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High Resolution HLA Matching in Bone Marrow Transplantation Dr. John Harvey & Dr. John Moppett NHSBT - H & I Dept. & Bristol Royal Hospital for Children.

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Presentation on theme: "High Resolution HLA Matching in Bone Marrow Transplantation Dr. John Harvey & Dr. John Moppett NHSBT - H & I Dept. & Bristol Royal Hospital for Children."— Presentation transcript:

1 High Resolution HLA Matching in Bone Marrow Transplantation Dr. John Harvey & Dr. John Moppett NHSBT - H & I Dept. & Bristol Royal Hospital for Children Filton

2 Histocompatibility & Immunogenetics Dept. NHSBT 1988 to years of providing an HLA typing and Donor Selection Service to the Bristol Royal Hospital for Children Bristol Royal Hospital for Children NHSBT - H & I Dept. & Bristol Royal Hospital for Children

3 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 – 2001 (HR - class II) 2002 – 2012 NHSBT - H & I Dept. & Bristol Royal Hospital for Children

4 Bristol Royal Hospital for Children Evolution of HLA typing methods at NHSBT, Bristol from 1988 to 2012 DatesClass I MethodClass II Method 1988 – 1992 Serology – low resolution RFLP – low resolution Serology – low resolution SSO – low resolution SSP/SSO – low resolution SSP/SSO – intermediate resolution SSP/SSO – high resolution SSO/SBT/SSP – high resolution NHSBT - H & I Dept. & Bristol Royal Hospital for Children

5 Bristol 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 Royal Hospital for Children

6 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; Petersdorf EW. HLA matching in allogeneic stem cell transplantation. Curr Opin Hematol. 2004;11: Petersdorf EW, Anasetti C, Martin PJ et al. Limits of HLA mismatching in unrelated hematopoietic cell transplantation. Blood. 2004;104: 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: 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: 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: 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: 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 Petersdorf EW. Optimal HLA matching in hematopoietic cell transplantation. Curr Opin Immunol. 2008;20: 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: 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: 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

7 Evidence for the influence of high resolution HLA matching NMDP 2001 Petersdorf EW et al. Blood 2001; 98:2922–2929 Petersdorf EW et al. New England Journal of Medicine, 2001; 345: NHSBT - H & I Dept. & Bristol Royal Hospital for Children 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.

8 HLA - A & B high resolution mismatch reduced overall survival HLA – C & DRB1 or DQB1 high resolution mismatch did not reduce overall survival NHSBT - H & I Dept. & Bristol Royal Hospital for Children Evidence for the influence of high resolution HLA matching JMDP 2002 Morishima Y et al. Blood. 2002;99:

9 Flomenberg N et al. Blood. 2004;104: Woolfrey A.E. et al. Blood 2010;112:563 NHSBT - H & I Dept. & Bristol Royal Hospital for Children 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 Evidence for the influence of high resolution HLA matching NMDP 2004 and 2010

10 Lee SJ et al. Blood. 2007;110: NHSBT - H & I Dept. & Bristol Royal Hospital for Children 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. Evidence for the influence of high resolution HLA matching NMDP 2007

11 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 NHSBT - H & I Dept. & Bristol Royal Hospital for Children Bray RA, Hurley CK, Kamani NR et al. Biol Blood Marrow Transplant. 2008;14:45-53

12 Current UK Practice NHSBT - H & I Dept. & Bristol Royal Hospital for Children 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.

13 Bristol Royal Hospital for Children 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

14 Bone Marrow Transplant in Bristol 1 st transplant September paediatric allogeneic BMT :- ALL 406 AML 155 Other leuks69 MDS60 SAA 76 Inborn errors 73 Other 30 NHSBT - H & I Dept. & Bristol Royal Hospital for Children 602 adult allogeneic BMT

15 Unrelated donor BMT for Paediatric ALL Bristol 1988–99 Green,A et al Blood. 1999;94: Bristol Royal Hospital for Children MUD MMUD NHSBT - H & I Dept. & Bristol Royal Hospital for Children

16 Unrelated donor BMT for Paediatric ALL Bristol 1988–99 Green,A et al Blood. 1999;94: Bristol Royal Hospital for Children MUD MMUD 40% mismatch when HR typed NHSBT - H & I Dept. & Bristol Royal Hospital for Children

17 Bristol Royal 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 Royal Hospital for Children

18 Bristol Royal Hospital for Children SCT for paediatric ALL 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 NHSBT - H & I Dept. & Bristol Royal Hospital for Children

19 Bristol Royal Hospital for Children Bristol MUD Transplants for ALL 1988 – 2001 Outcome according to HLA typing epoch Pre 2002 (OS 50%) NHSBT - H & I Dept. & Bristol Royal Hospital for Children Harvey et al. BMT in press

20 Bristol Royal Hospital for Children Bristol MUD Transplants for ALL 1988 – 2007 by HLA typing epoch Pre 2002 Harvey et al. BMT in press (OS 78.8%) (OS 50%) HR typed NHSBT - H & I Dept. & Bristol Royal Hospital for Children

21 Bristol Royal Hospital for Children Harvey et al. BMT in press Bristol Transplants for ALL 2002 – 2007 MSD MUD MMUD NHSBT - H & I Dept. & Bristol Royal Hospital for Children

22 Bristol Royal Hospital for Children NHSBT - H & I Dept. & Bristol Royal Hospital for Children Harvey et al. BMT in press Bristol Transplants for ALL 1988 – 2007

23 Bristol Royal Hospital for Children MMUD 50% 1 Ag MM 50% >1Ag MM MMUD 50% 1 Ag MM 50% >1Ag MM MMUD 50% 1 All MM 50% 1Ag MM MMUD 50% 1 All MM 50% 1Ag MM NHSBT - H & I Dept. & Bristol Royal Hospital for Children Bristol Transplants for ALL 1988 – 2007 Harvey et al. BMT in press

24 Bristol Royal Hospital for Children NHSBT - H & I Dept. & Bristol Royal Hospital for Children Harvey et al. BMT in press Bristol Transplants for ALL 1988 – 2007

25 NMDP 2 yr OS in paediatric ALL and AML UD transplants MacMillan et al BBMT 2008 NHSBT - H & I Dept. & Bristol Royal Hospital for Children

26 Incidence of relapse categorised by epoch and HLA match group. Bristol Royal Hospital for Children MSD 17/54 (31%)4/26 (15%) MUD 47/134 (35%)5/33 (15%) MMUD 22/75 (29%)3/16 (20%) Overall86/263 (32%)12/75 (16%) NHSBT - H & I Dept. & Bristol Royal Hospital for Children Harvey et al. BMT in press

27 p=0.026 p=n.s. Non Relapse Mortality NHSBT - H & I Dept. & Bristol Royal Hospital for Children Harvey et al. BMT in press

28 Acute Graft versus Host Disease Epoch 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 Bristol Royal Hospital for Children 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) NHSBT - H & I Dept. & Bristol Royal Hospital for Children Harvey et al. BMT in press

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

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

31 Additional Data

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

33

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


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