Basiliximab Induction in Adult Liver Transplant Recipients With 93% Rejection-Free Patient and Graft Survival at 24 Months

Basiliximab Induction in Adult Liver Transplant Recipients With 93% Rejection-Free Patient and Graft Survival at 24 Months C.B. Ramirez, C. Doria, F. DiFrancesco, M. Iaria, Y. Kang, and I.R. Marino ABSTRACT Induction with the use of interleukin-2 receptor monoclonal antibodies may avoid many of the adverse events associated with polyclonal antibodies and significantly impact on rejection-free long-term survival in orthotopic liver transplantation (OLTx). We describe our experience with the use of basiliximab induction therapy in adult OLTx recipients on tacrolimus-based immunosuppression. Forty-six consecutive deceased donor primary OLTx were analyzed. All patients received standard doses of basiliximab, tacrolimus, and steroids. Mycophenolate mofetil was also used as indicated. The mean follow-up period was 17.9 months. Forty-three patients remained rejection-free during follow-up. The actuarial patient and graft survival rate at 2 years was 93%. The rate of histology-proven hepatitis C virus (HCV) recurrence was 24%, with two progressing to severe cholestatic recurrent HCV. None of the study patients developed (cytomegalovirus (CMV) infection or posttransplant lymphoproliferative disease (PTLD). Results were compared to a historical group of 46 OLTx recipients on tacrolimus-based immunosuppression without basiliximab induction. The historical group had a rejection rate of 34% with lower patient and graft survival rates of 71.74% and 69.5%, respectively, at 24 months as well as a higher histological HCV recurrence rate of 77% (17/22), with three patients progressing to graft failure within 2 years. CMV infection and disease developed in 4.5% of the patients. Although PTLD was not observed, three recipients with hepatocellular carcinoma (HCC) developed and died of metastatic HCC. Induction with basiliximab in combination with tacrolimus-based immunosuppressive regimen reduces the incidence of rejection and improves rejection-free survival rate after OLTx without increasing the incidence of CMV, PTLD, or HCV recurrence.

B

ASILIXIMAB is a chimeric (human/murine) monoclonal antibody targeting the alpha chain (CD25) of the high-affinity interleukin (IL)-2 receptors in activated T lymphocytes. This, in turn, prevents acute cellular rejection (ACR) by inhibiting IL-2 driven T-lymphocyte proliferation. Although proven safe and effective in renal transplantation,1– 4 experience with basiliximab induction in liver transplantation is less extensive. This study aims to evaluate the efficacy and safety of basiliximab induction therapy in orthotopic liver transplant (OLTx) recipients on tacrolimus-based immunosuppressive regimen. PATIENTS AND METHODS From March 2003 to July 2005, 46 consecutive deceased donor primary OLTx recipients were analyzed (group I). Data were compared to a historical group (group II) of 46 deceased donor primary OLTx recipients transplanted from August 2001 to March

2003 and who survived more than 3 months post-OLTx. Table 1 illustrates that both groups had similar demographic characteristics except for age. Patients in group 1 received basiliximab induction with dual (tacrolimus, steroids) or triple (tacrolimus, mycophenolate mofetil [MME], steroids) maintenance immunosuppression. Patients in group II received the same dual or triple immunosuppression without basiliximab induction therapy. Basiliximab was administered in two doses at 20 mg intravenous bolus intraoperatively (after liver allograft reperfusion) and on the day 4 post-OLTx. Tacrolimus was administered at a dose of 0.15 mg/kg/d orally or by From the Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania. Address reprint requests to Dr Carlo Ramirez, Department of Surgery, Thomas Jefferson University, 605 College Bldg, 1025 Walnut Street, Philadelphia, PA 19107. E-mail: carlo.ramirez@ jefferson.edu

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0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.10.110

Transplantation Proceedings, 38, 3633–3635 (2006)

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RAMIREZ, DORIA, DIFRANCESCO ET AL Table 1. Characteristics and Results of Group I (Study Group) and Group II (Historical Group) Group I (n ⫽ 46)

Baseline patient characteristics Age (mean) Gender: male/female (n) Race/ethnicity (n) Caucasian African-American Others (Asian/Hispanic/Middle/Eastern) Packed red blood cells transfusion Cold ischemia time (min, mean) Primary liver disease Hepatitis C (HCV) cirrhosis Hepatitis B (HBV) cirrhosis Hepatocellular carcinoma (HCC) HCC ⫹ HCV cirrhosis HCC ⫹ HBV cirrhosis HCC ⫹ alcoholic cirrhosis HCC ⫹ cryptogenic cirrhosis HCC ⫹ NASH Alcoholic cirrhosis PSC/PBC/AIH Cryptogenic cirrhosis Other Results Patient survival rate at 2 years (Kaplan-Meier) Graft survival rate at 2 years (Kaplan-Meier) Acute rejection rate Histologic HCV recurrence rate Grade 1–2 Grade 3–4 Stage 1–2 Stage 3–4 Infection CMV Bacteremia Fungemia Malignancy Recurrence/metastasis PTLD

57.26 ⫾ 8.7 29/17 33 4 9 16.68 ⫾ 15.5 10.5 ⫾ 3.4 10 1 23 16 5 1 1 0 4 2 3 3

Group II (n ⫽ 46)

51.65 ⫾ 9.2 34/12 35 8 3 14.4 ⫾ 16.6 9.3 ⫾ 3.1 13 2 17 11 4 0 1 1 3 4 7 0

93.5% 93.5% 3 (7%) 8/26 (31%) 2 4 2 0

71.7% 69.5% 16 (34%) 17/24 (71%) 10 4 2 1

0 (0%) 11 (24%) 0 (0%)

2 (4.5%) 18 (4.5%) 1 (2.2%)

0 (0%) 0 (0%)

3 (17.6%) 0 (0%)

P Value

.003 .262 .111

.514 .230 .470 .557 .207

.694 .398 .180 .078 .0478 .0240 .001 .005

.153 .116 .315 .78 NS

Abbreviations: NASH, non-alcoholic steato-hepatitis; PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis; AIH, autoimmune hepatitis.

nasogastric tube in two divided doses, with doses adjusted to achieve target trough level of 10 to 15 ng/mL first month) and 5 to 10 ng/mL thereafter. Steroids were given intraoperatively as methylprednisolone 1 gram intravenously. This was followed by standard rapid taper schedule to prednisone, which was weaned off by the first post-OLTx month. Biopsy-proven acute cellular rejection was treated with methylprednisolone 1 gram intravenously followed by the 5-day steroid taper of methylprednisolone intravenously as described above. In case of severe rejection or steroid-resistant rejection, the protocol advised muromonab-CD3 (OKT3), and anti-CD3 monoclonal antibody, administration at 5 mg intravenously for 5 to 10 days after premedication. A diagnosis of hepatitis C virus (HCV) recurrence was made based on the liver biopsy findings associated with serum HCV RNA titers. Liver biopsy tissue HCV polymerase chain reaction was not done. We use the modified Scheuer scoring system5 in grading and evaluating the need for therapeutic intervention in chronic hepatitis after liver transplantation. This system utilizes the following

parameters: grade of necroinflammatory activity, which is based on the degree of periportal or portal activity and lobular activity, and stage of fibrosis or cirrhosis. The mean follow-up period was 17.9 months (range: 4.8 to 33.1 months). Data were analyzed using SPSS (Statistical Package for the Social Services, SPSS, Inc, Chicago, Ill, USA, version 12.0.1). Continuous variables were reported as means, medians, and standard deviations. Categorical variables were reported as numbers and/or percentage of patients with the reported characteristics. Survival analysis utilized Kaplan-Meier methodology.

RESULTS

In group I, 43 patients remained rejection-free during follow-up with an actuarial rejection-free probability of 95% within 3 months. The actuarial patient and graft survival rate (Kaplan-Meier estimated) at 24 months was 93.48%. Twenty-seven patients were completely off steroids within 3 months post-OLTx, and 85.4% by post-OLTx

BASILIXIMAB INDUCTION IN ADULT RECIPIENTS

monthly. The rate of histologically proven HCV recurrence was 30.8%, with two patients (7.7%) progressing to severe cholestatic recurrent HCV. None of the 46 study patients developed cytomegalovirus (CMV) infection or posttransplant lymphoproliferative disease (PTLD). Patients in group II had a significantly higher rejection rate of 34% with lower patient and graft survival rates of 71.74% and 69.5%, respectively, at 24 months. Furthermore, the historical group had a significantly higher histological HCV recurrence rate of 70.8% (17/24), with three patients (13.6%) progressing to graft failure within 2 years. CMV infection and disease developed in 2 (4.5%) patients. The incidence of bacteremia and fungemia was not significantly different between the two groups. Although PTLD was not observed, 3 (18%) recipients with hepatocellular carcinoma (HCC) developed and died of metastatic HCC. A summary of results is presented in Table 1. DISCUSSION

Induction therapy with antibodies may be utilized to reduce the risk of ACR in the immediate posttransplant period. However, traditional polyclonal and monoclonal antibodies may be associated with adverse effects such as cytokine release syndrome, anaphylaxis, serum sickness, anti-idiotype antibody formation, leukopenia, thrombocytopenia, and an increased susceptibility to infection (ie, CMV infection), and malignancy.6 On the other hand, monoclonal antibodies have a highly selective immunosuppressive activity and therefore have less adverse effects. This study demonstrates that basiliximab induction therapy in combination with either double (tacrolimus, steroids) or triple (tacrolimus, MMF, and steroids) maintenance regimen post-OLTx is associated with a low overall ACR rate of 7% and a superior 18-month rejection-free graft and patient survival rate of 93.48% compared to a historical group of patients who did not receive basiliximab induction. In our series, the majority (57%) of transplantations was performed for HCV cirrhosis with the histological HCV recurrence (31%) and cholestatic recurrent HCV (7.7%) rates falling within the ranges (14% to 72% and 10%, respectively) reported in the literature.7–10 Although these data demonstrated that the addition of basiliximab to a triple drug regimen did not seem to increase the incidence and severity of histological HCV recurrence, it did not show any significant advantages over other immunosuppressive regimen with regard to controlling the progression of HCV recurrence. Furthermore, none of the 46 study patients developed CMV infection nor developed PTLD in our study.

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Induction with basiliximab, in combination with tacrolimusbased immunosuppressive regimen, reduces the incidence of rejection and improves rejection-free survival rate after OLTx, without increasing the incidence of CMV, PTLD, or HCV recurrence. A limitation of this study is the use of historical controls transplanted during an earlier time period, which may not be comparable to the present study population because of other variables that may influence patients’ outcome after OLT, aside from the differences in immunosuppression. Furthermore, a longer follow-up period is necessary to make a valid conclusion with regard to the incidence of HCC recurrence in both groups in the medium term.

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