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In this study, the gastrointestinal microbiome was serially monitored in patients undergoing allogeneic hematopoietic-cell transplantation at four centers. Lower microbial diversity was associated with poorer outcomes after HCT.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered to be the strongest curative immunotherapy for various malignancies (primarily, but not limited to, haematologic malignancies). However, application of allo-HSCT is limited owing to its life-threatening major complications, such as graft-versus-host disease (GVHD), relapse and infections. Recent advances in large-scale DNA sequencing technology have facilitated rapid identification of the microorganisms that make up the microbiota and evaluation of their interactions with host immunity in various diseases, including cancer. This has resulted in renewed interest regarding the role of the intestinal flora in patients with haematopoietic malignancies who have received an allo-HSCT and in whether the microbiota affects clinical outcomes, including GVHD, relapse, infections and transplant-related mortality. In this Review, we discuss the potential role of intestinal microbiota in these major complications after allo-HSCT, summarize clinical trials evaluating the microbiota in patients who have received allo-HSCT and discuss how further studies of the microbiota could inform the development of strategies that improve outcomes of allo-HSCT.

This comparison of outcomes of allogeneic hematopoietic stem-cell transplantation in 1993–1997 and 2003–2007 shows that although patients had a somewhat poorer overall prognosis in the more recent period, the rate of death not preceded by relapse, the risk of relapse, and overall mortality decreased. Infections, graft-versus-host disease (GVHD), and liver, kidney, and pulmonary complications have been associated with high mortality after allogeneic hematopoietic-cell transplantation since the introduction of this procedure 40 years ago. 1 Changes in practice have decreased organ toxicity, 2 – 5 and improved prevention and treatment strategies have decreased the severity of acute GVHD. 6 – 9 The control of infectious complications has improved since the development of molecular methods for the detection of viral and fungal infections, the use of preemptive treatments, the introduction of new antifungal agents, and the prevention of nosocomial infection. 10 – 13 To examine the hypothesis that changes in the care of . . .

Pulmonary complications (PCs) cause significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HCT). Shifts in gut microbiota have been linked to HCT outcomes; however, their effect on PCs is unknown. To investigate whether changes in gut microbiota are associated with PCs after HCT. A single-center observational study was performed on 94 patients who underwent HCT from 2009 to 2011 and who were previously enrolled in a protocol for 16S ribosomal RNA sequencing of fecal microbiota. The primary endpoint, PC, was defined by new abnormal parenchymal findings on chest imaging in the setting of respiratory signs and/or symptoms. Outcomes were collected up to 40 months after transplant. Clinical and microbiota risk factors for PCs and mortality were evaluated using survival analysis. One hundred twelve PCs occurred in 66 (70.2%) subjects. A high comorbidity index (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.30-4.00; P = 0.004), fluoroquinolones (HR, 2.29, 95% CI, 1.32-3.98; P = 0.003), low baseline diversity (HR, 2.63; 95% CI, 1.22-5.32; P = 0.015), and γ-proteobacteria domination of fecal microbiota (HR, 2.64; 95% CI, 1.10-5.65; P = 0.031), which included common respiratory pathogens, predicted PCs. In separate analyses, low baseline diversity was associated with PCs that occurred preengraftment (HR, 6.30; 95% CI, 1.42-31.80; P = 0.016), whereas γ-proteobacteria domination predicted PCs postengraftment (HR, 3.68; 95% CI, 1.49-8.21; P = 0.006) and overall mortality (HR, 3.52; 95% CI, 1.28-9.21; P = 0.016). Postengraftment PCs were also independent predictors of death (HR, 2.50; 95% CI, 1.25-5.22; P = 0.009). This is the first study to demonstrate prospective changes in gut microbiota associated with PCs after HCT. Postengraftment PCs and γ-proteobacteria domination were predictive of mortality. This suggests an adverse relationship between the graft and lung, which is perhaps mediated by bacterial composition in the gut. Further study is warranted.

Advances in hematopoietic cell transplantation (HCT) have led to an increasing number of transplant survivors. However, long-term survival is challenged by late relapse, late complications and late non-relapse mortality, and HCT survivors need continued lifelong surveillance for screening, early detection and timely treatment of late complications such as secondary cancers, late infections and organ toxicity. Guidelines for screening and preventive practices for pediatric and adult survivors of autologous and allogeneic HCT were updated and published in 2012. However, several barriers to the care of HCT survivors and routine utilization of these guidelines in clinical practice exist. Examples include paucity of and challenges to conducting prospective randomized trials for screening and prevention of late complications, lack of resources to manage late effects at the level of transplant centers and community health care providers, and inadequate tools to facilitate care and followup of HCT survivors. We summarize the long-term followup guidelines in this review, discuss ways that providers can integrate and utilize them for the care of their patients, and identify areas for research that can inform and increase the utilization of screening and prevention guidelines in clinical practice.

We hypothesized that IV busulfan (Bu) dosing could be safely intensified through pharmacokinetic (PK-) dose guidance to minimize the inter-patient variability in systemic exposure (SE) associated with body-sized dosing, and that this should improve outcome of AML/MDS patients undergoing allogeneic stem cell transplantation. To test this hypothesis, we treated 218 patients (median age 50.7 years, male/female 50/50%) with fludarabine 40 mg/m 2 once daily x4, each dose followed by IV Bu, randomized to 130 mg/m 2 ( N =107) or PK-guided to average daily SE, AUC of 6000 μ M  min ( N =111), stratified for remission status and allo-grafting from HLA-matched donors. Toxicity and GvHD rates in the groups were similar; the risk of relapse or treatment-related mortality remained higher in the fixed-dose group throughout the 80-month observation period. Further, PK-guidance yielded safer disease control, leading to improved overall and PFS, most prominently in MDS patients and in AML patients not in remission at allogeneic stem cell transplantation. We conclude that AML/MDS patients receiving pretransplant conditioning treatment with our 4-day regimen may benefit significantly from PK-guided Bu dosing. This could be considered an alternative to fixed-dose delivery since it provides the benefit of precise dose delivery to a predetermined SE without increasing risk(s) of serious toxicity and/or GvHD.

PurposeThe survival rates of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) have improved. However, HSCT can induce significant long-term complications. Therefore, we investigated the late complications and risk factors for quality of life (QOL) post-HSCT.MethodsWe retrospectively analyzed 67 adult survivors over 2 years after HSCT between 2015 and 2018 at Ulsan University Hospital, Ulsan, Korea. The survey data including FACT-BMT, Hospital Anxiety and Depression Scale, and NCCN Distress Thermometer were collected as patient-reported outcomes using a tablet PC during a routine practice of survivorship clinic.ResultsThe median age was 46 years. The most common symptom was fatigue (80.6%). Younger age (< 60 years), acute lymphoblastic leukemia (ALL), chronic graft-versus-host disease (GVHD), and immunosuppressant use were significantly associated with worse QOL and depression. Additionally, younger survivors (< 60 years) showed significantly more fatigue and anxiety compared with elderly survivors (≥ 60 years). Female sex was significantly associated with lower physical well-being and higher distress than male sex.ConclusionYounger patients (< 60 years), female, ALL, chronic GVHD, and continuous immunosuppressant use were significant risk factors for worse QOL and depression. Hence, creating a more active survivorship care plan after HSCT, specifically for these patients, is required.

This multivariable analysis from the AdVance multicenter observational study assessed adenovirus (AdV) viremia peak, duration, and overall AdV viral burden—measured as time-averaged area under the viremia curve over 16 weeks (AAUC0-16)—as predictors of all-cause mortality in pediatric allo-HCT recipients with AdV viremia. In the 6 months following allo-HCT, 241 patients had AdV viremia ≥ 1000 copies/ml. Among these, 18% (43/241) died within 6 months of first AdV ≥ 1000 copies/ml. Measures of AdV viral peak, duration, and overall burden of infection consistently correlate with all-cause mortality. In multivariable analyses, controlling for lymphocyte recovery, patients with AdV AAUC0-16 in the highest quartile had a hazard ratio of 11.1 versus the lowest quartile (confidence interval 5.3–23.6); for peak AdV viremia, the hazard ratio was 2.2 for the highest versus lowest quartile. Both the peak level and duration of AdV viremia were correlated with short-term mortality, independent of other known risk factors for AdV-related mortality, such as lymphocyte recovery. AdV AAUC0-16, which assesses both peak and duration of AdV viremia, is highly correlated with mortality under the current standard of care. New therapeutic agents that decrease AdV AAUC0-16 have the potential of reducing mortality in this at-risk patient population.

The causes and rates of late patient-mortality following alloHCT for myelodysplastic syndromes or secondary acute myeloid leukemia were studied, to assess the contribution of relapse-related, treatment-related, and population factors. Data from EBMT on 6434 adults, who received a first alloHCT from January 2000 to December 2012, were retrospectively studied using combined land-marking, relative-survival methods and multi-state modeling techniques. Median age at alloHCT increased from 49 to 58 years, and the number of patients aged ≥65 years at alloHCT increased from 5 to 17%. Overall survival probability was 53% at 2 years and 35% at 10 years post-alloHCT. Survival probability at 5 years from the 2-year landmark was 88% for patients <45-year old and 63% for patients ≥65-year old at alloHCT. Cumulative incidence of nonrelapse mortality (NRM) for patients <45-year old at transplant was 7% rising to 25% for patients aged ≥65. For older patients, 31% of NRM-deaths could be attributed to population mortality. Favorable post-alloHCT long-term survival was seen; however, excess mortality-risk for all age groups was shown compared to the general population. A substantial part of total NRM for older patients was attributable to population mortality, information which aids the balanced explanation of post-HCT risk and helps improve long-term care.

Outcome of allogeneic stem cell transplantation (alloSCT) is hampered by substantial non-relapse mortality (NRM). Given its impact on organ function and immune response, the nutritional status has been suggested as relevant for NRM. We aimed to evaluate the association of NRM with nutritional status prior to alloSCT and in the post-SCT course. In a retrospective single-center study, we analyzed 128 alloSCTs. Besides standard characteristics, nutrition-associated parameters BMI, serum total protein, and serum albumin were recorded before conditioning and at various time points after alloSCT. Association with NRM was evaluated by univariate and multivariate survival analysis. The cohort comprised patients with a median BMI of 26 kg/m2 (16.7–46.9 kg/m2), median serum total protein of 59 g/l (41–77 g/l), and serum albumin of 36 g/l (22–46 g/l) before SCT. NRM at d+100 was 14.8% and at 1 year 26.6%. Prior to SCT, only serum albumin deficiency was associated with increased NRM (p = .010) in multivariate analysis. After SCT (d+30 and d+100), all nutrition-associated parameters decreased (p < .002), but no association of deteriorating nutritional status with NRM was found. In multivariate analysis, serum albumin (p = .03) and severe albumin deficiency (p = .02) correlated with NRM at d+30 and d+100, while BMI and serum total protein did not. In our study, albumin deficiency, particularly prior to alloSCT, shows a strong correlation with NRM. This finding may add to monitoring, risk evaluation, and counseling of patients and serve as a rational for interventions to improve the nutritional status in patients undergoing SCT.