A randomized phase 2 trial of oral vitamin A for graft-versus-host disease in children and young adults.

Vitamin A plays a key role in the maintenance of gastrointestinal homeostasis and promotes a tolerogenic phenotype in tissue resident macrophages. We conducted a prospective randomized double-blinded placebo-controlled clinical trial in which 80 hematopoietic stem cell transplant recipients were randomized 1:1 to receive pre-transplant high-dose vitamin A or placebo. A single oral dose of vitamin A of 4000 I.U/kg, maximum 250,000 I.U was given prior to conditioning. Primary endpoint was incidence of acute GVHD at day+100. In an intent-to-treat analysis, incidence of acute GVHD was 12.5% in vitamin A arm and 20% in placebo (p=0.5). Incidence of acute GI GVHD was 2.5% in the vitamin A arm (p=0.09) and 12.5% in placebo at day+180. Incidence of chronic GVHD was 5% in the vitamin A arm and 15% in placebo (p=0.02) at 1 year. In an "as treated" analysis, cumulative incidence of acute GI GVHD at day+180 was 0% in vitamin A recipients and 12.5% in placebo (p=0.02) and chronic GVHD incidence 2.7% in the vitamin A recipients and 15% in placebo (p=0.01). The only possibly attributable toxicity was asymptomatic grade 3 hyperbilirubinemia in one vitamin A recipient at day+30, which self-resolved. Absolute CCR9+ CD8+effector memory T-cells, reflecting gut T-cell trafficking, were lower in the vitamin A arm at day+30 after HSCT (p=0.01). Levels of serum amyloid A-1, a vitamin A transport protein with pro-inflammatory effects, were lower in the vitamin A arm. The vitamin A arm had lower IL-6, IL-8, ST2 levels and likely more favorable gut microbiome and short chain fatty acids. Pre-HSCT oral vitamin A is inexpensive, has low toxicity and reduces GVHD (clinicaltrials.gov NCT03202849).