Sirolimus Based Immunosuppression Results in Lower Incidence of Post-Transplantation Lymphoproliferative Disorders in Heart Transplant Recipients

Sirolimus Based Immunosuppression Results in Lower Incidence of Post-Transplantation Lymphoproliferative Disorders in Heart Transplant Recipients

S86 The Journal of Heart and Lung Transplantation, Vol 34, No 4S, April 2015 increase, 3.6 mm2 lumen area loss and 23.8% increase in plaque burden ...

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S86

The Journal of Heart and Lung Transplantation, Vol 34, No 4S, April 2015

increase, 3.6 mm2 lumen area loss and 23.8% increase in plaque burden without vessel remodeling at 1 yr but no further change at 2 yrs on RAPA. GS/VH analysis showed plaque composition is primarily dense calcium which significantly increased during yr 1 but no significant increase at yr 2 on RAPA. Conclusion: 17% of pts had significant increase in MIT at 1 yr post OHT, associated with lumen loss without compensatory vessel remodeling. VH analysis shows the increase in plaque burden is due to significant increase in dense calcium but not due to vulnerable plaque. There was no further progression of disease after RAPA initiation at yr 1. Further studies are needed to elucidate the mechanism behind the dense calcium increase and the stabilization of TAV by RAPA. Table 1 LAD IVUS GS and VH Parameters At Baseline, 1 And 2 Yrs Post OHT

Baseline (n= 25)

1 Yr (n= 25)

Maximal 0.5 ± 0.3 1.1 ± 0.4 Intimal Thickness (mm) Average 4.0 ± 0.7 3.4 ± 0.7 Lumen Diameter (mm) EEM Area 16.8 ± 4.6 16.7 ± 4.3 (mm2) Lumen Area 13.1 ± 4.4 9.5 ± 3.7 (mm2) Plaque 20.1 ± 13.4 43.9 ± Burden (%) 14.7 Fibrous Area 0.1 ± 0.2 0.5 ± 1.4 (mm2) Fibrofatty 0.0 ± 0.2 0.2 ± 0.4 Area (mm2) Necrotic Core 0.0 ± 0.2 0.1 ± 0.2 Are (mm2) Dense 0.5 ± 0.9 2.1 ± 1.8 Calcium Area (mm2) Fibrous (%) 8.8 ± 22.9 16.1 ± 27.9 Fibrofatty 5.7 ± 18.5 5.9 ± 13.3 (%) Necrotic Core 1.9 ± 7.9 3.1 ± 6.0 (%) Dense 18.1 ± 27.9 45.5 ± Calcium (%) 30.4

Baseline P Value to 1 Yr Baseline 2 Yr Change to 1 Yr (n= 14)

1 Yr to P value 2 Yr 1 Yr to Change 2 Yr

0.6 ± 0.4 < 0.001 1.0 ± 0.3

-0.1 ± 0.15 0.3

-0.6 ± 0.7 < 0.001 3.3 ± 0.6

-0.0 ± 0.96 0.3

-0.1 ± 4.2 0.94

15.9 ± 4.3 -0.6 ± 1.1 -3.6 ± 4.1 < 0.001 8.8 ± 3.1 -0.1 ± 1.8 23.8 ± < 0.001 44.8 ± 11.3-1.6 ± 14.5 9.2 0.2 ± 1.1 0.30 0.0 ± 0.0 -0.2 ± 0.4 0.1 ± 0.4 0.19 0.0 ± 0.0 -0.1 ± 0.1 0.0 ± 0.3 0.86 0.0 ± 0.0 -0.0 ± 0.1 1.8 ± 1.6 < 0.001 2.3 ± 1.3 -0.5 ± 1.3

0.12

3.1 ± 36.30.69

0.09

0.0 ± 0.0

-17.3 ± 30.5 -0.1 ± 0.97 0.0 ± 0.0 -4.6 ± 14.8 12.7 0.3 ± 9.9 0.87 0.0 ± 0.0 -2.8 ± 5.9 31.4 ± < 0.001 63.3 ± 12.311.7 ± 33.0 34.1

0.89 0.57 0.13 0.19 0.26 0.22

0.26 0.15 0.28

2( 15) A Multi-Center, Randomized, Open-Label, Parallel Group Phase IV Trial Investigating the Outcome on Renal Function, Efficacy and Safety of CNI-Reduction or Elimination With Everolimus in De Novo Heart Transplant: Recipients: The MANDELA Study Design T. Deuse ,1 C. Bara,1 M. Barten,1 S. Hirt,1 A. Doesch,1 C. Knosalla,1 C. Grinninger,1 J. Stypmann,1 M. Porstner,2 P. Wimmer,2 U. Schulz.1  1Mandela, Study Group, Germany; 2Novartis Pharma, Nuremberg, Germany. Purpose: The MANDELA study (NCT00862979) is designed to assess the benefit of either CNI-free or CNI-minimized EVR-based regimen after early conversion from standard treatment in de novo heart transplant recipients (HTxR).There is growing evidence on the beneficial use of everolimus (EVR) in heart transplantation supporting reduction or withdrawal of calcineurin inhibitor (CNI) therapy, mainly to maintain renal function, to avoid malignancies and to reduce progression of cardiac allograft vasculopathy. Methods: MANDELA is a multi-center, randomized, controlled, open-label, 12 month study. A total of 200 de novo HTxR (3 months post Tx) will be randomized (1:1) to receive either EVR (C0-h 5-10ng/mL) with reduced CNI (TAC C0-h 3-8 ng/mL or CsA C0-h 50-150 ng/mL) and steroids (≤ 0.3 mg/kg) or to receive EVR (C0-h 5-10 ng/mL) with mycophenolic acid (EC-MPS

max. 2880 mg/day or MMF max. 3g/day) and steroids (≤ 0.3 mg/kg). The primary objective is to assess whether a CNI-free regimen with Everolimus and MPA is associated with a better renal outcome (eGFR, MDRD) 12 months after randomization as compared to the CNI regimen. Key secondary objectives include: non-inferior efficacy (composite endpoint of BPAR of ISHLT 1990 grade ≥ 3A / ISHLT 2004 grade ≥ 2R, acute rejection, episodes of hemodynamic compromise, graft loss / re-transplant, death or loss to follow-up) and assessment of safety parameters as infections, hypertension, hyperlipidemia and diabetes. Results: As of September 2014, 144 patients have been randomized at 9 German heart transplant centers into the MANDELA study. Continuation of the study was well supported by a neutral data safety monitoring board. Conclusion: The MANDELA study might help to evaluate benefit on renal function of an EVR-based CNI-free regimen in HTxR after early conversion. 2( 16) Sirolimus Based Immunosuppression Results in Lower Incidence of Post-Transplantation Lymphoproliferative Disorders in Heart Transplant Recipients D. Vucicevic ,1 R.C. Daly,2 D.E. Steidley,1 R.L. Scott,1 W.K. Kremers,2 B.S. Edwards,2 K.S. Sudhir.3  1Mayo Clinic Arizona, Scottsdale, AZ; 2Mayo Clinic Rochester, Rochester, MN; 3Mayo Clinic Rochester, Rochester, AZ. Purpose: Post-transplantation lymphoproliferative disorders (PTLD) are a well-recognized complication of solid organ transplant, occurring in 2 to 9 percent of heart transplant recipients (HTx). EBV mismatch and higher levels of immunosuppression are predisposing factors. Clinical presentation can vary from benign proliferation of lymphoid tissue to aggressive large B-cell lymphomas. Because it has been shown to attenuate allograft vasculopathy and preserve renal function, sirolimus, a proliferation signal inhibitor, has been used in some programs as primary immunosuppression. Sirolimus inhibits lymphoproliferation in animal models and has been reported to be effective treatment for PTLD. The aim of our study was to investigate the incidence of PTLD in HTx on sirolimus based immunosuppression. Methods: We retrospectively reviewed heart transplant data at Mayo Clinic Rochester and Mayo Clinic Arizona. Information regarding demographics, immunosuppression, rejection, incidence of PTLD, EBV status and outcomes were abstracted. Patients were divided in two groups based on the use of sirolimus for maintenance immunosuppression. The incidence of PTLD was calculated for each group. Results: We identified 576 patients who received a heart transplant between 1988 and 2013, out of which 245 (42.5%) were on sirolimus based immunosuppression (SRL). The incidence of EBV mismatch was similar in both groups (p= 0.61). A total of 29 patients (5%) developed PTLD during the study period. The incidence of PTLD in HTx on sirolimus and non-sirolimus based immunosuppression was 0.8% (2/245) and 8.2% (27/331) respectively. The mean time to PTLD diagnosis was 61.1 months (range 2-175). Six patients were diagnosed with low grade lymphomas and 23 patients developed high grade disease. Treatment of PTLD included adjustments of the immunosuppression (7/29), rituximab alone (6/29) and rituximab with chemotherapy (13/29). Three patients did not receive any treatment due to advanced disease. 13 patients (44.8%) achieved complete remission. Conclusion: Our initial observations suggest that PTLD incidence is lower in HTx on SRL. The mechanism may be due to the powerful anti-proliferative effect of sirolimus. This study highlights another potential advantage of SRL which may improve long term survival following heart transplantation. 2( 17) Effect of Everolimus Immunotherapy on HLA Antibody Production in Heart Transplantation P. Rao ,1 L. Hong,2 D. Gjertson,2 I. Balaz,3 M.C. Fishbein,2 M. Deng,4 N. Harre,1 R. Leuchter,1 H.L. Banchs,5 D. DeNofrio,6 H.J. Eisen,7 G.A. Ewald,8 A. Kfoury,9 J.A. Kobashigawa,10 R.C. Starling,11 G. Torre-Amione,12 A. Van Bakel,13 E.F. Reed.1  1Pathology, UCLA, Los Angeles, CA; 2Pathology and Laboratory Medicine, UCLA, Los Angeles, CA; 3Discovery Research, Immucor, Inc., Stamford, CT; 4Cardiology, UCLA, Los Angeles, CA; 5Cardiology, University of Puerto