A Distinct Pattern of Non-HLA Polymorphisms Predicts an Increased Risk for GvHD without Benefit of GvL in HLA Matched Sibling Transplants for Chronic Myeloid Leukemia (CML).

Non-HLA polymorphisms (NHP) influence risk of GVHD and outcome of allogeneic hematopoietic stem cell transplants (HSCT) however their influence on GvHD vs GvL remains to be defined. A cohort of 291 CML HLA matched sibling transplants with known clinical risk factors; eg stage of disease, gender mismatch (female donor/male recipient), patient age and time from diagnosis to transplant as defined by the EBMT risk score, were typed via SNPs or microsatellites for cytokines (IL-1Ra, IL-4, IL-6, IL-10, IFN^gama, TNF^alfa, TNFR 11), steroid hormone receptors (VDR and ER^alfa) and NOD2/CARD15 mutations. TNFRII-196 allele R; IL-10 ATC/ACC; IL-1 Ra (allele 2) and IL-4T were significantly associated with survival using univariate analysis. Two clinical Cox proportional hazards models were generated for the statistical analysis and used as a basis for further development: (i) using the EBMT risk score as a single variable on an ordinal scale or (ii) using the individual clinical factors of the EBMT risk score as categorical variables. After step-wise variable selection using the significant genetic factors as candidates, the resulting multivariate models indicated that absence of TNFRII-196 R, i.e. down regulation of TNF^alfa in the recipient, absence of IL-10 ATC/ACC, i.e. intermediate IL-10 production in the donor and presence of IL-1Ra (allele 2) i.e. down regulation of IL-1 in the donor were associated with poor outcome. The addition of the genetic variables significantly improved the preferred model containing the EBMT risk score as a single variable. The Goodness of Fit of the models was assessed by Kaplan-Meier curves showing clinically relevant differences between good, intermediate and poor prognostic groups. The worst prognostic scores included the absence of ATA/ACC in the donor, evidenced by a steep change in survival probability. Relapse was associated with clinical factors; absence of female to male transplants; absence of bone marrow transplants and presence of T cell depletion but no significant association was found with genetic factors. This study suggests that distinct high risk patterns of NHP of patients and donors can be defined, which influences survival due to factors associated with an increased risk of GvHD without the potential benefit of increased GvL response. Data add to the clinical factors (eg age, sex, multiparity of the donor) where an unrelated donor might be the preferred choice compared to a high risk sibling donor.