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Disclosure Information:
Mark D. Stegall, M.D.
Disclosure Information:
Mark D. Stegall, M.D.
I have the following financial relationship to disclose Research/Grant support from: Alexion and Millenium Pharmaceuticals
I will discuss the following off label use and/or investigational use in my presentation: Eculizumab and Velcade
I have the following financial relationship to disclose Research/Grant support from: Alexion and Millenium Pharmaceuticals
I will discuss the following off label use and/or investigational use in my presentation: Eculizumab and Velcade
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AcknowledgmentsAcknowledgments
• James Gloor
• Suresh Raghavaiah
• Tayyab Diwan
• Cindy Groettum
• Jennie Wilson
• Justin Burns
• Dana Perry
• Walter Park
• Lynn Cornell
• James Gloor
• Suresh Raghavaiah
• Tayyab Diwan
• Cindy Groettum
• Jennie Wilson
• Justin Burns
• Dana Perry
• Walter Park
• Lynn Cornell
• Patrick Dean
• Steve DeGoey
• Manish Gandhi
• Jeff Winters
• Lynette Fix
• Kay Kosberg
• Surgeons, Nephrologists, Fellows and other staff
• Patrick Dean
• Steve DeGoey
• Manish Gandhi
• Jeff Winters
• Lynette Fix
• Kay Kosberg
• Surgeons, Nephrologists, Fellows and other staff
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Actual Death-Censored5 Year Graft Survival
Actual Death-Censored5 Year Graft Survival
70.7% vs 88.0%, p= 0.0006
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Actual 5 Year Graft SurvivalActual 5 Year Graft Survival
T cell AHG
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Actual 5 Year Outcomes After +XMKTx
Actual 5 Year Outcomes After +XMKTx
Rate of graft loss after 1 yearClass I only 1.6%/yr
Class II 7.0%/yr
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What this talk is not aboutWhat this talk is not about
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Hyperacute RejectionHyperacute Rejection
• Rare
• Very rare with a negative T cell AHG crossmatch
• Thus, PE or IVIG to achieve a –Tcell AHG pretransplant
• Very rare with anti-Class II alone
• Rare
• Very rare with a negative T cell AHG crossmatch
• Thus, PE or IVIG to achieve a –Tcell AHG pretransplant
• Very rare with anti-Class II alone
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Combined Cellular and Antibody Mediated Rejection
Combined Cellular and Antibody Mediated Rejection
• Most cases of AMR seen clinically in non-sensitized patients are a combination of cellular and antibody mediated rejection
• ?Role of non-compliance
• DSA levels may be transient
• Time of occurrence may be months to years after transplantation
• Most cases of AMR seen clinically in non-sensitized patients are a combination of cellular and antibody mediated rejection
• ?Role of non-compliance
• DSA levels may be transient
• Time of occurrence may be months to years after transplantation
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Bortezomib and AHRBortezomib and AHR
• 6 patients with combined cellular and humoral rejection (C4d+ and DSA by solid phase)
• Time of rejection episodes: POD 239, 95, 1766, 180, 2825,147
• All resolved
• 3 of 6 had transplant glomerulopathy on follow-up
• 6 patients with combined cellular and humoral rejection (C4d+ and DSA by solid phase)
• Time of rejection episodes: POD 239, 95, 1766, 180, 2825,147
• All resolved
• 3 of 6 had transplant glomerulopathy on follow-up
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Two TalksTwo Talks
Thursday
• Early Antibody Mediated Injury• Acute Antibody Mediated
(Humoral) Rejection
Friday
• Late Antibody Mediated Injury• Chronic AMR
Thursday
• Early Antibody Mediated Injury• Acute Antibody Mediated
(Humoral) Rejection
Friday
• Late Antibody Mediated Injury• Chronic AMR
Based on Experience with Sensitized Patients
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Differences Between Early and Late Antibody Mediated InjuryDifferences Between Early and Late Antibody Mediated Injury
• Early• First 6 weeks after transplant, rarely later• Incidence determined by DSA levels• C4d+• Microthrombi, some cells• Incidence higher with anti-Class I DSA
• Late• Rare early, increases over years• DSA levels usually low, C4d- common• A cellular infiltrate termed “peritubular”
capillaritis• Incidence higher and outcome worse with
anti-Class II DSA
• Early• First 6 weeks after transplant, rarely later• Incidence determined by DSA levels• C4d+• Microthrombi, some cells• Incidence higher with anti-Class I DSA
• Late• Rare early, increases over years• DSA levels usually low, C4d- common• A cellular infiltrate termed “peritubular”
capillaritis• Incidence higher and outcome worse with
anti-Class II DSA
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Differences Between Early and Late Antibody Mediated InjuryDifferences Between Early and Late Antibody Mediated Injury
• Early• First 6 weeks after transplant, rarely later• Incidence determined by DSA levels• C4d+• Microthrombi, some cells• Incidence higher with anti-Class I DSA
• Late• Rare early, increases over years• DSA levels usually low, C4d- common• A cellular infiltrate termed “peritubular”
capillaritis• Incidence higher and outcome worse with
anti-Class II DSA
• Early• First 6 weeks after transplant, rarely later• Incidence determined by DSA levels• C4d+• Microthrombi, some cells• Incidence higher with anti-Class I DSA
• Late• Rare early, increases over years• DSA levels usually low, C4d- common• A cellular infiltrate termed “peritubular”
capillaritis• Incidence higher and outcome worse with
anti-Class II DSA
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Desensitization???Desensitization???
There is no evidence that any current therapy “desensitizes”
patients—
i.e. blocks alloantibody production permanently
There is no evidence that any current therapy “desensitizes”
patients—
i.e. blocks alloantibody production permanently
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Desensitization???Desensitization???
Alternate Explanations
• Remove DSA by plasma exchange or block with IVIG—prevents hyperacute rejection
• Kidney absorbs the antibody after transplant—DSA reduced
• Memory response may or may not occur—early AMR
• Chronic injury is common, but not detected
Alternate Explanations
• Remove DSA by plasma exchange or block with IVIG—prevents hyperacute rejection
• Kidney absorbs the antibody after transplant—DSA reduced
• Memory response may or may not occur—early AMR
• Chronic injury is common, but not detected
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11oo Sensitization Sensitization
Naïve B Cell Plasmablast
T-helpercellAPC
Low-affinity AbsҮ
ү үү
ActivatedB Cell
Germinal Center ReactionGerminal Center Reaction
Ag
cytokines
ProliferationHypermutation
Affinity maturation
Memory CompartmentMemory CompartmentHigh-affinity Abs
Үү үү
MemoryB Cell
High-affinity AbsҮ
ү үү
Secondary Stimulation by Ag or CpG oligos,Bystander T cells
??
CD20+, CD27-CD138-, CD38-
CD20-, CD27-CD138-, CD38+
CD20-, CD27+-CD138-, CD38-
CD20-, CD27-CD138+, CD38+
Pathways to Antibody Production
Long-livedPC
PC?longevity
ү
Ag
Stegall et al Am J Transplant 2009; 9:998-1005.
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Plasma cellPlasma cell
• Only “B” Cells actually secreting antibody
• Short and long-lived
• Pre-existing PCs source of DSA in sensitized patients
• Newly-emerging PCs post-transplant (converted from naïve and memory B cells)
• Only “B” Cells actually secreting antibody
• Short and long-lived
• Pre-existing PCs source of DSA in sensitized patients
• Newly-emerging PCs post-transplant (converted from naïve and memory B cells)
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2. Positive Selection of CD 138+ cells
6 x 108
Mononuclear
cells
6 x 106
CD 138+ cells
1. Bone Marrow Aspiration in Sensitized Renal Allograft Candidate
ASCsCells in CD 138+ Fraction
25%
2%
8%
2%19%
44%
ASCs CD27+/20+ CD27+/20-
CD27-/20+ T cells Other
60 ml
Bone
Marrow
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PC ELISpot - Frequency of Tetanus and Allospecific PCs
PC ELISpot - Frequency of Tetanus and Allospecific PCs
Non-Sensitized
Tetanus Alloantibody
SensitizedSensitized Non-Sensitized
Perry et al Am J Transplant 2008; 8:133-143
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MethodsMethods
• Patients• Very high alloantibody levels• DSA that was deemed too high (BFXM > 450 or
MFI>10,000) for our current desensitization protocols.
• Monotherapy
• Endpoint: • Reduction in DSA-specific PC number• Reduction on DSA/response to Plasma exchange
• Patients• Very high alloantibody levels• DSA that was deemed too high (BFXM > 450 or
MFI>10,000) for our current desensitization protocols.
• Monotherapy
• Endpoint: • Reduction in DSA-specific PC number• Reduction on DSA/response to Plasma exchange
Transplantation 2011; 91:536-541
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Study Design.Study Design.
• Bone marrow Bortezomib Bone marrow
• Bortezomib therapy (1.3 mg / m2).
a) Phase 1 – 4 doses (n=4)
b) Phase 2 – 16 doses (n=5)
• Bone marrow Bortezomib Bone marrow
• Bortezomib therapy (1.3 mg / m2).
a) Phase 1 – 4 doses (n=4)
b) Phase 2 – 16 doses (n=5)
Transplantation 2011; 91:536-541
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Results - ELISPOTResults - ELISPOT
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Effect of Bortezomib on PCEffect of Bortezomib on PC
*One patient’s baseline marrow clotted and hence was excluded from analysis.*One patient’s baseline marrow clotted and hence was excluded from analysis.
Category (per ml marrow)
Baseline (Mean + SD)
Post Bortezomib (Mean + SD)
(n=8)
p value Paired T test
Allo spots (X 102) 16.7 + 14.5 6.2 + 3.6 0.048
TT spots (X 102) 25.2 + 15.7 13.2 + 8.1 0.032
Total Cells (X 106) 14.3 + 5.1 11.6 + 3.9 0.27
PC no (X 103) 21.5 + 8.6 15.5 + 12.1 0.21
Transplantation 2011; 91:536-541
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Effect Of PE.Effect Of PE.
0
100
200
300
400
500
600
700
Baseline Post PE Baseline Post PE
Bortezomib + PEPE only
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Effect of PEEffect of PE
Category Bortezomib + PE
(n=5) PE only
(n=8) p value
No of PE (Mean + SD) 11.4 + 2.7 11.6 + 3.9 0.9
Baseline – Post PE BFXM
(Mean + SD)272.6 + 92.1 95.4 + 72.2 0.008
% Change in BFXM CS (Mean + SD) 49.1 + 14.9 17.7 + 12.5 0.005
BFXM < 300 Post PE n (%) 3 (60) 0 (0) 0.035
Transplantation 2011; 91:536-541
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ConclusionsConclusions
• Proteasome inhibition depletes normal human plasma cells in vivo.
• Depletion is significant, but not complete -- ? increases safety and tolerability, but may limit effectiveness
• New PCs replace old ones quickly
• Proteasome inhibition depletes normal human plasma cells in vivo.
• Depletion is significant, but not complete -- ? increases safety and tolerability, but may limit effectiveness
• New PCs replace old ones quickly
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Conclusions: ClinicalConclusions: Clinical
• Improves efficacy of PE and increases the transplant rate in patients with extremely high levels of DSA
• Problems with bioavailability and irreversible binding
• May need more prolonged treatment or combine with other agents to increase efficacy
• Newer agents in development
• Improves efficacy of PE and increases the transplant rate in patients with extremely high levels of DSA
• Problems with bioavailability and irreversible binding
• May need more prolonged treatment or combine with other agents to increase efficacy
• Newer agents in development
Transplantation 2011; 91:536-541
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BortezomibBortezomib
• Weak impact with only 1-4 “cycles”
• Extend to 8 cycles now
• Weak impact with only 1-4 “cycles”
• Extend to 8 cycles now
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Prevention of Early Antibody Mediated Rejection
Prevention of Early Antibody Mediated Rejection
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Early Acute Antibody Mediated Rejection
Early Acute Antibody Mediated Rejection
• Common in +XMKTx (20-40%)
• Best correlated with DSA post-transplantation (BFXM >360, MFI >8000) ~ 90% incidence
• Baseline DSA also somewhat predictive
• Common in +XMKTx (20-40%)
• Best correlated with DSA post-transplantation (BFXM >360, MFI >8000) ~ 90% incidence
• Baseline DSA also somewhat predictive
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Associated with high DSA levels post-transplant
Early AMR: May cause early graft lossAssociated with shortened
graft survival
Expensive and increases morbidity
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Day 10
Day 28
Baseline Day 4 Day 10
Day 28
Baseline Day 4
Day 10
Day 28
Baseline Day 4Day 10
Day 28
Baseline Day 4
Low baseline DSA levels (B-FXM) without AHR
High baseline DSA levels (B-FXM) without AHR
Low baseline DSA levels (B-FXM) with AHR
High baseline DSA levels (B-FXM) with AHR
Burns et al Am J Transplant 2008; 8:2684-2694
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Early AMR (Burns et al)Early AMR (Burns et al)
• Time to rejection 11.3+5.9 d (range 4-21)
• All except 1 C4d+ peritubular capillaries at time of diagnosis
• 6 C4d+/-AHR 3 progressed to AHR
• Time to rejection 11.3+5.9 d (range 4-21)
• All except 1 C4d+ peritubular capillaries at time of diagnosis
• 6 C4d+/-AHR 3 progressed to AHR
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MCR: Actual 5 Year Outcomes after +XMKTx
MCR: Actual 5 Year Outcomes after +XMKTx
• All +XMKTx 2000-2006 (n= 154)• Retrospective LABscreen DSA (beads)
• 52 excluded• 8 lost to f/u• 11 no serum for DSA testing• 12 CDC+ prefailed desensitization • 16 no DSA (+XM)• 5 MFI <1000
• 102 included in the study & compared to 204 –XMKTx matched by age/gender
• All +XMKTx 2000-2006 (n= 154)• Retrospective LABscreen DSA (beads)
• 52 excluded• 8 lost to f/u• 11 no serum for DSA testing• 12 CDC+ prefailed desensitization • 16 no DSA (+XM)• 5 MFI <1000
• 102 included in the study & compared to 204 –XMKTx matched by age/gender
100% 5 yr graft survival
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DSA Specificity(MFI >1000)
DSA Specificity(MFI >1000)
Specificity n CDC+ MFI-I II__
• Class I alone 36 55.6% 9545 0
• Class I and II 20 45.7% 8849 7711
• Class II alone 46 0% 0 8922
Specificity n CDC+ MFI-I II__
• Class I alone 36 55.6% 9545 0
• Class I and II 20 45.7% 8849 7711
• Class II alone 46 0% 0 8922
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DSA Specificity(MFI >1000)
DSA Specificity(MFI >1000)
Specificity n CDC+ MFI-I II__
• Class I alone 36 55.6% 9545 0
• Class I and II 20 45.7% 8849 7711
• Class II alone 46 0% 0 8922
Specificity n CDC+ MFI-I II__
• Class I alone 36 55.6% 9545 0
• Class I and II 20 45.7% 8849 7711
• Class II alone 46 0% 0 8922
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DSA Specificity(MFI >1000)
DSA Specificity(MFI >1000)
Specificity n CDC+ MFI-I II__
• Class I alone 36 55.6% 9545 0
• Class I and II 20 45.7% 8849 7711
• Class II alone 46 0% 0 8922
Specificity n CDC+ MFI-I II__
• Class I alone 36 55.6% 9545 0
• Class I and II 20 45.7% 8849 7711
• Class II alone 46 0% 0 8922
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Rates of Early AMR and DSA Type
Rates of Early AMR and DSA Type
• Anti-Class I only 38.9%
• Anti-Class I and II 45.7%
• Anti-Class II only 15%
• Anti-Class I only 38.9%
• Anti-Class I and II 45.7%
• Anti-Class II only 15%
Explains why the T cell AHG crossmatch has worked well
historicallyProblem with Class II is late
injury
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Prevention vs Treatment?Prevention vs Treatment?
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Acute Humoral RejectionAcute Humoral Rejection
• Plasmapheresis
• IVIG• Lefaucheur C, Nochy D, Andrade J, et al. Comparison of combination
plasmapheresis/IVIg/anti-CD20 versus high-dose IVIg in the treatment of antibody-mediated rejection. Am J Transplant. 2009;9:1099-1107.
• Splenectomy
• Rituximab
• Bortezomib (proteasome inhibitor)
• Eculizumab (C-5 inhibitor)
• Plasmapheresis
• IVIG• Lefaucheur C, Nochy D, Andrade J, et al. Comparison of combination
plasmapheresis/IVIg/anti-CD20 versus high-dose IVIg in the treatment of antibody-mediated rejection. Am J Transplant. 2009;9:1099-1107.
• Splenectomy
• Rituximab
• Bortezomib (proteasome inhibitor)
• Eculizumab (C-5 inhibitor)
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HypothesisHypothesis
• Almost all cases of AMR show evidence of complement activation—C4d+ peritubular capillaries
• Inhibition of terminal complement activation with anti-C5 antibody (eculizumab) will prevent AMR in +XM Kidney Transplantation
• Almost all cases of AMR show evidence of complement activation—C4d+ peritubular capillaries
• Inhibition of terminal complement activation with anti-C5 antibody (eculizumab) will prevent AMR in +XM Kidney Transplantation
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Classical PathwayAntigen/Antibody Complexes
Lectin PathwayCarbohydrate Structures
Alternative PathwayM/O and Mammalian
Cell Membranes
Activated C1
C3
C3a
C4b2a
C3 Convertase
C3bBb
C3b C5
C3bBb3b
C4b2a3b
C5b-9
C6 C7 C8 C9
Weak Anaphylatoxin
Immune Complex Microbial Opsonization
C5 Convertase
C5 ConvertaseC3 Convertase
Potent AnaphylatoxinChemotaxis
Cell Activation
C3H20Tickover
Cell ActivationNeisseria Clearance
RBC Lysis
The Complement Cascade: Targeted InhibitionThe Complement Cascade: Targeted InhibitionThe Complement Cascade: Targeted InhibitionThe Complement Cascade: Targeted Inhibition
Activated MBL
C4+C2
Factor B+D
C3b
C5a
C5bXX
EculizumabTarget
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Am J Tx (2011) 11:2405-13
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Pretransplant Management Same in Both Groups
Pretransplant Management Same in Both Groups
<300
• No PE
• Monitor DSA post-transplant
<300
• No PE
• Monitor DSA post-transplant
>300
• Pretransplant PE to achieve T and B FXM <300
>300
• Pretransplant PE to achieve T and B FXM <300
Baseline T/B FXM
Thymoglobulin induction, Prograf, Mycophenolate mofetil, Prednisone
Am J Tx (2011) 11:2405-13
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1o Endpoint1o Endpoint
• Incidence of AMR in first 90 days post-transplant• Thrombotic microangiopathy• Graft dysfunction (↑>0.3 mg/dl)
• Protocol biopsies at day 0, 4, 7, 10, 14, 21, 28
• Serum for SABs and T/B FXM
• Incidence of AMR in first 90 days post-transplant• Thrombotic microangiopathy• Graft dysfunction (↑>0.3 mg/dl)
• Protocol biopsies at day 0, 4, 7, 10, 14, 21, 28
• Serum for SABs and T/B FXM
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Study DesignStudy Design
Historical Controls
N=51
• 1/1/05—10/1/07
• PE-based “desensitization”
• Consecutive Patients
Historical Controls
N=51
• 1/1/05—10/1/07
• PE-based “desensitization”
• Consecutive Patients
Anti-C5 Treated
N=26
6/1/08—09/27/10
• Added to existing PE-based protocol
Anti-C5 Treated
N=26
6/1/08—09/27/10
• Added to existing PE-based protocol
BFXM 200450MFI 3000-12,000+
1 patient in each group had BFXM <450, but failed to reach <300 with PE
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PatientsPatientsCategory
Eculizumab Group (n=26)
Control Group (n=51) p value
Female Sex 21 (81%) 40 (78%) 1.00
Age in years at time of transplantation(Mean + SD)
48.6 + 12.5 48.4 + 11.4 0.94
Ethnicity *
Caucasian White 24 (92%) 44 (86%) 0.85Hispanic 2 (7.7%) 5 (9.8%)
Black 0 (0%) 2 (3.9%)Cause of Renal Failure
Diabetes 1 (7.7%) 9 (18%) 0.52Polycystic disease 4 (15%) 7 (14%)Glomerulonephritis 4 (15%) 7 (14%)
Hypertension 3 (12%) 2 (3.9%)Other 11 (42%) 20 (39%)
Unknown 3 (12%) 6 (12%)Prior Kidney Transplant 13 (50%) 13 (25%) 0.043
Donor-Specific Alloantibody Levels
B flow crossmatch Baseline channel shift (mean + SD)
330 + 84 327 + 73 0.85
Anti-Donor HLA Single Antigen Bead Assay
Baseline mean fluorescence index (mean + SD)7188 + 3503 6473 + 4946 0.51
Antidonor Antibody Specificity Anti-Class 1 only 10 (38%) 30 (59%) 0.10 Anti-Class 2 only 7 (27%) 13 (25%) 1.00
Anti-Class 1 19 (73%) 38 (75%) 1.0Anti-Class 2 16 (62%) 21 (41%) 0.10
Both Anti-Class 1 and 2 9 (35%) 8 (16%) 0.082Pretransplant Plasma Exchange**
Number of patients receiving 18 (69%) 35 (69%) 1.00Number of PEs (mean + SD) 4.0 + 3.6 3.7 + 3.4 0.76
[WKK1]Is space does not allow keeping of both “anti-class xonly” and “andi-class x” I would keep “andi-class x” and drop “andi-class x only”. “andi-class x” better shows that the Eculizumab group has same or higher ab levels.
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ResultsResults
CategoryEculizumab
Group (n=26)
Control Group (n=51)
p value
Follow-up (mean months + SD, range)
11.9 + 6.1(3.0 – 27.5)
48.8 + 14.1(7.8 – 69.8)
Graft Survival at 1 year (n, %) 16/16 (100%) 49/51 (97%) 1.00
Antibody mediated rejection< 3months (n, %)
2 (7.7%) 21 (41%) 0.0031
Patients developing High DSA Levels < 3 months * 13 (50%) 22 (43%) 0.63
High DSA Biopsies C4d+ (n, %) 13 (100%) 20 (90.9%) 0.52
High DSA and C4d+ biopsies Showing AMR (n, %)
2 (15%) 20 (100%) <0.0001
Cellular Rejection <3 months (n, %) 1 (6.2%) 1 (2.0%) 0.42
[WKK1]Please include the graft loss data in the dataset.
Am J Tx (2011) 11:2405-13
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JASN 2010; 21:1398-1406JASN 2010; 21:1398-1406
AMR % with MFI3001-6000 = 36.4%
>6000 = 51.3%
AMR (n=2) No AMR (n=24)BFXM MFI BFXM MFI
250 7705 >200
371 1133 N=2 <3000
N=7 >3000
N=9 >6000
N=6 >10,000
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Day 10
Day 28
Baseline Day 4 Day 10
Day 28
Baseline Day 4
Day 10
Day 28
Baseline Day 4Day 10
Day 28
Baseline Day 4
Low baseline DSA levels (B-FXM) without AHR
High baseline DSA levels (B-FXM) without AHR
Low baseline DSA levels (B-FXM) with AHR
High baseline DSA levels (B-FXM) with AHR
Burns et al Am J Transplant 2008; 8:2684-2694
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ResultsResults
CategoryEculizumab
Group (n=26)
Control Group (n=51)
p value
Follow-up (mean months + SD, range)
11.9 + 6.1(3.0 – 27.5)
48.8 + 14.1(7.8 – 69.8)
Graft Survival at 1 year (n, %) 16/16 (100%) 49/51 (97%) 1.00
Antibody mediated rejection< 3months (n, %)
2 (7.7%) 21 (41%) 0.0031
Patients developing High DSA Levels < 3 months * 13 (50%) 22 (43%) 0.63
High DSA Biopsies C4d+ (n, %) 13 (100%) 20 (90.9%) 0.52
High DSA and C4d+ biopsies Showing AMR (n, %)
2 (15%) 20 (100%) <0.0001
Cellular Rejection <3 months (n, %) 1 (6.2%) 1 (2.0%) 0.42
Am J Tx (2011) 11:2405-13
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Control BFXM 550 =AMR
Eculizumab BFXM 604 =Nl
N=22 (43%)All AMR
N=13 (50%)2 AMR
Histology with High DSA post-TXBFXM >359 post-transplant
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Case: Early AMR with EculizumabCase: Early AMR with Eculizumab
• Elevated creatinine on POD #7 and 14
• Increased DSA
• Biopsy—thrombotic microangiopathy
• Eculizumab level therapeutic with no hemolytic activity
• Both treated with PE, resolved
• Cause unclear?
• Elevated creatinine on POD #7 and 14
• Increased DSA
• Biopsy—thrombotic microangiopathy
• Eculizumab level therapeutic with no hemolytic activity
• Both treated with PE, resolved
• Cause unclear?
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AMR and DSA IgMAMR High Response DSA IgM
Low DSA IgG
0
1000
2000
3000
4000
5000
6000
0 7 14 28
Days after transplantation
B8_IgG
B8_IgM
Day 7 - AMR
AMR High response of DSA IgM
0
2000
4000
6000
8000
10000
12000
14000
16000
0 7 14 27
Days after transplant
MF
I
A3_IgG
A23_IgG
B18_IgG
DR7_IgG
DR15_IgG
DR51_IgG
DR53_IgG
A3_IgM
A23_IgM
B18_IgM
DR7_IgM
DR53_IgM
Day 14 - AMR
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No DSA IgMHigh DSA IgGNo AMR or TG
No DSA IgMHigh DSA IgGNo AMR or TG
High response of DSA IgG. No AMR and No DSA IgM response
0
2000
4000
6000
8000
10000
12000
14000
16000
0 7 14 28
Days from transplant
MF
I
DQ4_IgG
DR15_IgG
DR4_IgG
DR51_IgG
DR53_IgG
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Plasma Exchange: Post Transplant
Plasma Exchange: Post Transplant
• Control group• BFXM >300 at baseline, 7 d PE
per protocol• Any AMR
• Eculizumab group• 1 patient per protocol early• 21 patients no PE per protocol• 2 patient with AMR
• Control group• BFXM >300 at baseline, 7 d PE
per protocol• Any AMR
• Eculizumab group• 1 patient per protocol early• 21 patients no PE per protocol• 2 patient with AMR
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CategoryEculizumab
(n=26)ControlGroup (n=51)
p value
Post-Transplant PE 3 (12.5%)
39 (76.5%)
<0.0001
Splenectomy in patients with AMR
0 9 (17.7%) 0.025
Graft DysfunctionΔ Cr (mg/dl)=Maximum - Nadir
in first month
0.45 + 0.37 0.93 + 1.15 0.0087
Other Outcomes: Morbidity
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ComplicationsComplications
• All patients receive pretransplant meningococcal vaccine
• No treatment related infections
• All patients receive pretransplant meningococcal vaccine
• No treatment related infections
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DSA Levels after TransplantDSA Levels after Transplant
• Levels change
• Specificities change
• Causes complex• Absorption by the allograft• Memory B cell response• Anti-idiotypic “blocking” Abs
• Levels change
• Specificities change
• Causes complex• Absorption by the allograft• Memory B cell response• Anti-idiotypic “blocking” Abs
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0
2000
4000
6000
8000
10000
12000
14000
16000
B35
B7
0
2000
4000
6000
8000
10000
12000
14000
16000
A30
DQ4
0
2000
4000
6000
8000
10000
12000
14000
16000
A24a
DR1a
0
2000
4000
6000
8000
10000
12000
14000
16000
A24a
B39a
DQ7a
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Late Results?Late Results?
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Stopping EculizumabGoal BFXM <200
Stopping EculizumabGoal BFXM <200
• No AMR after stopping eculizumab
• 4 weeks: 8 patients stopped
• 9 weeks: 6 stopped
• >9 weeks: 2 continued• 2 stopped at 1 year
• No AMR after stopping eculizumab
• 4 weeks: 8 patients stopped
• 9 weeks: 6 stopped
• >9 weeks: 2 continued• 2 stopped at 1 year
Am J Tx (2011) 11:2405-13
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Evidence of CHR in C5 inhibitor-treated patients?
Evidence of CHR in C5 inhibitor-treated patients?
Caveat: Trial not designed to test prevention of chronic humoral rejection
Different post-transplant treatments (some received only 1 month C5 inhibitor, most had no post-transplant plasma exchange)
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Eculizumab vs Historical Control 3 yr Death Censored Graft SurvivalEculizumab vs Historical Control
3 yr Death Censored Graft Survival
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Chronic Injury: Transplant Glomerulopathy
Chronic Injury: Transplant Glomerulopathy
This is the lesion of chronic AMR
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Late Events: Chronic Injury, Graft Loss and
Death
Late Events: Chronic Injury, Graft Loss and
DeathTransplant Glomerulopathy at 12 months
• Eculizumab 6.7% (1/15)
• Historical Controls 36% (15/42)
P=0.044
Graft loss and Death
• 2 graft losses at 2 years due to TG in eculizumab group
• 1 death due to Burkitt’s lymphoma at 2.5 years
Transplant Glomerulopathy at 12 months
• Eculizumab 6.7% (1/15)
• Historical Controls 36% (15/42)
P=0.044
Graft loss and Death
• 2 graft losses at 2 years due to TG in eculizumab group
• 1 death due to Burkitt’s lymphoma at 2.5 years
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Continuous EculizumabContinuous Eculizumab
Pt Eculiz Rx
weeks
AMR 3 mos
cg/ci
6 mos
cg/ci
1 yr
cg/ci
Cr* BFXM*
#9 52 No 1/1 1/1 1/2 3.1 121
0
2000
4000
6000
8000
10000
12000
14000
16000
DQ4a
DR15a
DR4a
DR51
DR53a
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BJ
0
2000
4000
6000
8000
10000
12000
B44
DR52a
A2
DQ6a
DR13a
BFXM - BJ
0
100
200
300
400
500
600
700
Single Antigen Beads MFI/DSA
B Flow Cytometric Crossmatch
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Conclusions: Terminal complement blockade
with eculizumab
Conclusions: Terminal complement blockade
with eculizumab
• Decreases the incidence of early AMR
• Prevents AMR and graft dysfunction with higher DSA levels post-transplant
• Decreases need for PE and splenectomy
• Decreased TG at 1 year?
• Chronic changes may require additional therapy
• Decreases the incidence of early AMR
• Prevents AMR and graft dysfunction with higher DSA levels post-transplant
• Decreases need for PE and splenectomy
• Decreased TG at 1 year?
• Chronic changes may require additional therapy
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Multicenter TrialMulticenter Trial
• 80 patients (1:1 randomization)
• Eculizumab vs Standard of Care (PE or IVIG)
• Central HLA Lab for entry criteria (BFXM >300) + DSA by flowbeads
• 1o Endpoint = AMR in first 90 d
• Eculizumab rescue for “refractory” rejection in standard of care arm
• 80 patients (1:1 randomization)
• Eculizumab vs Standard of Care (PE or IVIG)
• Central HLA Lab for entry criteria (BFXM >300) + DSA by flowbeads
• 1o Endpoint = AMR in first 90 d
• Eculizumab rescue for “refractory” rejection in standard of care arm
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Future StudiesFuture Studies
• Role of IgM in early AMR in eculizumab-treated patients?
• Role of more prolonged eculizumab therapy?
• Role of bortezomib vs eculizumab to treat new-onset AMR in patients not receiving eculizumab?
• Role of IgM in early AMR in eculizumab-treated patients?
• Role of more prolonged eculizumab therapy?
• Role of bortezomib vs eculizumab to treat new-onset AMR in patients not receiving eculizumab?
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Thank YouThank You
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Actual Death-Censored5 Year Graft Survival
Actual Death-Censored5 Year Graft Survival
70.7% vs 88.0%, p= 0.0006
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Actual 5 Year Outcomes After +XMKTx
Actual 5 Year Outcomes After +XMKTx
Rate of graft loss after 1 yearClass I only 1.6%/yr
Class II 7.0%/yr
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Histology at 5 Years*1/3 of grafts already lost
Histology at 5 Years*1/3 of grafts already lost
1 yr 5 yr
cg ptctis cg ptctis
-XM 3.5 7.7 9 7.8
+XM
I 8.4 20.9 50.0 47.%
I/II 37.8 44.4 58.3 63.7%
*75-80% capture rate