Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation.

BACKGROUND: Relationships between microbiota composition and clinical outcomes after allogeneic hematopoietic-cell transplantation have been described in single-center studies. Geographic variations in the composition of human microbial communities and differences in clinical practices across institutions raise the question of whether these associations are generalizable. METHODS: The microbiota composition of fecal samples obtained from patients who were undergoing allogeneic hematopoietic-cell transplantation at four centers was profiled by means of 16S ribosomal RNA gene sequencing. In an observational study, we examined associations between microbiota diversity and mortality using Cox proportional-hazards analysis. For stratification of the cohorts into higher- and lower-diversity groups, the median diversity value that was observed at the study center in New York was used. In the analysis of independent cohorts, the New York center was cohort 1, and three centers in Germany, Japan, and North Carolina composed cohort 2. Cohort 1 and subgroups within it were analyzed for additional outcomes, including transplantation-related death. RESULTS: We profiled 8767 fecal samples obtained from 1362 patients undergoing allogeneic hematopoietic-cell transplantation at the four centers. We observed patterns of microbiota disruption characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota was associated with a lower risk of death in independent cohorts (cohort 1: 104 deaths among 354 patients in the higher-diversity group vs. 136 deaths among 350 patients in the lower-diversity group; adjusted hazard ratio, 0.71; 95% confidence interval [CI], 0.55 to 0.92; cohort 2: 18 deaths among 87 patients in the higher-diversity group vs. 35 deaths among 92 patients in the lower-diversity group; adjusted hazard ratio, 0.49; 95% CI, 0.27 to 0.90). Subgroup analyses identified an association between lower intestinal diversity and higher risks of transplantation-related death and death attributable to graft-versus-host disease. Baseline samples obtained before transplantation already showed evidence of microbiome disruption, and lower diversity before transplantation was associated with poor survival. CONCLUSIONS: Patterns of microbiota disruption during allogeneic hematopoietic-cell transplantation were similar across transplantation centers and geographic locations; patterns were characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota at the time of neutrophil engraftment was associated with lower mortality. (Funded by the National Cancer Institute and others.).

Fecal microbiota diversity disruption and clinical outcomes after auto-HCT: a multicenter observational study.

We previously described clinically relevant reductions in fecal microbiota diversity in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Recipients of high-dose chemotherapy and autologous HCT (auto-HCT) incur similar antibiotic exposures and nutritional alterations. To characterize the fecal microbiota in the auto-HCT population, we analyzed 1161 fecal samples collected from 534 adult recipients of auto-HCT for lymphoma, myeloma, and amyloidosis in an observational study conducted at 2 transplantation centers in the United States. By using 16S ribosomal gene sequencing, we assessed fecal microbiota composition and diversity, as measured by the inverse Simpson index. At both centers, the diversity of early pretransplant fecal microbiota was lower in patients than in healthy controls and decreased further during the course of transplantation. Loss of diversity and domination by specific bacterial taxa occurred during auto-HCT in patterns similar to those with allo-HCT. Above-median fecal intestinal diversity in the periengraftment period was associated with decreased risk of death or progression (progression-free survival hazard ratio, 0.46; 95% confidence interval, 0.26-0.82; P = .008), adjusting for disease and disease status. This suggests that further investigation into the health of the intestinal microbiota in auto-HCT patients and posttransplant outcomes should be undertaken.

The microbe-derived short-chain fatty acids butyrate and propionate are associated with protection from chronic GVHD.

Studies of the relationship between the gastrointestinal microbiota and outcomes in allogeneic hematopoietic stem cell transplantation (allo-HCT) have thus far largely focused on early complications, predominantly infection and acute graft-versus-host disease (GVHD). We examined the potential relationship of the microbiome with chronic GVHD (cGVHD) by analyzing stool and plasma samples collected late after allo-HCT using a case-control study design. We found lower circulating concentrations of the microbe-derived short-chain fatty acids (SCFAs) propionate and butyrate in day 100 plasma samples from patients who developed cGVHD, compared with those who remained free of this complication, in the initial case-control cohort of transplant patients and in a further cross-sectional cohort from an independent transplant center. An additional cross-sectional patient cohort from a third transplant center was analyzed; however, serum (rather than plasma) was available, and the differences in SCFAs observed in the plasma samples were not recapitulated. In sum, our findings from the primary case-control cohort and 1 of 2 cross-sectional cohorts explored suggest that the gastrointestinal microbiome may exert immunomodulatory effects in allo-HCT patients at least in part due to control of systemic concentrations of microbe-derived SCFAs.

Financial Toxicity and Quality of Life in Patients Undergoing Stem-Cell Transplant Evaluation: A Single-Center Analysis.

PURPOSE: We investigated the prevalence of financial toxicity in a population undergoing hematopoietic cell transplantation (HCT) evaluation and measured its impact on post-transplant clinical and health-related quality-of-life outcomes. MATERIALS AND METHODS: This was a prospective study in patients undergoing evaluation for allogeneic HCT between January 1, 2018, and September 23, 2020, at a large academic medical center. Financial health was measured via a baseline survey and the comprehensive score for financial toxicity-functional assessment of chronic illness therapy (COST-FACIT) survey. The cohort was divided into three groups: none (grade 0), mild (grade 1), and moderate-high financial toxicity (grades 2-3). Health-related quality of life outcomes were measured at multiple time points. Multivariate logistic regression analysis evaluated factors associated with financial toxicity. Kaplan-Meier curves and log-rank tests was used to evaluate overall survival (OS) and nonrelapse survival. RESULTS: Of 245 patients evaluated for transplant, 176 (71.8%) completed both questionnaires (median age was 57 years, 63.1% were male, 72.2% were White, and 39.2% had myelodysplastic syndrome, 38.1% leukemia, and 13.6% lymphoma). At initial evaluation, 83 (47.2%) patients reported no financial toxicity, 51 (29.0%) with mild, and 42 (23.9%) with moderate-high financial toxicity. Patients with financial toxicity reported significant cost-cutting behaviors, including reduced spending on food or clothing, using their savings, or not filling a prescription because of costs (P < .0001). Quality of life was lower in patients with moderate-high financial toxicity at 6 months (P = .0007) and 1 year (P = .0075) after transplant. Older age (>62; odds ratio [OR], 0.33 [95% CI, 0.13 to 0.79]; P = .04) and income ≥$60,000 in US dollars (USD) (OR, 0.17 [95% CI, 0.08 to 0.38]; P < .0001) were associated with lower odds of financial toxicity. No association was noted between financial toxicity and selection for transplant, OS, or nonrelapse mortality. CONCLUSION: Financial toxicity was highly correlated with patient-reported changes in compensatory behavior, with notable impact on patient quality of life after transplant.

Efficacy of probiotic treatment as post-exposure prophylaxis for COVID-19: A double-blind, Placebo-Controlled Randomized trial.

BACKGROUND & AIMS: The COVID-19 pandemic continues to pose unprecedented challenges to worldwide health. While vaccines are effective, additional strategies to mitigate the spread/severity of COVID-19 continue to be needed. Emerging evidence suggests susceptibility to respiratory tract infections in healthy subjects can be reduced by probiotic interventions; thus, probiotics may be a low-risk, low-cost, and easily implementable modality to reduce risk of COVID-19. METHODS: In this initial study, we conducted a randomized, double-blind, placebo-controlled trial across the United States testing probiotic Lacticaseibacillus rhamnosus GG (LGG) as postexposure prophylaxis for COVID-19 in 182 participants who had household exposure to someone with confirmed COVID-19 diagnosed within ≤7 days. Participants were randomized to receive oral LGG or placebo for 28 days. The primary outcome was development of illness symptoms within 28 days of COVID-19 exposure. Stool was collected to evaluate microbiome changes. RESULTS: Intention-to-treat analysis showed LGG treatment led to a lower likelihood of developing illness symptoms versus placebo (26.4 % vs. 42.9 %, p = 0.02). Further, LGG was associated with a statistically significant reduction in COVID-19 diagnosis (log rank, p = 0.049) via time-to-event analysis. Overall incidence of COVID-19 diagnosis did not significantly differ between LGG and placebo groups (8.8 % vs. 15.4 %, p = 0.17). CONCLUSIONS: This data suggests LGG is associated with prolonged time to COVID-19 infection, reduced incidence of illness symptoms, and gut microbiome changes when used as prophylaxis ≤7 days post-COVID-19 exposure, but not overall incidence. This initial work may inform future COVID-19 prevention studies worldwide, particularly in developing nations where Lacticaseibacillus probiotics have previously been utilized to reduce other non-COVID infectious-morbidity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04399252, Date: 22/05/2020. https://clinicaltrials.gov/ct2/show/NCT04399252.

A pilot study to assess the feasibility of a remotely monitored high-intensity interval training program prior to allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Although allogeneic hematopoietic stem cell transplantation (HCT) can be a curative therapy for hematologic disorders, it is associated with treatment-related complications and losses in cardiorespiratory fitness and physical function. High-intensity interval training (HIIT) may be a practical way to rapidly improve cardiorespiratory fitness and physical function in the weeks prior to HCT. The primary aim of this study was to assess the feasibility of implementing a pre-HCT home-based HIIT intervention. The secondary aim was to evaluate pre to post changes in cardiorespiratory fitness and physical function following the intervention. METHODS: This was a single-arm pilot study with patients who were scheduled to undergo allogeneic HCT within six months. Patients were instructed to complete three 30-minute home-based HIIT sessions/week between the time of study enrollment and sign-off for HCT. Sessions consisted of a 5-minute warm-up, 10 high and low intervals performed for one minute each, and a 5-minute cool-down. Prescribed target heart rates (HR) for the high- and low-intensity intervals were 80-90% and 50-60% of HR reserve, respectively. Heart rates during HIIT were captured via an Apple Watch and were remotely monitored. Feasibility was assessed via retention, session adherence, and adherence to prescribed interval number and intensities. Paired t-tests were used to compare changes in fitness (VO2peak) and physical function [Short Physical Performance Battery (SPPB), 30-second sit to stand, and six-minute walk test (6MWT)] between baseline and sign-off. Pearson correlations were used to determine the relationship between intervention length and changes in cardiorespiratory fitness or functional measures. RESULTS: Thirteen patients (58.8±11.6 years) participated in the study, and nine (69.2%) recorded their training sessions throughout the study. Median session adherence for those nine participants was 100% (IQR: 87-107). Adherence to intervals was 92% and participants met or exceeded prescribed high-intensity HR on 68.8±34.8% of intervals. VO2peak improved from baseline to sign-off (14.6±3.1 mL/kg/min to 17.9±3.3 mL/kg/min; p<0.001). 30-second sit to stand and SPPB chair stand scores significantly improved in adherent participants. Improvements in 30-second sit to stand (13.8±1.5 to 18.3±3.3 seconds) and 6MWT (514.4±43.2 to 564.6±19.3) exceeded minimal clinically important improvements established in other chronic disease populations, representing the minimum improvement considered meaningful to patients. CONCLUSIONS: Findings demonstrate that implementing a pre-HCT home-based remotely monitored HIIT program is feasible and may provide benefits to cardiorespiratory fitness and physical function.

Home-Based Hematopoietic Cell Transplantation in the United States.

Patients undergoing allogeneic (allo) and autologous (auto) hematopoietic cell transplantation (HCT) require extensive hospitalizations or daily clinic visits for the duration of their transplantation. Home HCT, wherein patients live at home and providers make daily trips to the patient's residence to perform assessments and deliver any necessary interventions, may enhance patient quality of life and improve outcomes. We conducted the first study of home HCT in the United States to evaluate this model in the US healthcare setting and to determine the effect on clinical outcomes and quality of life. This case-control study evaluated patients who received home HCT at Duke University in Durham, North Carolina, from November 2012 to March 2018. Each home HCT patient was matched with 2 controls from the same institution who had received standard treatment based on age, disease, and type of transplant for outcomes comparison. Clinical outcomes were abstracted from electronic health records, and quality of life was assessed via Functional Assessment of Cancer Therapy-Bone Marrow Transplant. Clinical outcomes were compared with Student's t-test or Fisher's exact test (continuous variables) or chi-square test (categorical variables). Quality of life scores were compared using the Student t-test. All analyses used a significance threshold of 0.05. Twenty-five patients received home HCT, including 8 allos and 17 autos. Clinical outcomes were not significantly different between the home HCT patients and their matched controls; home HCT patients had decreased incidence of relapse within 1 year of transplantation. Pre-HCT quality of life was well preserved for autologous home HCT patients. This Phase I study demonstrated that home HCT can be successfully implemented in the United States. There was no evidence that home HCT outcomes were inferior to standard-of-care treatment, and patients undergoing autologous home HCT were able to maintain their quality of life. A Phase II randomized trial of home versus standard HCT is currently underway to better compare outcomes and costs.

Geriatric Assessment Reveals Actionable Impairments in Hematopoietic Stem Cell Transplantation Candidates Age 18 to 80 Years.

Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative treatment for both malignant and nonmalignant hematologic diseases; however, reported rates of treatment-related mortality approach 30%. Outcomes are worse in patients who begin HCT with functional impairments. To detect such impairments, a geriatric assessment (GA) is recommended in adults age ≥65 years. Younger HCT candidates also may be impaired because of chemotherapy regimens pre-HCT. Therefore, we hypothesized that GA can be beneficial for adult patients of all ages and subsequently created a clinical pretransplantation optimization program to assess all HCT candidates using a modified GA. One-hundred fifty-seven patients were evaluated in 4 functional domains- physical, cognitive, nutritional, and psychological-at 2 time points prior to HCT-new patient evaluation (NPE) and sign-off (SO)-between October 2017 and January 2020. At NPE, 80.9% of the patients had at least 1 domain with a functional impairment, and physical (P = .006), cognitive (P = .04), and psychological (P = .04) impairments were associated with an increased likelihood of not proceeding to HCT. In addition, patients age 18 to 39 years were more likely than older patients to have a physical function impairment (P = .001). Between NPE and SO, 51.9% of the patients had resolution of 1 or more impairments, and nutritional impairment at SO was predictive of worse overall survival (P = .01). Our study shows that GA can identify functional impairments in patients of all ages. Early identification of impairments could facilitate referrals to supportive care and resolution of impairments prior to HCT, suggesting that GA could be recommended for HCT candidates of all ages.