Contribution of molecular testing histocompatability in improving haematopoietic stem cell transplant outcomes

  • John Harvey

Student thesis: Doctoral Thesis


Recently published studies indicate that matching at the allelic level for human Leucocyte antigens (HLA) between donors and recipients in unrelated haematopoietic stem cell transplants (HSCT) improves overall patient survival. These contemporaneous multicentre studies looked at stem cell transplants for which donors were initially selected using low/medium resolution HLA typing. Donor/recipient pairs were then retyped retrospectively to the allelic level for HLA and transplant outcomes were analysed. The overall effect of prospective allelic matching for HLA upon an active paediatric transplant program has not been reported.

Cross-sectional study
In this study, the current practice of allelic matching for stem cell transplantation in the United Kingdom and Ireland was reviewed. This cross-sectional analysis showed that there is still considerable scope to influence and improve laboratory and clinical practice to the benefit of patients undergoing stem cell transplantation. The study established that allelic matching was not universally adopted in the United Kingdom and matching strategies between transplant units varied considerably between units.

Impact of prospective allelic matching on haematopoietic stem cell transplant programs The study aimed to establish the overall impact of introducing allelic matching at HLA -A, -B, -C, -DRB1 and -DQB1 in a well established transplant program. This has not previously been reported as all previous studies involve retrospective high resolution typing post transplant. This study reviews Human HLA matching over the 20 years of a transplant program for 356 paediatric acute lymphoblastic leukaemia (ALL) patients. The study shows that the introduction of allelic matching in 2002 resulted in a more than 25% improved disease free survival at two and five years post transplant in this cohort of patients. It also shows that the outcome for allelic matched unrelated donor transplants was comparable to that of sibling transplants. The analysis investigated whether other developments in patient treatment might confound the analysis. The analysis showed no other factor could explain the improved survival. The 2008 European Bone Marrow Handbook when discussing paediatric ALL transplantation states, there are no reported studies that compare HLA identical sibling transplants with unrelated donor transplants matched on allele level . The establishment of the importance of allelic matching in paediatric ALL stem cell transplants in this study is novel and highly relevant clinical data.

Influencing Professional Practice
Using the position of chairperson for an inter professional group working party, I wrote the first draft of Guidelines for selection and HLA matching of related, adult unrelated donors and umbilical cord units for haematopoietic stem cell transplantation . Suggestions and comments were received from other contributors for amendments to the document which is to be adopted by the professional bodies listed. These guidelines form part of this thesis with the author having writen the first draft document and played the major role in their research and writing while chairing the writing working party (~90% contribution to final document, excluding clinical notes for scientists). The guidelines should impact the current practice of those selecting related or unrelated adult stem cell donors and cord blood units for haematopoietic stem cell transplantation. The guidelines promote best clinical practice and are approved of by a working party from the following professional bodies:

-Children s Cancer and Leukaemia Group (CCLG)
-British Society for Histocompatibility and Immunogenetics (BSHI)
-British Society for Blood and Marrow Transplantation(BSBMT)
-British Transplant Society (BTS)
-Royal College of Pathologists (RCPath)
-Institute of Biomedical Science (IBMS)

Non-HLA genomic differences in haematopoietic stem cell transplantation

In the 16th international histocompatibility workshop to be held in 2012, one research group aim is to look at the influence of ethnicities and ethnic differences between donors and recipients on stem cell transplant outcomes. The research hypothesis of the group is Donor-recipient ethnicity may affect the risk of acute GvHD and other transplant associated outcomes after HLA matched unrelated HCT . The final part of this thesis looks at donor/recipient differences in Short Tandem Repeat (STR) allele lengths at multiple STR loci. The weighted average allele size difference (WAASD) is used as a proxy for genetic distance between donor and recipient in HLA matched transplants. The study examined the effect of this metric on transplant survival. The study argues that this may be a more appropriate genetic measure than ethnic difference. This is especially the case in societies such as North America, where populations are composed of highly variable admixtures of differing ancestral background. The data shows highly significant differences in survival for high and low WAASD values.
Date of Award2011
Original languageEnglish
Awarding Institution
  • University of Portsmouth
SupervisorDavid Rogers (Supervisor) & Graham Mills (Supervisor)

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