-
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
-
-
-
-
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.
-
2.
The prognostic value of patient-reported outcomes in allogeneic hematopoietic stem cell transplantation: exploratory analysis of a randomized nutrition intervention trial
Gudmundstuen, A. M., Efficace, F., Tjønnfjord, G. E., Skaarud, K. J., Cottone, F., Hjermstad, M. J., Iversen, P. O.
Annals of hematology. 2023
Abstract
Whether patient-reported outcomes (PROs) can predict overall survival (OS) and non-relapse mortality (NRM) among recipients of allogeneic stem cell transplantation (allo-HSCT), is unclear. We performed an exploratory analysis of the prognostic value of patient-reported outcomes (PROs) among 117 recipients of allogeneic stem cell transplantation (allo-HSCT) who participated in a randomized nutrition intervention trial. Cox proportional hazards models were used to investigate possible associations between PROs collected pre-allo-HSCT (baseline) using scores from the EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30) and 1-year overall survival (OS), whereas logistic regression was used to study associations between these PROs and 1-year non-relapse mortality (NRM). Multivariable analyses indicated that only the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and the European Bone Marrow Transplantation (EBMT) risk score were associated with 1-year OS. In the multivariable model including clinical-sociodemographic factors for 1-year NRM, our analysis showed that living alone (p=0.009), HCT-CI (p=0.016), EBMT risk score (p=0.002), and stem cell source (p=0.046) could be associated with 1-year NRM. Moreover, in the multivariable model, our analysis showed that only appetite loss from the QLQ-C30 was associated with 1-year NRM (p=0.026). In conclusion, in this specific setting, our analysis suggests that the commonly used HCT-CI and EBMT risk scores could be predictive for both 1-year OS and 1-year NRM, whereas baseline PROs in general were not.
-
3.
Efficacy and Safety of Synbiotics in Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation: A Randomized, Double-blinded, Placebo-controlled Pilot Study
Mizutani, Y., Kawamoto, S., Takahashi, M., Doi, H., Wakida, K., Tabuchi, S., Tanda, M., Soga, A., Chijiki, R., Takakura, H., et al
Internal medicine (Tokyo, Japan). 2023
Abstract
Objective High-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT) is an effective treatment option for relapsed and refractory aggressive malignant lymphoma. However, patients frequently experience treatment-induced gastrointestinal symptoms. Synbiotics, including live microorganisms and nondigestible food ingredients, reportedly ameliorate chemotherapy-induced mucosal damage. In this study, we assessed the efficacy and safety of synbiotics in patients undergoing auto-HSCT. Methods This randomized, double-blinded study included patients with malignant lymphoma eligible for auto-HSCT. The patients were randomly assigned to either a synbiotic group receiving Bifidobacterium longum (BB536) and guar gum or a placebo group receiving a placebo containing dextrin. The supplements were administered twice daily from the start of conditioning chemotherapy up to 28 days after auto-HSCT. The primary endpoint was the duration of total parenteral nutrition (TPN). Results In total, 12 patients were included and randomized. The median duration of TPN was 15 (range, 12-33) days in the synbiotic group and 17.5 (range, 0-32) days in the placebo group. The median duration of grade ≥3 diarrhea was shorter in the synbiotic group than in then placebo group (2.5 vs. 6.5 days), as was the duration of hospital stay (31.5 vs. 43 days). The oral intake and quality of life regarding diarrhea and anorexia improved in the synbiotic group after engraftment. Synbiotic infections, including bacteremia, were not observed. Conclusion Synbiotics may reduce gastrointestinal toxicity, thereby reducing nutritional problems and improving the quality of life of patients undergoing auto-HSCT, without severe adverse events.
-
4.
Gut microbiota intervention by pre and probiotics can induce regulatory T cells and reduce the risk of severe acute GVHD following allogeneic hematopoietic stem cell transplantation
Yazdandoust, E., Hajifathali, A., Roshandel, E., Zarif, M. N., Pourfathollah, A. A., Parkhideh, S., Mehdizadeh, M., Amini-Kafiabad, S.
Transplant immunology. 2023;78:101836
Abstract
BACKGROUND Acute graft-versus-host disease (aGVHD) is one of the leading causes of limitation and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Numerous studies have shown that changes in the gut microbiome diversity increased post-transplant problems, including the occurrence of aGVHD. Probiotics and prebiotics can reconstitute the gut microbiota and thus increase bacterial metabolites such as short-chain fatty acids (SCFAs) that have immunomodulatory effects preventing aGVHD in recipients of allo-HSCTs. METHODS/STUDY DESIGN We conducted a pilot randomized clinical trial to investigate whether oral synbiotics are associated with the prevention or reduction in occurrence/severity and mitigate complications of aGVHD following allo-HSCT. A commercially available synbiotic mixture containing high levels of 7 safe bacterial strains plus fructo-oligosaccharides as a prebiotic was administered to allo-HSCT recipients. Out of 40 allo-HSCT patients, 20 received daily a synbiotic 21 days prior to transplantation (days -21 to day 0). In contrast, in the control group 20 recipients of allo-HSCT did not receive a symbiotic therapy. RESULTS Within first 100 days of observation, the incidence of severe (grade III/IV) aGVHD in the a synbiotic-therapy group was 0% (0 out of 20 patients), whereas it was 25% (5 out of 20 patients) in the control group (P = 0.047). The median percentage of CD4 + CD25 + Foxp3+ regulatory T cells (Tregs) among CD4+ lymphocytes on day 28 after HSCT in the synbiotic group was higher (2.54%) than in control group (1.73%; P = 0.01). There was no difference in Treg cells on day 7 after HSCT between two groups. However, the median percentage and the absolute count of Tregs in patients who experience aGVHD was significantly lower on days 7 and 28 after HSCT (both P < 0.05). The overall 12-month survival (OS) rate was higher (90%) in the symbiotic-treated patients than in the control group (75%), but the difference was not statistically significant (P = 0.234). CONCLUSION Our preliminary findings suggest that synbiotic intake before and during the conditioning regimen of allo-HSCT patients may lead to a reduction in the incidence and severity of aGVHD through the induction of CD4 + CD25 + Foxp3+ regulatory T cells, thus contributing to the improvement of transplant outcomes. Much larger studies are needed to confirm our observations.
-
5.
Loading dose vitamin D3 improves vitamin D insufficiency in adults undergoing hematopoietic stem cell transplantation: A randomized controlled trial
Bai, N., Lee, K., Limvorapitak, W., Liu, E., Kendler, D., Broady, R., White, J.
PloS one. 2023;18(10):e0284644
Abstract
Allogeneic hematopoietic stem cell transplant (aHSCT) patients are well known to be at high risk of vitamin D (vit D) deficiency. This study assessed whether a loading dose (100,000 IU) of vitamin D3 pre-aHSCT could effectively achieve and maintain sufficient post-transplant vit D levels (serum total 25 hydroxy vitamin D (25(OH)D) ≥ 75nmol/L). Dual-energy X-ray absorptiometry (DXA) was also conducted for bone health evaluation. 74 patients were enrolled and randomly assigned, in a 1:1 ratio, either to the high vit D group (single loading dose (100,000 IU) plus 2,000 IU vit D3 daily) or the control group (2,000 IU vit D3 daily). Vit D levels were measured at three time points (baseline, day 30 and day 100 post-aHSCT). At baseline, fewer than 50% patients had a sufficient 25(OH)D (control: 42.9%; high vit D: 43.6%). The proportion of patients with sufficient 25(OH)D (nmol/L) was increased at day 30 and day 100, with a trend of higher proportion in the high vit D group at day 30 (high vit D vs. control: 89.7% vs. 74.3%, p = 0.08). The increased 25(OH)D was significantly higher in the high vit D group at day 30 (high vit D vs. control: 29±25.2 vs. 14 ±21.9, p = 0.01). Insufficient vit D level before transplant (baseline) was an independent risk factor for vit D insufficiency (serum 25(OH)D < 75nmol/L) post-aHSCT (OR = 4.16, p = 0.03). DXA suggested significant bone loss for total hip in both groups, and in the femoral neck for the control group only. In conclusion, single loading dose vitamin D3 significantly increased total 25(OH)D levels at day 30 post-transplant, and the intervention was especially beneficial for patients with baseline vit D insufficiency. We acknowledge that the primary outcome at day 100 post-aHSCT indicating superiority of loading dose versus daily dose supplementation was not met.
-
6.
Daytime-restricted parenteral feeding is associated with earlier oral intake in children following stem cell transplant
Wang, Y. M., Taggart, C. B., Huber, J. F., Davies, S. M., Smith, D. F., Hogenesch, J. B., Dandoy, C. E.
The Journal of clinical investigation. 2023;133(4)
-
7.
No Effect of Vitamin C Administration on Neutrophil Recovery in Autologous Stem Cell Transplantation for Myeloma or Lymphoma: A Blinded, Randomized Placebo-Controlled Trial
van Gorkom, G. N. Y., Boerenkamp, L. S., Gijsbers, Blmg, van Ojik, H. H., Wodzig, Wkwh, Wieten, L., Van Elssen, Chmj, Bos, G. M. J.
Nutrients. 2022;14(22)
Abstract
Vitamin C is an important micronutrient for various immune cells. It increases phagocytic cell function and is necessary for T and natural killer (NK) cell development. Patients in need of an autologous hematopoietic stem cell transplantation (HSCT) are often vitamin C-depleted. We therefore hypothesized that vitamin C supplementation could improve immune recovery in autologous HSCT patients. This blinded, placebo-controlled trial included 44 patients randomized to receive vitamin C or a placebo. The following outcome measures used were clinical and immunological parameters, among others: time to neutrophil recovery, serum, and intracellular vitamin C values. Twenty-one patients received vitamin C, and 23 received a placebo. The time to neutrophil recovery did not differ between the two groups at 11.2 days (p = 0.96). There were no differences in hospitalization time (19.7 vs. 19.1 days, p = 0.80), the incidence of neutropenic fever (57% vs. 78%, p = 0.20), or 3-month overall survival (90.5% vs. 100%, p = 0.13). Bacteremia seemed to occur less in the vitamin C group (10% vs. 35%, p = 0.07). Our study shows no benefit from vitamin C supplementation on neutrophil recovery and hospitalization, despite possible lower rates of bacteremia in the vitamin C group. Therefore, we do not advise vitamin C supplementation in this treatment group.
-
8.
Effect of vitamin C on immune reconstitution after bone marrow transplantation
Urbalejo-Ceniceros, V. I., Rocha-González, H. I., Acosta-Maldonado, B. L., Valero-Saldaña, L. M., Hernández-Alcantara, A. E., Pérez-Camargo, D. A.
International Journal of Clinical Pharmacology and Therapeutics. 2022;60(9):384-391
Abstract
BACKGROUND Vitamin C is an essential nutrient for the adequate function and maturation of the immune system. In vitro studies show that the development, proliferation, and functioning of T cells requires vitamin C, especially for natural killer (NK) cells. Their deficiency during the acute phase post-transplantation could cause greater morbidity and mortality in these patients. A prospective clinical trial using high-dose vitamin C was performed to determine if vitamin C supplementation improves reconstitution of NK lymphocytes after hematopoietic stem cell transplantation (HSCT). MATERIALS AND METHODS We enrolled 24 patients who underwent autologous HSCT for multiple myeloma and lymphoma. Patients were randomized to receive standard treatment or standard treatment plus 20 g vitamin C once daily (1 - 10 days) and 500 mg twice daily (11 - 100 days) after transplantation. RESULTS NK and CD3(+) lymphocytes showed an increase from days +30 to +100 only in the vitamin C-treated group. Patients in the vitamin C group had a lower frequency of infections. No severe adverse events were reported. CONCLUSION Our results suggest that high-dose vitamin C supplementation is an effective and safe therapeutic option to decrease the frequency of infections and enhance immune reconstitution after HSCT.
-
9.
Stoss therapy is safe for treatment of vitamin D deficiency in pediatric patients undergoing HSCT
Bodea, J., Beebe, K., Campbell, C., Salzberg, D., Miller, H., Adams, R., Mirea, L., Castillo, P., Horn, B., Bansal, S., et al
Bone marrow transplantation. 2021
Abstract
Vitamin D deficiency remains common among pediatric patients undergoing hematopoietic stem cell transplant (HSCT) despite both aggressive and standard of care strategies. This study examined the safety and efficacy of single high-dose oral vitamin D therapy (Stoss therapy) for treatment of vitamin D deficiency in HSCT recipients. Patients ages 1-21 years presenting for HSCT were randomized to receive either Stoss regimen plus weekly/daily supplementation or standard of care, per US Endocrine Society guidelines. Among the total 48 subjects, 22 (46%) were randomized to Stoss and 26 (54%) to control arms. Baseline 25-hydroxyvitamin D (25-OHD) levels were insufficient/deficient in total of 34 (71%) patients, without difference between treatment groups. The Stoss regimen was well tolerated and no toxicity was observed. At Day +30, mean 25-OHD levels were significantly higher (P?=?0.04) with Stoss (42.3?±?12?µg/l) compared to controls (35.6?±?14.3?µg/l), and a higher proportion of Stoss patients had adequate vitamin D levels than controls (85% vs 65%). Stoss therapy is a safe and efficacious treatment option for vitamin D deficiency in children undergoing HSCT and may achieve sufficient levels more rapidly than standard of care. This trial was registered at www.clinicaltrials.gov as NCT03176849.
-
10.
Mortality and microbial diversity after allogeneic hematopoietic stem cell transplantation: secondary analysis of a randomized nutritional intervention trial
Skaarud, K. J., Hov, J. R., Hansen, S. H., Kummen, M., Valeur, J., Seljeflot, I., Bye, A., Paulsen, V., Lundin, K. E. A., Trøseid, M., et al
Scientific reports. 2021;11(1):11593
Abstract
Gut mucosal barrier injury is common following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and associated with poor clinical outcomes. Diet is critical for microbial diversity, but whether nutritional support affects microbiota and outcome after allo-HSCT is unknown. We present a secondary analysis of a randomized controlled nutritional intervention trial during allo-HSCT. We investigated if the intervention influenced gut microbiota, short-chain fatty acids (SCFAs), and markers of gut barrier functions, and if these parameters were associated with clinical outcomes. Fecal specimens were available from 47 recipients, and subjected to 16S rRNA gene sequencing. We found no significant differences between the intervention group and controls in investigated parameters. We observed a major depletion of microbiota, SCFAs, and altered markers of gut barrier function from baseline to 3 weeks post-transplant. One-year mortality was significantly higher in patients with lower diversity at 3 weeks post-HSCT, but not related to diversity at baseline. The relative abundance of Blautia genus at 3 weeks was higher in survivors. Fecal propionic acid was associated with survival. Markers of gut barrier functions were less strongly associated with clinical outcomes. Possibly, other strategies than dietary intervention are needed to prevent negative effects of gut microbiota and clinical outcomes after allo-HSCT.ClinicalTrials.gov (NCT01181076).