Monitoring HLA- specific antibodies Matthew J. Everly, PharmD, BCPS One Lambda Inc. In patients...
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Transcript of Monitoring HLA- specific antibodies Matthew J. Everly, PharmD, BCPS One Lambda Inc. In patients...
Monitoring HLA-specific antibodies
Matthew J. Everly, PharmD, BCPSOne Lambda Inc.
In patients undergoing desensitization
Monitoring HLA-specific antibodies
Matthew J. Everly, PharmD, BCPSOne Lambda Inc.
In all transplant patients
In all transplant patients
Preformed anti-HLA DSA+ Patient
Screening De Novo anti-HLA DSA
Monitoring Removal of anti-HLA DSA
What we know about donor specific anti-HLA antibodies …
in transplant patients
Donor Specific
Anti-HLA Antibodies
allograft rejection
allograft failure=
What we do not know …
How to monitor anti-HLA DSA?
How to treat anti-HLA DSA?
Transplant PatientDSA + at Transplant DSA - at Transplant
DSA + at Transplant“Preformed DSA”
DSA - at Transplant
≥35% Acute Antibody Mediated Rejection
Dunn et al. Am J Transplant 2011;11:2132
Up to 15% 1- year Graft Failure Rate (non-desensitized)
Lefacheur et al. Am J Transplant 2008;8:324
DSA + at Transplant“Preformed DSA”
DSA - at Transplant
<5% Acute Antibody Mediated Rejection
Dunn et al. Am J Transplant 2011;11:2132
De novo anti-HLA DSA in the first yearAnd beyond
Everly et al. Am J Transplant 2012; In submissionSmith et al. Am J Transplant 2011;11:312
Preformed DSA PatientAnti-HLA
Major concern with preformed anti-HLA DSA is the associated AMR Risk
Pre
form
ed D
SA
Pat
ient
Amico et al. Transplantation 2009;87:1681
DSA+ at Transplant with AMR (n=37)
Pre
form
ed D
SA
Pat
ient
Lefaucheur et al. Am J Transplant 2008;8:324
DSA+ AMR+, n=21
DSA + (no AMR), n=22
DSA – (at transplant)
n=194
DSA Associated AMR riskis not uniform over the post-transplant period
Gloor et al. Am J Transplant 2010;10:582
119
Positive Crossmatch
Pre
form
ed D
SA
Pat
ient
Pre
form
ed D
SA
Pat
ient
DSA+ high MFISum >10,000 MFI (n=66)
DSA+ low MFI Sum 5,000-10,000 (n=16)
DSA- (n=12)
Gloor et al. Am J Transplant 2010;10:582
DSA+ low MFI Sum 0 - 5,000 MFI (n=23)
Amico et al. Transplantation 2009;87:1681
334 Negative CDC Crossmatch
67 (20%)Anti-HLA DSA +Pre-Transplant
Aims:
What is the clinical relevance of preformed DSA?
What anti-HLA DSA characteristics are predictive of DSA?
Pre
form
ed D
SA
Pati
ent
Pre
form
ed D
SA
Pati
ent
Amico et al. Transplantation 2009;87:1681
Lefaucheur et al. Am J Transplant 2008;8:324
237Negative T- & B-CellCDC Crossmatch
194 (82%)Anti-HLA DSA -Pre-Transplant
43 (18%)Anti-HLA DSA +Pre-Transplant
Pre
form
ed D
SA
Pati
ent
Pre
form
ed D
SA
Pat
ient
DSA+ high MFI
DSA+ low MFI
DSA-
Lefaucheur et al. Am J Transplant 2008;8:324
13/21 (62%) of AMR in first 45 days post-transplant
Dunn et al. Am J Transplant 2011;11:2132
587 patients CDC XM- with single antigen bead
testing at transplant
Pre
form
ed D
SA
Pati
ent
Pre
form
ed D
SA
Pati
ent
DSA+ high MFI
DSA+ low MFI
DSA-
Dunn et al. Am J Transplant 2011;11:2132
DSA+
3rd party HLA+ or Neg.
Pre
form
ed D
SA
Pat
ient
Gloor et al. (n=49) Lefaucheur et al. (n=21) Dunn et al. (n=46)
7.5 days
16.5 days
16days
Median Time to Acute Antibody Mediated Rejection
Can monitoring identify the preformed anti-HLA DSA patients at
risk of AMR ?
Burns et al. Am J Transplant 2008;10:2684
70Positive Crossmatch
Pre
form
ed D
SA
Pat
ient
41High anti-HLA DSA
(Flow Channel Shift >300)
29Low anti-HLA DSA
(Flow Channel Shift <300)
Pre
form
ed D
SA
Pat
ient
Low DSA, NO AMR
High DSA, NO AMR
Low DSA, AMR+
High DSA, AMR+
Burns et al. Am J Transplant 2008;8:2684
116 Flow Negative Crossmatch, but DSA Positive
Pre
form
ed D
SA
Pati
ent
Clinical Transplants 2011. In Press
Pre
form
ed D
SA
Pati
ent
Possible DSA Monitoring Time Points
Pre-Transplant, Day of Transplant
1 week
2 weeks
4 weeks
8 weeks
Pre
form
ed D
SA
Pat
ient
DSA+ high MFI
DSA+ low MFI
DSA-
Gloor et al. Am J Transplant 2010;10:582
DSA+ high MFISum >10,000 MFI (n=66)
DSA+ low MFI Sum 5,000-10,000 (n=16)
DSA- (n=12)
DSA+ low MFI Sum 0 - 5,000 MFI (n=23)
?
Transplant Glomerulopathy Risk
47% of XM+ AMR+ Patients
41% of XM+ AMR- Patients
Gloor et al. Am J Transplant 2010;10:582
Pre
form
ed D
SA
Pat
ient
Kidney Int 2011;10:582
69 patients Flow Positive Crossmatch
33Group 1
Convert to Flow XM -
15Group 2
Remain Flow XM +
11 excluded no DSA, or not clear group
Pre
form
ed D
SA
Pat
ient
Group 1 Group 2
Group 2
Group 1
Kimball et al. Kidney Int 2011;10:582
Pre
form
ed D
SA
Pat
ient Monitoring Time Points
Pre-Transplant, Day of Transplant
1 week
2 weeks
4 weeks
8 weeks
6 months
12 months
After 12 months ?
* If patient’s DSA remain persistently positive – treatment may be useful to improve outcomes.
Wit
h f
or
cause
bio
psy
Rationale to monitor DSA
Preformed DSA
Identify a patient
1. at risk of AMR2. at risk of Chronic Antibody
Damage3. who should receive treatment
for Antibodies
Pre-Transplant DSA - Patient
Screening for De Novo DSA
Early Acute Antibody Mediated Rejection
Preformed DSA De Novo DSA
<5%>35%
DSA+ high MFI
DSA+ low MFI
DSA-
Scr
eeni
ng fo
r D
e N
ovo
DS
A
Gill et al. Transplantation 2010;89:178
Rationale to monitor DSA
De Novo DSA
Identify a patient
1. at risk of AMR2. at risk of Chronic Antibody
Damage3. who should receive treatment
for Antibodies
Everly et al. Am J Transplant. 2012; In SubmissionRebellato et al. Clinical Transplants 2011; In Press
East Carolina University (Rebellato et al.)
DSA +De N
ovo
An
ti-H
LA6227%
Everly et al. Am J Transplant. 2012; In SubmissionRebellato et al. Clinical Transplants 2011; In Press
0.000.100.200.300.400.500.600.700.800.901.00
0 1 2 3 4 5 6 7 8 9 10 11 12
Year Post-transplant
10%3-4%
De
Nov
o D
SA
Inci
denc
e
Everly et al. Presented at American Transplant Congress 2011, PhiladelphiaEverly et al. Am J Transplant 2012. In Submission
patients transplanted between 1995-2004 who had survived more than one year243
19224patients excludedDSA positive at the time of transplant
51173HLA Abs
patients with no HLA Abs
11756de novo DSA (25%)
NDSA (52%)NDSA= non donor-specific antibody
Smith J et al. Am J Transplant. 2011;11:312-9
When do HEART TRANSPLANT
patients develop de-novo DSA?
05
1015202530354045
1 2 3 4 5 6 7 8 9 10 11
% D
SA
+v
e p
ati
en
ts
Year of DSA appearance
22
6 63 1
51
72%
N=57
13
Smith J et al. Am J Transplant. 2011;11:312-9
0
10
20
30
40
50
60
70
80
90
100
Per
cent
Allo
graf
t Sur
viva
l
0 12 24 36 48 60
Months after DSA Appearance
De novo anti-HLA DSA Positive (n=62)
15%
28%
42%
Everly et al. Am J Transplant 2012. In Submission
0.000.100.200.300.400.500.600.700.800.901.00
0 1 2 3 4 5Year from DSA to CAV or Graft Loss (GL)
What is the risk for heart failure after de novo anti-HLA DSA appears?
24%
37%
20%probability
of failure
n=51
Pro
port
ion
Su
rviv
ing
5 patients develop DSA after CAV:4 CII Abs, 1 both classes of Abs
Smith J et al. Am J Transplant. 2011;11:312-9
Rationale to monitor DSA
De Novo DSA
Identify a patient
1. at risk of AMR2. at risk of Chronic Antibody
Damage3. who should receive treatment
for Antibodies
Scr
eeni
ng fo
r D
e N
ovo
DS
A
Monitoring Time Points
Pre-Transplant
1 week
2 weeks
4 weeks
8 weeks
6 months
12 months
Biannually after 1 year
Wit
h f
or
cause
bio
psy
Removing DSAIn Acute Antibody Mediated Rejection
Reduction of Donor Specific Antibody Levels Prevents Renal Allograft Loss
p = 0.043 (Log-Rank)
Statistically significant at the α = 0.05 level
Time from Transplantation (Months)
0 6 12 18 24 30 36 42 48 54 60 66 72
Por
por
tion
of A
llogr
afts
Su
rviv
ing
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0DSA Reduction > 50%(N = 6; NO Allografts Lost)
DSA Reduction < 50%(N = 10; 7 Allografts Lost)
University of Cincinnati, Cincinnati, OHEverly et al. Am J Transplant 2009;9:1-9
Log Rank p=0.021
Antibody Reduction Responders (n=7, NO Allograft Loss)
Antibody Reduction Non-Responders(n=23, 12 Allografts Lost)
Log-rank p=0.033
0
10
20
30
40
50
60
70
80
90
100
Pe
rce
nt
All
og
raft
Su
rviv
al
0 12 24 36 48 60 72 84 96
Months after Transplantation
Brody Medical School at Eastern Carolina University, Greenville, NCEverly, et al. Transplantation.
Lefaucheur et al. Am J Transplant 2009;9:1099
Despite Histologic Improvements …
Antibody removal after AMR improves outcomes
Removing DSAIn patients with preformed DSA
Impact of proteasome inhibitor on anti-donor HLA antibody production after kidney transplantation
Mayo Clinic Trial – Mark Stegall M.D.
Rem
ovin
g D
SA
2 cycles of bortezomib … wait 2 months … possible 2 more cycles of bortezomib
Rem
ovin
g D
SA
Kimball et al. Clinical Transplants 2011; In press
IVIg + plasmapheresis 3 times per weekFor 2 weeks
Rem
ovin
g D
SA
Kimball et al. Clinical Transplants 2011; In press
In the patient with persistent preformed anti-HLA DSA positive …
Antibody removal may improve outcomes
Removing DSAIn patients with stable allograft function
Hachem et al. J Heart Lung Transplant 2010;29:973
Rem
ovin
g D
SA
61 lung transplant patients Serial single antigen bead
testing after transplant
61
All DSA positive
All preemtive treatment
IVIg for at least 6 months(+/- Rituximab)
Patients in 2011
Hachem et al. J Heart Lung Transplant 2010;29:973
Rem
ovin
g D
SA
Everly et al. Transplantation 2012; In Press.
Rem
ovin
g D
SA
26
All DSA positive
All preemtive treatment
All with no dysfunction at DSA appearance
Patients in 2011
26 DSA Class II Alone
50% (n=13)
DSA Class I Alone
23% (n=6)
Both DSA Classes
27% (n=7)
- 65% of patients had ONLY a single DSA positive at the time of treatment
- 39% of class II were DQ DSA
Male Gender 24 (92)
Age at Transplant 29.3 ± 9
# of HLA mismatch 2.9 ± 1.4
Bortezomib on days 1, 4, 8, 11 Plasmapheresis (n=14) on same days with bortezomib
Rituximab (n=9) single doseCorticosteroid pulse – (all patients)
Bortezomib Alone(n=11)
Txp DSA(MFI > 1000)
85 days (median time to DSA – range from 6 - 536)
SCr - 1.17 ± 0.22 SCr - 1.26 ± 0.27
Reduction of DSAmax MFI by at least 50%
26 Patients
24 – Greater than 50% reduction in DSAmax MFI
2 – Less than 50% reduction in DSAmax MFI
Median time to 50% reduction 37 days
Rem
ovin
g D
SA
Remission (n=8)
Relapsed (n=10)
Partial/No Response (n=8)(only a 50% reduction)
MedianSerum Creatinine Change from Start of
Treatment to last follow-up
6.5% Scr Increase
41% Scr Increase
46% Scr Increase
In the patient with persistent de novo anti-HLA DSA …
Antibody removal may improve outcomes
Removing DSA
Improves Outcomes
Problem with Treating anti-HLA DSA
RemissionRefractory
Relapse
Rem
ovin
g D
SA
“ A rapid partial response (50% reduction of DSAmax with 1 month of treatment was associated with a complete response”
DSA-
Whe
n R
emov
ing
DS
A
Post-Treatment Monitoring Time Points
Prior to start of treatment
1 month(possibly 2 months if not using plasmspheresis)
Refr
act
ory
Rem
issi
on
Continued monitoring if
continued treatment
At 3 & 6 months then every 6
months
Relapse ?
Summary
Nearly All transplant patients can benefit for some degree of monitoring …
Pre
form
ed D
SA
Pati
ent
Amico et al. Transplantation 2009;87:1681
AMR Appears Early
Pre
form
ed D
SA
Pat
ient
Burns et al. Am J Transplant 2008;8:2684
Monitoring Early Identifies those AT RISK of AMR
Pre
form
ed D
SA
Pat
ient
Group 1 Group 2
Group 2
Group 1
Kimball et al. Kidney Int 2011;10:582
Monitoring Late Identifies those AT RISK of Failure
Pre
form
ed D
SA
Pat
ient
Monitoring Time Points
Pre-Transplant
1 week
2 weeks
4 weeks
8 weeks
6 months
12 months
After 12 months, annually
Wit
h f
or
cause
bio
psy
Everly et al. Presented at American Transplant Congress 2011, PhiladelphiaEverly et al. Am J Transplant 2012. In Submission
De novo anti-HLA DSA appears at
any time post transplant & Identifies those AT RISK of Failure
Scr
eeni
ng fo
r D
e N
ovo
DS
A
DSA-
Scr
eeni
ng fo
r D
e N
ovo
DS
A
Monitoring Time Points
Pre-Transplant
6 months
12 months
Annually after 1 year Wit
h f
or
cause
bio
psy
RemovingDSA
Improves Outcomes
DSA Relapse
DSA Relapse
DSA-
Whe
n R
emov
ing
DS
A
Post-Treatment Monitoring Time Points
Prior to start of treatment
1 month(possibly 2 months if not using plasmspheresis)
Refr
act
ory
Rem
issi
on
Continued monitoring if
continued treatment
At 3 & 6 months then every 6
months
Relapse ?
Thank You