Matthew J Everly PharmD BCPS One Lambda Inc In patients undergoing desensitization Monitoring HLAspecific antibodies Matthew J Everly PharmD BCPS One Lambda Inc In all transplant patients ID: 425588
Download Presentation The PPT/PDF document "Monitoring HLA-specific antibodies" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Monitoring HLA-specific antibodies
Matthew J. Everly, PharmD, BCPSOne Lambda Inc.
In patients undergoing desensitizationSlide2
Monitoring HLA-specific antibodies
Matthew J. Everly, PharmD, BCPSOne Lambda Inc.
In
all
transplant patients Slide3
In
all transplant patients Preformed anti-HLA DSA+ Patient
Screening De Novo anti-HLA DSAMonitoring Removal of anti-HLA
DSASlide4
What we know about donor specific anti-HLA antibodies …Slide5
in transplant patients
Donor Specific Anti-HLA Antibodies allograft rejectionallograft failure
=Slide6
What we do not know …Slide7
How to monitor anti-HLA DSA?
How to treat anti-HLA DSA? Slide8
Transplant Patient
DSA + at Transplant
DSA - at TransplantSlide9
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;8:324Slide10
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
y
ear
And beyond
Everly et al. Am J Transplant 2012; In submission
Smith et al. Am J Transplant 2011;11:312Slide11
Preformed DSA Patient
Anti-HLASlide12
Major concern with preformed anti-HLA DSA is the associated AMR RiskSlide13
Preformed DSA Patient
Amico et al. Transplantation 2009;87:1681DSA+ at Transplant with AMR (n=37)Slide14
Preformed DSA Patient
Lefaucheur et al. Am J Transplant 2008;8:324
DSA+ AMR+, n=21
DSA + (no AMR), n=22
DSA –
(at transplant)
n=194Slide15
DSA Associated AMR riskis
not uniform over the post-transplant period Slide16
Gloor et al. Am J Transplant 2010;10:582
119
Positive Crossmatch
Preformed DSA PatientSlide17
Preformed DSA Patient
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)Slide18
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?
Preformed DSA PatientSlide19
Preformed DSA Patient
Amico et al. Transplantation 2009;87:1681Slide20
Lefaucheur et al. Am J Transplant 2008;8:324
237
Negative T- & B-CellCDC Crossmatch 194 (82%)Anti-HLA DSA -
Pre-Transplant
43
(18%)
Anti-HLA DSA +
Pre-Transplant
Preformed DSA PatientSlide21
Preformed DSA Patient
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-transplantSlide22
Dunn et al. Am J Transplant 2011;11:2132
587 patients
CDC XM- with single antigen bead testing at transplantPreformed DSA PatientSlide23
Preformed DSA Patient
DSA+ high MFI
DSA+ low MFI
DSA-
Dunn et al. Am J Transplant 2011;11:2132
DSA+
3
rd
party HLA+ or Neg.Slide24
Preformed DSA PatientGloor et al. (n=49)
Lefaucheur et al. (n=21) Dunn et
al. (n=46) 7.5 days
16.5
days
16
days
Median Time
to Acute Antibody Mediated Rejection Slide25
Can monitoring identify the preformed anti-HLA DSA patients at risk of AMR
?Slide26
Burns et al. Am J Transplant 2008;10:2684
70Positive Crossmatch
Preformed DSA Patient
41
High anti-HLA DSA
(Flow Channel Shift >300)
29
Low anti-HLA DSA
(Flow Channel Shift <300)Slide27
Preformed DSA PatientLow DSA, NO AMR
High DSA, NO AMRLow DSA, AMR+High DSA, AMR+
Burns et al. Am J Transplant 2008;8:2684Slide28
116
Flow Negative Crossmatch, but DSA PositivePreformed DSA Patient
Clinical Transplants 2011. In PressSlide29
Preformed DSA PatientPossible DSA Monitoring Time PointsPre-Transplant, Day of Transplant1
week2 weeks4 weeks8 weeksSlide30
Preformed DSA Patient
DSA+ high MFI
DSA+ low MFI
DSA-
Gloor et al. Am J Transplant 2010;10:582
DSA+ high MFI
Sum >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)
?Slide31
Transplant Glomerulopathy Risk
47% of XM+ AMR+ Patients
41% of XM+ AMR- Patients
Gloor et al. Am J Transplant 2010;10:582Slide32
Preformed DSA Patient
Kidney Int 2011;10:582
69 patients Flow Positive Crossmatch
33
Group 1
Convert to Flow XM -
15
Group 2
Remain Flow XM +
11 excluded no DSA, or not clear group Slide33
Preformed DSA Patient
Group 1Group 2
Group 2Group 1
Kimball et al. Kidney Int 2011;10:582Slide34
Preformed DSA PatientMonitoring Time PointsPre-Transplant, Day of Transplant
1 week2 weeks4 weeks8 weeks6 months12 monthsAfter 12 months ?
* If patient’s DSA remain persistently positive – treatment may be useful to improve outcomes.
With
for cause
biopsySlide35
Rationale to monitor DSA
Preformed DSA
Identify a patient at risk of AMRat risk of Chronic Antibody Damagew
ho should receive treatment for AntibodiesSlide36
Pre-Transplant DSA - PatientScreening for De Novo DSASlide37
Early Acute Antibody Mediated Rejection
Preformed DSA
De Novo DSA
<5%
>35%Slide38
DSA+ high MFI
DSA+ low MFI
DSA-
Screening for De Novo DSA
Gill et al. Transplantation 2010;89:178Slide39
Rationale to monitor DSA
De Novo DSA
Identify a patient at risk of AMRat risk of Chronic Antibody Damagew
ho should receive treatment for AntibodiesSlide40
Everly et al. Am J Transplant. 2012; In Submission
Rebellato et al. Clinical Transplants 2011; In PressEast Carolina University (Rebellato et al.)Slide41
DSA +De NovoAnti-HLA
62
27%
Everly et al. Am J Transplant. 2012; In Submission
Rebellato et al. Clinical Transplants 2011; In PressSlide42
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
0
1
2
3
4
5
6
7
8
9
10
11
12
Year Post-transplant
10
%
3-4
%
De Novo DSA Incidence
Everly et al. Presented at American Transplant Congress 2011, Philadelphia
Everly et al. Am J Transplant 2012. In SubmissionSlide43
patients transplanted between 1995-2004 who had survived more than one year243
19
224
patients excluded
DSA positive at the time of transplant
51
173
HLA Abs
patients with no HLA Abs
117
56
de novo DSA
(25%)
NDSA (52%)
NDSA= non donor-specific antibody
Smith J et al. Am J Transplant. 2011;11:312-9Slide44
When do HEART TRANSPLANT patients develop de-novo DSA?
22
6
6
3
1
5
1
72%
N=57
13
Smith J et al. Am J Transplant. 2011;11:312-9Slide45
0
10
20
30
40
50
60
70
80
90
100
Percent Allograft Survival
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 SubmissionSlide46
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
0
1
2
3
4
5
Year 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
Proportion Surviving
5 patients develop DSA after CAV:
4 CII Abs, 1 both classes of Abs
Smith J et al. Am J Transplant. 2011;11:312-9Slide47
Rationale to monitor DSA
De Novo DSA
Identify a patient at risk of AMRat risk of Chronic Antibody Damagew
ho should receive treatment for AntibodiesSlide48
Screening for De Novo DSAMonitoring Time PointsPre-Transplant
1 week2 weeks4 weeks8 weeks6 months12 monthsBiannually after 1 year
With for cause biopsySlide49
Removing
DSA
In Acute Antibody Mediated RejectionSlide50
Reduction of Donor Specific Antibody Levels Prevents Renal Allograft Loss
p = 0.043 (Log-Rank)Statistically significant at the α = 0.05 level
University of Cincinnati, Cincinnati, OH
Everly 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
Percent Allograft Survival
0
12
24
36
48
60
72
84
96
Months after Transplantation
Brody Medical School
at Eastern Carolina University, Greenville, NC
Everly, et al. Transplantation. Slide51
Lefaucheur et al. Am J Transplant 2009;9:1099Slide52
Despite Histologic Improvements …Antibody removal after AMR improves outcomesSlide53
Removing
DSA
In patients with preformed DSASlide54
Impact of
proteasome inhibitor on anti-donor HLA antibody production after kidney transplantationMayo Clinic Trial – Mark Stegall M.D.Removing DSA
2 cycles of bortezomib … wait 2 months … possible 2 more cycles of bortezomibSlide55
Removing DSA
Kimball et al. Clinical Transplants 2011; In press
IVIg + plasmapheresis 3 times per weekFor 2 weeks Slide56
Removing DSA
Kimball et al. Clinical Transplants 2011; In pressSlide57
In the patient with persistent preformed anti-HLA DSA positive …
Antibody removal may improve outcomesSlide58
Removing
DSA
In patients with stable allograft function Slide59
Hachem et al. J Heart Lung Transplant 2010;29:973
Removing DSA
61 lung transplant patients Serial single antigen bead testing after transplantSlide60
61
All
DSA positive
All
preemtive treatment
IVIg
for at least 6 months
(+/- Rituximab)
Patients in 2011Slide61
Hachem et al. J Heart Lung Transplant 2010;29:973
Removing DSASlide62
Everly et al. Transplantation 2012; In Press.
Removing DSASlide63
2
6
All
DSA positive
All
preemtive treatment
All
with
no
dysfunction at DSA appearance
Patients in 2011Slide64
2
6
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 DSASlide65
Male Gender 24 (92)Age at Transplant29.3 ± 9# of HLA mismatch
2.9 ± 1.4
Bortezomib on days 1, 4, 8, 11 Plasmapheresis (n=14) on same days with bortezomibRituximab (n=9) single doseCorticosteroid pulse – (all patients)Bortezomib Alone(n=11)
B
+
P
+
R
(n=15)Slide66
Txp
DSA
(MFI > 1000)
85 days
(median time to DSA – range from 6 - 536)
SCr - 1.17 ± 0.22
SCr - 1.26 ± 0.27Slide67
Reduction of DSAmax MFI by at least 50%
26 Patients24 – Greater than 50% reduction in DSAmax MFI
2 – Less than 50% reduction in DSAmax MFI
Median time to 50% reduction
37 daysSlide68
Removing DSARemission (n=8)
Relapsed (n=10) Partial/No Response (n=8)(only a 50% reduction)
MedianSerum Creatinine Change from Start of Treatment to last follow-up6.5% Scr Increase
41%
Scr
Increase
46%
Scr IncreaseSlide69
In the patient with persistent de novo anti-HLA DSA …
Antibody removal may improve outcomesSlide70
Removing
DSA
Improves OutcomesSlide71
Problem with Treating anti-HLA DSA
RemissionRefractoryRelapseSlide72
Removing DSA
“ A rapid partial response (50% reduction of DSAmax with 1 month of treatment was associated with a complete response”Slide73
DSA-
When Removing DSAPost-Treatment Monitoring Time PointsPrior to start of treatment
1 month(possibly 2 months if not using plasmspheresis)Refractory
Remission
Continued monitoring
if continued treatment
At 3 & 6 months then every 6 months
Relapse ?Slide74
SummarySlide75
Nearly All transplant patients can benefit for some degree of monitoring …Slide76
Preformed DSA Patient
Amico et al. Transplantation 2009;87:1681
AMR Appears EarlySlide77
Preformed DSA Patient
Burns et al. Am J Transplant 2008;8:2684
Monitoring Early Identifies those AT RISK of AMRSlide78
Preformed DSA Patient
Group 1Group 2
Group 2Group 1
Kimball et al. Kidney Int 2011;10:582
Monitoring Late Identifies those AT RISK of FailureSlide79
Preformed DSA PatientMonitoring Time PointsPre-Transplant 1 week
2 weeks4 weeks8 weeks6 months12 monthsAfter 12 months, annually
With for cause biopsySlide80
Everly et al. Presented at American Transplant Congress 2011, Philadelphia
Everly et al. Am J Transplant 2012. In SubmissionDe novo anti-HLA DSA appears at any time post transplant &
Identifies those AT RISK of Failure Screening for De Novo DSASlide81
DSA-
Screening for De Novo DSAMonitoring Time PointsPre-Transplant 6 months
12 monthsAnnually after 1 yearWith for cause biopsySlide82
Removing
DSA
Improves Outcomes
DSA Relapse
DSA RelapseSlide83
DSA-
When Removing DSAPost-Treatment Monitoring Time PointsPrior to start of treatment1 month
(possibly 2 months if not using plasmspheresis)Refractory
Remission
Continued monitoring
if continued treatment
At 3 & 6 months then every 6 months
Relapse ?Slide84
Thank
You
meverly@terasakilab.org