Compared with placebo, a high dose of oral vitamin A given before a hematopoietic cell transplant (HCT) did not reduce the incidence of acute graft-versus-host disease (GVHD) in children. However, the results of a phase II study published in Blood found that high-dose vitamin A given pre-HCT reduced chronic GVHD in this population and reduced acute gastrointestinal (GI) GVHD in an as-treated analysis.1
Vitamin A maintains immune homeostasis in the gut, coordinating innate and adaptive immunity, and induces a tolerogenic phenotype of gut resident dendritic cells. These cells then produce lower levels of pro-inflammatory cytokines, such as interleukin-6. It has been previously shown that low plasma vitamin A levels are associated with higher incidence of acute GI GVHD.2
“Our study could change clinical practice,” said corresponding author Pooja Khandelwal, MD, of Cincinnati Children’s Hospital Medical Center in Ohio. “Oral vitamin A is a simple, affordable intervention with minimal toxicity when offered as a single dose once before conditioning chemotherapy and, if validated in larger-scale studies, could prevent clinically relevant GVHD.”
In this prospective, randomized, double-blind, placebo-controlled trial, 80 patients scheduled to undergo HCT were randomly assigned in a 1:1 ratio to receive pretransplant high-dose vitamin A (4,000 IU/kg to a maximum of 250,000 IU) or placebo. The groups of vitamin A (median age = 6.9 years) and placebo (median age = 8.5 years) recipients presented with similar transplant characteristics. Participants with vitamin D levels below 50 ng/mL received a single high dose of vitamin D.
Of the patients assigned vitamin A, seven received an additional half-dose of oral vitamin A as their vitamin A levels dropped below their enrollment levels; one patient did not take the assigned vitamin A dose; and two patients had significant delays between dosing and undergoing an HCT. These patients were included in the intent-to-treat analysis but excluded from the as-treated analysis.
The primary endpoint was the incidence of grade 1-4 acute GVHD by day 100 post-HCT (day +100). Secondary endpoints included grade 2-4 acute GVHD by day +180, acute GI GVHD by day +180, steroid-refractory acute GVHD by day +180, and chronic GVHD by one year.
“Vitamin A was given once, orally, before starting conditioning chemotherapy to children who had vitamin A levels below the 75th percentile of normal range for age,” Dr. Khandelwal said. “Optimizing vitamin D levels before giving vitamin A could be important, as both act on similar nuclear receptors, and adequate levels of vitamin D are likely crucial to see the fullest effects of vitamin A.”
In the intent-to-treat analysis, no significant between-group differences were seen in the incidence of grade 1-4 acute GVHD, which the authors explained was driven by the incidence of grade 1 skin GVHD in both groups, a condition that was responsive to steroids. The grade 1-4 acute GVHD incidence by day +100 was 12.5% in the vitamin A group versus 20% in the placebo group (p=0.5). The respective cumulative incidences of grade 2-4 acute GVHD by day +180 were 2.5% and 12.5% (p=0.09). The cumulative incidence of acute GI GVHD by day +180 was 2.5% in the vitamin A group versus 12.5% in the placebo group (p=0.09). However, significant differences were seen in the chronic GVHD incidences at one year, which was 5% for vitamin A and 15.3% for placebo (p=0.02). The grades of chronic GVHD were moderate in the vitamin A group and moderate or severe in the placebo group.
In the as-treated analysis, the grade 1-4 acute GVHD incidence by day +100 was 8% in the vitamin A group and 20% in the placebo group (p=0.2). The respective cumulative incidences for both grade 2-4 acute GVHD and acute GI GVHD were 0% and 12.5% (p=0.02). The cumulative incidences of steroid-refractory acute GVHD by day +180 was 0% in the vitamin A group and 10% in the placebo group (p=0.049). At one year, the respective chronic GVHD incidences were 2.7% and 15.3% (p=0.01).
The intervention, which cost around $1.25 per patient, had no clinically significant adverse effects. One vitamin A recipient experienced asymptomatic grade 3 hyperbilirubinemia at day +30, which self-resolved.
“High-dose oral vitamin A had minimal toxicity and was well tolerated, as timing was before chemotherapy-induced nausea and emesis,” Dr. Khandelwal said.
Limitations to the study included the incomplete availability of biospecimens, such as gut resident dendritic cells, and the heterogenous patient population on various acute GVHD prophylactic regimens. Because of patient safety concerns, the researchers unblinded the study after finding a significant difference in chronic GVHD in one group. The authors noted that they will need to confirm the findings in future studies before conclusions are drawn.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
- Khandelwal P, Langenberg L, Luebbering N, et al. A randomized phase 2 trial of oral vitamin A for graft-versus-host disease in children and young adults [published online ahead of print, 2024 Jan 16]. Blood. doi: 10.1182/blood.2023022865.
- Lounder DT, Khandelwal P, Dandoy CE, et al. Lower levels of vitamin A are associated with increased gastrointestinal graft-versus-host disease in children. Blood. 2017;129(20):2801-2807.