3/6/2017
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 does include discussion of off-label or
investigational use of IVIG, rituximab, bortezomib and
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.
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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 biatrial enlargement 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.
2.
3.
4.
5.
Cyclophosphamide
Intravenous Immune globulin
Rituximab
Methotrexate
Bortezomib
TREATMENT OF ALLOANTIBODIES
•
•
•
•
REMOVE THEM
NEUTRALIZE THEM
SHUT OFF PRODUCTION
PREVENT FUTURE PRODUCTION
Chih S, Patel J. J Heart Lung Transplant 2016;35:962-72.
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Colvin MM et al. Circulation 2015;131:1608-39.
Leech SH et al. Clin Transplant 2006;20:476-484.
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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;
66:800-805.
•
•
•
10 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 pts with freedom from recurrent
rejection episodes, some with up to 5
years of follow-up.
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INTRAVENOUS IMMUNOGLOBULIN
•
DOSING
•
SIDE EFFECTS
–
–
–
–
–
–
1 – 2 GM/KG IV IN DIVIDED DOSES
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;24:1337-42.
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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;93:572-7.
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
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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 cPRA pre-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
•
Anti B-cell Mab
–
–
–
–
•
•
Irreversible proteasome inhibitor
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
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Colvin MM et al. Circulation 2015;131:1608-39.
Chi S et al. Am J Transplant 2013;13:1069-74.
Colvin MM et al. Circulation 2015;131:1608-39.
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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 biatrial enlargement 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.
2.
3.
4.
5.
Cyclophosphamide
Intravenous Immune globulin
Rituximab
Methotrexate
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 biatrial enlargement 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
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Kobashigawa J et al. J Heart Lung Transplant 2009;28:213-25.
Chih S, Patel J. J Heart Lung Transplant 2016;35:962-72.
10