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Immunosuppression and Outcomes in Elderly Lung Transplant Recipients
S410
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
target dose; no titration was needed with L-CsA. Reported symptoms were (L-CsA vs CsA-PG): pharyngeal soreness 1% vs. 43%; cough 22% vs. 36%; dyspnea 7% vs. 25%; wheezing 1% vs. 7%; discontinuation due to symptoms caused by aerosol administration 0% vs. 7%. Adherence to investigational therapy (L-CsA vs CsA-PG) was 80% vs 60%. Conclusion: L-CsA administered via an L-CsA specific PARI investigational eFlow® nebulizer improved tolerability and adherence compared to CsA-PG, another investigational aerosolized cyclosporine. LCsA uses lower total dose exposure to achieve constant levels of drug in the airway. 1034 Immunosuppression and Outcomes in Elderly Lung Transplant Recipients J.K. McDermott, P. Nguyen, J.L. Parker, R.J. Hadley, A. Kumar, G. Sathiyamoorthy, M. Leacche, E.T. Murphy and R.E. Girgis. Spectrum Health Hospitals, Grand Rapids, MI. Purpose: Elderly subjects (>65 yr) represent a rapidly growing proportion of lung transplant recipients (LTR). Immunosenescence may be associated with an increased risk of infections, less rejection and reduced immunosuppression (IS) therapy requirements. We sought to compare IS and early outcomes in elderly and younger LTR. Methods: This is a single-center retrospective study of 85 LTR; 49 < 65 yr (Gp A) and 36 aged ≥ 65 (Gp B). Episodes of infection and acute rejection and the IS regimen during the first post-transplant year were compared. Overall survival was analyzed with the Kaplan-Meier method. Results: Mean age was 54 y (12) for Gp A and 68 (2) in Gp B. Gp B had a larger proportion with Idiopathic Interstitial pneumonia (64% vs. 31%) and single lung transplants (64% vs. 27%). Median follow-up duration was 35 m (IQR: 24-46). There was no difference in the incidence, frequency or severity of infections. At least one infection occurred during the 1st year in 60% of Gp A and 66% of Gp B with a mean number of 1.12 (1.4) and 1.34 (1.2) in A and B, respectively (=0.37). Bacterial, fungal or CMV pneumonia during the first year occurred in 23% of both groups. Acute rejection grade ≥2 during the first year was observed in 30% of Gp A and 50% of Gp B (P=0.12). At 1 yr post-transplant, only 48% and 58% of Gps A and B, respectively, were on our standard IS regimen of TAC/MMF/pred (P=0.4). MMF discontinuation accounted for 91% and 90% of non-standard IS regimens. Azathioprine was used in 20% of Gp A and 13% of Gp B, whereas everolimus was used in 5% and 8%. TAC trough levels were comparable during the first year in both groups, although Gp B had a significantly lower dose requirement at hospital discharge and 3 m, but not 1 yr. During the entire observation period, neutropenia (<1000/ml) occurred in 43% vs. 36% (p=0.53) and de novo DSA in 31% and 19% (P=0.35), in A and B, respectively. More Gp B subjects developed a malignancy (21% vs. 10% (=0.22), including 2 that were fatal. BOS grade 1 or higher developed in 20% of A and 10% of B at last followup. Survival was not significantly different between the groups with 1 and 3 yr survival of 98% and 86% in A and 94% and 79% in B, respectively (=0.37). Conclusion: In our experience, IS management in elderly LTR was similar to younger recipients with no differences in infection, rejection or survival. A trend towards an increased incidence of malignancy in older recipients mandates vigilant screening. 1035 Correlation of Tacrolimus Levels and Metabolizer Status Based on CYP3A5 Polymorphism in Indian Lung Transplant Recipients A. Jindal,1 V. Rahulan,2 S. Sagadevan,2 P. Dutta,2 and S. Attawar.2 1Pulmonary Critical Care and Sleep Medicine, Institute of Heart & Lung Transplant, Gleneagles Global Health City, Chennai, Tamil Nadu, India; and the 2Pulmonary Critical Care and Sleep Medicine, Institute of Heart & Lung Transplant, Gleneagles Global Health City, Chennai, India. Purpose: Tacrolimus (Tac) variable pharmacokinetics influences its efficacy and toxicity. CYP3A5 gene polymorphism leads to marked
differences in metabolism of Tac. Aim is to assess the impact of CYP3A5 polymorphism on Tac. dose. Methods: Retrospective analysis of 3 months post-op, weekly Tac. levels, on lung transplant recipients between 01/2018 to 09/2018. Tac levels monitored every 3 days, aiming therapeutic range of 8 to 12 ng/mL. Monitoring continued twice weekly for 4 weeks, then weekly till 12 weeks. Genomic DNA was extracted from 0.1 ml of blood by silica column based protocol. A few ng of the DNA sample was subjected to AS-rtPCR-MPA in duplicates, thus yielding a total of 2 replicates. CYP3A5 polymorphisms was detected from each of the 2 replicates, thus dividing the patients into poor, intermediate or extensive metabolizer phenotypes Results: 18 patients were divided into 3 groups - poor, intermediate, and rapid metabolizers, n = 5, 10, 3 respectively. As shown in Graph 1, most variation in weekly mean Tac dose was noted in rapid metabolizers. C/D ratio (Concentration Dose ratio) was calculated using the formula: C/D ratio = blood Tacrolimus trough level / daily Tac. dose, and plotted over time, displaying significant variation in the rapid metabolizers. Conclusion: Results suggest CYP3A5 genetic polymorphism significantly influences Tac. pharmacokinetics. This can help plan Tac. dose, obtain therapeutic levels, & minimize toxicity. Larger studies are required to establish the clinical correlation across age, sex and ethnic variations.
Demographic data variable n Mean age (years) Gender Male Female Mean height (cm) Mean Weight (Kg) Mean BMI (Kg/ m2) Mean Tac dose (mg/day)
Metabolizer Status Poor 5 41.2
Intermediate 10 54.2
Rapid 3 40
1 4 159 62.6 24.8 1.5
8 2 169.7 65.3 22.6 2.9
1 2 165.7 59 21.1 1.5
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
target dose; no titration was needed with L-CsA. Reported symptoms were (L-CsA vs CsA-PG): pharyngeal soreness 1% vs. 43%; cough 22% vs. 36%; dyspnea 7% vs. 25%; wheezing 1% vs. 7%; discontinuation due to symptoms caused by aerosol administration 0% vs. 7%. Adherence to investigational therapy (L-CsA vs CsA-PG) was 80% vs 60%. Conclusion: L-CsA administered via an L-CsA specific PARI investigational eFlow® nebulizer improved tolerability and adherence compared to CsA-PG, another investigational aerosolized cyclosporine. LCsA uses lower total dose exposure to achieve constant levels of drug in the airway. 1034 Immunosuppression and Outcomes in Elderly Lung Transplant Recipients J.K. McDermott, P. Nguyen, J.L. Parker, R.J. Hadley, A. Kumar, G. Sathiyamoorthy, M. Leacche, E.T. Murphy and R.E. Girgis. Spectrum Health Hospitals, Grand Rapids, MI. Purpose: Elderly subjects (>65 yr) represent a rapidly growing proportion of lung transplant recipients (LTR). Immunosenescence may be associated with an increased risk of infections, less rejection and reduced immunosuppression (IS) therapy requirements. We sought to compare IS and early outcomes in elderly and younger LTR. Methods: This is a single-center retrospective study of 85 LTR; 49 < 65 yr (Gp A) and 36 aged ≥ 65 (Gp B). Episodes of infection and acute rejection and the IS regimen during the first post-transplant year were compared. Overall survival was analyzed with the Kaplan-Meier method. Results: Mean age was 54 y (12) for Gp A and 68 (2) in Gp B. Gp B had a larger proportion with Idiopathic Interstitial pneumonia (64% vs. 31%) and single lung transplants (64% vs. 27%). Median follow-up duration was 35 m (IQR: 24-46). There was no difference in the incidence, frequency or severity of infections. At least one infection occurred during the 1st year in 60% of Gp A and 66% of Gp B with a mean number of 1.12 (1.4) and 1.34 (1.2) in A and B, respectively (=0.37). Bacterial, fungal or CMV pneumonia during the first year occurred in 23% of both groups. Acute rejection grade ≥2 during the first year was observed in 30% of Gp A and 50% of Gp B (P=0.12). At 1 yr post-transplant, only 48% and 58% of Gps A and B, respectively, were on our standard IS regimen of TAC/MMF/pred (P=0.4). MMF discontinuation accounted for 91% and 90% of non-standard IS regimens. Azathioprine was used in 20% of Gp A and 13% of Gp B, whereas everolimus was used in 5% and 8%. TAC trough levels were comparable during the first year in both groups, although Gp B had a significantly lower dose requirement at hospital discharge and 3 m, but not 1 yr. During the entire observation period, neutropenia (<1000/ml) occurred in 43% vs. 36% (p=0.53) and de novo DSA in 31% and 19% (P=0.35), in A and B, respectively. More Gp B subjects developed a malignancy (21% vs. 10% (=0.22), including 2 that were fatal. BOS grade 1 or higher developed in 20% of A and 10% of B at last followup. Survival was not significantly different between the groups with 1 and 3 yr survival of 98% and 86% in A and 94% and 79% in B, respectively (=0.37). Conclusion: In our experience, IS management in elderly LTR was similar to younger recipients with no differences in infection, rejection or survival. A trend towards an increased incidence of malignancy in older recipients mandates vigilant screening. 1035 Correlation of Tacrolimus Levels and Metabolizer Status Based on CYP3A5 Polymorphism in Indian Lung Transplant Recipients A. Jindal,1 V. Rahulan,2 S. Sagadevan,2 P. Dutta,2 and S. Attawar.2 1Pulmonary Critical Care and Sleep Medicine, Institute of Heart & Lung Transplant, Gleneagles Global Health City, Chennai, Tamil Nadu, India; and the 2Pulmonary Critical Care and Sleep Medicine, Institute of Heart & Lung Transplant, Gleneagles Global Health City, Chennai, India. Purpose: Tacrolimus (Tac) variable pharmacokinetics influences its efficacy and toxicity. CYP3A5 gene polymorphism leads to marked
differences in metabolism of Tac. Aim is to assess the impact of CYP3A5 polymorphism on Tac. dose. Methods: Retrospective analysis of 3 months post-op, weekly Tac. levels, on lung transplant recipients between 01/2018 to 09/2018. Tac levels monitored every 3 days, aiming therapeutic range of 8 to 12 ng/mL. Monitoring continued twice weekly for 4 weeks, then weekly till 12 weeks. Genomic DNA was extracted from 0.1 ml of blood by silica column based protocol. A few ng of the DNA sample was subjected to AS-rtPCR-MPA in duplicates, thus yielding a total of 2 replicates. CYP3A5 polymorphisms was detected from each of the 2 replicates, thus dividing the patients into poor, intermediate or extensive metabolizer phenotypes Results: 18 patients were divided into 3 groups - poor, intermediate, and rapid metabolizers, n = 5, 10, 3 respectively. As shown in Graph 1, most variation in weekly mean Tac dose was noted in rapid metabolizers. C/D ratio (Concentration Dose ratio) was calculated using the formula: C/D ratio = blood Tacrolimus trough level / daily Tac. dose, and plotted over time, displaying significant variation in the rapid metabolizers. Conclusion: Results suggest CYP3A5 genetic polymorphism significantly influences Tac. pharmacokinetics. This can help plan Tac. dose, obtain therapeutic levels, & minimize toxicity. Larger studies are required to establish the clinical correlation across age, sex and ethnic variations.
Demographic data variable n Mean age (years) Gender Male Female Mean height (cm) Mean Weight (Kg) Mean BMI (Kg/ m2) Mean Tac dose (mg/day)
Metabolizer Status Poor 5 41.2
Intermediate 10 54.2
Rapid 3 40
1 4 159 62.6 24.8 1.5
8 2 169.7 65.3 22.6 2.9
1 2 165.7 59 21.1 1.5