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

• Published in: Blood Vol. 143; no. 12; pp. 1181 - 1192
• Main Authors: Khandelwal, Pooja, Langenberg, Lucille, Luebbering, Nathan, Lake, Kelly E., Butcher, Abigail, Bota, Kylie, Ramos, Kristie N., Taggart, Cynthia, Choe, Hannah, Vasu, Sumithira, Teusink-Cross, Ashley, Koo, Jane, Wallace, Gregory, Romick-Rosendale, Lindsey, Watanabe-Chailland, Miki, Haslam, David B., Lane, Adam, Davies, Stella M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.03.2024
• Subjects: Child; Graft vs Host Disease - drug therapy; Graft vs Host Disease - etiology; Hematopoietic Stem Cell Transplantation - adverse effects; Humans; Prospective Studies; Vitamin A; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2023022865

•High-dose oral vitamin A pre-HSCT was feasible with minimal toxicity in a randomized double-blinded placebo-controlled trial in children.•Vitamin A given in a presumed homeostatic environment before HSCT may lower GVHD. [Display omitted] 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 recipients of hematopoietic stem cell transplantation (HSCT) were randomized 1:1 to receive pretransplant high-dose vitamin A or placebo. A single oral dose of vitamin A of 4000 IU/kg, maximum 250 000 IU was given before conditioning. The primary end point was incidence of acute graft-versus-host disease (GVHD) at day +100. In an intent-to-treat analysis, incidence of acute GVHD was 12.5% in the vitamin A arm and 20% in the placebo arm (P = .5). Incidence of acute gastrointestinal (GI) GVHD was 2.5% in the vitamin A arm (P = .09) and 12.5% in the placebo arm at day +180. Incidence of chronic GVHD was 5% in the vitamin A arm and 15% in the placebo arm (P = .02) at 1 year. In an “as treated” analysis, cumulative incidence of acute GI GVHD at day +180 was 0% and 12.5% in recipients of vitamin A and placebo, respectively (P = .02), and cumulative incidence of chronic GVHD was 2.7% and 15% in recipients of vitamin A and placebo, respectively (P = .01). The only possibly attributable toxicity was asymptomatic grade 3 hyperbilirubinemia in 1 recipient of vitamin A 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 = .01). Levels of serum amyloid A-1, a vitamin A transport protein with proinflammatory effects, were lower in the vitamin A arm. The vitamin A arm had lower interleukin-6 (IL-6), IL-8, and suppressor of tumorigenicity 2 levels and likely a more favorable gut microbiome and short chain fatty acids. Pre-HSCT oral vitamin A is inexpensive, has low toxicity, and reduces GVHD. This trial was registered at www.ClinicalTrials.gov as NCT03202849. Low levels of vitamin A have been associated with the development of gastrointestinal graft-versus-host disease (GVHD). Khandelwal et al report on the results of a randomized, placebo-controlled phase 2 trial in which a single dose of oral vitamin A given to children prior to conditioning resulted in no improvement in the incidence of acute GVHD compared to placebo but was associated with lower rates of chronic GVHD.