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Pretransplantation vitamin A plasma levels and risk of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 55, pages 1457–1459 (2020)Cite this article

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Acute graft-versus-host disease (aGVHD) is a major cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HSCT) [1]. Vitamin A—an essential nutrient involved in epithelial integrity and immune regulation [2, 3]—seems to have a detrimental effect on aGVHD in experimental models [4,5,6,7] (yet some conflicting data exist [8]), primarily attributable to its upregulation of gut-homing receptors on T cells. This was recently challenged by a clinical study [9], which found that patients with vitamin A plasma levels below the median had a threefold higher incidence of aGVHD (mainly gastrointestinal) compared with patients with levels above the median. Moreover, in the patients, vitamin A plasma levels were negatively correlated with the expression of the gut-homing receptor CCR9 on effector memory T cells. These findings imply that vitamin A supplementation in patients undergoing HSCT may reduce the risk of aGVHD, and several clinical trials have already been initiated (NCT03039257, NCT03202849, and NCT03719092). However, in the study, vitamin A plasma levels were measured posttransplantation at a time when many cases of aGVHD occurred. Since vitamin A plasma levels decrease during inflammation [10], lower levels could merely be a reflection, and not the cause, of aGVHD. We therefore examined the association between vitamin A plasma levels measured pretransplantation and the risk of aGVHD.

We conducted a cohort study of all patients (aged >18 years) who underwent their first HSCT with myeloablative conditioning at Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark from 1 April 2015 to 31 August 2018. All patients had an EDTA plasma sample drawn around day –21 (day 0 being the day of hematopoietic stem cell infusion) for storage at –80 °C in a research biobank. Plasma vitamin A (retinol) was measured using BioRad vitamin A/E high-performance liquid chromatography kits (BioRad, München, Germany). Patient and transplant characteristics were compared using Fisher’s exact test for categorical data and Wilcoxon rank-sum test for continuous data. Cumulative incidence functions of aGVHD (defined and graded according to the Keystone criteria), gastrointestinal aGVHD and non-relapse mortality were compared using Gray’s test, treating relapse and death-without-relapse-or-aGVHD as competing risks (only relapse for non-relapse mortality). Cause-specific hazard ratios (HRs) were estimated by crude and a priori-defined adjusted Cox models with censoring at day +100, relapse or death. Confidence intervals (CIs) are reported as 95% CIs. Statistical analyses were performed using R version 3.4.1 (R Foundation for Statistical Computing, Vienna, Austria). The study was performed in accordance with the Helsinki Declaration and was approved by the Greater Copenhagen Regional Ethics Committee (approval nr. H-18012746).

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Acknowledgements

This work was supported by grants from the Danish National Research Foundation (grant number DNRF126) through PERSIMUNE, Else og Mogens Wedell-Wedellsborgs Fond, Frøken Amalie Jørgensens Mindelegat, Grosserer Valdemar Foersom og hustru Thyra Foersom født Ottos Fond, Handelsgartner Ove William Buhl Olesen og ægtefælle fru Edith Buhl Olesen’s Mindelegat, Karen A. Tolstrups Fond, Rigshospitalets Forskningspulje, Tømrermester Jørgen Holm og Hustru Elisa f. Hansens Mindelegat. The authors would like to thank Camilla Roepstorff and Heidi Petersen for their excellent work as data managers.

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  1. Bone Marrow Transplant Unit, Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Lars K. Gjærde, Niels S. Andersen, Lone S. Friis, Brian Kornblit, Søren L. Petersen, Ida Schjødt & Henrik Sengeløv

  2. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Lars K. Gjærde, Sisse R. Ostrowski & Henrik Sengeløv

  3. Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Sisse R. Ostrowski

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  1. Lars K. Gjærde
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Correspondence to Lars K. Gjærde.

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Gjærde, L.K., Andersen, N.S., Friis, L.S. et al. Pretransplantation vitamin A plasma levels and risk of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 55, 1457–1459 (2020). https://doi.org/10.1038/s41409-019-0760-5

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