Review

BSHI Guideline: HLA matching and donor selection for haematopoieticprogenitor cell transplantation

A-M. Little*,, A. Green, J. Harvey, S. Hemmatpour, K. Latham, S. G. E. Marsh,**,K. Poulton, & D. Sage

Summary

A review of the British Society for Histocompatibilityand Immunogenetics (BSHI) Guideline for selectionand HLA matching of related, adult unrelated donorsand umbilical cord units for haematopoietic progenitorcell transplantation was undertaken by a BSHIappointed writing committee. Literature searches wereperformed, and the data extracted were presented as rec-ommendations according to the GRADE nomenclature.

List of recommendations

All laboratories performing H&I testing for allo-geneic HPC transplantation should follow EFI stan-dards and be accredited by EFI and UKAS/CPA(Grade 1A)

HLA typing definitions as described by Nunes et al.(2011) and here should be used (Grade 1A)

HLA typing results should use official WHO HLANomenclature (Grade 1A)

The clinical urgency should be made available tothe individual performing the related and unrelateddonor search (Grade 1B)

HLA high-resolution typing should be performed onpotential matching; mismatching and haploidentical

related donors when familial haplotypes cannot befully assigned (Grade 1A)

Patients and selected related donors should betyped for HLA-A, -B, -C, -DRB1 and -DQB1 (+/DPB1) (Grade 1A)

All patients and donors must have their HLA typeconfirmed on a second sample pretransplant (Grade1A)

The patient should be high-resolution typed priorto submitting the HLA type for an unrelated donorsearch (Grade 1A)

A 10/10 high-resolution HLA-A, -B, -C, -DRB1and -DQB1-matched unrelated PBSC or bone mar-row donor should be used where possible (Grade1A)

Where a 10/10 matched PBSC or bone marrowdonor is not available a single mismatch at HLA-A,-B, -C, -DRB1 or -DQB1 is acceptable (Grade 1A)

Alternative progenitor cell donors (cord blood orhaploidentical) should be considered early in thedonor search when a patient is unlikely to have anHLA-matched unrelated donor (Grade 1A)

HLA-DRB3, -DRB4, -DRB5 typing should be per-formed and, when a choice of otherwise equallymatched and appropriate (e.g. CMV status) donorsis available, mismatches for these should be mini-mized (Grade 2A)

For unrelated donor selection, HLA-DPB1 typingshould be performed and when a choice of other-wise equally matched and appropriate (e.g. CMVstatus) donors is available, nonpermissive mis-matches should be minimized (Grade 2C)

For mismatched related and unrelated donor selec-tion, HVG mismatches are favoured over bidirec-tional and GVH mismatches (Grade 2C)

UCB units should be HLA typed to high-resolutionHLA-A, -B, -C, -DRB1, -DQB1 (Grade 1B)

Selection of UCB units should follow national con-sensus guidelines published by Hough et al. (2016)(Grade 1A)

HLA alloantibody testing of the recipient should beperformed at the time of donor search and shouldbe repeated at the time of donor work-up request ifan HLA-mismatched donor is selected (Grade 1A)

*Histocompatibility and Immunogenetics Laboratory, Gartnavel Gen-eral Hospital, Glasgow, UK, Institute of Infection, Immunity andInflammation, College of Medical, Veterinary and Life Sciences,University of Glasgow, Glasgow, UK, Histocompatibility and Immu-nogenetics Laboratory, NHS Blood and Transplant, Filton, UK, Histo-compatibility and Immunogenetics Laboratory, NHS Blood andTransplant, London, Tooting, UK, Anthony Nolan Research Institute,Royal Free Hospital, London, UK, **Cancer Institute, University Col-lege London, London, UK, Transplantation Laboratory, ManchesterRoyal Infirmary, Manchester, UK and Chair, British Society for His-tocompatibility & Immunogenetics

Received 22 March 2016; revised 6 May 2016; accepted 6 June2016

Correspondence: Ann-Margaret Little, Histocompatibility andImmunogenetics Laboratory, Gartnavel General Hospital, 21 ShelleyRoad, Glasgow G12 0ZD, UK. Tel: 0141 301 7749; Fax: 0141 3017761; E-mail: alittle1@nhs.net

2016 John Wiley & Sons LtdInternational Journal of Immunogenetics, 2016, 43, 263286 263

doi: 10.1111/iji.12282

The clinical team must be made aware of any HLAalloantibody incompatibility for a selected donor(Grade 1A)

When a choice of equally well-matched donors isavailable, avoid selection of donors against whichthe patient has HLA alloantibodies (Grade 1A)

HLA alloantibody testing should be performed incases of failed engraftment if the donor is HLAmismatched (Grade 1B)

The guideline published by Emery et al. (2013) rec-ommending CMV matching between patient anddonor should be followed (Grade 1A)

Major ABO incompatibilities should be avoidedwhen there is a choice of HLA- and CMV-matcheddonors (Grade 1A)

Male donors should be preferentially chosen wherethe patient has multiple HLA-, CMV- and ABO-matched donors (Grade 1C)

Younger donors should be preferentially selected(Grade 1B)

Homozygosity and novel HLA alleles identifiedwithin DNA extracted from patients with a highfrequency of circulating tumour cells should be con-firmed by family studies or using DNA extractedfrom nondiseased cells (Grade 2A)

Individuals actively involved in the provision of adonor selection service should undertake CPD, andthe service should be directed by a RCPath Fellowand Consultant in H&I (Grade 1A)

Scope

These evidence-based recommendations expand andadapt previous guidance (Harvey et al., 2012).

Method

This guideline was produced by the following actions:1 A writing committee (authors of this manuscript)

comprising Histocompatibility and Immunogenet-ics (H&I) scientists providing an H&I clinicalservice for related and unrelated donorhaematopoietic progenitor cell transplantation wasestablished. Ann-Margaret Little was appointed asthe chair of the committee.

2 A search of peer-reviewed literature to 31 June2015 was undertaken.

3 Recommendations were produced from evidenceobtained from the literature search. Due to thespecialist nature of histocompatibility testing inthe context of haematopoietic progenitor cell allo-transplantation, there are few large and/or multi-centre studies in this field and meta-analyses arenot available. Some recommendations are basedon both literature review and consensus of expertopinion.

4 The GRADE nomenclature was used to evaluatethe impact of evidence and to define the strength

of the recommendations [http://www.gradeworkinggroup.org/intro.htm#criteria].

For each recommendation the quality of evidencehas been graded as:

A (high)B (moderate)C (low)D (very low)

For each recommendation, the strength of recom-mendation has been indicated as one of the following:

Level 1 (we recommend)Level 2 (we suggest)Not graded (where there is not enough evidence toallow formal grading)

Disclaimer

These recommendations represent consensus opinionfrom experts in the field of H&I within the UK. Theyrepresent a snapshot of the evidence available at thetime of writing. This evidence may become supersededwith time. It is recognized that recommendations havebeen made even when the evidence is weak. The BSHIcannot attest to the accuracy, completeness or cur-rency of the opinions and information containedherein and does not accept any responsibility or liabil-ity for any loss or damage caused to any practitioneror any third party as a result of any reliance beingplaced on this guideline or as a result of any inaccu-rate or misleading opinion contained in the guideline.

Background

The infusion (transplantation) of haematopoietic pro-genitor stem cells (HPC) into a patient with haemato-logical failure due to malignant or nonmalignant causescan result in successful engraftment of donor-derivedHPC which undergo haemopoiesis to replace the mal-functioning cells of the patients immune system. HPCtransplantation is also referred to as bone marrowtransplantation (as the HPCs may be taken from thebone marrow of the donor) and stem cell transplanta-tion. HPC transplants have been successfully performedsince the late 1960s. The effectiveness of these trans-plants in terms of patient overall survival and disease-free survival has improved with each decade due tomore accurate histocompatibility matching betweendonor and patient; improved patient conditioning pro-tocols; use of therapeutic agents; prevention and treat-ment of infections; and post-transplant supportive care.The HPCs that are transplanted are derived from

the following sources:

Autologous HPC: the cells are taken from thepatientSyngeneic HPC: the donor is genetically identical to

the patient, for example an identical twin

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264 A-M. Little et al.

http://www.gradeworkinggroup.org/intro.htm#criteriahttp://www.gradeworkinggroup.org/intro.htm#criteria

Allogeneic HPC: the donor is not genetically identi-cal to the patient and can be related or unrelated.This guideline describes the selection of donors for

allogeneic HPC

HLA matching donors and patients in HPC transplantation

Amongst the many factors that contribute to successfultransplantation, the most significant is the degree ofhistocompatibility between donor and patient. Com-patibility is primarily assessed by the degree of sharingof genes that encode human leucocyte antigen (HLA)proteins and secondarily by additional genetic factorssuch as blood group and nongenetic factors includingcytomegalovirus (CMV) infection status.HLA proteins are found on the cell surface of most

cells within the human body. There are two differentclasses of HLA proteins: HLA class I (includes HLA-A, H