Genetic Variation In Recipient BAFF Modulates Phenotype of Chronic GvHD After HCT

Chronic graft-versus-host disease (cGvHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT). National Institute of Health (NIH) consensus criteria classification of GvHD has prognostic significance, with classic and overlap cGvHD showing better survival. Patients with classic and overlap cGvHD have clinical features mimicking autoimmune diseases. Single nucleotide polymorphisms (SNPs) of B-cell activating factor (BAFF) have been associated with development of connective tissue disorders and autoimmune diseases. BAFF is a cytokine of the tumor necrosis factor family which plays an important role in both normal and post HCT B-cell homeostasis. Elevated BAFF to B-cell ratio after HCT can predict for the development of cGvHD. We hypothesized that recipient and/or donor BAFF SNPs would be associated with the phenotype of GvHD following HCT. Adult patients undergoing HCT (cord transplant excluded) at a single center (1999-2008), with a minimum survival of 120 days, and with the availability of pre-transplant recipient and donor germline DNA samples were included (n=164). GvHD was phenotyped per NIH criteria. Twenty tagSNPs of the BAFF gene were identified using previously published criteria. Genotyping was performed with the GoldenGate assay of the VeraCode technology using the BeadXpress reader system. P-values were generated using logistic regression and adjusted for false discovery rate (FDR). GvHD after day 100 occurred in 124 (76%) patients [delayed/recurrent acute GvHD (aGVHD) (n=23), overlap GvHD (n=29) and classic cGvHD (n=72)]. Patients with classic and overlap cGvHD had improved overall survival (OS) compared to patients with aGvHD and no GvHD (P=0.007). Due to shared clinical phenotype and similar survival characteristics, overlap and classic cGvHD were combined into a single outcome variable to test for association with BAFF SNPs. In univariate analyses, there were no differences in patient characteristics between classic/overlap vs. acute/no GvHD. Variables included in analysis were: age, gender, race, disease diagnoses, disease risk, stem cell source, regimen intensity, donor type, HLA match, GvHD prophylaxis, use of irradiation, CMV serostatus, aGVHD grade prior to day 100, bilirubin level and platelet count at day 100 post allo-SCT. In single SNP analyses 9 (donor-2, recipient-7) of the 20 tag SNPs had significant P values of <0.05 when comparing classic/overlap cGvHD vs. aGvHD/no GvHD. Remainder of the analyses were on recipient SNPs only. Adjusting for FDR, 4 recipient SNPs remained significant and included in multivariate analyses using classic chronic/overlap cGvHD as reference category. All 4 BAFF SNPs, rs16972217 [odds ratio (OR) 2.72, 95% CI 1.38 –5.39, P=0.004], rs7993590 [OR 2.35 95% CI 1.22–4.55,P=0.011], rs12428930 [OR 2.53, 95% CI 1.27–5.04, P=0.008] and rs2893321 [OR 2.48, 95% CI 1.25–4.92,P=0.009] were independent predictors of late/recurrent aGvHD or no aGVHD (Figure), adjusted for “conventional” predictors of cGvHD [donor status (related vs. unrelated), stem cell source (bone marrow vs. peripheral blood stem cells), and aGvHD prior to day 100 (grade 0–1 vs. 2–4)]. Our study is the first to show that genetic variation of BAFF can predict the phenotype of GvHD after HCT. None of the known clinical predictors of limited/extensive cGVHD were associated with classic or overlap cGvHD. Correlations of serum BAFF levels with BAFF SNPs are being studied. The ability of BAFF SNPs to predict efficacy of rituximab in prevention and treatment of cGVHD needs to be investigated to allow for an individualized approach in the management of GvHD.