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
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
Actual Death-Censored5 Year Graft Survival
Actual Death-Censored5 Year Graft Survival
70.7% vs 88.0%, p= 0.0006
Actual 5 Year Graft SurvivalActual 5 Year Graft Survival
T cell AHG
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
What this talk is not aboutWhat this talk is not about
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
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
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
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
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
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
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
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
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.
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)
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
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
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
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
Results - ELISPOTResults - ELISPOT
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
Effect Of PE.Effect Of PE.
0
100
200
300
400
500
600
700
Baseline Post PE Baseline Post PE
Bortezomib + PEPE only
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
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
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
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
Prevention of Early Antibody Mediated Rejection
Prevention of Early Antibody Mediated Rejection
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
Associated with high DSA levels post-transplant
Early AMR: May cause early graft lossAssociated with shortened
graft survival
Expensive and increases morbidity
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
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
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
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
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
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
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
Prevention vs Treatment?Prevention vs Treatment?
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)
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
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
Am J Tx (2011) 11:2405-13
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
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
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
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.
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
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
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
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
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
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?
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
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
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
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
ComplicationsComplications
• All patients receive pretransplant meningococcal vaccine
• No treatment related infections
• All patients receive pretransplant meningococcal vaccine
• No treatment related infections
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
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
Late Results?Late Results?
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
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)
Eculizumab vs Historical Control 3 yr Death Censored Graft SurvivalEculizumab vs Historical Control
3 yr Death Censored Graft Survival
Chronic Injury: Transplant Glomerulopathy
Chronic Injury: Transplant Glomerulopathy
This is the lesion of chronic AMR
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
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
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
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
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
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?
Thank YouThank You
Actual Death-Censored5 Year Graft Survival
Actual Death-Censored5 Year Graft Survival
70.7% vs 88.0%, p= 0.0006
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
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