high resolution hla matching in bone marrow transplantation dr. john harvey & dr. john moppett...

High Resolution HLA Matching in Bone Marrow Transplantation

Dr. John Harvey & Dr. John Moppett

NHSBT - H & I Dept. & Bristol Royal Hospital for Children

Filton

http://www.uhbristol.nhs.uk/

Histocompatibility & Immunogenetics Dept.

NHSBT

1988 to 201224 years of providing an HLA typing and Donor Selection

Service to the Bristol Royal Hospital for

Children

Bristol Royal Hospital for ChildrenNHSBT - H & I Dept. & Bristol Royal Hospital for Children

Bristol Royal Hospital for Children

Resolution levels used By NHSBT, Bristol for donor selection at differing HLA typing epochs

Adapted from - BLOOD, 2011 VOL. 118, No.23

1988 -1999

2000 – 2001 (HR - class II)

2002 – 2012



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

SSP/SSO – high resolution

2002 - 2012 SSO/SBT/SSP – high resolution

SSO/SBT/SSP – high resolution



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).


Literature on influence of high resolution HLA matching1.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; 2600-26062.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. 4560-45669.Petersdorf EW. Optimal HLA matching in hematopoietic cell transplantation. Curr Opin Immunol. 2008;20:588-593.10.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


Evidence for the influence of high resolution HLA matching

NMDP 2001

Petersdorf EW et al. Blood 2001; 98:2922–2929Petersdorf EW et al. New England Journal of Medicine, 2001; 345:1794-8000


• 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.

John Moppett

Use the same author format - prob surname and initial no 1st name

•HLA - A & B high resolution mismatch reduced overall survival

•HLA – C & DRB1 or DQB1 high resolution mismatch did not reduce overall survival



JMDP 2002

Morishima Y et al. Blood. 2002;99:4200-4206

Flomenberg N et al. Blood. 2004;104:1923-1930Woolfrey A.E. et al. Blood 2010;112:563


•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


NMDP 2004 and 2010

Lee SJ et al. Blood. 2007;110:4576-4583


•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.


NMDP 2007

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

Current UK Practice


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

•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.


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

Bone Marrow Transplant in Bristol

• 1st transplant September 1987

• 872 paediatric allogeneic BMT :-

• ALL 406

• AML 155

• Other leuks69

• MDS 60

• SAA 76

• Inborn errors 73

• Other 30


• 602 adult allogeneic BMT

Unrelated donor BMT for Paediatric ALL Bristol 1988–99

Green,A et alBlood. 1999;94:2236-2246


MUD

MMUD


Unrelated donor BMT for Paediatric ALL Bristol 1988–99

Green,A et alBlood. 1999;94:2236-2246


MUD

MMUD

40% mismatch when HR typed40% mismatch when HR typed



Does the introduction of high resolution matching at HLA class I and II improve Survival in Matched

Unrelated Donor Transplant for Childhood ALL?



• 1988-2007 356 SCT for paediatric ALL

• 2002-2007 80 SCT after the introduction of HR typing

Improved Survival in Matched Unrelated Donor Transplant for Childhood ALL

since the introduction of high resolution matching at HLA class I and II?

Harvey et al. BMT in press



Bristol MUD Transplants for ALL 1988 – 2001

Outcome according to HLA typing epoch

Pre 2002(OS 50%)




Bristol MUD Transplants for ALL 1988 – 2007

by HLA typing epoch

2002-07

Pre 2002


(OS 78.8%)

(OS 50%)

HR typedHR

typed




Bristol Transplants for ALL 2002 – 2007

MSDMUD

MMUD



MMUD

50% 1 Ag MM50% >1Ag MM

MMUD

50% 1 Ag MM50% >1Ag MM

MMUD

50% 1 All MM50% 1Ag MM

MMUD

50% 1 All MM50% 1Ag MM




NMDP 2 yr OS in paediatric ALL and AML UD transplants

2003 -

1999-021996-981987-95

MacMillan et al BBMT 2008


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%)



p=0.026

p=n.s.

Non Relapse Mortality



Acute Graft versus Host Disease

Epoch

1988-07 1988-92 1993-95 1996-99 2000-01 2002-07

No. patients developed > grade II

aGvHD in each epoch (aGvHD and died)

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


•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)



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.



Acknowledgements

Clinical• Dr Jackie Cornish• Dr Colin Steward• Dr Michelle Cummins

Scientific• Dr Ann Green• Dr Leigh Keen• Dr Steve Culliford• Mrs Elizabeth Wroe Statistical

• Dr Linda Hunt• Dr Yi Li


Additional Data


•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 DRB1*04:04;

• Single examples of 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).

Retrospective Retyping analysis


Bristol Royal Hospital for ChildrenBristol NHSBT - H & I Dept. & Bristol Royal 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 1.00

4 Ag HLA

A+B+C+DR 1.00

Ag denotes antigen mismatch and Al denotes allelic mismatch


-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

The following parameters were analysed using Cox Prop. Hazard and Binary logistic regression modelling for both univariate

and multivariate analysis


high resolution hla matching in bone marrow transplantation dr. john harvey & dr. john moppett...

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