Transcript High Resolution HLA Matching in bone marrow transplantation

High Resolution HLA Matching in
Bone Marrow Transplantation
Dr. John Harvey
&
Dr. John Moppett
Filton
NHSBT - H & I Dept.
&
Bristol Royal Hospital for Children
Histocompatibility & Immunogenetics Dept.
NHSBT
1988 to 2012
24 years of providing an HLA typing and
Donor Selection Service to the
Bristol Royal Hospital for Children
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Resolution levels used By NHSBT, Bristol for donor
selection at differing HLA typing epochs
1988 -1999
2000 – 2001 (HR - class II)
2002 – 2012
Adapted from - BLOOD, 2011 VOL. 118, No.23
NHSBT - H & I Dept.
&
Hospital
for Children
Bristol Bristol
Royal Royal
Hospital
for Children
Evolution of HLA typing methods at NHSBT, Bristol from
1988 to 2012
Dates
Class I Method
Class II Method
1988 – 1992
Serology – low
resolution
RFLP – low
resolution
1993 - 1995
Serology – low
resolution
SSO – low resolution
1996 - 1999
SSP/SSO – low
resolution
SSP/SSO – low
resolution
2000 - 2001
SSP/SSO –
intermediate
resolution
SSO/SBT/SSP – high
resolution
SSP/SSO – high
resolution
2002 - 2012
NHSBT - H & I Dept.
&
SSO/SBT/SSP – high
resolution
Hospital
for Children
Bristol Bristol
Royal Royal
Hospital
for Children
HLA High Resolution Typing at NHSBT
1. Intermediate type obtained using the Luminex
platform Sequence Specific Oligonucleotide (SSO)
method.
2. High resolution type obtained using group
specific Sequence Based Typing (SBT).
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Literature on influence of high resolution HLA matching
1.Morishima,Y.; Sasazuki,T.; Inoko,H.et al., The clinical significance of human leukocyte antigen (HLA) allele
compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched
unrelated donors. Blood. 2002;99; 2600-2606
2.Petersdorf EW. HLA matching in allogeneic stem cell transplantation. Curr Opin Hematol. 2004;11:386-391.
3.Petersdorf EW, Anasetti C, Martin PJ et al. Limits of HLA mismatching in unrelated hematopoietic cell
transplantation. Blood. 2004;104:2976-2980.
4.Flomenberg N, Baxter-Lowe LA, Confer D et al. Impact of HLA class I and class II high-resolution matching
on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong
adverse effect on transplantation outcome. Blood. 2004;104:1923-1930.
5.Lee SJ, Klein J, Haagenson M et al. High-resolution donor-recipient HLA matching contributes to the success
of unrelated donor marrow transplantation. Blood. 2007;110:4576-4583.
6.Petersdorf EW, Gooley T, Malkki M, Horowitz M. Clinical significance of donor-recipient HLA matching on
survival after myeloablative hematopoietic cell transplantation from unrelated donors. Tissue Antigens. 2007;69
Suppl 1:25-30.
7.Petersdorf E, Bardy P, Cambon-Thomsen A et al. 14thInternational HLA and Immunogenetics Workshop:
report on hematopoietic cell transplantation. Tissue Antigens. 2007;69 Suppl 1:17-24.
8.Shaw, B. E., Gooley, T. A., Malkki, M., et al. 2007, "The importance of HLA-DPB1 in unrelated donor
hematopoietic cell transplantation", Blood, vol. 110, no. 13, pp. 4560-4566
9.Petersdorf EW. Optimal HLA matching in hematopoietic cell transplantation. Curr Opin Immunol. 2008;20:588593.
10.Macmillan ML, Davies SM, Nelson GO et al. Twenty years of unrelated donor bone marrow transplantation
for pediatric acute leukemia facilitated by the National Marrow Donor Program. Biol Blood Marrow Transplant.
2008;14:16-22.
11.Bray RA, Hurley CK, Kamani NR et al. National marrow donor program HLA matching guidelines for
unrelated adult donor hematopoietic cell transplants. Biol Blood Marrow Transplant. 2008;14:45-53.
12.Shaw P.J. et al Outcome of paediatric bone marrow transplantation for leukaemia and myelodysplasia using
matched sibling, mismatched related or matched unrelated donors. Blood 2010
NHSBT - H & I Dept.
&
Bristol Royal Hospital for Children
Evidence for the influence of high resolution HLA matching
NMDP 2001
• HLA - DRB1 single high resolution mismatches
negatively affects transplant outcome.
• HLA - A,B & C single antigen serological defined
mismatch transplants negatively affects transplant
outcome.
• HLA - A,B & C single high resolution DNA defined
mismatch did not affect transplant outcome.
Petersdorf EW et al. Blood 2001; 98:2922–2929
Petersdorf EW et al. New England Journal of Medicine, 2001; 345:1794-8000
NHSBT - H & I Dept.
&
Bristol Royal Hospital for Children
Evidence for the influence of high resolution HLA matching
JMDP 2002
•HLA - A & B high resolution mismatch reduced
overall survival
•HLA – C & DRB1 or DQB1 high resolution mismatch
did not reduce overall survival
Morishima Y et al.
Blood. 2002;99:4200-4206
NHSBT - H & I Dept.
&
Bristol Royal Hospital for Children
Evidence for the influence of high resolution HLA matching
NMDP 2004 and 2010
•HLA – A,B,C & DR single high resolution mismatches associate with a
significant reduction in overall survival.
• Antigenic mismatches had a stronger effect than allelic mismatches.
•HLA – DQ and DP mismatches not associated with decreased overall
survival.
•HLA – C should be included in matching algorithims
•60% of mismatches were only detected by high resolution typing.
•Low resolution matching gives only a 56% chance that the transplant pair
will be matched at high resolution
Flomenberg N et al. Blood. 2004;104:1923-1930
Woolfrey A.E. et al. Blood 2010;112:563
NHSBT - H & I Dept.
&
Bristol Royal Hospital for Children
Evidence for the influence of high resolution HLA matching
NMDP 2007
•Confirmed the importance of high resolution HLA – A, B,C,
and DRB1 matching on improved patient survival and stated
that both antigenic and allelic mismatches had equal
weighting.
•Single mismatches at HLA DQ and DP was not associated
with changes in overall survival.
Lee SJ et al.
Blood. 2007;110:4576-4583
NHSBT - H & I Dept.
&
Bristol Royal Hospital for Children
NMDP HLA Matching Guidelines for UD Adult SCT
•Took the literature and distilled HLA donor matching guidelines
for optimal stem cell transplant outcome in adults
•Recommend high resolution HLA – A,B,C & DRB1 match as
minimum requirement for optimal patient survival (8/8 match)
•They also state that where the patients condition may rapidly
deteriorate then it is reasonable to accept a single high
resolution (or antigen) mismatch and progress rapidly to
transplant
Bray RA, Hurley CK, Kamani NR et al.
Biol Blood Marrow Transplant. 2008;14:45-53
NHSBT - H & I Dept.
&
Bristol Royal Hospital for Children
Current UK Practice
•Cross sectional study in 2009 of the interaction between the
HLA laboratory and the transplant units they served from the
laboratory perspective (100% return of survey).
•Very diverse arrangements throughout the UK in every step of
donor selection.
•60% of matched unrelated transplants in the UK are low to
intermediate matched at class I and high resolution matched at
class II.
Harvey J, Green A.
Survey of human leukocyte antigen matching criteria used in donor selection for
haematopoietic stem cell transplantation in the United Kingdom and Ireland.
Hum Immunol. 2009;70 supplement 1:S97
NHSBT - H & I Dept.
&
Bristol Royal Hospital for Children
How does this relate to the costs of Transplantation?
Assuming a high res. HLA class II and an intermediate res.
Class I would be performed
Additional cost of HR typing patient and 4 donors
= £700
Cost of transplant between £80k & £100k
Additional cost is less than 1% of transplant
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Bone Marrow Transplant in Bristol
• 1st transplant September 1987
• 872 paediatric allogeneic BMT :• ALL
406
• SAA
76
• AML
155
• Inborn errors
73
• Other
30
• Other leuks 69
• MDS
60
• 602 adult allogeneic BMT
NHSBT - H & I Dept.
&
Bristol Royal Hospital for Children
Unrelated donor BMT for Paediatric ALL
Bristol 1988–99
MUD
MMUD
Green,A et al
Blood. 1999;94:2236-2246
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Unrelated donor BMT for Paediatric ALL
Bristol 1988–99
40% mismatch
when HR typed
MUD
MMUD
Green,A et al
Blood. 1999;94:2236-2246
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Does the introduction of high resolution
matching at HLA class I and II improve
Survival in Matched Unrelated Donor
Transplant for Childhood ALL?
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Improved Survival in Matched Unrelated Donor
Transplant for Childhood ALL since the
introduction of high resolution matching at HLA
class I and II?
• 1988-2007
356 SCT for paediatric ALL
• 2002-2007
80 SCT after the introduction
of HR typing
Harvey et al. BMT in press
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Bristol MUD Transplants for ALL 1988 – 2001
Outcome according to HLA typing epoch
Pre 2002
(OS 50%)
Harvey et al. BMT in press
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Bristol MUD Transplants for ALL 1988 – 2007
by HLA typing epoch
HR
typed
2002-07
(OS 78.8%)
Pre 2002
(OS 50%)
Harvey et al. BMT in press
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Bristol Transplants for ALL 2002 – 2007
MSD
MUD
MMUD
Harvey et al. BMT in press
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Bristol Transplants for ALL 1988 – 2007
Harvey et al. BMT in press
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Bristol Transplants for ALL 1988 – 2007
MMUD
MMUD
50% 1 Ag MM
50% >1Ag MM
50% 1 All MM
50% 1Ag MM
Harvey et al. BMT in press
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Bristol Transplants for ALL 1988 – 2007
Harvey et al. BMT in press
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
NMDP 2 yr OS in paediatric ALL and AML UD transplants
2003 1999-02
1996-98
1987-95
MacMillan et al BBMT 2008
NHSBT - H & I Dept.
&
Bristol Royal Hospital for Children
Incidence of relapse categorised by epoch and HLA
match group.
1988-2001
2002-2007
MSD
17/54 (31%)
4/26 (15%)
MUD
47/134 (35%)
5/33 (15%)
MMUD
22/75 (29%)
3/16 (20%)
Overall
86/263 (32%)
12/75 (16%)
Harvey et al. BMT in press
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Non Relapse Mortality
p=n.s.
p=0.026
Harvey et al. BMT in press
NHSBT - H & I Dept.
&
Bristol Royal Hospital for Children
Acute Graft versus Host Disease
•aGvHD (gr II–IV) 53/356 = 15%
•associated with increased TRM (p=0.002)
•Incidence reduced since 2002 = 9% (p= n.s.)
•Death with GvHD 64% pre 2002,14% post 2002 (p=0.001)
Epoch
No. patients
developed > grade II
aGvHD in each epoch
(aGvHD and died)
1988-07
1988-92
1993-95
1996-99
2000-01
2002-07
53 (34)
12 (7)
9 (8)
15 (10)
10 (8)
7 (1)
p=0.001*
*analysis of OS and aGvHD using chi square test for trends
Harvey et al. BMT in press
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Conclusion
•HR typing improves the outcome of MUD BMT by
reducing NRM
•This improvement is not seen in less than fully
matched transplants
•HR-MUD have equivalent outcomes to MSD
transplants
•HR typing at class I and II should be standard for
UD BMT and is cost effective.
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Acknowledgements
Scientific
• Dr Ann Green
• Dr Leigh Keen
• Dr Steve Culliford
• Mrs Elizabeth Wroe
NHSBT - H & I Dept.
&
Clinical
• Dr Jackie Cornish
• Dr Colin Steward
• Dr Michelle Cummins
Statistical
• Dr Linda Hunt
• Dr Yi Li
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Additional Data
Retrospective Retyping analysis
•15 Consecutive Matched Unrelated Transplant pairs from 1996 & 1997 retyped
at high resolution
• Six of the fifteen pairs had previously unidentified HLA mismatches (40%).
• The allelic mismatches detected were:
• Two examples of HLA-DRB1*04:01 v
• Single examples of
DRB1*04:04;
DRB1*14:01 v DRB1*14:04,
B*44:02 v B*44:03 and
C*07:01 v C*07:02.
• Two further HLA Cw antigen mismatches: HLA Cw*1203 and
Cw*1601( previously HLA-Cw blanc specificities).
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children
Selected Mismatches before and after introduction of HR typing
2002 - 2007
1988 - 2001
Loci mismatches
numbers
Loci mismatches
numbers
1 Al HLA A
3.00
1 Ag HLA A
17.00
1 Ag HLA A
1.00
1 Ag HLA B
3.00
1 Ag HLA C
2.00
1 Ag HLA C
11.00
1 Al HLA C
1.00
1 Ag HLA DQ
7.00
1 Al HLA DQB1
3.00
1 Ag HLA DR
3.00
1 Al HLA DRB1
1.00
2 Ag HLA A+B
5.00
2 Ag HLA A+C
3.00
2 Ag HLA A+C
8.00
2 Ag HLA B+C
2.00
2 Ag HLA B+C
10.00
2 Ag HLA B+DQ
5.00
2 Ag HLA DR+DQ
1.00
2 Ag HLA C+DR
1.00
3 Ag HLA 2B+C
1.00
3 Ag HLA A+B+C
1.00
3 Ag HLA B+2C
4 Ag HLA
A+B+C+DR
1.00
1.00
Ag denotes antigen mismatch and Al denotes allelic mismatch
Bristol NHSBT - H & I Dept.
&
Bristol
Royal
Hospital
Bristol
Royal
Hospitalfor
forChildren
Children
The following parameters were analysed using Cox
Prop. Hazard and Binary logistic regression
modelling for both univariate and multivariate
analysis
-Disease status at time of transplant
-CMV match status
-Stem Cell Source
-Gender match status
-HLA match grade
-Age of donor and recipient
-Days to engraftment
-Time in days from diagnosis to transplant
-Incidence of relapse
NHSBT - H & I Dept.
&
Bristol Bristol
Royal Royal
Hospital
for Children
Hospital
for Children