3/6/2017. Treatment of Detected Antibodies. I have financial relationship(s) with: Thoratec/St. Jude/Abbott Consultant CareDx Consultant/Speaker

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1 Treatment of Detected Antibodies Sean Pinney, MD Director, Advanced Heart Failure & Transplantation Mount Sinai Hospital New York, NY Sean Pinney, MD Associate Professor of Medicine Icahn School of Medicine at Mount Sinai New York, NY USA I have financial relationship(s) with: Thoratec/St. Jude/Abbott Consultant CareDx Consultant/Speaker My presentation doesinclude discussion of off-label or investigational use of IVIG, rituximab, bortezomiband eculizumab. LEARNING OBJECTIVES 1. Describe the various approaches to treating donor specific antibodies. 2. Describe the indications, side effects and clinical outcomes associated with intravenous immunoglobulin. 3. Describe the current expert consensus recommendations for the treatment of antibody-mediated rejection. 1

2 Pre-Test A 24-year-old AA woman with peri-partum cardiomyopathy presents for her 3-month protocol biopsy following uncomplicated heart transplant. She has normal resting hemodynamics. The biopsy is read as ISHLT 0R and pamr-2. Her tacrolimus level is 10 ng/ml.blood chemistries are normal except for an elevated creatinine and egfr=34 ml/min/1.73 m. Echocardiogram shows biatrialenlargement with normal biventricular function. A solid phase assay detected a class I DSA (A2 = 1976 MFI) and a class II DSA (DR7 = 10,968 MFI). You elect to admit her for treatment with intravenous corticosteroids. According to the recent expert white paper regarding AMR, which of the following is the most appropriate additional treatment: 1. Cyclophosphamide 2. Intravenous Immune globulin 3. Rituximab 4. Methotrexate 5. Bortezomib TREATMENT OF ALLOANTIBODIES REMOVE THEM NEUTRALIZE THEM SHUT OFF PRODUCTION PREVENT FUTURE PRODUCTION Chih S, Patel J. J Heart Lung Transplant 2016;35:

3 Colvin MM et al. Circulation 2015;131: Leech SH et al. Clin Transplant 2006;20:

4 Jolles S et al. Clin Exp Immunol 2005;142:1-11. INTRAVENOUS IMMUNOGLOBULIN POOLED PREDOMINANTLY IgG ANTIBODIES ANTI-IDIOTYPIC ANTIBODIES (INHIBIT HLA-SPECIFIC ALLOANTIBODIES) POLYCLONAL PREPARATIONS HAVE ACTIVITY AGAINST CLASS I & II HLA MOLECULES, COSTIMULATORY MOLECULES, CYTOKINES AND CYTOKINE RECEPTORS, AND T-CELL RECEPTORS SATURATION OF FC RECEPTORS ON MACROPHAGES COMMONLY USED AS DESENSITIZATION HAS NEVER BEEN SYSTEMATICALLY STUDIED TO REDUCE AMR INCIDENCE AFTER TRANSPLANT IVIG FOR ANTIBODY-MEDIATED REJECTION Jordan SC et al. Transplantation 1998; 66: patients with severe allograft rejection, four of whom developed AR episodes associated with high levels of DSA. IVIG resulted in rapid improvements with AR resolution noted within 2-5 days 9/10 ptswith freedom from recurrent rejection episodes, some with up to 5 years of follow-up. 4

5 INTRAVENOUS IMMUNOGLOBULIN DOSING 1 2 GM/KG IV IN DIVIDED DOSES SIDE EFFECTS HEADACHE, BACKACHE, CHILLS ACUTE RENAL FAILURE (AVOID SUCROSE-CONTAINING PREPARATIONS) ACUTE THROMBOSIS RASH, ECZEMA PSEUDOHYPONATREMIA RITUXIMAB (Rituxan) Chimeric monoclonal antibody against CD20 on B-cells. Fc portion binds to FcγR on NK cells, macrophages and monocytes Complement-dependent cytotoxicity Cell-mediated apoptosis through CD20 cross-linking Single dose of 375 mg/m2 is sufficient to deplete circulating B-cells for up to 6-12 months with variable reduction in the spleen Infusion related reactions may occur manageable with pre-infusion acetaminophen, corticosteroids and diphenhydramine RITUXIMAB FOR AMR Garrett HE et al. J Heart Lung Transplant 2005;24:

6 BORTEZOMIB (Velcade) Reversible 26S proteasome inhibitor that depletes plasma cells through apoptosis Adequate plasma cell depletion is limited by long-lived populations in the spleen, lymph nodes and bone marrow Reduces HLA antibody (Class I > Class II) Usually administered following plasmapheresis Efficacy as a single-agent for AMR has not been studied Side effects include peripheral neuropathy (10%) BORTEZOMIB (Velcade) Everly MJ et al. Transplantation 2012;93: ALEMTUZUMAB (Campath) Humanized anti-cd52 monoclonal antibody CD52 on T-and B-cells, macrophages, monocytes and NK cells. Effective depletion of mature lymphocytes without myeloablation Approved for lymphoma and leukemia treatment (CLL) Used for induction, desensitization and occasionally AMR 6

7 ECULIZUMAB Complement inhibitor Blocks C5 conversion to C5a-b and the subsequent membrane attack complex Approved for PNH and atypical HUS Animal data and case reports One case series of 9 patients receiving eculizumab + ATG Average cprapre-transplant was 92%. Actuarial survival at 12 months was 89%. 1 intra-operative death resulting from purulent mediastinitis. 75% 12-month freedom from any treated rejection and AMR Patel J et al. J Heart Lung Transplant 2015;34(suppl):S31. FUTURE THERAPIES Carfilzomib Irreversible proteasome inhibitor Anti B-cell Mab Belimumab Atacicept Affect B-lymphocyte stimulator AKA B-cell activation factor of the tumor necrosis family C1 esterase inhibitors Tocilizumab IL6R inhibitor YOU ARE ENTERING A DATA-FREE ZONE 7

8 Colvin MM et al. Circulation 2015;131: Chi S et al. Am J Transplant 2013;13: Colvin MM et al. Circulation 2015;131:

9 Post-Test A 24-year-old AA woman with peri-partum cardiomyopathy presents for her 3-month protocol biopsy following uncomplicated heart transplant. She has normal resting hemodynamics. The biopsy is read as ISHLT 0R and pamr-2. Her tacrolimus level is 10 ng/ml.blood chemistries are normal except for an elevated creatinine and egfr=34 ml/min/1.73 m. Echocardiogram shows biatrialenlargement with normal biventricular function. A solid phase assay detected a class I DSA (A2 = 1976 MFI) and a class II DSA (DR7 = 10,968 MFI). You elect to admit her for treatment with intravenous corticosteroids. According to the recent expert white paper regarding AMR, which of the following is the most appropriate additional treatment: 1. Cyclophosphamide 2. Intravenous Immune globulin 3. Rituximab 4. Methotrexate 5. Bortezomib Post-Test A 24-year-old AA woman with peri-partum cardiomyopathy presents for her 3-month protocol biopsy following uncomplicated heart transplant. She has normal resting hemodynamics. The biopsy is read as ISHLT 0R and pamr-2. Her tacrolimus level is 10 ng/ml.blood chemistries are normal except for an elevated creatinine and egfr=34 ml/min/1.73 m. Echocardiogram shows biatrialenlargement with normal biventricular function. A solid phase assay detected a class I DSA (A2 = 1976 MFI) and a class II DSA (DR7 = 10,968 MFI). You elect to admit her for treatment with intravenous corticosteroids. According to the recent expert white paper regarding AMR, which of the following is the most appropriate additional treatment: 1. Cyclophosphamide 3. Rituximab 4. Methotrexate 5. Bortezomib THANK YOU 9

10 Kobashigawa J et al. J Heart Lung Transplant 2009;28: Chih S, Patel J. J Heart Lung Transplant 2016;35: