Impact of HLA-DPB1 Haplotypes on Outcome of 10/10 Matched Unrelated Hematopoietic Stem Cell Donor Transplants Depends on MHC-Linked Microsatellite Polymorphisms

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Impact of HLA-DPB1 Haplotypes on Outcome of 10/10 Matched Unrelated Hematopoietic Stem Cell Donor Transplants Depends on MHC-Linked Microsatellite Polymorphisms Florence Bettens, Jakob Passweg, Urs Schanz, Yves Chalandon, Dominik Heim, Tayfun Güngör, Georg Stussi, Grazia Nicoloso, Helen Baldomero, Alois Gratwohl, Jean-Marie Tiercy Biology of Blood and Marrow Transplantation Volume 18, Issue 4, Pages 608-616 (April 2012) DOI: 10.1016/j.bbmt.2011.09.011 Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Impact of HLA haplotype, HLA-DPB1 and MHC-linked microsatellite polymorphisms on outcome after HLA-A/B/C/DRB1/DQB1-compatible unrelated donor HSCT. (A) Impact of common/conserved haplotype on OS after 10/10 HLA allele matched unrelated donor HSCT. Common/conserved haplotype (high probability category) 107 patients, noncommon/conserved haplotype (low/intermediate category) 103 patients. For definitions, see [2]. (B) Cumulative incidence of significant aGVHD (grade II-IV) according the HLA-DPB1 matching status (see Table 2). 0 MM corresponds to a 12 of 12 antigen matched donor recipient pair, 1-2 MM includes 10-11 of 12 antigen matched pairs (bidirectional MM), 1 MM GVHD includes 11 of 12 antigen matched pairs with a DP1 MM in the GVHD direction only, 1 MM rej includes 11 of 12 matched pairs with a DPB1 mismatch in rejection direction only. (C) OS according to DPB1 matching status (see Table 2). 0 MM, 1 MM rej includes 12 of 12 antigen matched donor recipient pairs and 11 of 12 antigen matched pairs with a DPB1 mismatch in the rejection direction. 1-2 MM bi and 1 MM GVHD includes 10 of 12 antigen matched pairs and 11 of 12 antigen matched pairs with a DPB1 mismatch in the GVHD direction. (D) Kaplan-Meier OS estimates in 10 of 10 matched patients by combining donor DPB1 matching status and TNFd4/d5 genotype. Patients transplanted with a DPB1-mismatched and TNFd4/d5-positive donor (56 of 203, lower curve) show a higher mortality compared with patients transplanted with a DPB1 matched/1 DPB1 MM rejection only and a d4/d5-negative donor (upper curve, 31 of 203) (OS: 28% versus 72%, P = .001). TNFd4/d5 alone (21 of 203) and DPB1 mismatching alone (95 of 203) had less of an impact (60% ± 28% and 55% ± 20%, respectively, intermediate curves). Biology of Blood and Marrow Transplantation 2012 18, 608-616DOI: (10.1016/j.bbmt.2011.09.011) Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 MHC-resident MPs and survival. The 6 MP loci analyzed in this study are schematically represented on the HLA region with the total number of alleles detected in this patient and donor cohort. Three genotypes were significantly associated with OS. Presence of TNFd4 and/or d5 MP alleles in patient (80 of 205) (P = .007) or donor (77 of 203) (P = .003) was associated with lower survival compared with TNFd4/d5-negative patient/donor pairs. Donor MP D6S2749-231 allele (72 of 203) was also associated with lower OS (P = .02). Patient (46 of 203) and donor (40 of 202) D6S510 were associated with lower mortality risk (P = .01 and P = .075, respectively). The association of D6S265-182 with lower survival is of borderline significance (P = .053). Biology of Blood and Marrow Transplantation 2012 18, 608-616DOI: (10.1016/j.bbmt.2011.09.011) Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Survival probability for each EBMT risk score category as a function of the 2 donor-associated genetic risks, HLA-DPB1 MM and/or TNFd4/d5. Survival probability at 5 years by EBMT risk score, with low-risk (no DP mismatch, TNFd4/d5-negative, diamonds), intermediate-risk (either DP mismatch or TNFd4/d5-positive, squares), or high-risk genetic factors (DP mismatch and TNFd4/d5-positive, triangles). Having 1 or 2 of the genetic risk factors conferred an increased risk of mortality for each of the 3 EBMT risk score groups. Biology of Blood and Marrow Transplantation 2012 18, 608-616DOI: (10.1016/j.bbmt.2011.09.011) Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions