Effect of HLA-Matching on Outcome of Hematopoietic Stem Cell Transplantation from Unrelated Donors: A IBMDR-GITMO Study.

Background HLA-matching between patient and donor is critical for outcome of haematopoietic stem cell transplantation (HSCT) performed from an unrelated donor, together with other non-HLA factors. A 10/10-matched donor is the most suitable for HSCT, when possible; however, a certain degree of HLA-incompatibility has to be accepted when such a donor is not available.

Aim of the study This is a prospective multicenter GITMO study in which patients were enrolled as 6/6” matched (matched at loci A, B at low resolution level and DRB1 at high resolution) or as “5/6” matched (one low-resolution mismatch (MM) at locus A or B). High resolution typing is now available as well.

Patients. Eligible were patients with a haematological malignancy, aged > 18 years old, activating an unrelated donor search in Italy from January 1999 to June 2006. Patients with chronic myeloid leukaemia were excluded from the analysis. A total of 1069 patient-donor pairs were analyzed; median follow-up for alive pts was 23 months (range: 3–96). According to disease status at HSCT, pts were classified as “early” (de novo acute myeloid or lymphoblastic leukemia in first complete remission, n=241) and “advanced” (all others, n=828) pts. Univariate and multivariate analysis with Cox regression included main non-HLA factors known to be associated with HSCT outcome. No differences in overall survival (OS) was observed between 5/6-matched (n=101) and 6/6-matched (n=968) pts (fig.1). There was a non-statistically significant trend toward a lower relapse-related death (RRD) in 5/6-matched compared to 6/6-matched pts was observed (5y-RRD: 18% vs 24%, respectively; p=0.13). We then proceeded to test the effect of the C locus: in multivariate analysis, the presence of an antigenic MM at locus C was associated with a worse OS, regardless of matching at loci A or B (RR 1.18, 95% C.I.: 1.00–1.40, p=0.05); the presence of a MM at locus B and/or C significantly affected transplant-related mortality (TRM) (RR 1.57, 95% C.I.: 1.02–2.44, p=0.04; RR 1.31, 95% C.I.: 1.04–1.65, p=0.02, respectively), MM at locus B or C was also associated with development of grade II-IV acute graft-versus-host disease (aGVHD) on multivariate analysis, together with “non-use” of ATG (ATG use: RR 0.70, 95% C.I. 0.52–0.95, p=0.02).

Conclusions, The outcome of so called 5/6 and 6/6 HLA matched unrelated donor transplants is comparable: this may be due to the fact that the C locus is not taken in to account in the “5/6 or 6/6” definition. Indeed a mismatch at locus C is associated with worse outcome. MM at locus B or C, but not at locus A, increases the risk of developing grade II-IV aGVHD. Use of ATG reduces aGVHD rates, thus attenuating the adverse effect of MMs at loci B and C on HSCT outcome.