Vitamin A keeps the GVHD away?

In this issue of Blood, 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 prior to conditioning resulted in no decrease in the incidence of acute graft-versus-host disease (GVHD) compared with placebo (12.5% vs 20%, P = .5), but showed surprisingly lower rates of chronic GVHD (5% vs 15%, P = .02).¹ 

Effective approaches to the prevention of GVHD remain of high importance for patients undergoing allogeneic hematopoietic cell transplantation (HCT). Historical approaches to GVHD prophylaxis have been marred by limited efficacy.² More recently, wider application of high-dose posttransplant cyclophosphamide (PTCy) has proven to be a superior approach to prevent both acute and chronic GVHD.³ However, concerns about delayed lymphocyte recovery and infectious risks after PTCy remain, and additional room for improvement in efficacy exists, especially in chronic GVHD.

Much interest surrounds the development of therapeutics that target intestinal biology, given the complex interplay between the immune system and the intestinal microbiome in acute GVHD pathophysiology.⁴ The authors describe an easy and inexpensive investigational approach to enhance GVHD prophylaxis with vitamin A supplementation. Building on their previous work,⁵ the rationale for vitamin A in the setting of allogeneic HCT is to decrease inflammatory cytokines by inducing a tolerogenic dendritic cell phenotype along the intestines.⁶ By enacting this biological shift prior to HCT, the intervention may be able to limit the subsequent development of lower gastrointestinal (GI) acute GVHD.

Although the trial did not meet its primary end point, the acute GVHD findings are compelling. The primary end point was acute GVHD, regardless of grade or organ involvement. More pertinent to the study rationale, the rates of lower GI acute GVHD were quite low (2.5%) for participants receiving vitamin A, but did not meet statistical significance compared with placebo in this moderately sized trial. Select correlative studies from both blood and stool support the biological action of vitamin A over placebo. Where do we go from here? A logical next step would be to conduct a larger trial of vitamin A supplementation in adult allogeneic HCT recipients. It is unclear how vitamin A would impact the incidence of severe, lower GI acute GVHD in this setting, given the already low rates of severe GVHD with PTCy prophylaxis. Of note, only 2 participants received PTCy in the study.

The chronic GVHD findings were unexpected. Currently, the development of chronic GVHD is not thought to be directly impacted by early changes in intestinal biology or microbiome composition.⁷ It could be that the authors have unearthed a previously unrecognized pathway for prevention of chronic GVHD, but other contributing factors must be considered. Although similarly distributed among participants in both arms, significant heterogeneity exists in both patient (underlying diagnosis) and transplant (donor match, stem cell source, choice of GVHD prophylaxis) characteristics. Subsequent trials should strive to administer vitamin A to participants receiving a single GVHD prophylaxis to limit potential confounding factors. This key secondary end point also warrants further investigation in a larger trial of adults, where the incidence of chronic GVHD is typically higher than that observed in pediatric populations.⁸ 

Khandelwal and colleagues should be congratulated for conducting this randomized, placebo-controlled trial in pediatric transplant recipients. Their findings are thought-provoking, hold much promise, and warrant future research to better characterize the potential impact of this simple, yet novel, approach to preventing GVHD.

Conflict-of-interest disclosure: Z.D. receives research support from Incyte, Regimmune, and Taiho Oncology, and has received consulting fees from Sanofi, Incyte, MorphoSys AG, Inhibrx, PharmaBiome AG, and Ono Pharmaceutical.