Vitamin D Deficiency Predicts Acute Cutaneous Graft-Versus-Host Disease in Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation

Background: Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Previous studies have suggested the immunomodulatory effects of vitamin D may play a role in ameliorating acute GVHD pathogenesis. Vitamin D has been shown to suppress T_h1 and T_h17 cytokine production, inhibit differentiation and maturation of dendritic cells, promote T_h2-cell development, and increase expression of regulatory T-cells.  We performed a retrospective analysis to evaluate whether serum vitamin D levels on day 30 after HSCT are predictive of organ-specific GVHD.

Methods: Fifty-four patients undergoing allogeneic HSCT at the University of Pennsylvania between January 2008 and December 2012 were included in the analysis. Serum 25-hydroxyvitamin D (25OHD) concentrations were determined on day 30 following HSCT. We analyzed patients in two groups according to their median day-30 25(OH)D concentration (<20 and ≥20 ng/mL). The associations between vitamin D levels and other variables were conducted using Pearson correlations and t-tests. We then used a landmark analysis to estimate the impact of day 30 vitamin D levels on subsequent clinical outcomes. Univariate analyses were performed using cumulative incidence and Cox regression analyses. Multivariable models were constructed using the backward elimination method. We also conducted immunophenotyping of day-30 peripheral blood samples on patients who had low vs. normal vitamin D levels.

Results: The median 25(OH)D concentration on day 30 was 20 ng/mL (range 6 - 50), reflecting severe vitamin D deficiency in half of the patients. Vitamin D levels significantly correlated with age, disease type, need for TPN during transplant and day-30 albumin levels. In multivariate analysis of outcomes, day-30 vitamin D levels inversely correlated with risk of acute skin GVHD (HR 0.27; 0.07 – 1.01; p=0.05). This association was specific to patients undergoing reduced-intensity conditioned (RIC) HSCT (p<0.001) and not myeloablative HSCT (p=0.44). Vitamin D deficient patients expressed > 4-fold higher levels of CCR4, a skin-homing receptor, on peripheral blood T-cells as detected on flow cytometric analysis (p=0.036). Day 30 vitamin D levels did not significantly impact the risk of gastrointestinal (HR 2.16; 0.76 – 6.09; p=0.15) or hepatic GVHD (HR 0.31; 0.078 – 1.24; p=0.1). No differences were observed in overall acute grade 2-4 GVHD, chronic GVHD, OS or non-relapse mortality.

Conclusion: Vitamin D deficiency on day 30 after allogeneic HSCT is associated with significantly increased risk of grade 2-4 cutaneous acute GVHD and increased expression of CCR4 on peripheral blood T-cells in patients undergoing RIC HSCT. Vitamin D may confer a protective effect against acute skin GVHD via reduction in CCR4 expression.