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1.
A randomized phase 2 trial of oral vitamin A for graft-versus-host disease in children and young adults
Khandelwal, P., Langenberg, L., Luebbering, N., Lake, K., Butcher, A., Werling, K., Ramos, K. N., Taggart, C., Choe, H. K., Vasu, S., et al
Blood. 2024
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Editor's Choice
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 hematopoietic stem cell transplant recipients were randomized 1:1 to receive pre-transplant high-dose vitamin A or placebo. A single oral dose of vitamin A of 4000 I.U/kg, maximum 250,000 I.U was given prior to conditioning. Primary endpoint was incidence of acute GVHD at day+100. In an intent-to-treat analysis, incidence of acute GVHD was 12.5% in vitamin A arm and 20% in placebo (p=0.5). Incidence of acute GI GVHD was 2.5% in the vitamin A arm (p=0.09) and 12.5% in placebo at day+180. Incidence of chronic GVHD was 5% in the vitamin A arm and 15% in placebo (p=0.02) at 1 year. In an "as treated" analysis, cumulative incidence of acute GI GVHD at day+180 was 0% in vitamin A recipients and 12.5% in placebo (p=0.02) and chronic GVHD incidence 2.7% in the vitamin A recipients and 15% in placebo (p=0.01). The only possibly attributable toxicity was asymptomatic grade 3 hyperbilirubinemia in one vitamin A recipient 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=0.01). Levels of serum amyloid A-1, a vitamin A transport protein with pro-inflammatory effects, were lower in the vitamin A arm. The vitamin A arm had lower IL-6, IL-8, ST2 levels and likely more favorable gut microbiome and short chain fatty acids. Pre-HSCT oral vitamin A is inexpensive, has low toxicity and reduces GVHD (clinicaltrials.gov NCT03202849).
PICO Summary
Population
Children aged 12 months and over with pre transplant vitamin A levels below 75th centile of normal range for age, from a single centre in USA (n=80)
Intervention
A single oral dose of vitamin A of 4000 I.U/kg, maximum 250,000 I.U prior to conditioning pre-transplant (n=40)
Comparison
Placebo (n=40)
Outcome
In an intent-to-treat analysis, incidence of acute GVHD was 12.5% in vitamin A arm and 20% in placebo. Incidence of acute GI GVHD was 2.5% in the vitamin A arm and 12.5% in placebo at day+180. Incidence of chronic GVHD was 5% in the vitamin A arm and 15% in placebo at 1 year. In an "as treated" analysis, cumulative incidence of acute GI GVHD at day+180 was 0% in vitamin A recipients and 12.5% in placebo and chronic GVHD incidence 2.7% in the vitamin A recipients and 15% in placebo. The only possibly attributable toxicity was asymptomatic grade 3 hyperbilirubinemia in one vitamin A recipient 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. Levels of serum amyloid A-1, a vitamin A transport protein with pro-inflammatory effects, were lower in the vitamin A arm. The vitamin A arm had lower IL-6, IL-8, ST2 levels and likely more favorable gut microbiome and short chain fatty acids.
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2.
Secondary Oral Cancer after Systemic Treatment of Hematological Malignancies and Oral GVHD: A Systematic Review
Janowiak-Majeranowska, A., Osowski, J., Mikaszewski, B., Majeranowski, A.
Cancers. 2022;14(9)
Abstract
(1) Purpose: In this article, the authors decided to systematically review the available literature to identify potential correlations regarding secondary oral carcinoma occurring after hematological systemic treatment and oral chronic graft-versus-host disease. (2) Methods: Medline (PubMed) and Scopus (Elsevier) databases were searched, including articles from the years 2002-2022. The 33 unique results were assessed by a PRISMA flowchart, and we rejected 24 papers and included 9 articles in the review. (3) Results: The majority of patients suffered from the oral form of chronic graft-versus-host disease before the diagnosis of oral malignancy. Two common cancer sites were the tongue and buccal mucosa. The exact percentage of secondary oral carcinoma after hematopoietic stem cell transplantation could not be estimated due to a lack of data. (4) Conclusions: Every physician taking part in the follow-up of patients after hematological treatment should be aware of the possibility of secondary neoplastic disease in the oral cavity, especially in patients with oral graft-versus-host disease. Proper follow-up protocols and monitoring are needed in this patient group as the cause of these cancers appears to be multifactorial.
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3.
Pre-transplantation vitamin E levels and acute graft-versus-host disease after non-myeloablative allogeneic hematopoietic cell transplantation
Gjærde, L. K., Ostrowski, S. R., Jørgensen, N. R., Schierbeck, F., Andersen, N. S., Friis, L. S., Kornblit, B., Petersen, S. L., Schjødt, I., Sengeløv, H.
Transplant immunology. 2022;74:101650
Abstract
BACKGROUND Low pre-transplantation plasma vitamin E levels have been associated with increased risk of acute graft-versus-host disease (GvHD) after myeloablative allogeneic hematopoietic cell transplantation (allo-HCT). We aimed to investigate the association between pre-transplantation plasma vitamin E levels and acute GvHD in patients undergoing allo-HCT with non-myeloablative conditioning. METHODS In a cohort of 194 adults who underwent non-myeloablative allo-HCT at Rigshospitalet between July 2015 and December 2019, we measured pre-transplantation plasma vitamin E levels by high-performance liquid chromatography in stored plasma samples. Univariable ordinary least squares linear models were used to investigate associations between vitamin E levels and patient characteristics. A multivariable logistic regression model was used to estimate the association between vitamin E levels and grade II-IV acute GvHD, adjusted for recipient age, donor age, female-male donor-recipient pairing, and donor type. RESULTS The median (Q1, Q3) pre-transplantation plasma vitamin E level was 32.3 (26.4, 40.4) μmol/L. No patients had a vitamin E level below the normal reference range. Vitamin E levels were higher in females (mean difference: 8.0 μmol/L, 95% confidence interval [CI]: 4.9, 11.1 μmol/L) and in patients transplanted for acute leukemia (mean difference: 6.2 μmol/L, CI: 3.0, 9.4 μmol/L). Grade II-IV acute GvHD developed in 33 (17%) patients. Patients who developed acute GvHD had similar pre-transplantation vitamin E levels compared with patients who did not develop grade II-IV acute GvHD (mean difference: 0.7 μmol/L, bootstrap CI: -3.3, 4.7 μmol/L). In the adjusted logistic regression model, an increase in the pre-transplantation vitamin E level from 26.4 (Q1) to 40.4 (Q3) μmol/L was associated with an odds ratio of grade II-IV acute GvHD of 1.17 (CI: 0.64, 2.12). CONCLUSIONS Contrary to the previously reported association between pre-transplantation vitamin E levels and acute GvHD after myeloablative allo-HCT, we did not find support for an association in patients who received non-myeloablative conditioning. The potential protective effects of vitamin E may not be efficacious in the reduced inflammatory response following non-myeloablative conditioning.
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Pre-transplantation plasma vitamin D levels and acute graft-versus-host disease after myeloablative hematopoietic cell transplantation in adults
Gjærde, L. K., Ostrowski, S. R., Andersen, N. S., Friis, L. S., Kornblit, B., Petersen, S. L., Schjødt, I., Sengeløv, H.
Transplant immunology. 2021;:101437
Abstract
BACKGROUND The association between vitamin D and acute graft-versus-host disease (GvHD) remains controversial, especially for patients receiving myeloablative conditioning. METHODS We measured pre-transplantation plasma vitamin D (25-hydroxyvitamin D(3)?+?D(2)) levels by competitive electrochemiluminescence in plasma samples from 116 adult patients who underwent a myeloablative allogeneic transplantation at Rigshospitalet, Copenhagen between July 2015 and August 2018. RESULTS The median (Q1, Q3) pre-transplantation plasma vitamin D level was 64 (47, 85) nmol/L (normal range: 50-160?nmol/L). Vitamin D insufficiency (<50?nmol/L) and moderate deficiency (<25?nmol/L) were observed in 29% and 8% of patients, respectively. No patients had a severe deficiency (<12?nmol/L). Pre-transplantation vitamin D levels were slightly higher in patients who later developed grade II-IV acute GvHD (mean difference: 8.1?nmol/L), but the 95% confidence interval [CI] encompassed clinically insignificant differences (CI: -2.2, 19.2?nmol/L). From multivariable logistic regression, we found that a patient with a pre-transplantation vitamin D level of 85?nmol/L (Q3) had 1.5 times higher odds of grade II-IV acute GvHD than a patient with a level of 47?nmol/L (Q1; CI of odds ratio: 0.84, 2.7; adjusted for patient age, donor type, use of anti-thymocyte globulin, and use of 12?Gy total-body irradiation). Patients with pre-transplantation vitamin D insufficiency (N?=?34) had a cumulative incidence of grade II-IV acute GvHD similar to that of patients with vitamin D sufficiency (26% [CI: 11%, 42%] versus 35% [CI: 25%, 46%], respectively). CONCLUSIONS Our data did not support an association between pre-transplantation vitamin D levels or vitamin D insufficiency and acute GvHD in adult patients receiving myeloablative conditioning.
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5.
Challenging and Practical Aspects of Nutrition in Chronic Graft-versus-Host Disease
Pereira, A. Z., Gonçalves, S. E. A., Rodrigues, M., Hamerschlak, N., Flowers, M. E.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020;26(11):e265-e270
Abstract
There is a paucity of information about nutrition in chronic graft-versus-host disease (GVHD). The role of nutrition is important because malnutrition is strongly associated with severe chronic GVHD manifestations. There is a high prevalence of metabolic syndrome and osteoporosis in this setting. Here we review the literature, describe main aspects of nutrition and discuss macronutrients (ie, vitamins), micronutrients (ie, Mg, Zn, Ca, and K) and supplements (probiotics and omega 3 fatty acids). A search was carried out in March 2020 using PubMed. Databases were screened for searching terms in titles and abstracts referring to chronic GVHD, nutrition intervention, protein, and body composition. Data were extracted for the following outcomes: nutrition, nutrition intervention, chronic GVHD, nutrition deficiencies, diet, vitamin, dry eye, probiotic, protein, and body composition. In this report, we summarize interventional nutrition studies reported in oncology and metabolic syndrome settings and describe our nutritional clinical practice in hematopoietic cell transplantation and chronic GVHD. The impact of nutrition evaluation and intervention on muscle mass loss, dry eye, dysgeusia, metabolic syndrome, osteoporosis, and comorbidities associated with chronic GVHD need to be studied prospectively.
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Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Graft- versus -host disease
Pereira, A. Z., Vigorito, A. C., Almeida, A. M., Candolo, A. A., Silva, A. C. L., Brandao-Anjos, A. E. P., Sa, B. L., Souza, C. L. S., Castro Junior, C. G., Oliveira, J. S. R., et al
Einstein (Sao Paulo, Brazil). 2020;18:eAE4799
Abstract
The Brazilian Consensus on Nutrition in Hematopoietic Stem Cell Transplantation: Graft- versus -host disease was approved by Sociedade Brasileira de Transplante de Medula Ossea , with the participation of 26 Brazilian hematopoietic stem cell transplantation centers. It describes the main nutritional protocols in cases of Graft- versus -host disease, the main complication of hematopoietic stem cell transplantation.
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Oral nutritional support to adult patients with acute intestinal Graft Versus Host Disease (GVHD): A proposal for dietary intervention as a model to clinical trials
Chiconato, G. C., Campos, D. J., Thomaz, A. C., Moreira Funke, V. A., Vilela, R. M.
Clinical nutrition ESPEN. 2020;40:369-375
Abstract
BACKGROUND Acute Graft Versus Host Disease (GVHD) affects about 20%-80% of the patients after the hematopoietic stem cell transplant (HSCT) and it is amongst the main causes of morbidity and mortality both in children and adults. The intestine is one of the most affected organs by GVHD causing important alterations in the nutritional status and quality of life, considering that the dysfunctional intestine could decrease food intake as well as an inappropriate dietary plan could worsen the clinical condition. In addition to GVHD, chemotherapy conditioning regimen suppresses the immune system, promotes mucositis and increases the risk of infectious complications. Taking the above into consideration, when per oral diet is possible; the food choices should be carefully planned and monitored to promote nutritional support and avoid worsening the intestinal function and clinical condition. OBJECTIVE This work was aimed to present a practice guideline proposal, to be validated, based on literature review, regarding to oral dietary recommendations for acute intestinal GVHD after HTSC. METHODS Two research phases were defined: Phase one: evidence-based literature review; Phase 2: Practice Guideline Proposal. 1: Evidence based literature review SEARCH METHODS A literature review (1997-2019) was performed including PubMed, in English, and Lilacs, in Portuguese electronic database to address the subject of dietary intervention for intestinal GVHD related to the HSCT, with children and adults, whose receiving oral or tube feeding nutrition therapy. SELECTION CRITERIA The study selection was based on the PRISMA method. Controlled clinical trials were searched. Randomization was not possible considering the rare condition. DATA COLLECTION AND ANALYSIS Two independent authors assessed the abstracts of the selected studies to determine the articles feasible to compose the review as the base to elaborate the practice guideline proposal protocol, object of the present study. To determine the level of evidence of the selected article, GRADE criteria were used. MAIN RESULTS One controlled clinical trial study was included. The study was developed in Japan with a total of 35 patients. The dietary plan was characterized by gradual increasing food consistency/density. They found better nutritional parameters in the treated group, however, following GRADE criteria, we rated the quality of evidence as very low. AUTHORS' CONCLUSIONS We could not demonstrate confidence in the effect estimate based on the selected study. However, considering the lack of literature information and the relevance of the topic, we decided to proceed and propose a practice guideline for an oral diet protocol for acute intestinal GVHD as a reference to be a starting point to validate protocols in future clinical trials. 2: Practice Guideline Proposal The criteria to elaborate the protocol were based on the RIGHT Statement. In addition to the literate information about diet and intestinal health, recommendations already adopted in the Service of Bone Marrow Transplant in the Complex Hospital of Clinics of Curitiba, in the state of Paraná, Brazil, were also considered.
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Vitamin D deficiency is not associated with graft versus host disease after hematopoietic stem cell transplantation: A meta-analysis
Chiengthong, K., Cheungpasitporn, W., Thongprayoon, C., Lertjitbanjong, P., Cato, L. D., Bathini, T., Ungprasert, P., Mao, M. A., Chokesuwattanaskul, R.
Journal of evidence-based medicine. 2020
Abstract
OBJECTIVE Vitamin D status plays an important role in immunoregulation, and a deficiency is believed to be related to Graft Versus Host Disease (GVHD) in patients after hematopoietic stem cell transplantation (HSCT). We aim to study the association between vitamin D deficiency and GVHD after HSCT. METHODS A literature search was conducted utilizing MEDLINE, EMBASE, and The Cochrane Library Database from inception to July 2019. Eligible studies were required to(1) be clinical trials or observational studies (cohort, case-control, or cross-sectional studies);(2) provide data to calculate the odds ratios (OR) of GVHD in HSCT patients with vitamin D deficiency. Two reviewers independently extracted the data and assessed the risk of bias. Pooled odds ratios (OR) with 95% confidence interval (CI) were estimated using random-effects meta-analysis through the Comprehensive Meta-Analysis 3.3 software. RESULTS In total, 8 observational studies consisting of 1335 HSCT patients were enrolled in this systematic review. Overall, there was no significant association between vitamin D deficiency and acute GVHD (OR = 1.06, 95% CI 0.74-1.53, P > 0.05). There was no significant association between vitamin D deficiency and chronic GVHD (OR = 1.75, 95% CI 0.72-4.26, P > 0.05). Funnel plots and Egger regression asymmetry test were performed and showed no publication bias. CONCLUSION There is not a statistically significant association between vitamin D deficiency and neither acute nor chronic GVHD.
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Vitamin E and acute graft-versus-host disease after myeloablative allogeneic hematopoietic cell transplantation
Gjaerde, L. K., Ostrowski, S. R., Minculescu, L., Andersen, N. S., Friis, L. S., Kornblit, B., Petersen, S. L., Schjødt, I., Sengeløv, H.
European journal of haematology. 2020
Abstract
OBJECTIVES Vitamin E has antioxidant and immunomodulatory effects that might influence the development of acute graft-versus-host disease (GvHD). We investigated the association between plasma vitamin E levels and acute GvHD. METHODS We studied 115 adults who underwent myeloablative allogeneic hematopoietic cell transplantation between July 2015 and August 2018. Vitamin E was measured by high-performance liquid chromatography in stored plasma samples obtained pre-transplantation at day -23 (±15 days) and post-transplantation at day +28 (±3 days). RESULTS Pre-transplantation vitamin E levels were inversely associated with grade II-IV acute GvHD (hazard ratio 0.68 per 10 µmol/L increase, 95% confidence interval [CI]: 0.47-0.98). The association remained after adjustment for known prognostic factors for acute GvHD. Patients with levels below the median had a cumulative incidence of grade II-IV acute GvHD of 46% (CI: 33-59%) versus 21% (CI: 10-32%) in patients with levels above the median. No clear association with non-relapse mortality, relapse, or chronic GvHD was found. Post-transplantation vitamin E levels (measured in 72 [63%] patients) were correlated with pre-transplantation levels (? = .31) but were not associated with subsequent grade II-IV acute GvHD. CONCLUSIONS High pre-transplantation vitamin E levels were associated with less acute GvHD.
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Prebiotics protect against acute graft-versus-host disease and preserve the gut microbiota in stem cell transplantation
Yoshifuji, K., Inamoto, K., Kiridoshi, Y., Takeshita, K., Sasajima, S., Shiraishi, Y., Yamashita, Y., Nisaka, Y., Ogura, Y., Takeuchi, R., et al
Blood advances. 2020;4(19):4607-4617
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Abstract
Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, management of aGVHD is important for successful transplantation. Mucosal damage and alteration of the gut microbiota after allo-HSCT are key factors in the development of aGVHD. We conducted a prospective study to evaluate the ability of prebiotics, which can alleviate mucosal damage and manipulate the gut microbiota, to mitigate posttransplantation complications, including aGVHD. Resistant starch (RS) and a commercially available prebiotics mixture, GFO, were administered to allo-HSCT recipients from pretransplantation conditioning to day 28 after allo-HSCT. Prebiotic intake mitigated mucosal injury and reduced the incidence of all aGVHD grades combined and of aGVHD grades 2 to 4. The cumulative incidence of skin aGVHD was markedly decreased by prebiotics intake. Furthermore, the gut microbial diversity was well maintained and butyrate-producing bacterial population were preserved by prebiotics intake. In addition, the posttransplantation fecal butyrate concentration was maintained or increased more frequently in the prebiotics group. These observations indicate that prebiotic intake may be an effective strategy for preventing aGVHD in allo-HSCT, thereby improving treatment outcomes and the clinical utility of stem cell transplantation approaches. This study was registered on the University Hospital Medical Information Network (UMIN) clinical trials registry (https://www.umin.ac.jp/ctr/index.htm) as #UMIN000027563.