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Proteasome Inhibitor Therapy for Antibody-Mediated Lung Transplant Rejection
Abstracts
S89 223 Use of Sirolimus in Lung Transplantation: A Single Center Experience L.J. Stuckey,1 C.E. Bartos,2 H.A. McCullough,2 R.D. Florn,2 V.N. Lama,3 J. Lin,4 K.M. Chan.3 1Department of Pharmacy Services, University of Michigan Health System, Ann Arbor; 2Transplant Center, University of Michigan Health System, Ann Arbor; 3Department of Internal Medicine, Division of Pulmonary & Critical Care Medicine, University of Michigan Health System, Ann Arbor; 4Section of Thoracic Surgery, University of Michigan Health System, Ann Arbor. Purpose: Sirolimus is an effective immunosuppressive agent in solid organ transplantation although its use in lung transplant recipients is limited to patients more than 3 months after the procedure due to the risk of anastamotic dehiscence. Sirolimus is used as an alternative immunosuppressant in our program for the treatment of refractory rejection, bronchiolitis obliterans syndrome (BOS), and calcineurin renal intolerance. Our experience with the use of this agent is described. Methods and Materials: Patients transplanted from 2000-2011 who were converted to sirolimus post-transplant were evaluated in a retrospective fashion. All patients initially received a calcineurin inhibitor (CNI), an antiproliferative agent, and prednisone. Variables examined included baseline characteristics, reason to initiate sirolimus, adverse effects (AEs), and renal function. Results: 49 of 345 (14%) patients transplanted between 2000-2011 were converted to sirolimus post-transplant. Reasons for converting included development of BOS (55%), AEs of CNI (hyperkalemia, nephrotoxicity, and neurotoxicity)(22%), worsening renal function (12%), leucopenia (8%), and acute rejection (2%). Median time to conversion was 945 days (79-3756 days). Sirolimus was combined with a CNI in 47% of patients. Patients remained on sirolimus for a median of 135 days (1-3013 days). Sirolimus was discontinued in 42 patients (86%) due to AEs (55%), death (24%), infection (9%), or other reasons (12%). Most common AEs leading to discontinuation were suspected pulmonary toxicity (48%), thrombocytopenia (13%), anemia (9%), and delayed wound healing (9%). Renal function declined after the initiation of sirolimus to its discontinuation (mean 62 ml/min v. 58 ml/min (sirolimus alone) and 56 ml/min (sirolimus with CNI)). Conclusions: Our single center experience demonstrates a high discontinuation rate of sirolimus in lung transplant recipients due to its numerous adverse effects. The utility of sirolimus for preventing allograft rejection is overshadowed by its toxicity which should be considered prior to its initiation.
UZLeuven, Leuven, Belgium; 2Histopathology, KU/UZLeuven, Leuven, Belgium. Purpose: Lymphocytic airway inflammation, the pathological correlate of acute airway rejection, is an important risk factor for later chronic lung allograft rejection. We hypothesized that azithromycin (AZI) could control lymphocytic airway inflammation. Methods and Materials: Fifteen double-lung transplant recipients with allograft dysfunction due to lymphocytic airway inflammation were prospectively treated with AZI for 3 months. Airflow measurements (FVC, FEV1, FEF25-75 and Tiffeneau) and FeNO were assessed before, during and up to 6 months after the start of AZI. Local inflammation, assessed on airway biopsy (‘B-grade’) and in bronchoalveolar lavage fluid (IL-6 and IL-8 protein levels, cell total and differential counts) as well as systemic inflammation (C-reactive protein) were compared between baseline and after 3 months of treatment. Results: Following initiation of AZI, airflow returned to baseline levels as soon as after 1 month and further improved thereafter. FeNO decreased to baseline (Figure 1). After 3 months of treatment, histologic lymphocytic airway inflammation and IL-8 levels, total and differential total cell counts (macrophages, neutrophils and eosinophils) as well as CRP significantly decreased compared to baseline (Table 1). Conclusions: AZI is beneficial in controlling post-transplant lymphocytic airway inflammation. Trial Registration NCT01109160 (AZI002).
224 Proteasome Inhibitor Therapy for Antibody-Mediated Lung Transplant Rejection J.A. Iuppa,1 K.B. Bain,1 C.A. Witt,2 E.P. Trulock,2 D.E. Byers,2 R.R. Hachem.2 1Pharmacy Department, Barnes-Jewish Hospital, St. Louis, MO; 2Division of Pulmonary and Critical Care Medicine, Washington University-School of Medicine, St. Louis, MO. Purpose: Antibody mediated rejection (AMR) is a significant challenge after lung transplantation and no consensus exists on the optimal therapeutic approach. Bortezomib may serve as a treatment option by eradicating the antibody-producing plasma cells. We report clinical experience with bortezomib for AMR after lung transplantation. Methods and Materials: Five lung transplant recipients with clinical AMR and donor-specific antibodies (DSA) (defined as MFI 4 2000) were treated with bortezomib (1.3 mg/m2). Serial measurements of DSA were conducted by single antigen bead on Luminex, OneLambda. The immunodominant DSA (iDSA) was assigned to the DSA with the highest MFI value at the time of diagnosis. Results: In this cohort, AMR developed a median of 10.5 months after transplant; bortezomib treatment resulted in elimination of iDSA in 2 patients (1, 2), and a 50% reduction without clearance in another (3). The remaining two patients (4, 5) had persistent DSA without decline in MFI. Despite iDSA reduction in patients 1, 2, and 3, this did not translate to a meaningful clinical benefit (absence of resolution of acute
S90
The Journal of Heart and Lung Transplantation, Vol 32, No 4S, April 2013
iDSA Patient Patient Patient Patient Patient
1 2 3 4 5
MFI at Diagnosis
DQ6 4516 DPB1 4726 DR53 13052 DQ2 7094 DQ7 3698
MFI at last follow-up
Resolution of acute AMR
o2000 o2000 3123 11217 6210
No Yes Yes No Yes
AMR in patient 1). During therapy, one patient experienced grade IV thrombocytopenia; otherwise, side effects were mild and transient. Prior to AMR, all patients had normal graft function; however, all 3 patients surviving to hospital discharge developed chronic, severe graft dysfunction. Two of the 5 patients are still alive 132 (2) and 230 (5) days after treatment for AMR. Conclusions: Although these preliminary results do not support a strong clinical or immunological response to bortezomib, we cannot exclude a prescribing bias for use in more severe cases of AMR. Bortezomib treatment for AMR warrants further investigation to fully elucidate its potential benefit. 225 World Wide Experience with Induction in Lung Transplantation for Cystic Fibrosis: Is Induction Necessary? C.A. Beaty,1 T.J. George,1 A. Kilic,1 A.S. Shah,1 C.A. Merlo.2 1Division of Cardiac Surgery, Johns Hopkins Medical Institutions, Baltimore, MD; 2Division of Pulmonology, Johns Hopkins Medical Institutions, Baltimore, MD. Purpose: Patients with Cystic Fibrosis (CF) often have chronic infections at the time of lung transplantation (LTx). Induction therapy may increase infection risk and worsen outcomes. We evaluated the effect of induction therapy on post-transplant outcomes in CF patients. Methods and Materials: We reviewed all primary adult LTx recipients with CF in the International Society for Heart and Lung Transplantation database from 1/1991-6/2011. Primary stratification was by induction therapy(no induction, inter-leukin 2[IL2] receptor antagonists, antilymphocyte/thymocyte globulins [ATG] or alemtuzumab). The primary outcome was survival(30 days, 1 year and 5 years). Secondary outcomes evaluated at 1 year included rejection, infection, forced expiratory volume in 1 second (FEV1) and bronchiolitis obliterans syndrome(BOS). Multivariate Cox and logistic regression models were used to evaluate the effects of induction therapy on outcomes. Results: 5,907 subjects composed our final cohort. In bivariable models, induction significantly decreased mortality, infection and length of stay; while improving FEV1 at 1 year. After adjustment, induction therapy was associated with improved 1 year survival(HR:0.81, p¼0.047). Alemtuzumab, when compared to no induction, was associated with improved survival at 1-year (HR:0.29, p¼0.03). While mortality varied between induction regimens, there were no statistically significant differences in infection, rejection, or FEV1 at 1 year.
Conclusions: Induction therapy for CF improves early survival without increasing infection risk. Alemtuzumab may improve survival when compared to other induction regimens. Further study is needed to fully evaluate the role of induction therapy in CF patients undergoing LTx. 226 Chronic Renal Failure in Lung Transplant Recipients Is Predicted by Tacrolimus Toxicity Events B.D. Fox,1,2 D. Rozengarten,1 Y. Raviv,1,2 S. Yitzhakian,1 M.R. Kramer.1,2 1Pulmonology, Rabin Medical Center, Petach Tikva, Israel; 2Medicine, Tel Aviv University, Tel Aviv, Israel. Purpose: Chronic renal failure (CRF) is common in lung transplant (LT) recipients. Tacrolimus (Tac) exposure is an accepted risk factor for CRF but little is known about the quantitative relationship between Tac levels and LT-CRF. Methods and Materials: Review of 173 LT recipients transplanted 2003-2010. Data were extracted on Tac levels and serum creatinine (Cr). Renal failure was defined as a doubling of Cr from baseline, further defined as chronic (sustained over Z3 months), acutely post LT (o1 month). Data were analyzed between the date of LT until the first ‘renal endpoint’ was reached – either CRF, end of laboratory follow-up, everolimus therapy or death without CRF. Tac toxicity was defined as trough 420ng/dl. The area-under-thecurve of Tac levels over time (AUC:TacTime) was calculated for each patient. Results: During median 698 [IQR 133-1482] days of follow-up, 77 patients developed CRF, see table 1. In univariate analysis, LT-CRF was associated with slightly higher median Tac levels (p¼0.002), higher log (AUC:TacTime) (po0.0001), more Tac-toxicity events (po0.0001) and post-LT acute renal failure (p¼0.04). Of note, age at LT, baseline creatinine, median Tac dose, pre-LT smoking status and pre-LT hypertension were not associated with development of LT-CRF. In a multivariate model, only FK toxicity events were significantly associated with development of LT-CRF (RR 2.93, 95% CI 2.09-4.34). Conclusions: Tac toxicity events are strongly associated with future development of CRF.
Univariate Analysis
Age Male Sex % Diagnosis (%) Emphysema IPF CF Other PreLT HTN % PreLT Smoking Baseline Creat (mg/dl) Acute RF post LT Median FK Dose (mg) Median FK level (pg/ml) Log(LevelTime AUC) FK Toxicity Events
No CRF n¼96
CRF n¼77
p
51(15) 63
52(11) 61
0.69 0.74 0.87
31 40 10 19 23 58 0.78 (0.3) 33 4.5(3.8) 10.7(2.1) 10.8(2.3) 1 [0,1]
30 45 9 16 27 62 0.76 (0.22) 19 3.8(2.2) 11.5(1.5) 11.9(1.6) 3[2,3]
0.58 0.78 0.52 0.04 0.15 0.002 o0.0001 o0.0001
Data shown as mean (SD) or median [IQR] or %; analysis by t-test, wilcoxon test or chi-square, depending on data. 227 Dynamic BMI Changes in Patients Implanted with Continuous Flow Left Ventricular Assist Devices: Evidence for Reversibility of Cardiac Cachexia and Impact on Survival D.M. Kobrin,1 J.P. Donnelly,1 A.L. Acker,1 J.L. Howard,1 C.M. Zalewski,1 S.L. Walsh,1 C.E. Hill,1 M.L. O’Hara,1 J.F. Marble,2
S89 223 Use of Sirolimus in Lung Transplantation: A Single Center Experience L.J. Stuckey,1 C.E. Bartos,2 H.A. McCullough,2 R.D. Florn,2 V.N. Lama,3 J. Lin,4 K.M. Chan.3 1Department of Pharmacy Services, University of Michigan Health System, Ann Arbor; 2Transplant Center, University of Michigan Health System, Ann Arbor; 3Department of Internal Medicine, Division of Pulmonary & Critical Care Medicine, University of Michigan Health System, Ann Arbor; 4Section of Thoracic Surgery, University of Michigan Health System, Ann Arbor. Purpose: Sirolimus is an effective immunosuppressive agent in solid organ transplantation although its use in lung transplant recipients is limited to patients more than 3 months after the procedure due to the risk of anastamotic dehiscence. Sirolimus is used as an alternative immunosuppressant in our program for the treatment of refractory rejection, bronchiolitis obliterans syndrome (BOS), and calcineurin renal intolerance. Our experience with the use of this agent is described. Methods and Materials: Patients transplanted from 2000-2011 who were converted to sirolimus post-transplant were evaluated in a retrospective fashion. All patients initially received a calcineurin inhibitor (CNI), an antiproliferative agent, and prednisone. Variables examined included baseline characteristics, reason to initiate sirolimus, adverse effects (AEs), and renal function. Results: 49 of 345 (14%) patients transplanted between 2000-2011 were converted to sirolimus post-transplant. Reasons for converting included development of BOS (55%), AEs of CNI (hyperkalemia, nephrotoxicity, and neurotoxicity)(22%), worsening renal function (12%), leucopenia (8%), and acute rejection (2%). Median time to conversion was 945 days (79-3756 days). Sirolimus was combined with a CNI in 47% of patients. Patients remained on sirolimus for a median of 135 days (1-3013 days). Sirolimus was discontinued in 42 patients (86%) due to AEs (55%), death (24%), infection (9%), or other reasons (12%). Most common AEs leading to discontinuation were suspected pulmonary toxicity (48%), thrombocytopenia (13%), anemia (9%), and delayed wound healing (9%). Renal function declined after the initiation of sirolimus to its discontinuation (mean 62 ml/min v. 58 ml/min (sirolimus alone) and 56 ml/min (sirolimus with CNI)). Conclusions: Our single center experience demonstrates a high discontinuation rate of sirolimus in lung transplant recipients due to its numerous adverse effects. The utility of sirolimus for preventing allograft rejection is overshadowed by its toxicity which should be considered prior to its initiation.
UZLeuven, Leuven, Belgium; 2Histopathology, KU/UZLeuven, Leuven, Belgium. Purpose: Lymphocytic airway inflammation, the pathological correlate of acute airway rejection, is an important risk factor for later chronic lung allograft rejection. We hypothesized that azithromycin (AZI) could control lymphocytic airway inflammation. Methods and Materials: Fifteen double-lung transplant recipients with allograft dysfunction due to lymphocytic airway inflammation were prospectively treated with AZI for 3 months. Airflow measurements (FVC, FEV1, FEF25-75 and Tiffeneau) and FeNO were assessed before, during and up to 6 months after the start of AZI. Local inflammation, assessed on airway biopsy (‘B-grade’) and in bronchoalveolar lavage fluid (IL-6 and IL-8 protein levels, cell total and differential counts) as well as systemic inflammation (C-reactive protein) were compared between baseline and after 3 months of treatment. Results: Following initiation of AZI, airflow returned to baseline levels as soon as after 1 month and further improved thereafter. FeNO decreased to baseline (Figure 1). After 3 months of treatment, histologic lymphocytic airway inflammation and IL-8 levels, total and differential total cell counts (macrophages, neutrophils and eosinophils) as well as CRP significantly decreased compared to baseline (Table 1). Conclusions: AZI is beneficial in controlling post-transplant lymphocytic airway inflammation. Trial Registration NCT01109160 (AZI002).
224 Proteasome Inhibitor Therapy for Antibody-Mediated Lung Transplant Rejection J.A. Iuppa,1 K.B. Bain,1 C.A. Witt,2 E.P. Trulock,2 D.E. Byers,2 R.R. Hachem.2 1Pharmacy Department, Barnes-Jewish Hospital, St. Louis, MO; 2Division of Pulmonary and Critical Care Medicine, Washington University-School of Medicine, St. Louis, MO. Purpose: Antibody mediated rejection (AMR) is a significant challenge after lung transplantation and no consensus exists on the optimal therapeutic approach. Bortezomib may serve as a treatment option by eradicating the antibody-producing plasma cells. We report clinical experience with bortezomib for AMR after lung transplantation. Methods and Materials: Five lung transplant recipients with clinical AMR and donor-specific antibodies (DSA) (defined as MFI 4 2000) were treated with bortezomib (1.3 mg/m2). Serial measurements of DSA were conducted by single antigen bead on Luminex, OneLambda. The immunodominant DSA (iDSA) was assigned to the DSA with the highest MFI value at the time of diagnosis. Results: In this cohort, AMR developed a median of 10.5 months after transplant; bortezomib treatment resulted in elimination of iDSA in 2 patients (1, 2), and a 50% reduction without clearance in another (3). The remaining two patients (4, 5) had persistent DSA without decline in MFI. Despite iDSA reduction in patients 1, 2, and 3, this did not translate to a meaningful clinical benefit (absence of resolution of acute
S90
The Journal of Heart and Lung Transplantation, Vol 32, No 4S, April 2013
iDSA Patient Patient Patient Patient Patient
1 2 3 4 5
MFI at Diagnosis
DQ6 4516 DPB1 4726 DR53 13052 DQ2 7094 DQ7 3698
MFI at last follow-up
Resolution of acute AMR
o2000 o2000 3123 11217 6210
No Yes Yes No Yes
AMR in patient 1). During therapy, one patient experienced grade IV thrombocytopenia; otherwise, side effects were mild and transient. Prior to AMR, all patients had normal graft function; however, all 3 patients surviving to hospital discharge developed chronic, severe graft dysfunction. Two of the 5 patients are still alive 132 (2) and 230 (5) days after treatment for AMR. Conclusions: Although these preliminary results do not support a strong clinical or immunological response to bortezomib, we cannot exclude a prescribing bias for use in more severe cases of AMR. Bortezomib treatment for AMR warrants further investigation to fully elucidate its potential benefit. 225 World Wide Experience with Induction in Lung Transplantation for Cystic Fibrosis: Is Induction Necessary? C.A. Beaty,1 T.J. George,1 A. Kilic,1 A.S. Shah,1 C.A. Merlo.2 1Division of Cardiac Surgery, Johns Hopkins Medical Institutions, Baltimore, MD; 2Division of Pulmonology, Johns Hopkins Medical Institutions, Baltimore, MD. Purpose: Patients with Cystic Fibrosis (CF) often have chronic infections at the time of lung transplantation (LTx). Induction therapy may increase infection risk and worsen outcomes. We evaluated the effect of induction therapy on post-transplant outcomes in CF patients. Methods and Materials: We reviewed all primary adult LTx recipients with CF in the International Society for Heart and Lung Transplantation database from 1/1991-6/2011. Primary stratification was by induction therapy(no induction, inter-leukin 2[IL2] receptor antagonists, antilymphocyte/thymocyte globulins [ATG] or alemtuzumab). The primary outcome was survival(30 days, 1 year and 5 years). Secondary outcomes evaluated at 1 year included rejection, infection, forced expiratory volume in 1 second (FEV1) and bronchiolitis obliterans syndrome(BOS). Multivariate Cox and logistic regression models were used to evaluate the effects of induction therapy on outcomes. Results: 5,907 subjects composed our final cohort. In bivariable models, induction significantly decreased mortality, infection and length of stay; while improving FEV1 at 1 year. After adjustment, induction therapy was associated with improved 1 year survival(HR:0.81, p¼0.047). Alemtuzumab, when compared to no induction, was associated with improved survival at 1-year (HR:0.29, p¼0.03). While mortality varied between induction regimens, there were no statistically significant differences in infection, rejection, or FEV1 at 1 year.
Conclusions: Induction therapy for CF improves early survival without increasing infection risk. Alemtuzumab may improve survival when compared to other induction regimens. Further study is needed to fully evaluate the role of induction therapy in CF patients undergoing LTx. 226 Chronic Renal Failure in Lung Transplant Recipients Is Predicted by Tacrolimus Toxicity Events B.D. Fox,1,2 D. Rozengarten,1 Y. Raviv,1,2 S. Yitzhakian,1 M.R. Kramer.1,2 1Pulmonology, Rabin Medical Center, Petach Tikva, Israel; 2Medicine, Tel Aviv University, Tel Aviv, Israel. Purpose: Chronic renal failure (CRF) is common in lung transplant (LT) recipients. Tacrolimus (Tac) exposure is an accepted risk factor for CRF but little is known about the quantitative relationship between Tac levels and LT-CRF. Methods and Materials: Review of 173 LT recipients transplanted 2003-2010. Data were extracted on Tac levels and serum creatinine (Cr). Renal failure was defined as a doubling of Cr from baseline, further defined as chronic (sustained over Z3 months), acutely post LT (o1 month). Data were analyzed between the date of LT until the first ‘renal endpoint’ was reached – either CRF, end of laboratory follow-up, everolimus therapy or death without CRF. Tac toxicity was defined as trough 420ng/dl. The area-under-thecurve of Tac levels over time (AUC:TacTime) was calculated for each patient. Results: During median 698 [IQR 133-1482] days of follow-up, 77 patients developed CRF, see table 1. In univariate analysis, LT-CRF was associated with slightly higher median Tac levels (p¼0.002), higher log (AUC:TacTime) (po0.0001), more Tac-toxicity events (po0.0001) and post-LT acute renal failure (p¼0.04). Of note, age at LT, baseline creatinine, median Tac dose, pre-LT smoking status and pre-LT hypertension were not associated with development of LT-CRF. In a multivariate model, only FK toxicity events were significantly associated with development of LT-CRF (RR 2.93, 95% CI 2.09-4.34). Conclusions: Tac toxicity events are strongly associated with future development of CRF.
Univariate Analysis
Age Male Sex % Diagnosis (%) Emphysema IPF CF Other PreLT HTN % PreLT Smoking Baseline Creat (mg/dl) Acute RF post LT Median FK Dose (mg) Median FK level (pg/ml) Log(LevelTime AUC) FK Toxicity Events
No CRF n¼96
CRF n¼77
p
51(15) 63
52(11) 61
0.69 0.74 0.87
31 40 10 19 23 58 0.78 (0.3) 33 4.5(3.8) 10.7(2.1) 10.8(2.3) 1 [0,1]
30 45 9 16 27 62 0.76 (0.22) 19 3.8(2.2) 11.5(1.5) 11.9(1.6) 3[2,3]
0.58 0.78 0.52 0.04 0.15 0.002 o0.0001 o0.0001
Data shown as mean (SD) or median [IQR] or %; analysis by t-test, wilcoxon test or chi-square, depending on data. 227 Dynamic BMI Changes in Patients Implanted with Continuous Flow Left Ventricular Assist Devices: Evidence for Reversibility of Cardiac Cachexia and Impact on Survival D.M. Kobrin,1 J.P. Donnelly,1 A.L. Acker,1 J.L. Howard,1 C.M. Zalewski,1 S.L. Walsh,1 C.E. Hill,1 M.L. O’Hara,1 J.F. Marble,2