Transcript Antibody Mediated Rejection in Heart Transplantation: Case

Antibody-Mediated Rejection in Heart
Transplantation
Stefanie L. Drahuschak
PharmD Candidate Class of 2014
University of Pittsburgh
School of Pharmacy
Objectives
 Describe the major differences between hyperacute, acute,
and chronic rejection.
 List the treatment options for antibody-mediated rejection.
 Apply the concepts of antibody-mediated rejection to a
patient case.
Patient JL: CC
 Presented to PUH ED on 1/18/14 with c/o
 Increasing SOB
 Abdominal distension
 Intermittent vomiting after eating
 Has been worsening over last 3 months
Patient JL
 58 yo WM s/p OHTx in 6/2009 secondary to ICM
 No known drug allergies
 PMHx
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s/p CABG 4/2009
BiVAD placement 5/2009
Episodic grade 1 cellular rejection, resolved 5/13
Antibody-mediated rejection (class II DSAs)
CKD -> ESRD 2/2 AMR tx, on HD T/Th/S
T2DM
Hypertension
Hyperlipidemia
Peripheral vascular disease
JL: Family and Social Hx
 Family Hx
 Family history is listed as non-contributory for this patient
 Social Hx
 20 pack year history, quit 2009
 Denies EtOH or illicit drug use
 Lives with wife and dogs
 Retired post office employee
JL: Home Medications
Medication
Dosage
Frequency
Aspirin
81mg
Once daily
Atorvastatin
40 mg
qHS
Docusate
100 mg
Once daily prn
Ergocalciferol
50,000 units
Once weekly
Furosemide
80 mg
Once daily
Lantus
10 units
qHS
Humalog
SSI
TID AC
Magnesium oxide
400 mg
Once daily
Methadone
5 mg
5 tabs daily prn
Metolazone
2.5 mg
Once daily
Oxycodone
5 mg
2 tabs q6h prn
Pantoprazole
40 mg
Once daily
Miralax
17 g
Once daily
Bactrim DS
800/160mg
1 tab q MWF
Tacrolimus
1 mg
7 mg q 12h
JL: Pertinent Findings
 Upon presentation to PUH ED
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LE edema
Ascites, volume overloaded
Elevated BNP (2859)
K 6.1, bicarbonate 34
BUN 29, SCr 6.2
Troponin negative
LFTs and CBC WNL
CXR showed right-sided pleural effusion
JL: Inpatient Progression
 Initial differential: volume overload due to underdialysis
 Previous RHC (1/13/14): PCWP 33, PA 45, RA 29, RV 32
 Underwent HD session
 TTE (1/21/14)
 Findings consistent with OHTx, no significant changes from
TTE on 9/6/13
 Patient d/c’ed 1/24/14 with good allograft function and
improved volume status
JL: History of Rejection
 Episodic grade 1 cellular rejection
 Resolved as of May 2013
 Antibody-mediated rejection (class II DSAs) s/p
 Pulse steroids 4/2013
 IVIg, rituximab, and plasmaphoresis 4/2013
 Plasmapheresis, IVIg, and carfilzomib 6-7/2013
Review of Rejection
Review of Rejection
 Rejection in any transplanted organ is mediated by activation
of T cells and antigen-presenting cells, such as B cells,
macrophages, and dendritic cells.
 Acute rejection is mainly caused by infiltration of T cells into
the graft
 Causing inflammation
 Chronic rejection is due to interactions between the graft and
cellular cytokines, CD4 and CD8 T cells, and B cells
Review of Rejection
 Hyperacute rejection
 Occurs within minutes of surgery when donor-specific
antibodies are present in the recipient
 Has become uncommon in kidney and heart transplantation due
to extensive pre-op screening
 Treated with supportive care and re-transplantation if possible
Review of Rejection
 Acute rejection
 Most common in the first few months following transplantation
but can occur at any time
 CD8 cells respond to the HLA class I differences between
donor and recipient and CD4 cells respond to HLA class II
differences
 Both CD4 and CD8 can attack the allograft
 May affect up to 20% of kidney transplant patients
 ~18% of liver transplantation patients
 >60% of heart transplantation recipients will experience acute
rejection, with 90% occurring within the first 6 months
 Recurrent episodes lead to chronic rejection
Review of Rejection
 Chronic rejection
 A major cause of graft loss
 Occurs more slowly and over time compared with acute
rejection
 Humoral immune system and antibodies against graft both play
a role
 Chronic inflammation and other disease states lead to rejection
over time
 Caused by thickening of the vessel walls and narrowing of their
vasculature
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Results in inadequate blood supply to the graft  ischemia  death
Antibody-Mediated Rejection
(AMR)
Antibody-Medicated Rejection
 Also referred to as vascular or humoral rejection
 Characterized by the presence of antibodies directed against HLA
antigens on the donor vasculature – Donor Specific Antibodies
(DSAs)
 Screening for DSAs routinely post-transplantation can help prevent
rejection episodes
 Associated with a significantly worse survival and shown to
predispose patients to coronary vasculopathy
 Less common than cellular rejection and generally occurs in the
first 3 months post-transplantation
Antibody-Mediated Rejection
 Associated with an increased fatality rate
 Increased risk factors for AMR include
 Female gender, elevated PRA, CMV+, positive crossmatch, and
prior sensitization to muromonab (OKT3)
 To date, there are no FDA-approved immunosuppressive
agents for AMR treatment
 All agents are used off-label
Rose, et al.
 66% of heart recipients produced anti-HLA lymphocytotoxic
antibodies post-transplantation
 Antibodies were not donor antigen-specific, but their
presence correlated with adverse outcomes
 Graft arteriosclerosis
 Lower graft survival rate
Findings in AMR of Heart
J Heart Lung Transplant. 2009;25(2):153-59
Diagnosis – Cardiac Biopsy
 Standardized Cardiac Biopsy Grading
 Grade 0R
 No rejection or inflammation detected
 Grade 1R (1A or 1B)
 A=focal infiltrate without necrosis
 B=diffuse but sparse infiltrate without necrosis
 Grade 2R
 One focus only with aggressive infiltration and/or myocyte damage
 Grade 3R (3A or 3B)
 A=Multifocal aggressive infiltrates and/or myocyte damage
 B=Diffuse inflammatory process with necrosis
 Grade 4R
 Diffuse aggressive polymorphous ± infiltrate ± edema ± hemorrhage ±
vasculitis, with necrosis
AMR Diagnosis
 If features suggestive of AMR seen, diagnosis can be
confirmed by either
 Immunofluorescence microscopy
 Immunoperoxidase light microscopy using antibodies directed
against CD68, CD31, and CD4
 Serum should be drawn and tested for DSA HLA Class I and
II antibodies and non-HLA antibodies
 If positive, a positive diagnosis for AMR should be made
JL: Diagnosis
 Patient presented to ED in April 2013 with c/o dyspnea and
volume overload x 2 days, severe back spasms
 Concern for rejection due to history and some noncompliance
 TTE: overall left ventricular function worse since previous
TTE, EF 30-35%
 RHC: PCWP 21, PA 28, RA 15, RV 15
 Elevated pressures  volume overload
 Biopsy showed grade 1R
AMR Treatment - Plasmapheresis
 The removal, treatment, and return of blood plasma from
circulation
 Blood is removed from patient through needle or catheter
and plasma and blood are separated via centrifugation or
filtration
 Blood is returned to patient and plasma is treated (antibodies
removed) then also returned to patient
 Offers the quickest short-term answer to removing
antibodies from blood, but requires concomitant
immunosuppressive therapy
AMR Treatment - IVIg
 IVIg = Intravenous immunoglobulin
 A blood product containing pooled polyvalent IgG antibodies
extracted from plasma of multiple donors (at least 1,000)
 IVIg suppresses inflammation, which occurs in rejection, by a
MOA that is not fully understood
 Used in combination with rituximab for treatment of AMR
and also for desensitization in pre-transplant patients who are
highly sensitized
AMR Treatment - Rituximab
 A chimeric anti-CD20 monoclonal antibody
 An anti-neoplastic agent
 MOA
 Binds directly to CD20 that is located on pre-B and mature B
cells
 CD20 regulates an early step in the activation process for cell
cycle initiation and differentiation
 Ultimately mediates B cell lysis
AMR Treatment - Rituximab
 Faguer S, et al.
 2 g/kg IVIg on week 0, rituximab on weeks 3 and 4, second
dose of IVIg on week 5
 Following therapy, PRA levels were reduced significantly (from
77 ± 19% before infusion to 44 ± 30% after second infusion)
 Transplant was then possible in 16 of the 20 patients
 12-month patient and allograft survival rates were 100% and
94%, respectively
JL: AMR Treatment
 April 3-5, 2013
 3 days of methylprednisolone 1 gm IV once daily
 April 13-15, 2013
 Plasmapheresis
 April 15-16, 2013
 IVIG 0.5 g/kg x 2 days
 Premedicated with APAP, diphenhydramine, famotidine, but not well
tolerated
 Did not receive 2nd dose due to elevated creatinine
 April 19, 2013
 Rituximab 675 mg IV once
Patient JL
 May 9, 2013: patient returns to ED with c/o N/V x 1 week
with minimal PO tolerance
 RHC (5/11): RA 18, RV 43/19, PA 43/23 (31) and wedge
25 (elevated pressures)
 Patient remained in house with intermediate plasmapheresis
and IVIg
 Biopsy on 5/11 revealed grade 0R
 EF decreased to 25-30% from 55% on admission
 Biopsy one week prior revealed grade 0R, but notable for
strong class II DSAs
AMR Refractory Treatment
 Bortezomib (Velcade®)
 Proteasome inhibitor, first in its class, approved 2003
 Indicated as an antineoplastic agent for multiple myeloma
 Reversible inhibitor of the 26S proteasome
 26S proteasome regulates protein expression and function by degradation
of modified proteins (damaged, poorly folded)
 Prevents peptide generation, which reduces class I MHC expression
 Negatives: peripheral neuropathy and $$$
 To date, no randomized controlled trials have been conducted
for AMR treatment
 Some case reports have been published on the efficacy of bortezomib-
based regimens
Eckman, et al.
 First reported use of bortezomib in refractory AMR in
cardiac allograft
 65 yo woman who developed HF 5 years post-op (biopsy
proven CD4+AMR with three DSAs identifed)
 Treated with a single bortezomib cycle with plasmapheresis
prior to each dose
 Within 2 weeks of treatment, clinical improvement was
noted with CD4 resolution on biopsy and improved DSA
levels
AMR Refractory Treatment
 Carfilzomib (Kyprolis®)
 Proteasome inhibitor FDA approved July 20, 2012
 Indication: multiple myeloma, relapsed after at least 2 prior
therapies
 MOA
 Irreversibly binds to active sites of 20S proteasome
 Even less data available with no clinical trials relating to AMR
 Dosing: administered IV over 2-10 minutes on two consecutive
days each week for three weeks (days 1, 2, 8, 9, 15, 16)
followed by a 12-day rest period (28 day cycle)
 $$$$$$$$$
Patient JL: AMR Treatment
 June 5, 2013:
 Plasmaphoresis
 1.5 volume
 IVIg 100 mg/kg
 Carfilzomab (Kyprolis®) 20 mg/m2
 Days 1,2  days 8,9  days 15, 16
JL: Post-Treatment
 TTE (6/21): LV function had improved from TTE on
5/30/13
 EF 45%, markedly improved from 25-30%
 DSAs negative from 6/19
 RHC (6/24): RA 13, wedge 21 - improving
 Patient was able to be d/c’ed 7/5/13
JL Assessment/Plan
 1) Acute HF 2/2 AMR s/p OHTx 6/2009
 Underwent plasmaphoresis, IVIG, and carfilzomab
 Pressors and inotropes weaned
 Tacrolimus 6 mg q12h (goal 8-10), Myfortic 720 mg BID,
Valcyte 450 mg qMN/Th, dapsone 100 mg daily
 Lasix 80 mg on non-HD days for volume control
 Patient must closely for s/sx of rejection (fever, unexplained
pains, weakness)
 Biopsies and DSAs should be checked regularly
Follow-up
 Patients who have several episodes of documented AMR
should be followed on future biopsies
 Should be monitored for the production of donor-specific
HLA class I and class II antibodies
Conclusion
 AMR is a significant cause of graft loss in transplantation
population
 Can be screened for and potentially prevented with
appropriate immunosuppression and monitoring
 Can be treated with a combination of novel approaches, none
of which are FDA approved for their use as AMR treatment
 Ongoing clinical trials and novel agents give hope for a more
treatment options in the future
References
 1) Dipiro JT, Talbert RL,Yee GC, et al. “Solid-Organ Transplantation”. Pharmacotherapy,
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Ed. Schonder KS, Johnson HJ. New York, NY: The McGraw-Hill Companies, Inc, 2011.
1537-58.
2) Parham P. “Transplantation of Tissues and Organs”. The Immune System, Ed. New York,
NY: Garland Science, Taylor & Francis Group, LLC, 2009. 454-83.
3) Reed EF, Demetris AJ, Hammond E, et al. Acute Antibody-mediated Rejection of
Cardiac Transplants. J Heart Lung Transplant. 2006;25(2):153-59.
4) Rose EA, Smith CR, Petrossian GA, et al. Humoral immune responses after cardiac
transplantation: correlation with fatal rejection and graft atherosclerosis. Surgery.
1989;106:203-7.
5) Billingham ME, et al. A working formulation for the standardization of nomenclature
in the diagnosis of heart and lung rejection: heart rejection study group. J Heart Trans.
1990;9(6):587-93.
6) Mosquera Reboredo JM, Vazquez Martul E. Diagnostic criteria of antibody-mediated
rejection in kidney transplants. Nefrologia. 2011;31(4):382-91.
7) Hartung H-P, Mouthon L, Ahmed R, et al. Clinical applications of intravenous
immunoglobulins (IVIG) – beyond immunodeficiencies and neurology. Clin Exp Immunol.
2009; 158(1): 23-33.
References
 8) Faguer S, Kamar N, Guilbeaud-Frugier C, et al. Rituximab
therapy for acute humoral rejection after kidney
transplantation. Transplantation. 2007;83:1277-80.
 9) Sadaka B, Alloway RR, Shields AR, et al. Proteasome
inhibitors proteasome inhibition for antibody-mediated
allograft rejection. Seminars in Hematology. 2012;49(3):26369.
 10) Velcade® [package insert]. Cambridge, MA: Millennium
Pharmaceuticals, Inc; 2012.
 11) Kyprolis® [package insert]. San Francisco, CA: Onyx
Pharmaceuticals, Inc; 2012.
Questions?