Vitamin A before stem cell transplant ‘potentially practice changing’ to lower GVHD risk
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Key takeaways:
- Vitamin A supplementation reduced GVHD with low toxicity among children and young adults prior to HSCT.
- The results are potentially practice changing for patients in low-resource environments.
High-dose oral vitamin A prior to hematopoietic stem cell transplantation reduced the incidence of graft-versus-host disease with minimal toxicity, according to study data published in Blood.
Results from a randomized phase 2 trial showed improvements in both the incidence of acute graft-versus-host disease (GVHD) and acute gastrointestinal (GI) GVHD 180 days or more after transplant compared with placebo, researchers wrote.
“Our randomized phase 2 study found that a high dose of oral vitamin A given before HSCT reduces chronic GVHD in pediatric recipients of allogeneic HSCT in intent-to-treat and as-treated analyses, and additionally reduces acute GI GVHD in an as-treated analysis,” Pooja Khandelwal, MD, associate professor at Cincinnati Children’s Hospital Medical Center, and colleagues wrote. “The intervention had no clinically significant adverse effects and cost ~$1.25 per patient. This strategy is potentially practice changing, particularly in low-resource environments.”
Background, methods
Vitamin A is important for GI homeostasis maintenance and also promotes a tolerogenic phenotype in tissue resident macrophages, according to background information provided by study investigators.
Khandelwal and colleagues conducted a prospective, double-blinded trial to evaluate the anti-inflammatory capabilities of high-dose vitamin A supplementation prior to hematopoietic stem cell transplantation (HSCT) and its effect on the incidence of GVHD.
Researchers randomly assigned 80 patients to receive either pretransplant high-dose vitamin A or placebo.
Eligible patients included individuals who had pre-HSCT serum vitamin A levels below the 75th centile of normal range for age, had been scheduled to undergo an allogeneic HSCT and could tolerate enteral medications; children aged at least 12 months could participate, with all underlying diagnoses eligible.
The incidence of GVHD by day 100 or longer after HSCT served as the study’s primary endpoint. Secondary endpoints included incidence of grade 2 to grade 4 acute GVHD, steroid-refractory acute GVHD and acute GI GVHD by day 180 or longer, and 1-year incidence of chronic GVHD.
Patients received a single dose of vitamin A at 4,000 IU/kg (maximum of 250,000 IU) prior to conditioning.
Results, next steps
Among patients in the intent-to-treat population, researchers noted an incidence of acute GVHD of 12.5% among patients that received vitamin A and 20% for those who received placebo.
Researchers also reported an acute GI GVHD rate of 2.5% in the vitamin A arm and 12.5% in the placebo arm at day +180.
A separate “as treated” study population analysis showed no cases of acute GI GVHD at day +180 in the vitamin A cohort compared with a cumulative incidence rate of 12.5% in the placebo cohort.
The same “as treated” analysis revealed a cumulative incidence of chronic GVHD of 2.7% among patients in the vitamin A cohort and 15% in the placebo cohort.
Study investigators observed one case of treatment-related toxicity attributed to vitamin A supplementation — one patient who received vitamin A 30 days or more after transplant experienced self-resolving asymptomatic grade 3 hyperbilirubinemia.
Study limitations identified by the researchers included a heterogenous patient population that received various regimens for acute GVHD prophylaxis.
“Our data will need to be confirmed in future studies before firm conclusions are drawn,” researchers wrote.
Despite no plans in the original study design, researchers performed a blinded interim data analysis with incomplete enrollment to determine any effect the COVID-19 pandemic had on the results.
“After observing a statistically significant difference in the incidence of chronic GVHD in [one] arm, our medical monitor advised us to unblind the study because of patient safety concerns,” Khandelwal and colleagues wrote “We proceeded with unblinding and releasing our results early, recognizing that this could inflate the study type I error, a further limitation of this study. We recognize the importance of replicating and extending these studies to adult recipients of HSCT, and this work is underway.”
In an accompanying editorial, Zachariah DeFilipp, MD, of the blood and marrow transplant program at Massachusetts General Hospital stated that although the study did not meet its primary endpoint, the data it produced still generated encouraging findings to support vitamin A supplementation prior to HSCT.
He agreed with the original researchers that a larger trial including adults would be a good next step to investigate this topic, while also applauding the researchers for producing eye-opening data related to chronic GVHD.
“It is unclear how vitamin A would impact the incidence of severe, lower GI acute GVHD in [adult allogeneic HCT recipients], given the already low rates of severe GVHD with [posttransplant cyclophosphamide] prophylaxis,” DeFilipp wrote.
“The chronic GVHD findings were unexpected,” he added. “Currently, the development of chronic GVHD is not thought to be directly impacted by early changes in intestinal biology or microbiome composition. It could be that the authors have unearthed a previously unrecognized pathway for prevention of chronic GVHD, but other contributing factors must be considered.”
References:
- DeFilipp Z, et al. Blood. 2024;doi:10.1182/blood.2024023828.
- Khandelwal P, et al. Blood. 2024;doi:10.1182/blood.2023022865.
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