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

ABSTRACT: 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.

Ruxolitinib Pharmacokinetics and Pharmacodynamics in Children with Acute and Chronic Graft-versus-Host Disease.

We evaluated the pharmacokinetics (PK) of oral ruxolitinib in children with steroid-refractory acute graft-versus-host disease (aGVHD) (age <12 years) and chronic GVHD (cGVHD) (age ≤18 years) using our published pediatric dosing. PK sampling was performed before and 2 hours after ruxolitinib administration in patients with established cGVHD. More extensive PK analyses were performed in patients with newly diagnosed aGVHD or cGVHD before and .5, 1, 2, 4, and 6 hours after ruxolitinib administration in patients weighing >10 kg and before, 3+, and 6+ hours in children weighing <10 kg. pSTAT1, pSTAT3, and pSTAT5 expression levels were measured on CD4+ and CD8+ T cells before and 2 hours after ruxolitinib administration as a pharmacodynamic marker of JAK/STAT inhibition. Thirteen patients were prospectively enrolled, including 8 with existing cGVHD (age 0 to ≤18 years), 4 with new-onset steroid-refractory aGVHD (age 0 to <12 years) and 1 with newly diagnosed steroid-refractory cGVHD. Great variability in PK was seen. Mean oral clearance (CL/F) was 7.76 ± 4.09 L/h (range, 3.1 to 15.3 L/h). The average elimination half-life was 2.32 ± 1.0 hours. Mean ruxolitinib clearance was higher in children age <2 years versus those age >2 years (12.1 ± 3.0 L/h versus 5.7 ± 2.8 L/h; P = .005) and was reduced with concurrent treatment with azoles and azithromycin. We saw a variable reduction in pSTAT1/3/5 expression on T cells at time of peak ruxolitinib absorption (2 hours after dosing). Children <10 kg had lower ruxolitinib exposure, possibly due to inherent increased drug clearance or variability in dosing methods, leading to decreased drug absorption.