (creati-nine levels: 1.3 60.3 versus 1.4 6 0.6 mg/dL), and immunosuppressant monotherapy (29.1% versus 44.3%), were not sig-nificantly different between the AL and non-AL groups, respectively (P > 0.05). The number of rejection episodes (12versus 42, P ¼ 0.02) and the number of patients with new-onset hypertension (3 versus 15, P ¼ 0.03) were lower in the ALgroup, although the incidence of all posttransplant infections was higher with AL (63.6% versus 44.3%, P ¼ 0.03), primarilybecause of an increase in viral infections. In conclusion, a steroid-free AL induction regimen was associated with less hyper-tension and rejection but with more infectious complications; thus, the overall benefit of AL induction in LT recipients iscalled into question. Liver Transpl 17:32-37, 2011. VC 2011 AASLD.

Received June 7, 2010; accepted August 21, 2010.

The practice of induction therapy is increasing in livertransplantation (LT) centers. This is likely related to thehigher percentage of patients with cirrhosis and periop-erative renal dysfunction and thus to the need to delaythe administration of nephrotoxic immunosuppressiveagents such as calcineurin inhibitors. In addition, bydepleting alloreactive clonal populations, lymphodeple-tion therapy may theoretically promote immunosuppres-sion minimization or even withdrawal, although the lat-ter practice is not widely accepted.1,2 Alemtuzumab (AL)or Campath-1H (Genzyme, Cambridge, MA) is a human-ized rat monoclonal antibody directed against the CD52antigen on peripheral blood mononuclear cells.3 Its effi-cacy as induction therapy for preventing rejection aftersolid organ transplantation has been reported, althoughit is Food and Drug Administration–approved only for thetreatment of chronic lymphocytic leukemia.4,5 The avail-able data concerning the use of AL induction in LT recipi-

ents are limited to only a few previous reports that havedemonstrated mixed results.6-8 In addition, rapidly pro-gressive hepatitis C virus (HCV) recurrence has beenassociated with AL induction, likely because of profoundlymphodepletion.9 In this article, we report the outcomesof HCV-negative LT recipients who received a steroid-freeAL induction regimen followed by calcineurin inhibitorand mycophenolate mofetil (MMF) therapy and comparethem to the outcomes of similar patients receiving astandard immunosuppressive regimen without ALinduction. Our goal was to determine any risks or bene-fits of AL induction therapy for the design of futureimmunosuppressive protocols in this population.

PATIENTS AND METHODS

This study is a retrospective case-control study ofHCV-negative LT recipients receiving AL induction

Abbreviations: AL, alemtuzumab; CMV, cytomegalovirus; Dþ/R�, donor-positive/recipient-negative; HCV, hepatitis C virus; LT,liver transplantation; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil.

Address reprint requests to Josh Levitsky, M.D., M.S., Division of Hepatology, Department of Medicine, Northwestern University FeinbergSchool of Medicine, 676 North Saint Clair Street, Suite 1900, Chicago, IL 60611. FAX: 312-695-0036; E-mail: j-levitsky@northwestern.edu

DOI 10.1002/lt.22180View this article online at wileyonlinelibrary.com.LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

LIVER TRANSPLANTATION 17:32-37, 2011

VC 2011 American Association for the Study of Liver Diseases.

therapy at Northwestern Memorial Hospital between2002 and 2006. Patients with HCV or acute liver fail-ure and those receiving split, living related, donor af-ter cardiac death, or combined organ transplantswere excluded from the analysis. The controls con-sisted of all LT recipients with similar inclusion crite-ria who did not receive AL induction and underwenttransplantation in the previous era at our institution.Because AL induction was the standard of care fornon-HCV patients between 2002 and 2006, no con-current control group was available for that time pe-riod; therefore, a control group from the previous era(1997-2003) was used. The reviewed records includedour institution’s paper and electronic medical andtransplant databases. The study protocol wasapproved by our institutional review board and wascompliant with the Health Insurance Portability andAccountability Act.

Both AL-induced patients and controls received in-travenous methylprednisolone (500 mg in the operat-ing room, 250 mg on postoperative day 1, and 125 mgon postoperative day 2). The immunosuppression pro-tocol for the AL-induced patients was as follows: in-travenous AL (30 mg) in the operating room; tacroli-mus (0.2 mg/kg/day), which was started onpostoperative day 1; and MMF (2000 mg daily), whichwas started on postoperative day 2. This group didnot receive corticosteroids for maintenance immuno-suppression, except after the treatment of acute cellu-lar rejection. The control group received tacrolimus(0.2 mg/kg/day), which was started on postoperativeday 1, and prednisone (20 mg daily), which wasstarted on day 3. Prednisone was tapered off within 6months, except for those who required it for other rea-sons. Similar tacrolimus trough levels were targetedfor the 2 groups (10-12 ng/mL in the first month and5-10 ng/mL thereafter).

Protocol liver biopsies were not performed at ourinstitution. In both groups, liver biopsy was per-formed when acute cellular rejection was suspected,but no formal criteria for the performance of biopsywere followed (ie, at the discretion of the treating phy-sician). A protocol for the management of acute cellu-lar rejection was followed for both groups: (1) intrave-nous methylprednisolone (500 mg) was used for 3days and was followed by a steroid taper to predni-sone (20 mg) at the end of 7 days, and (2) biopsy-con-firmed steroid-refractory rejection was treated with in-travenous muromonab-CD3 (5 mg daily) for 7 to 10days. Rejection was graded according to standardcriteria.10

All AL-induced patients and controls received oralvalganciclovir or ganciclovir for 3 to 6 months for cy-tomegalovirus (CMV) prophylaxis according to the do-nor/recipient status: donor-positive/recipient-nega-tive (Dþ/R�) patients received 6 months of antiviralprophylaxis, whereas patients with all other serotypesreceived 3 months of antiviral prophylaxis. Allpatients received oral nystatin for 3 months and tri-methoprim/sulfamethoxazole for 1 year for fungaland Pneumocystis carinii pneumonia prophylaxis,

respectively. No patients discontinued anti-infectiveprophylaxis earlier than these established time points.Infectious complications within 2 years of transplan-tation were recorded in the same transplant data-bases and electronic medical records for both groupsand for both LT eras. All infections were confirmed byculture, viral titer, or tissue analysis or, in someinstances, clinically (ie, varicella and herpes simplexskin infections).

The primary outcome of the study was the incidenceof acute rejection within 2 years after transplantation.Secondary outcomes that were assessed included therates of patient and graft survival, infection, renaldysfunction, malignancy, and metabolic abnormalities(hypertension and diabetes), and the percentages ofpatients on immunosuppressant monotherapy at 2years. New-onset hypertension was diagnosed when 2or more recordings of a systolic blood pressure greaterthan 140 mm Hg and a diastolic blood pressuregreater than 90 mm Hg occurred in conjunction withthe use of postoperative antihypertensive agents formore than 3 months, in the absence of preexistinghypertension. New-onset diabetes was diagnosed ifthe fasting glucose level was greater than 126 mg/dLor any value was greater than 200 mg/dL in conjunc-tion with the use of postoperative hypoglycemicagents for more than 3 months, in the absence of pre-existing diabetes. The Student t test and chi-squareanalysis were used for parametric variables, and theWilcoxon rank-sum test and Fisher’s exact test wereperformed for comparisons of nonparametric continu-ous and categorical variables, respectively. Kaplan-Meier analyses of patient and graft survival were per-formed, and comparisons were made between the ALand non-AL groups by the log-rank test. A P valueless than 0.05 was considered statistically significant.

RESULTS

Demographics

One hundred eight LT recipients received the ALinduction regimen in the time period of the study.Patients were excluded from our analysis for the fol-lowing reasons: undergoing combined liver-kidneytransplantation (39), being HCV-positive (12), under-going living donor transplantation (1), and undergoingtransplantation for acute liver failure (1). Thus, 55AL-induced recipients without HCV met the inclusioncriteria for the study group. Eighty-five non-AL con-trols without HCV meeting similar inclusion criteriawere randomly selected. The patient characteristicswere comparable in the 2 groups, except that the cre-atinine level at transplantation was higher in the ALgroup versus the non-AL group (1.3 6 0.6 versus 1.16 0.5 mg/dL, P ¼ 0.03; Table 1).

Rejection

Eleven patients (20%) in the AL group had 12 epi-sodes of rejection, whereas 24 patients (30.3%) in thecontrol group had 42 episodes of rejection (Table 2).

LIVER TRANSPLANTATION, Vol. 17, No. 1, 2011 LEVITSKY ET AL. 33

The mean number of days to first rejection was lowerin the AL group versus the non-AL group (37.5 6 47.3versus 79.9 6 202.9 days), although this was not

statistically significant (P ¼ 0.5). Thus, although theoverall percentages of patients developing at least 1episode of rejection were similar in the 2 groups (P ¼0.13), the non-AL controls had statistically more epi-sodes of rejection over time (�2 per patient; P ¼ 0.02).There was 1 severe rejection episode in the AL groupthat required muromonab-CD3; there were 3 severerejection episodes in the control group, and 2 requiredmuromonab-CD3. All rejection episodes resolved andno patients developed chronic rejection or lost theirgraft. The total number of biopsy procedures washigher in the non-AL control group versus the ALgroup (55 versus 25, P ¼ 0.008) as there were morerejection episodes in the control group.

Patient and Graft Survival

There were 11 deaths (20%) in the AL cohort due tofollowing etiologies: sepsis (2), ischemic cholangiop-athy and graft failure (1), malignancy (5: recurrenthepatoma, leukemia, metastatic angiosarcoma, glio-blastoma multiforme, and metastatic colon carci-noma), cardiac arrest (2), and unknown (1). Tenpatients (11.8%) died in the non-AL control group forthe following reasons: sepsis (1), respiratory failure(3), malignancy [4: recurrent hepatoma (3) and recur-rent cholangiocarcinoma (1)], and gastrointestinalbleeding (2). According to Kaplan-Meier analysis, 2-year patient survival was not significantly differentbetween the AL and non-AL groups (Fig. 1). Twopatients in the AL group and 5 patients in the non-ALgroup underwent retransplantation (1.8% versus7.1%, P ¼ 0.15). One of the 2 patients in the AL grouphad ischemic cholangiopathy, and the other had he-patic artery thrombosis. The causes of retransplanta-tion in the non-AL group included ischemic cholangi-opathy (2), hepatic artery thrombosis (1), portal veinthrombosis (1), and primary nonfunction (1). Two-

TABLE 2. Two-Year Patient Outcomes

AL Group (n ¼ 55) Non-AL Group (n ¼ 85) P Value

RejectionPatients [n (%)] 11 (20) 24 (30.3) 0.13Episodes (n) 12 42 0.02

Steroid-refractory [n (%)] 1 (1.8) 3 (3.8) 0.88InfectionPatients [n (%)] 35 (63.6) 35 (44.3) 0.03

Episodes (n) 50 42 0.001

Viral (n) 13 2 <0.0001

Bacterial (n) 29 32 0.22Fungal (n) 8 8 0.43

White blood cell count (1 � 103 cells/lL) 3.6 6 2.3 4.3 6 2.6 0.27Creatinine (mg/dL) 1.3 6 0.3 1.4 6 0.6 0.25Dialysis [n (%)] 1 (1.8) 0 (0) 0.87Retransplantation [n (%)] 2 (1.8) 5 (7.1) 0.15Monotherapy [n (%)] 16 (29.1) 35 (44.3) 0.07Malignancy [n (%)] 7 (12.7) 15 (18.9) 0.33New-onset diabetes [n (%)] 3 (5.5) 11 (13.9) 0.11New-onset hypertension [n (%)] 3 (5.5) 15 (18.9) 0.03

TABLE 1. Patient Characteristics

AL Group

(n ¼ 55)

Non-AL

Group

(n ¼ 85) P Value

Male (%) 67.3 60.8 0.37Age (years) 52.7 6 10.4 50.3 6 10.6 0.2Caucasian (%) 72.2 78.6 0.56Pre-LT complications (%)Ascites 75.2 64.5 0.28Hepaticencephalopathy

43.7 52.1 0.34

Varicealhemorrhage

28.5 31.1 0.68

Etiology (%)Alcohol 29.2 31.6 0.75Cryptogenic 27.2 15.2 0.08Autoimmune 23.6 32.9 0.25Hepatitis B virus 9.1 11.4 0.67Hepatocellularcarcinoma

7.2 12.6 0.25

Other 10.9 8.9 0.69Calculated MELD

score21.3 6 7.6 19.5 6 7.6 0.18

Creatinine(mg/dL)

1.3 6 0.6 1.1 6 0.5 0.03

Pre-LT diabetes(%)

29.1 40.5 0.24

Body massindex atLT (kg/m2)

31.2 6 6.4 29.9 6 5.8 0.35

CMV Dþ/R�status (%)

18.2 17.6 0.68

Donor age (years) 43.7 6 8.9 47.7 6 6.8 0.55Cold ischemia

time (hours)8.7 6 2.4 7.6 6 2.2 0.09

34 LEVITSKY ET AL. LIVER TRANSPLANTATION, January 2011

year graft survival was also not significantly differentbetween the AL and non-AL groups (Fig. 2).

Infectious Complications

The rate of posttransplant infections was significantlyhigher in the AL group versus the control group, pri-marily because of viral etiologies. Thirty-five patients(63.6%) in the AL group had a total of 50 episodes,whereas 35 patients (44.3%) in the control group hada total of 42 episodes (Table 2). There was no signifi-cant difference in the mean number of days from LTto the first infection (any type) between the AL andnon-AL groups (154.5 6 218.2 versus 320.1 6 636.8days, P ¼ 0.15). In addition, 4 of 35 AL patients and 5of 35 non-AL patients experienced rejection within 90days of the first infectious episode (P ¼ 0.87).Although the bacterial and fungal infection rates werenot statistically different, the rate of viral infectionswas significantly higher in the AL group versus thecontrol group (13/55 versus 2/85, P < 0.0001). In theAL group, 14% of the viral infections (80% in the Dþ/R� group and 83.3% in the first post-LT year) weredue to CMV, 8% were due to varicella zoster virus,and 2% were due to herpes simplex virus; the viralinfections in the non-AL group (2%) occurred in thesecond post-LT year and were due to varicella zoster.Two of the Dþ/R� patients with CMV infections inthe AL group had end organ involvement (CMV dis-ease: colitis and hepatitis) that responded to intrave-nous ganciclovir therapy. All the varicella and herpesinfections were localized to the skin and not ophthal-mologic or disseminated. None of the patients hadpostherpetic neuralgia or other complications.

Other Outcomes

The rates of development of renal dysfunction, malig-nancy, leukopenia, and new-onset diabetes and thepercentages of patients who were on a single immuno-

suppressive agent at 2 years were not statistically dif-ferent between the 2 groups (Table 2). However, theincidence of new-onset hypertension was higher inthe non-AL group versus the AL group (18.9% versus5.5%, P ¼ 0.03)

DISCUSSION

Our study demonstrates some potential benefits andrisks of AL induction in LT recipients. Although thetotal number of rejection episodes and the rate ofnew-onset hypertension were lower with AL inductiontherapy, the risk of infection was significantly higherthan the risk in the non–AL-induced cohort. The ben-efit of avoiding more than 1 acute rejection episodeappears to be counteracted by the risk of viral infec-tions (particularly CMV). Our findings are not surpris-ing because AL causes profound, long-lasting lympho-depletion, which subsequently leads to a lower rate oflate rejection but a higher risk of late-onset infections.In addition, none of the other major endpoints,including patient and graft survival, renal dysfunc-tion, and the percentage weaned to maintenancemonotherapy, were different between the AL-inducedand non–AL-induced groups. Therefore, the overalladded advantage of AL induction in LT recipients isquestionable.

AL has been used successfully as induction ther-apy, mainly for patients undergoing nonhepatic solidorgan transplantation. Steroid-free regimens designedto reduce the incidence of metabolic complicationsfrom steroids have been used with AL induction. ALuse has been thought to additionally promote the con-cept of prope tolerance: allograft function is main-tained with minimal immunosuppression, so the inci-dence of long-term adverse effects of calcineurininhibitors, such as nephrotoxicity, may be reduced.11

The data on AL use for LT are, however, limited toreports from single centers. Researchers at the Uni-versity of Miami reported their experience with AL

Figure 1. Kaplan-Meier analysis demonstrating no difference inlong-term patient survival between AL-infused LT recipients andnon–AL-infused LT recipients.

Figure 2. Kaplan-Meier analysis demonstrating no difference inlong-term graft survival between AL-infused LT recipients andnon–AL-infused LT recipients.

LIVER TRANSPLANTATION, Vol. 17, No. 1, 2011 LEVITSKY ET AL. 35

induction in 40 patients and updated their resultswith a subsequent study of 77 patients.7,8 Theseobservations showed a significant reduction in theacute rejection rate in the AL group versus the non-AL group, but there was no significant difference inthe patient or graft survival rates or in the rates ofopportunistic infections between the groups. The ALgroup also had a lower incidence of nephrotoxicity,which was thought to be due to the use of lower calci-neurin inhibitor doses and trough levels. They alsoreported AL use for intestinal and multivisceral trans-plantation and demonstrated a trend toward reducedrejection with AL induction without an increase in theincidence of opportunistic infections.6

Although our results are somewhat similar to thoseof other reports in terms of rejection (there were fewerpatients with multiple rejection episodes in our ALgroup), we observed a significantly higher rate of viralinfectious complications.6-9,12,13 This occurred eventhough we used a single-dose, steroid-free AL inductionregimen, whereas others used repeat AL dosing. Thediscrepancy in infectious outcomes could be related toseveral important factors. Our standard 30-mg AL dose(instead of weight-based dosing) may have contributedto the overimmunosuppressed state. In addition, oursteroid-free protocol involved the use of adjunctiveMMF because we were concerned about rejection withcalcineurin inhibitor monotherapy immediately aftertransplantation. However, other studies not using MMFreported reduced rejection rates without increases ininfectious complications,7-9 so the combination of ALand MMF in our patients likely led to more marrow tox-icity. It is also worth noting that no patients in the non-AL group had CMV infections, and this was likelybecause of the lower intensity of their immunosuppres-sion regimen (higher number of rejection episodes).That said, this control group’s unusually low rate of vi-ral infections contributed to the statistically significantdifference versus the AL group and also might not berepresentative of rates seen in similar cohorts in the lit-erature. Finally, it is possible that differences in thedosing and length of antiviral prophylaxis in ourcohorts and other studies could explain the observeddiscrepancy. Notably, the majority of our AL patientswho developed a CMV infection had undergone previ-ous dose reductions of valganciclovir to 450 mg everyother day because of lymphopenia. This furtheremphasizes the importance of maintaining adequateantiviral prophylaxis and avoiding other marrow-sup-pressive therapy (ie, MMF) in this population.

Our study is consistent with other reports demon-strating a higher risk of infectious complications. In astudy by Silveira et al.,14 the incidence of cryptococco-cal infections was significantly higher in patientsreceiving more than 1 dose of AL versus those receiv-ing conventional immunosuppression without induc-tion. In another study by Peleg et al.,15 organ trans-plant recipients receiving AL did not experience anincreased incidence of opportunistic infections unlessthey were being treated with AL for rejection and withmore than 1 AL dose. On the basis of our data and

others’ data, a number of general conclusions can bemade. First, prolonged anti-infectious prophylaxis(particularly antiviral prophylaxis) may be required af-ter AL induction. Second, much less maintenanceimmunosuppression, particularly in the LT popula-tion, may be needed with AL induction. Calcineurininhibitor monotherapy with or without steroids maybe adequate to prevent rejection and not lead tohigher rates of infection. Finally, weight-based singledoses of AL for induction are likely to reduce compli-cations in comparison with standard or multiple-dos-ing regimens. These conclusions are, however, basedonly on the limited data available and not on random-ized controlled trials.

Finally, the issue of HCV-positive recipientsdeserves mention. These patients have been excludedfrom previous studies because it has been demon-strated that AL-induced lymphodepletion may resultin rapidly progressive HCV recurrence and graft fail-ure.10 This has not been demonstrated consistentlywith other lymphodepletion (anti-thymocyte globulin)and nonlymphodepletion (interleukin-2 inhibitor)induction protocols in this population. Because 4 ofour 12 initial HCV-positive recipients developed rapidHCV recurrence and graft failure after AL induction(these patients were excluded from this report; thedata are not shown), we discontinued this practice inmid 2002 and used AL induction only in non-HCVpatients. Hence, unless other data prove otherwise,HCV-positive patients should not be given AL as ei-ther induction or rejection therapy.

Our study has several limitations. The collecteddata are retrospective in nature and subject to poten-tial bias. In addition, our data concern patients whowere followed at a single institution and may not beapplicable to recipients at other centers. The patientsin the 2 groups did not undergo transplantation dur-ing the same period because non-HCV patientsbetween 2002 and 2006 received AL induction. Toaddress this issue, we randomly selected patientsfrom a pool of previous patients meeting inclusion cri-teria similar to those for the AL group; however, pred-nisone (not MMF) was used in the control group. Acontrol group with identical immunosuppressionexcept for AL (tacrolimus and MMF alone with noprednisone) was unfortunately not available at ourinstitution for comparison. However, the baselinecharacteristics of the 2 populations, except for theimmunosuppressive regimen and a small difference inthe creatinine levels, were similar, so the impact ofthis confounder is likely low.

In conclusion, in light of the risks and benefits, ourobservations suggest that induction therapy with ALin all LT recipients (HCV-positive and HCV-negative)does not appear to be beneficial in comparison with astandard regimen. Prolonged anti-infective prophy-laxis and minimized immunosuppression are likelyneeded to reduce infectious complications if AL induc-tion is being considered. Further prospective studiesaddressing these concerns are required to justify theuse of AL in the LT population.

36 LEVITSKY ET AL. LIVER TRANSPLANTATION, January 2011

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