disclosure information: mark d. stegall, m.d. i have the following financial relationship to...

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


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


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

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)


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


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


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


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

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



70.7% vs 88.0%, p= 0.0006



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

disclosure information: mark d. stegall, m.d. i have the following financial relationship to...

Documents

dsa slide

antibody mediated rejection

dsa late rare early

transplantation slide

yr slide

years dsa levels

velcade slide

followup slide