HLA-DPB1 regulatory region genotype predicts acute GVHD

Oct 1 2015

By Lynda Williams, Senior medwireNews Reporter

Analysis of a HLA-DPB1 regulatory region variant has shed light on the risk of acute graft-versus-host disease (GVHD) in patients undergoing haematopoietic cell transplantation from an unrelated donor.

Effie Petersdorf, from Fred Hutchinson Cancer Research Center in Seattle, Washington, USA, and team began investigating the mechanisms behind HLA-DPB1 mismatch-related GVHD by genotyping the variant rs9277534 in 3505 individuals.

Finding that HLA-DPB1 expression was significantly lower in patients with rs9277534A than rs9277534G, the researchers followed up 2029 patients who underwent transplantation for acute leukaemia, chronic myeloid leukaemia or myelodysplastic syndrome.

In all, 1441 patients received transplants from unrelated donors who were matched by HLA-A, B, C, DRB1 and DQB1 with a single HLA-DPB1 mismatch in the graft-versus-host vector of incompatibility. Meanwhile, 588 recipients were given a transplant matched by HLA-A, B, C, D, DRB1, DQB1 and DPB1.

Patients who received transplants that were mismatched to their donor by the rs9277534G variant were a significant 1.32 times more likely to develop grade II, III or IV acute GVHD than recipients whose mismatch was linked to rs9277534A.

The rs9277534G variant mismatch was also associated with a significant 1.34 times greater risk of grade III or IV acute GVHD, the researchers report in The New England Journal of Medicine.

But patients with a rs9277534G-linked mismatch were less likely to relapse than those with a rs9277534A-linked mismatch, with a hazard ratio of 0.80, which the authors say is “consistent with a graft-versus-leukemia effect”.

And because the increased risk of GVHD was balanced out by the reduced risk of relapse, the overall all-cause mortality rate was comparable in the two populations. Of the 753 patients who died without disease recurrence, 31.6% had infection, 29.3% organ toxicity or failure and 19.8% developed GVHD. The remaining 19.3% died of other causes.

Nevertheless, further analysis revealed that among recipients whose donors were rs9277534A-linked HLA-DPB1, patients with rs9277534G were significantly more likely than recipients with rs9277534A to experience grade II, III or IV acute GVHD (HR=1.54) and grade III or IV GVHD (HR=1.50).

The presence of rs9277534G was also associated with an increased risk of acute GVHD in patients with HLA-A, B, C, DRB1, DQB1 and DPB1-matched transplantation, compared with its absence.

“These data suggest a schema in which minor histocompatibility antigens presented by highly expressed HLA molecules provoke robust graft-versus-host alloreactivity from the donor cells, as compared with HLA molecules expressed at low levels on the cell surface”, the researchers write.

Petersdorf et al conclude that this new information on HLA-DPB1 expression could be used to guide donor selection and reduce the risk of acute GVHD, noting that 55% of recipients with rs9277534AG could have been matched to donors by this genotype when unrelated donor searching was performed.

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