Alemtuzumab Induction in Non-Hepatitis C Positive Liver Transplant Recipients

LIVER TRANSPLANTATION 17:32-37, 2011 ORIGINAL ARTICLE Alemtuzumab Induction in Non-Hepatitis C Positive Liver Transplant Recipients Josh Levitsky, 1,2 Kavitha Thudi, 1 Michael G. Ison, 1,3 Edward Wang, 1,4 and Michael Abecassis 1 1 Comprehensive Transplant Center, 2 Division of Hepatology, Department of Medicine, 3 Division of Infectious Diseases, Department of Medicine, and 4 Division of Biostatistics and Epidemiology, Department of 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 outcomes of hepatitis C virus negative LT recipients who received AL induction followed by tacrolimus and mycophenolate mofetil without steroids to cohort who received no AL induction, tacrolimus, and a steroid taper. Fifty-five AL-induced recipients were compared to 85 non AL-induced recipients with similar characteristics. Two-year patient survival (80% versus 88.2%, P ¼ 0.0665) and graft survival (76.4% versus 82.4%, P ¼ 0.1792) were not significantly different between the AL and non-al groups, respectively. Other outcomes, including acute rejection (20% versus 30.3%), renal dysfunction (creatinine levels: 1.3 60.3 versus 1.4 6 0.6 mg/dl), and immunosuppressant monotherapy (29.1% versus 44.3%), were not significantly different between the AL and non-al groups, respectively (P > 0.05). The number of rejection episodes (12 versus 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 AL group, although the incidence of all posttransplant infections was higher with AL (63.6% versus 44.3%, P ¼ 0.03), primarily because of an increase in viral infections. In conclusion, a steroid-free AL induction regimen was associated with less hypertension and rejection but with more infectious complications; thus, the overall benefit of AL induction in LT recipients is called 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 liver transplantation (LT) centers. This is likely related to the higher percentage of patients with cirrhosis and perioperative renal dysfunction and thus to the need to delay the administration of nephrotoxic immunosuppressive agents such as calcineurin inhibitors. In addition, by depleting alloreactive clonal populations, lymphodepletion therapy may theoretically promote immunosuppression minimization or even withdrawal, although the latter practice is not widely accepted. 1,2 Alemtuzumab (AL) or Campath-1H (Genzyme, Cambridge, MA) is a humanized rat monoclonal antibody directed against the CD52 antigen on peripheral blood mononuclear cells. 3 Its efficacy as induction therapy for preventing rejection after solid organ transplantation has been reported, although it is Food and Drug Administration approved only for the treatment of chronic lymphocytic leukemia. 4,5 The available data concerning the use of AL induction in LT recipients are limited to only a few previous reports that have demonstrated mixed results. 6-8 In addition, rapidly progressive hepatitis C virus (HCV) recurrence has been associated with AL induction, likely because of profound lymphodepletion. 9 In this article, we report the outcomes of HCV-negative LT recipients who received a steroid-free AL induction regimen followed by calcineurin inhibitor and mycophenolate mofetil (MMF) therapy and compare them to the outcomes of similar patients receiving a standard immunosuppressive regimen without AL induction. Our goal was to determine any risks or benefits of AL induction therapy for the design of future immunosuppressive protocols in this population. PATIENTS AND METHODS This study is a retrospective case-control study of HCV-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 Feinberg School 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.22180 View 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 VC 2011 American Association for the Study of Liver Diseases.

LIVER TRANSPLANTATION, Vol. 17, No. 1, 2011 LEVITSKY ET AL. 33 therapy at Northwestern Memorial Hospital between 2002 and 2006. Patients with HCV or acute liver failure and those receiving split, living related, donor after cardiac death, or combined organ transplants were excluded from the analysis. The controls consisted of all LT recipients with similar inclusion criteria who did not receive AL induction and underwent transplantation in the previous era at our institution. Because AL induction was the standard of care for non-hcv patients between 2002 and 2006, no concurrent control group was available for that time period; therefore, a control group from the previous era (1997-2003) was used. The reviewed records included our institution s paper and electronic medical and transplant databases. The study protocol was approved by our institutional review board and was compliant with the Health Insurance Portability and Accountability Act. Both AL-induced patients and controls received intravenous methylprednisolone (500 mg in the operating room, 250 mg on postoperative day 1, and 125 mg on postoperative day 2). The immunosuppression protocol for the AL-induced patients was as follows: intravenous AL (30 mg) in the operating room; tacrolimus (0.2 mg/kg/day), which was started on postoperative day 1; and MMF (2000 mg daily), which was started on postoperative day 2. This group did not receive corticosteroids for maintenance immunosuppression, except after the treatment of acute cellular rejection. The control group received tacrolimus (0.2 mg/kg/day), which was started on postoperative day 1, and prednisone (20 mg daily), which was started on day 3. Prednisone was tapered off within 6 months, except for those who required it for other reasons. Similar tacrolimus trough levels were targeted for the 2 groups (10-12 ng/ml in the first month and 5-10 ng/ml thereafter). Protocol liver biopsies were not performed at our institution. In both groups, liver biopsy was performed when acute cellular rejection was suspected, but no formal criteria for the performance of biopsy were followed (ie, at the discretion of the treating physician). A protocol for the management of acute cellular rejection was followed for both groups: (1) intravenous methylprednisolone (500 mg) was used for 3 days and was followed by a steroid taper to prednisone (20 mg) at the end of 7 days, and (2) biopsy-confirmed steroid-refractory rejection was treated with intravenous muromonab-cd3 (5 mg daily) for 7 to 10 days. Rejection was graded according to standard criteria. 10 All AL-induced patients and controls received oral valganciclovir or ganciclovir for 3 to 6 months for cytomegalovirus (CMV) prophylaxis according to the donor/recipient status: donor-positive/recipient-negative (Dþ/R ) patients received 6 months of antiviral prophylaxis, whereas patients with all other serotypes received 3 months of antiviral prophylaxis. All patients received oral nystatin for 3 months and trimethoprim/sulfamethoxazole for 1 year for fungal and Pneumocystis carinii pneumonia prophylaxis, respectively. No patients discontinued anti-infective prophylaxis earlier than these established time points. Infectious complications within 2 years of transplantation were recorded in the same transplant databases and electronic medical records for both groups and for both LT eras. All infections were confirmed by culture, viral titer, or tissue analysis or, in some instances, clinically (ie, varicella and herpes simplex skin infections). The primary outcome of the study was the incidence of acute rejection within 2 years after transplantation. Secondary outcomes that were assessed included the rates of patient and graft survival, infection, renal dysfunction, malignancy, and metabolic abnormalities (hypertension and diabetes), and the percentages of patients on immunosuppressant monotherapy at 2 years. New-onset hypertension was diagnosed when 2 or more recordings of a systolic blood pressure greater than 140 mm Hg and a diastolic blood pressure greater than 90 mm Hg occurred in conjunction with the use of postoperative antihypertensive agents for more than 3 months, in the absence of preexisting hypertension. New-onset diabetes was diagnosed if the fasting glucose level was greater than 126 mg/dl or any value was greater than 200 mg/dl in conjunction with the use of postoperative hypoglycemic agents for more than 3 months, in the absence of preexisting diabetes. The Student t test and chi-square analysis were used for parametric variables, and the Wilcoxon rank-sum test and Fisher s exact test were performed for comparisons of nonparametric continuous and categorical variables, respectively. Kaplan- Meier analyses of patient and graft survival were performed, and comparisons were made between the AL and non-al groups by the log-rank test. A P value less than 0.05 was considered statistically significant. RESULTS Demographics One hundred eight LT recipients received the AL induction regimen in the time period of the study. Patients were excluded from our analysis for the following reasons: undergoing combined liver-kidney transplantation (39), being HCV-positive (12), undergoing living donor transplantation (1), and undergoing transplantation for acute liver failure (1). Thus, 55 AL-induced recipients without HCV met the inclusion criteria for the study group. Eighty-five non-al controls without HCV meeting similar inclusion criteria were randomly selected. The patient characteristics were comparable in the 2 groups, except that the creatinine level at transplantation was higher in the AL group versus the non-al group (1.3 6 0.6 versus 1.1 6 0.5 mg/dl, P ¼ 0.03; Table 1). Rejection Eleven patients (20%) in the AL group had 12 episodes of rejection, whereas 24 patients (30.3%) in the control group had 42 episodes of rejection (Table 2).

34 LEVITSKY ET AL. LIVER TRANSPLANTATION, January 2011 The mean number of days to first rejection was lower in the AL group versus the non-al group (37.5 6 47.3 versus 79.9 6 202.9 days), although this was not TABLE 1. Patient Characteristics Non-AL AL Group (n ¼ 55) Group (n ¼ 85) P Value Male (%) 67.3 60.8 0.37 Age (years) 52.7 6 10.4 50.3 6 10.6 0.2 Caucasian (%) 72.2 78.6 0.56 Pre-LT complications (%) Ascites 75.2 64.5 0.28 Hepatic 43.7 52.1 0.34 encephalopathy Variceal 28.5 31.1 0.68 hemorrhage Etiology (%) Alcohol 29.2 31.6 0.75 Cryptogenic 27.2 15.2 0.08 Autoimmune 23.6 32.9 0.25 Hepatitis B virus 9.1 11.4 0.67 Hepatocellular 7.2 12.6 0.25 carcinoma Other 10.9 8.9 0.69 Calculated MELD 21.3 6 7.6 19.5 6 7.6 0.18 score Creatinine 1.3 6 0.6 1.1 6 0.5 0.03 (mg/dl) Pre-LT diabetes 29.1 40.5 0.24 (%) Body mass 31.2 6 6.4 29.9 6 5.8 0.35 index at LT (kg/m 2 ) CMV Dþ/R 18.2 17.6 0.68 status (%) Donor age (years) 43.7 6 8.9 47.7 6 6.8 0.55 Cold ischemia 8.7 6 2.4 7.6 6 2.2 0.09 time (hours) statistically significant (P ¼ 0.5). Thus, although the overall percentages of patients developing at least 1 episode of rejection were similar in the 2 groups (P ¼ 0.13), the non-al controls had statistically more episodes of rejection over time (2 per patient; P ¼ 0.02). There was 1 severe rejection episode in the AL group that required muromonab-cd3; there were 3 severe rejection episodes in the control group, and 2 required muromonab-cd3. All rejection episodes resolved and no patients developed chronic rejection or lost their graft. The total number of biopsy procedures was higher in the non-al control group versus the AL group (55 versus 25, P ¼ 0.008) as there were more rejection episodes in the control group. Patient and Graft Survival There were 11 deaths (20%) in the AL cohort due to following etiologies: sepsis (2), ischemic cholangiopathy and graft failure (1), malignancy (5: recurrent hepatoma, leukemia, metastatic angiosarcoma, glioblastoma multiforme, and metastatic colon carcinoma), cardiac arrest (2), and unknown (1). Ten patients (11.8%) died in the non-al control group for the following reasons: sepsis (1), respiratory failure (3), malignancy [4: recurrent hepatoma (3) and recurrent cholangiocarcinoma (1)], and gastrointestinal bleeding (2). According to Kaplan-Meier analysis, 2- year patient survival was not significantly different between the AL and non-al groups (Fig. 1). Two patients in the AL group and 5 patients in the non-al group underwent retransplantation (1.8% versus 7.1%, P ¼ 0.15). One of the 2 patients in the AL group had ischemic cholangiopathy, and the other had hepatic artery thrombosis. The causes of retransplantation in the non-al group included ischemic cholangiopathy (2), hepatic artery thrombosis (1), portal vein thrombosis (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 Rejection Patients [n (%)] 11 (20) 24 (30.3) 0.13 Episodes (n) 12 42 0.02 Steroid-refractory [n (%)] 1 (1.8) 3 (3.8) 0.88 Infection Patients [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 0.22 Fungal (n) 8 8 0.43 White blood cell count (1 10 3 cells/ll) 3.6 6 2.3 4.3 6 2.6 0.27 Creatinine (mg/dl) 1.3 6 0.3 1.4 6 0.6 0.25 Dialysis [n (%)] 1 (1.8) 0 (0) 0.87 Retransplantation [n (%)] 2 (1.8) 5 (7.1) 0.15 Monotherapy [n (%)] 16 (29.1) 35 (44.3) 0.07 Malignancy [n (%)] 7 (12.7) 15 (18.9) 0.33 New-onset diabetes [n (%)] 3 (5.5) 11 (13.9) 0.11 New-onset hypertension [n (%)] 3 (5.5) 15 (18.9) 0.03

LIVER TRANSPLANTATION, Vol. 17, No. 1, 2011 LEVITSKY ET AL. 35 Figure 1. Kaplan-Meier analysis demonstrating no difference in long-term patient survival between AL-infused LT recipients and non AL-infused LT recipients. Figure 2. Kaplan-Meier analysis demonstrating no difference in long-term graft survival between AL-infused LT recipients and non AL-infused LT recipients. year graft survival was also not significantly different between the AL and non-al groups (Fig. 2). Infectious Complications The rate of posttransplant infections was significantly higher in the AL group versus the control group, primarily 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 had a total of 42 episodes (Table 2). There was no significant difference in the mean number of days from LT to the first infection (any type) between the AL and non-al groups (154.5 6 218.2 versus 320.1 6 636.8 days, P ¼ 0.15). In addition, 4 of 35 AL patients and 5 of 35 non-al patients experienced rejection within 90 days of the first infectious episode (P ¼ 0.87). Although the bacterial and fungal infection rates were not statistically different, the rate of viral infections was significantly higher in the AL group versus the control group (13/55 versus 2/85, P < 0.0001). In the AL group, 14% of the viral infections (80% in the Dþ/ R group and 83.3% in the first post-lt year) were due to CMV, 8% were due to varicella zoster virus, and 2% were due to herpes simplex virus; the viral infections in the non-al group (2%) occurred in the second post-lt year and were due to varicella zoster. Two of the Dþ/R patients with CMV infections in the AL group had end organ involvement (CMV disease: colitis and hepatitis) that responded to intravenous ganciclovir therapy. All the varicella and herpes infections were localized to the skin and not ophthalmologic or disseminated. None of the patients had postherpetic neuralgia or other complications. Other Outcomes The rates of development of renal dysfunction, malignancy, leukopenia, and new-onset diabetes and the percentages of patients who were on a single immunosuppressive agent at 2 years were not statistically different between the 2 groups (Table 2). However, the incidence of new-onset hypertension was higher in the non-al group versus the AL group (18.9% versus 5.5%, P ¼ 0.03) DISCUSSION Our study demonstrates some potential benefits and risks of AL induction in LT recipients. Although the total number of rejection episodes and the rate of new-onset hypertension were lower with AL induction therapy, the risk of infection was significantly higher than the risk in the non AL-induced cohort. The benefit of avoiding more than 1 acute rejection episode appears to be counteracted by the risk of viral infections (particularly CMV). Our findings are not surprising because AL causes profound, long-lasting lymphodepletion, which subsequently leads to a lower rate of late rejection but a higher risk of late-onset infections. In addition, none of the other major endpoints, including patient and graft survival, renal dysfunction, and the percentage weaned to maintenance monotherapy, were different between the AL-induced and non AL-induced groups. Therefore, the overall added advantage of AL induction in LT recipients is questionable. AL has been used successfully as induction therapy, mainly for patients undergoing nonhepatic solid organ transplantation. Steroid-free regimens designed to reduce the incidence of metabolic complications from steroids have been used with AL induction. AL use has been thought to additionally promote the concept of prope tolerance: allograft function is maintained with minimal immunosuppression, so the incidence of long-term adverse effects of calcineurin inhibitors, such as nephrotoxicity, may be reduced. 11 The data on AL use for LT are, however, limited to reports from single centers. Researchers at the University of Miami reported their experience with AL

36 LEVITSKY ET AL. LIVER TRANSPLANTATION, January 2011 induction in 40 patients and updated their results with a subsequent study of 77 patients. 7,8 These observations showed a significant reduction in the acute rejection rate in the AL group versus the non- AL group, but there was no significant difference in the patient or graft survival rates or in the rates of opportunistic infections between the groups. The AL group also had a lower incidence of nephrotoxicity, which was thought to be due to the use of lower calcineurin inhibitor doses and trough levels. They also reported AL use for intestinal and multivisceral transplantation and demonstrated a trend toward reduced rejection with AL induction without an increase in the incidence of opportunistic infections. 6 Although our results are somewhat similar to those of other reports in terms of rejection (there were fewer patients with multiple rejection episodes in our AL group), we observed a significantly higher rate of viral infectious complications. 6-9,12,13 This occurred even though we used a single-dose, steroid-free AL induction regimen, whereas others used repeat AL dosing. The discrepancy in infectious outcomes could be related to several important factors. Our standard 30-mg AL dose (instead of weight-based dosing) may have contributed to the overimmunosuppressed state. In addition, our steroid-free protocol involved the use of adjunctive MMF because we were concerned about rejection with calcineurin inhibitor monotherapy immediately after transplantation. However, other studies not using MMF reported reduced rejection rates without increases in infectious complications, 7-9 so the combination of AL and MMF in our patients likely led to more marrow toxicity. It is also worth noting that no patients in the non- AL group had CMV infections, and this was likely because of the lower intensity of their immunosuppression regimen (higher number of rejection episodes). That said, this control group s unusually low rate of viral infections contributed to the statistically significant difference versus the AL group and also might not be representative of rates seen in similar cohorts in the literature. Finally, it is possible that differences in the dosing and length of antiviral prophylaxis in our cohorts and other studies could explain the observed discrepancy. Notably, the majority of our AL patients who developed a CMV infection had undergone previous dose reductions of valganciclovir to 450 mg every other day because of lymphopenia. This further emphasizes the importance of maintaining adequate antiviral prophylaxis and avoiding other marrow-suppressive therapy (ie, MMF) in this population. Our study is consistent with other reports demonstrating a higher risk of infectious complications. In a study by Silveira et al., 14 the incidence of cryptococcocal infections was significantly higher in patients receiving more than 1 dose of AL versus those receiving conventional immunosuppression without induction. In another study by Peleg et al., 15 organ transplant recipients receiving AL did not experience an increased incidence of opportunistic infections unless they were being treated with AL for rejection and with more than 1 AL dose. On the basis of our data and others data, a number of general conclusions can be made. First, prolonged anti-infectious prophylaxis (particularly antiviral prophylaxis) may be required after AL induction. Second, much less maintenance immunosuppression, particularly in the LT population, may be needed with AL induction. Calcineurin inhibitor monotherapy with or without steroids may be adequate to prevent rejection and not lead to higher rates of infection. Finally, weight-based single doses of AL for induction are likely to reduce complications in comparison with standard or multiple-dosing regimens. These conclusions are, however, based only on the limited data available and not on randomized controlled trials. Finally, the issue of HCV-positive recipients deserves mention. These patients have been excluded from previous studies because it has been demonstrated that AL-induced lymphodepletion may result in rapidly progressive HCV recurrence and graft failure. 10 This has not been demonstrated consistently with other lymphodepletion (anti-thymocyte globulin) and nonlymphodepletion (interleukin-2 inhibitor) induction protocols in this population. Because 4 of our 12 initial HCV-positive recipients developed rapid HCV recurrence and graft failure after AL induction (these patients were excluded from this report; the data are not shown), we discontinued this practice in mid 2002 and used AL induction only in non-hcv patients. Hence, unless other data prove otherwise, HCV-positive patients should not be given AL as either induction or rejection therapy. Our study has several limitations. The collected data are retrospective in nature and subject to potential bias. In addition, our data concern patients who were followed at a single institution and may not be applicable to recipients at other centers. The patients in the 2 groups did not undergo transplantation during the same period because non-hcv patients between 2002 and 2006 received AL induction. To address this issue, we randomly selected patients from a pool of previous patients meeting inclusion criteria similar to those for the AL group; however, prednisone (not MMF) was used in the control group. A control group with identical immunosuppression except for AL (tacrolimus and MMF alone with no prednisone) was unfortunately not available at our institution for comparison. However, the baseline characteristics of the 2 populations, except for the immunosuppressive regimen and a small difference in the creatinine levels, were similar, so the impact of this confounder is likely low. In conclusion, in light of the risks and benefits, our observations suggest that induction therapy with AL in all LT recipients (HCV-positive and HCV-negative) does not appear to be beneficial in comparison with a standard regimen. Prolonged anti-infective prophylaxis and minimized immunosuppression are likely needed to reduce infectious complications if AL induction is being considered. Further prospective studies addressing these concerns are required to justify the use of AL in the LT population.

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