Original Clinical ScienceçGeneral
Evaluation of Alemtuzumab Versus Basiliximab Induction: A Retrospective Cohort Study in Lung Transplant Recipients Laura K. Whited, PharmD,1 Michael J. Latran, PharmD,1 Zubair A. Hashmi, MD,2 I-Wen Wang, MD, PhD,2 Thomas C. Wozniak, MD,2 Michael D. Duncan, MD,3 David W. Roe, MD,3 Maher A. Baz, MD,3 and Chadi A. Hage, MD3 Background. Acute cellular rejection (ACR) is a major early complication after lung transplantation (LT) and is a risk factor for chronic rejection. Induction immunosuppression has been used as a strategy to reduce early ACR. Recently, our LT program changed our primary induction protocol from basiliximab with standard maintenance immunosuppression to alemtuzumab induction with reduced dose maintenance immunosuppression. The objective of this study was to compare incidence of ACR after this change in the first 6 months after transplantation. Methods. A retrospective, cohort review of patients 18 years or older, which received their first LT between January 2010 and September 2012. Results. The primary outcome was comparison of average lung biopsy scores at 6 months. Secondary outcomes included development of grade A2 or higher rejection, infectious outcomes, overall graft and patient survival. At 6 months, the average biopsy score was significantly lower in the alemtuzumab group than the basiliximab group (0.12 ± 0.29 vs 0.74 ± 0.67; P < 0.0001) (Table 2). Grade 2 or higher rejection was significantly higher in the basiliximab group (P < 0.0001). Conclusions. Alemtuzumab provided superior outcomes in regard to average biopsy score and lower incidence of grade 2 or higher rejection at 6 months. There were no differences in infectious complications or overall graft or patient survival between the 2 groups.
(Transplantation 2015;99: 2190–2195)
L
ung transplantation (LT) is the treatment of choice for patients with end-stage lung disease. Long-term posttransplant survival is approximately 50% at 5 years, whereas 5-year survival rates for other solid organ transplants are approximately 80%.1-3 Poor survival associated with LT is due to the high frequency of allograft rejection, with chronic rejection (CR) being the most common cause of mortality in patients surviving more than 1 year. Acute cellular rejection (ACR) occurs in approximately 40% to 70% of lung transplant patients in the first 12 months, and is due to host T cells Received 13 May 2014. Revision requested 11 June 2014. Accepted 16 December 2014. 1
Department of Pharmacy, Methodist Hospital, Indiana University Health, Indianapolis, IN.
2
Department of Thoracic Transplant Surgery, Methodist Hospital, Indiana University Health, Indianapolis, IN.
3 Department of Pulmonary Critical Care Medicine, Methodist Hospital, Indiana University Health, Indianapolis, IN.
The authors declare no funding for this study or conflicts of interest. L.W. participated in performance of research, research design, writing of the paper, data collection, and analysis. M.L. participated in performance of research, research design, writing of paper, and data analysis. Z.H., I.-W.W., T.W., M.D., and D.R. participated in writing of the paper. C.H. and M.B. participated in research design, writing of the paper, and data analysis. Correspondence: Michael J. Latran, PharmD, Department of Pharmacy, Indiana University Health-Methodist Hospital, 1701 N Senate Ave, AG 401, Indianapolis, IN 46202. ([email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/15/9910-2190 DOI: 10.1097/TP.0000000000000687
2190
www.transplantjournal.com
infiltrating the donated graft.4,5 Acute cellular rejection has been identified as a strong risk factor for the development of CR or bronchiolitis obliterans syndrome (BOS), the leading cause of mortality in LT.1-3,6 Commonly used immunosuppressive regimens in LT include a calcineurin inhibitor, glucocorticoid, antimetabolite, with or without an induction agent, such as antithymocyte globulin or an interleukin (IL)-2 receptor antagonist. Induction therapy has been increasingly used at the time of transplant to prevent early ACR and allow for minimization of maintenance immunosuppression (MI). Minimizing MI may lead to reduced complications, such as glucocorticoid and calcineurin inhibitor induced diabetes, hypertension, and renal dysfunction. Among lung transplant patients receiving induction therapy the most commonly used agent is the IL-2 receptor inhibitor, basiliximab (Simulect; Novartis Pharmaceuticals Corporation, Basel, Switzerland).1 Alemtuzumab (Campath; Genzyme, Boston, MA), a potent immunosuppressive agent approved for the treatment of lymphocytic leukemia, is increasingly being studied as an induction agent in LT as well as other solid organ transplants.6 Alemtuzumab is a humanized monoclonal antibody directed against CD52 glycoprotein, which is found on B and T lymphocytes, monocytes, and natural killer cells.1 Alemtuzumab administration leads to profound lymphophenia, which makes it attractive for use in induction immunosuppression (IS).1 Although this profound lymphophenia may reduce ACR and allow for reduced MI, there is concern for increased rates of infection, hematological, and oncologic adverse effects, such as posttransplant lymphoproliferative disorder. Transplantation
■
October 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
■
Volume 99
■
Number 10
Whited et al
© 2015 Wolters Kluwer
Though available literature in lung transplant recipients has shown lower rejection rates with the use of alemtuzumab, differences in mortality and infection rates have remained unchanged.6,7 Few studies exist directly comparing alemtuzumab induction to basiliximab induction in combination with modern immunosuppressive regimens in lung transplant recipients. The purpose of this single-center retrospective study is to compare the efficacy and incidence of adverse events in lung transplant recipients receiving basiliximab induction with standard MI compared to patients receiving alemtuzumab induction in combination with a reduced dose MI regimen. MATERIALS AND METHODS Patient Selection
This retrospective cohort study included lung transplant recipients transplanted at Indiana University Health-Methodist Hospital between January 2010 and September 2012. Before August 2011, basiliximab was the induction agent of choice at our institution. After August 2011, our protocol changed to use alemtuzumab as our standard induction agent. Patients were included in the study if they were 18 years or older and were receiving their first lung transplant. Patients were excluded from this study if they received a retransplant, a multiorgan transplant, or transferred care to another transplant center within 1 year of transplantation. Patients were followed up for 6 months after transplantation. The study was approved by the Institutional Review Board at Indiana University. Medication Protocol
Induction IS, MI, and infection prophylaxis were dictated by the treatment protocols used by the transplant program. Alemtuzumab was administered as a 30-mg subcutaneous injection on postoperative day 0 as soon as possible on arrival to the intensive care unit (ICU), whereas basiliximab was given intravenously as a 20-mg infusion in the operating room and then 20 mg on postoperative day 4. Subcutaneous administration of alemtuzumab was used to limit infusionrelated reactions. In the operating room, patients in both treatment groups also received methylprednisolone 500 mg intravenously before each lung transplanted. It should be noted that our institution's practice is not to administer alemtuzumab to Epstein-Barr virus (EBV)–negative recipients. All patients received a triple-drug MI therapy consisting of a tacrolimus, mycophenolate mofetil, and prednisone. Patients who received alemtuzumab were started on a reduced dose MI regimen, which consisted of prednisone 5 mg daily, tacrolimus with a goal serum trough concentration of 10 to 12 ng/mL starting 48 to 72 hours post-op, and mycophenolate 500 mg twice daily. Patients who received basiliximab induction received a standard MI regimen, which consisted of a minimum of prednisone 20 mg daily, tacrolimus with a goal of 12 to 15 ng/mL starting immediately postoperative, and mycophenolate 1000 mg twice daily. The prednisone dose in the basiliximab group is tapered over the first 12 months with a goal of 5 mg. Patients in each group received the following antimicrobial prophylaxis: sulfamethoxazole/trimethoprim single strength 1 tablet orally every Monday, Wednesday, and Friday for Pneumocystis jirovecii, voriconazole 200 mg daily for 3 months and nystatin for antifungal prophylaxis, and valgancyclovir 900 mg daily, adjusted for renal function, for 1 year for cytomegalovirus (CMV). Valacyclovir
2191
500 mg by mouth twice daily for 3 months was used in place of valganciclovir as viral prophylaxis for patients who were CMV donor and recipient negative. No changes were adopted in terms of surgical technique. Biopsy and Treatment of Rejection
Patients in each group underwent surveillance bronchoscopy with transbronchial lung biopsy at 1 and 3 months after transplantation and as needed for graft dysfunction. Pathological grading of lung rejection was graded according to the 2007 International Society of Heart and Lung Transplantation consensus guidelines. Therefore, grade 0 was defined as no rejection, grade 1 as minimal, grade 2 as mild or lowgrade rejection, grade 3 as moderate or intermediate-grade rejection, and grade 4 as severe or high-grade rejection. Treatment of rejection was based on biopsy results as well as presence of graft dysfunction.8 Grade 1 rejection and first episode of grade 2 or higher rejection were treated with intravenous steroids. Repeat episodes of rejection were typically treated with antithymocyte globulin or alemtuzumab based on time after transplantation, peripheral T-cell subset counts, previous episodes of rejection, and graft function. Study Outcomes
The primary outcome of this study was to compare the total average biopsy score in each group at 6 months after transplantation. Average biopsy score was calculated by adding total grade A and B scores and dividing by number of biopsies. Secondary endpoints included the average A score, average B score, time to first grade 2 rejection, episodes of grade A2 or higher rejection at 6 months, development of donor-specific antibodies, average serum tacrolimus trough concentration at 6 months, development of primary graft dysfunction, infectious outcomes, incidence of graft failure, and incidence of death at 6 months. Infectious outcomes included the incidence of CMV infection and disease, other opportunistic infections, and other infections occurring either postoperatively or requiring hospitalization. Cytomegalovirus outcomes were defined according to the international consensus guidelines.8,9 Cytomegalovirus infection was defined as “evidence of CMV replication regardless of symptoms.” Cytomegalovirus disease was defined as “evidence of CMV infection with attributable symptoms,” and is further delineated into CMV viremia and tissue invasive disease.9,10 All other culture positive infections were grouped according to the treatment locations; infections treated as inpatient or outpatient. Graft failure was defined as the patient being relisted for LT or requiring extracorporeal membrane oxygenator at 6 months after transplantation.3 Statistical Analysis
Continuous variables were compared using Student t test or Wilcoxon Mann–Whitney U test for nonparametric data. Categorical variables were compared using χ2 or Fisher exact test. The Kaplan-Meier method was used to analyze survival and time until first grade A2 or higher rejection. Stepwise logistic regression was conducted to identify independent risk factors for grade 2 or higher rejection. A 2tailed P value less than 0.05 was considered statistically significant. Analyses were performed using the statistical software package SAS 9.2 (SAS institute, Cary, NC).
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
2192
Transplantation
■
October 2015
■
Volume 99
■
Number 10
RESULTS Baseline Characteristics and Medication Use
Ninety-three patients were identified in the Organ Transplant Tracking Record as receiving lung transplants at Indiana University Health from January 2010 and September 2012. Four patients were excluded, 3 were retransplanted, and 1 was lost to follow-up, leaving a total of 89 patients in the study: 44 patients in the basiliximab group and 45 patients in the alemtuzumab group. The baseline characteristics between the 2 groups were comparable with respect to sex, ethnicity, reason for transplant, HLA mismatches, EBV mismatch, EBV-negative recipient, CMV risk group, lung allocation score, ischemic time, and length of postoperative ICU stay (Table 1). Patients in the basiliximab group were younger than those in the alemtuzumab group (57 vs 62 years, respectively; P < 0.002). The majority of patients who underwent transplant in each group received bilateral transplant (98% in basiliximab group vs 84% in the alemtuzumab group; P = 0.0582). The posttransplant length of stay was significantly shorter in the basiliximab group than the alemtuzumab group: (median 18 vs 24 days respectively (P < 0.027). There were significantly more posttransplant biopsies performed in the basiliximab group (P = 0.0003) (Table 1). Primary Outcome
At 6 months, the average biopsy score was significantly lower in the alemtuzumab group than the basiliximab group (0.12 ± 0.29 vs 0.74 ± 0.67 respectively; P < 0.0001) (Table 2). Secondary Outcomes
A statistically significant difference in development of a grade A2 or higher rejection within the first 6 months after transplantation was found, occurring in 20 basiliximab patients 0(46.5%) versus 1 alemtuzumab patient (2.2%)
www.transplantjournal.com
(P < 0.0001). The first grade 2 or higher rejection occurred 158 days after transplantation in the alemtuzumab group compared to a mean of 50.2 ± 35.58 days in the basiliximab group (P = 0.006). Kaplan-Meier estimates comparing freedom from grade A2 or higher rejection within the first 6 months and 1 year after transplantation were similar showing a significant difference in favor of alemtuzumab (log rank P < 0.0001) (Figures 3 and 4). There was no statistically significant difference between infectious outcomes between the 2 groups (Table 2). Bacterial infections were the most common type of infection, when compared to fungal and viral; however, no significant difference was found between the 2 groups (71% alemtuzumab vs 62% basiliximab, P = 0.5127) (Figure 1). Mortality at 6 months was not significantly different between the basiliximab and alemtuzumab groups, with an overall survival at 6 months of 90% in each group (log rank P = 0.9819) (Figure 2). Forced expiratory volume-1 at 3 and 6 months were reviewed in all patients, and there were no cases of BOS-p or BOS stage identified in any patient at these time points. As expected, the mean dose of prednisone was significantly lower in the alemtuzumab than the basiliximab groups at 6 months; 10 ± 4.3 versus 5.7 ± 1.3 (P < 0.0001). No significant difference was found in serum creatinine at 6 months between the basiliximab and alemtuzumab groups: 1.14 mg/dL versus 1.45 mg/dL, respectively (P = 0.147). The average serum tacrolimus trough concentration at 6 months was not found to be significantly different between the 2 groups: 11.13 ± 2.39 ng/mL in the basiliximab group compared to 10.63 ± 2.31 ng/mL in the alemtuzumab group (P = 0.3657). A stepwise logistic regression was performed to identify independent risk factors for grade 2 or higher rejection within the first 6 months after transplantation. Independent variables included induction agent, indication for transplant, age, sex, ethnicity, CMV risk, and steroid dose at 6 months.
TABLE 1.
Baseline characteristics Basiliximab (n = 44)
Recipient age (median, IQR), y Sex, male % Ethnicity: white, % Underlying disease (n), % COPD IPF CF Bilateral transplant, n (%) HLA mismatches (median, IQR) EBV mismatch (donor +, recipient−), n (%) EBV negative recipients, n (%) CMV mismatch (donor +, recipient−), n (%) Length of stay (median, IQR), d Length of ICU stay (median, IQR), d LAS (median, IQR) Ischemia time (min) (mean ± SD) Number of biopsies performed(median, IQR)
57 (12.5) 47.7 91 15 (34.1) 19 (43.2) 5 (11) 43 (98) 5 (1) 2 (4.5) 3 (6.8) 10 (22.7) 18 (17) 6 (14) 38.24 (10.27) 509.45 ± 152.18 3 (2)
Alemtuzumab (n = 45)
62 (11) 64.4 91 20 (44.4) 21 (46.7) 3 (7) 38 (84) 5 (1) 0 (0) 0 (0) 11 (24.4) 24 (18) 10 (16) 40.44 (10.92) 447.75 ± 168.6 2 (3)
IPF, idiopathic pulmonary fibrosis; CF, cystic fibrosis; LAS, lung allocation score; IQR, interquartile range.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
P
0.002 0.112 0.437 0.274
0.058 0.558 0.24 0.12 0.337 0.027 0.094 0.329 0.355 0.0003
Whited et al
© 2015 Wolters Kluwer
2193
TABLE 2.
Results of primary and secondary outcomes
Average biopsy score at 6 mo (mean ± SD) Average A score (mean ± SD) Average B score (mean ± SD) POD of first grade 2 rejection (mean ± SD) Grade A2 or higher rejection at 6 mo n (%) Average tacrolimus level at 6 mo (mean ± SD) CMV disease, n (%) Infection post-transplant, n (%) Donor-specific antibodies, n (%) POD of DSA (median, IQR) Primary graft dysfunction, n (%) Prednisone dose at 6 mo (mean ± SD)
Basiliximab (n = 43)
Alemtuzumab (n = 45)
P
0.74 ± 0.67 0.47 ± 0.43 0.29 ± 0.31 50.2 ± 35.58 20 (46.5) 11.13 ± 2.39 1 (2.3) 21 (48) 9 (20.9) 36 (47) 8 (18.6) 10 ± 4.3
0.12 ± 0.29 0.029 ± 0.12 0.093 ± 0.25 158 1 (2.2) 10.63 ± 2.31 3 (6.7) 20 (44) 15 (33.3) 38 (30) 6 (13.3) 5.7 ± 1.3
Evaluation of Alemtuzumab Versus Basiliximab Induction: A Retrospective Cohort Study in Lung Transplant Recipients Laura K. Whited, PharmD,1 Michael J. Latran, PharmD,1 Zubair A. Hashmi, MD,2 I-Wen Wang, MD, PhD,2 Thomas C. Wozniak, MD,2 Michael D. Duncan, MD,3 David W. Roe, MD,3 Maher A. Baz, MD,3 and Chadi A. Hage, MD3 Background. Acute cellular rejection (ACR) is a major early complication after lung transplantation (LT) and is a risk factor for chronic rejection. Induction immunosuppression has been used as a strategy to reduce early ACR. Recently, our LT program changed our primary induction protocol from basiliximab with standard maintenance immunosuppression to alemtuzumab induction with reduced dose maintenance immunosuppression. The objective of this study was to compare incidence of ACR after this change in the first 6 months after transplantation. Methods. A retrospective, cohort review of patients 18 years or older, which received their first LT between January 2010 and September 2012. Results. The primary outcome was comparison of average lung biopsy scores at 6 months. Secondary outcomes included development of grade A2 or higher rejection, infectious outcomes, overall graft and patient survival. At 6 months, the average biopsy score was significantly lower in the alemtuzumab group than the basiliximab group (0.12 ± 0.29 vs 0.74 ± 0.67; P < 0.0001) (Table 2). Grade 2 or higher rejection was significantly higher in the basiliximab group (P < 0.0001). Conclusions. Alemtuzumab provided superior outcomes in regard to average biopsy score and lower incidence of grade 2 or higher rejection at 6 months. There were no differences in infectious complications or overall graft or patient survival between the 2 groups.
(Transplantation 2015;99: 2190–2195)
L
ung transplantation (LT) is the treatment of choice for patients with end-stage lung disease. Long-term posttransplant survival is approximately 50% at 5 years, whereas 5-year survival rates for other solid organ transplants are approximately 80%.1-3 Poor survival associated with LT is due to the high frequency of allograft rejection, with chronic rejection (CR) being the most common cause of mortality in patients surviving more than 1 year. Acute cellular rejection (ACR) occurs in approximately 40% to 70% of lung transplant patients in the first 12 months, and is due to host T cells Received 13 May 2014. Revision requested 11 June 2014. Accepted 16 December 2014. 1
Department of Pharmacy, Methodist Hospital, Indiana University Health, Indianapolis, IN.
2
Department of Thoracic Transplant Surgery, Methodist Hospital, Indiana University Health, Indianapolis, IN.
3 Department of Pulmonary Critical Care Medicine, Methodist Hospital, Indiana University Health, Indianapolis, IN.
The authors declare no funding for this study or conflicts of interest. L.W. participated in performance of research, research design, writing of the paper, data collection, and analysis. M.L. participated in performance of research, research design, writing of paper, and data analysis. Z.H., I.-W.W., T.W., M.D., and D.R. participated in writing of the paper. C.H. and M.B. participated in research design, writing of the paper, and data analysis. Correspondence: Michael J. Latran, PharmD, Department of Pharmacy, Indiana University Health-Methodist Hospital, 1701 N Senate Ave, AG 401, Indianapolis, IN 46202. ([email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/15/9910-2190 DOI: 10.1097/TP.0000000000000687
2190
www.transplantjournal.com
infiltrating the donated graft.4,5 Acute cellular rejection has been identified as a strong risk factor for the development of CR or bronchiolitis obliterans syndrome (BOS), the leading cause of mortality in LT.1-3,6 Commonly used immunosuppressive regimens in LT include a calcineurin inhibitor, glucocorticoid, antimetabolite, with or without an induction agent, such as antithymocyte globulin or an interleukin (IL)-2 receptor antagonist. Induction therapy has been increasingly used at the time of transplant to prevent early ACR and allow for minimization of maintenance immunosuppression (MI). Minimizing MI may lead to reduced complications, such as glucocorticoid and calcineurin inhibitor induced diabetes, hypertension, and renal dysfunction. Among lung transplant patients receiving induction therapy the most commonly used agent is the IL-2 receptor inhibitor, basiliximab (Simulect; Novartis Pharmaceuticals Corporation, Basel, Switzerland).1 Alemtuzumab (Campath; Genzyme, Boston, MA), a potent immunosuppressive agent approved for the treatment of lymphocytic leukemia, is increasingly being studied as an induction agent in LT as well as other solid organ transplants.6 Alemtuzumab is a humanized monoclonal antibody directed against CD52 glycoprotein, which is found on B and T lymphocytes, monocytes, and natural killer cells.1 Alemtuzumab administration leads to profound lymphophenia, which makes it attractive for use in induction immunosuppression (IS).1 Although this profound lymphophenia may reduce ACR and allow for reduced MI, there is concern for increased rates of infection, hematological, and oncologic adverse effects, such as posttransplant lymphoproliferative disorder. Transplantation
■
October 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
■
Volume 99
■
Number 10
Whited et al
© 2015 Wolters Kluwer
Though available literature in lung transplant recipients has shown lower rejection rates with the use of alemtuzumab, differences in mortality and infection rates have remained unchanged.6,7 Few studies exist directly comparing alemtuzumab induction to basiliximab induction in combination with modern immunosuppressive regimens in lung transplant recipients. The purpose of this single-center retrospective study is to compare the efficacy and incidence of adverse events in lung transplant recipients receiving basiliximab induction with standard MI compared to patients receiving alemtuzumab induction in combination with a reduced dose MI regimen. MATERIALS AND METHODS Patient Selection
This retrospective cohort study included lung transplant recipients transplanted at Indiana University Health-Methodist Hospital between January 2010 and September 2012. Before August 2011, basiliximab was the induction agent of choice at our institution. After August 2011, our protocol changed to use alemtuzumab as our standard induction agent. Patients were included in the study if they were 18 years or older and were receiving their first lung transplant. Patients were excluded from this study if they received a retransplant, a multiorgan transplant, or transferred care to another transplant center within 1 year of transplantation. Patients were followed up for 6 months after transplantation. The study was approved by the Institutional Review Board at Indiana University. Medication Protocol
Induction IS, MI, and infection prophylaxis were dictated by the treatment protocols used by the transplant program. Alemtuzumab was administered as a 30-mg subcutaneous injection on postoperative day 0 as soon as possible on arrival to the intensive care unit (ICU), whereas basiliximab was given intravenously as a 20-mg infusion in the operating room and then 20 mg on postoperative day 4. Subcutaneous administration of alemtuzumab was used to limit infusionrelated reactions. In the operating room, patients in both treatment groups also received methylprednisolone 500 mg intravenously before each lung transplanted. It should be noted that our institution's practice is not to administer alemtuzumab to Epstein-Barr virus (EBV)–negative recipients. All patients received a triple-drug MI therapy consisting of a tacrolimus, mycophenolate mofetil, and prednisone. Patients who received alemtuzumab were started on a reduced dose MI regimen, which consisted of prednisone 5 mg daily, tacrolimus with a goal serum trough concentration of 10 to 12 ng/mL starting 48 to 72 hours post-op, and mycophenolate 500 mg twice daily. Patients who received basiliximab induction received a standard MI regimen, which consisted of a minimum of prednisone 20 mg daily, tacrolimus with a goal of 12 to 15 ng/mL starting immediately postoperative, and mycophenolate 1000 mg twice daily. The prednisone dose in the basiliximab group is tapered over the first 12 months with a goal of 5 mg. Patients in each group received the following antimicrobial prophylaxis: sulfamethoxazole/trimethoprim single strength 1 tablet orally every Monday, Wednesday, and Friday for Pneumocystis jirovecii, voriconazole 200 mg daily for 3 months and nystatin for antifungal prophylaxis, and valgancyclovir 900 mg daily, adjusted for renal function, for 1 year for cytomegalovirus (CMV). Valacyclovir
2191
500 mg by mouth twice daily for 3 months was used in place of valganciclovir as viral prophylaxis for patients who were CMV donor and recipient negative. No changes were adopted in terms of surgical technique. Biopsy and Treatment of Rejection
Patients in each group underwent surveillance bronchoscopy with transbronchial lung biopsy at 1 and 3 months after transplantation and as needed for graft dysfunction. Pathological grading of lung rejection was graded according to the 2007 International Society of Heart and Lung Transplantation consensus guidelines. Therefore, grade 0 was defined as no rejection, grade 1 as minimal, grade 2 as mild or lowgrade rejection, grade 3 as moderate or intermediate-grade rejection, and grade 4 as severe or high-grade rejection. Treatment of rejection was based on biopsy results as well as presence of graft dysfunction.8 Grade 1 rejection and first episode of grade 2 or higher rejection were treated with intravenous steroids. Repeat episodes of rejection were typically treated with antithymocyte globulin or alemtuzumab based on time after transplantation, peripheral T-cell subset counts, previous episodes of rejection, and graft function. Study Outcomes
The primary outcome of this study was to compare the total average biopsy score in each group at 6 months after transplantation. Average biopsy score was calculated by adding total grade A and B scores and dividing by number of biopsies. Secondary endpoints included the average A score, average B score, time to first grade 2 rejection, episodes of grade A2 or higher rejection at 6 months, development of donor-specific antibodies, average serum tacrolimus trough concentration at 6 months, development of primary graft dysfunction, infectious outcomes, incidence of graft failure, and incidence of death at 6 months. Infectious outcomes included the incidence of CMV infection and disease, other opportunistic infections, and other infections occurring either postoperatively or requiring hospitalization. Cytomegalovirus outcomes were defined according to the international consensus guidelines.8,9 Cytomegalovirus infection was defined as “evidence of CMV replication regardless of symptoms.” Cytomegalovirus disease was defined as “evidence of CMV infection with attributable symptoms,” and is further delineated into CMV viremia and tissue invasive disease.9,10 All other culture positive infections were grouped according to the treatment locations; infections treated as inpatient or outpatient. Graft failure was defined as the patient being relisted for LT or requiring extracorporeal membrane oxygenator at 6 months after transplantation.3 Statistical Analysis
Continuous variables were compared using Student t test or Wilcoxon Mann–Whitney U test for nonparametric data. Categorical variables were compared using χ2 or Fisher exact test. The Kaplan-Meier method was used to analyze survival and time until first grade A2 or higher rejection. Stepwise logistic regression was conducted to identify independent risk factors for grade 2 or higher rejection. A 2tailed P value less than 0.05 was considered statistically significant. Analyses were performed using the statistical software package SAS 9.2 (SAS institute, Cary, NC).
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
2192
Transplantation
■
October 2015
■
Volume 99
■
Number 10
RESULTS Baseline Characteristics and Medication Use
Ninety-three patients were identified in the Organ Transplant Tracking Record as receiving lung transplants at Indiana University Health from January 2010 and September 2012. Four patients were excluded, 3 were retransplanted, and 1 was lost to follow-up, leaving a total of 89 patients in the study: 44 patients in the basiliximab group and 45 patients in the alemtuzumab group. The baseline characteristics between the 2 groups were comparable with respect to sex, ethnicity, reason for transplant, HLA mismatches, EBV mismatch, EBV-negative recipient, CMV risk group, lung allocation score, ischemic time, and length of postoperative ICU stay (Table 1). Patients in the basiliximab group were younger than those in the alemtuzumab group (57 vs 62 years, respectively; P < 0.002). The majority of patients who underwent transplant in each group received bilateral transplant (98% in basiliximab group vs 84% in the alemtuzumab group; P = 0.0582). The posttransplant length of stay was significantly shorter in the basiliximab group than the alemtuzumab group: (median 18 vs 24 days respectively (P < 0.027). There were significantly more posttransplant biopsies performed in the basiliximab group (P = 0.0003) (Table 1). Primary Outcome
At 6 months, the average biopsy score was significantly lower in the alemtuzumab group than the basiliximab group (0.12 ± 0.29 vs 0.74 ± 0.67 respectively; P < 0.0001) (Table 2). Secondary Outcomes
A statistically significant difference in development of a grade A2 or higher rejection within the first 6 months after transplantation was found, occurring in 20 basiliximab patients 0(46.5%) versus 1 alemtuzumab patient (2.2%)
www.transplantjournal.com
(P < 0.0001). The first grade 2 or higher rejection occurred 158 days after transplantation in the alemtuzumab group compared to a mean of 50.2 ± 35.58 days in the basiliximab group (P = 0.006). Kaplan-Meier estimates comparing freedom from grade A2 or higher rejection within the first 6 months and 1 year after transplantation were similar showing a significant difference in favor of alemtuzumab (log rank P < 0.0001) (Figures 3 and 4). There was no statistically significant difference between infectious outcomes between the 2 groups (Table 2). Bacterial infections were the most common type of infection, when compared to fungal and viral; however, no significant difference was found between the 2 groups (71% alemtuzumab vs 62% basiliximab, P = 0.5127) (Figure 1). Mortality at 6 months was not significantly different between the basiliximab and alemtuzumab groups, with an overall survival at 6 months of 90% in each group (log rank P = 0.9819) (Figure 2). Forced expiratory volume-1 at 3 and 6 months were reviewed in all patients, and there were no cases of BOS-p or BOS stage identified in any patient at these time points. As expected, the mean dose of prednisone was significantly lower in the alemtuzumab than the basiliximab groups at 6 months; 10 ± 4.3 versus 5.7 ± 1.3 (P < 0.0001). No significant difference was found in serum creatinine at 6 months between the basiliximab and alemtuzumab groups: 1.14 mg/dL versus 1.45 mg/dL, respectively (P = 0.147). The average serum tacrolimus trough concentration at 6 months was not found to be significantly different between the 2 groups: 11.13 ± 2.39 ng/mL in the basiliximab group compared to 10.63 ± 2.31 ng/mL in the alemtuzumab group (P = 0.3657). A stepwise logistic regression was performed to identify independent risk factors for grade 2 or higher rejection within the first 6 months after transplantation. Independent variables included induction agent, indication for transplant, age, sex, ethnicity, CMV risk, and steroid dose at 6 months.
TABLE 1.
Baseline characteristics Basiliximab (n = 44)
Recipient age (median, IQR), y Sex, male % Ethnicity: white, % Underlying disease (n), % COPD IPF CF Bilateral transplant, n (%) HLA mismatches (median, IQR) EBV mismatch (donor +, recipient−), n (%) EBV negative recipients, n (%) CMV mismatch (donor +, recipient−), n (%) Length of stay (median, IQR), d Length of ICU stay (median, IQR), d LAS (median, IQR) Ischemia time (min) (mean ± SD) Number of biopsies performed(median, IQR)
57 (12.5) 47.7 91 15 (34.1) 19 (43.2) 5 (11) 43 (98) 5 (1) 2 (4.5) 3 (6.8) 10 (22.7) 18 (17) 6 (14) 38.24 (10.27) 509.45 ± 152.18 3 (2)
Alemtuzumab (n = 45)
62 (11) 64.4 91 20 (44.4) 21 (46.7) 3 (7) 38 (84) 5 (1) 0 (0) 0 (0) 11 (24.4) 24 (18) 10 (16) 40.44 (10.92) 447.75 ± 168.6 2 (3)
IPF, idiopathic pulmonary fibrosis; CF, cystic fibrosis; LAS, lung allocation score; IQR, interquartile range.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
P
0.002 0.112 0.437 0.274
0.058 0.558 0.24 0.12 0.337 0.027 0.094 0.329 0.355 0.0003
Whited et al
© 2015 Wolters Kluwer
2193
TABLE 2.
Results of primary and secondary outcomes
Average biopsy score at 6 mo (mean ± SD) Average A score (mean ± SD) Average B score (mean ± SD) POD of first grade 2 rejection (mean ± SD) Grade A2 or higher rejection at 6 mo n (%) Average tacrolimus level at 6 mo (mean ± SD) CMV disease, n (%) Infection post-transplant, n (%) Donor-specific antibodies, n (%) POD of DSA (median, IQR) Primary graft dysfunction, n (%) Prednisone dose at 6 mo (mean ± SD)
Basiliximab (n = 43)
Alemtuzumab (n = 45)
P
0.74 ± 0.67 0.47 ± 0.43 0.29 ± 0.31 50.2 ± 35.58 20 (46.5) 11.13 ± 2.39 1 (2.3) 21 (48) 9 (20.9) 36 (47) 8 (18.6) 10 ± 4.3
0.12 ± 0.29 0.029 ± 0.12 0.093 ± 0.25 158 1 (2.2) 10.63 ± 2.31 3 (6.7) 20 (44) 15 (33.3) 38 (30) 6 (13.3) 5.7 ± 1.3
