Late cardiovascular morbidity and mortality following pediatric allogeneic hematopoietic cell transplantation.
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ABSTRACT:
SUBMITTER: Duncan CN
PROVIDER: S-EPMC6158112 | biostudies-literature | 2018 Oct
REPOSITORIES: biostudies-literature
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Late cardiovascular morbidity and mortality following pediatric allogeneic hematopoietic cell transplantation.
Duncan Christine N CN Brazauskas Ruta R Huang Jiaxing J Shaw Bronwen E BE Majhail Navneet S NS Savani Bipin N BN Flowers Mary E D MED Battiwalla Minoo M Beebe Kristen K Dietz Andrew C AC Dvorak Christopher C CC Giller Roger R Jacobsohn David A DA Kletzel Morris M Martin Paul L PL Nemecek Eneida R ER Nuechterlein Brandon B Talano Julie-An JA Pulsipher Michael A MA Baker K Scott KS
Bone marrow transplantation 20180326 10
We analyzed late cardiovascular outcomes of 661 patients who survived at least 2 years from hematopoietic cell transplantation for childhood hematologic malignancy between 1995 and 2008. Center for International Blood and Marrow Transplant Research data was supplemented with surveys focused on cardiotoxicity and potential risk factors. The median duration of follow-up was 97 months (range 24-230). 4.2% of survivors experienced at least one of the primary outcomes including coronary artery diseas ...[more]
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Project description:IntroductionAllogeneic hematopoietic cell transplantation (allo-HCT) offers a potential cure for high-risk hematological malignancy; however, long-term survivors experience increased cardiovascular morbidity and mortality. It is unclear how allo-HCT impacts cardiovascular function in the short-term. Thus, this 3-month prospective study sought to evaluate the short-term cardiovascular impact of allo-HCT in hematological cancer patients, compared to an age-matched non-cancer control group.MethodsBefore and ~3-months following allo-HCT, 17 hematological cancer patients (45 ± 18 years) underwent cardiopulmonary exercise testing to quantify peak oxygen uptake (VO2peak)-a measure of integrative cardiovascular function. Then, to determine the degree to which changes in VO2peak are mediated by cardiac vs. non-cardiac factors, participants underwent exercise cardiac MRI (cardiac reserve), resting echocardiography (left-ventricular ejection fraction [LVEF], global longitudinal strain [GLS]), dual-energy x-ray absorptiometry (lean [LM] and fat mass [FM]), blood pressure (BP) assessment, hemoglobin sampling, and arteriovenous oxygen difference (a-vO2diff) estimation via the Fick equation. Twelve controls (43 ± 13 years) underwent identical testing at equivalent baseline and 3-month time intervals.ResultsSignificant group-by-time interactions were observed for absolute VO2peak (p = 0.006), bodyweight-indexed VO2peak (p = 0.015), LM (p = 0.001) and cardiac reserve (p = 0.019), which were driven by 26, 24, 6, and 26% reductions in the allo-HCT group (all p ≤ 0.001), respectively, as no significant changes were observed in the age-matched control group. No significant group-by-time interactions were observed for LVEF, GLS, FM, hemoglobin, BP or a-vO2diff, though a-vO2diff declined 12% in allo-HCT (p = 0.028).ConclusionIn summary, allo-HCT severely impairs VO2peak, reflecting central and peripheral dysfunction. These results indicate allo-HCT rapidly accelerates cardiovascular aging and reinforces the need for early preventive cardiovascular intervention in this high-risk group.
| S-EPMC9797839 | biostudies-literature
Project description:Over the past decade, advances have been made in the care of patients undergoing transplantation. We conducted a study to determine whether these advances have improved the outcomes of transplantation.We analyzed overall mortality, mortality not preceded by relapse, recurrent malignant conditions, and the frequency and severity of major complications of transplantation, including graft-versus-host disease (GVHD) and hepatic, renal, pulmonary, and infectious complications, among 1418 patients who received their first allogeneic transplants at our center in Seattle in the period from 1993 through 1997 and among 1148 patients who received their first allogeneic transplants in the period from 2003 through 2007. Components of the Pretransplant Assessment of Mortality (PAM) score were used in regression models to adjust for the severity of illness at the time of transplantation.In the 2003-2007 period, as compared with the 1993-1997 period, we observed significant decreases in mortality not preceded by relapse, both at day 200 (by 60%) and overall (by 52%), the rate of relapse or progression of a malignant condition (by 21%), and overall mortality (by 41%), after adjustment for components of the PAM score. The results were similar when the analyses were limited to patients who received myeloablative conditioning therapy. We also found significant decreases in the risk of severe GVHD; disease caused by viral, bacterial, and fungal infections; and damage to the liver, kidneys, and lungs.We found a substantial reduction in the hazard of death related to allogeneic hematopoietic-cell transplantation, as well as increased long-term survival, over the past decade. Improved outcomes appear to be related to reductions in organ damage, infection, and severe acute GVHD. (Funded by the National Institutes of Health.).
| S-EPMC3017343 | biostudies-literature
Project description:BackgroundLong-term mortality after hematopoietic cell transplantation (HCT) is conventionally calculated from the time of HCT, ignoring temporal changes in survivors' mortality risks. Conditional survival rates, accounting for time already survived, are relevant for optimal delivery of survivorship care but have not been widely quantified. We estimated conditional survival by elapsed survival time in allogeneic HCT patients and examined cause-specific mortality.MethodsWe calculated conditional survival rates and standardized mortality ratio for overall and cause-specific mortality in 4485 patients who underwent HCT for malignant hematologic diseases at a large transplant center during 1976-2014. Statistical tests were two-sided.ResultsThe 5-year survival rate from HCT was 48.6%. After surviving 1, 2, 5, 10, and 15 years, the subsequent 5-year survival rates were 71.2%, 78.7%, 87.4%, 93.5%, and 86.2%, respectively. The standardized mortality ratio was 30.3 (95% confidence interval [CI] = 29.2 to 35.5). Although the standardized mortality ratio declined in longer surviving patients, it was still elevated by 3.6-fold in survivors of 15 years or more (95% CI = 3.0 to 4.1). Primary disease accounted for 50% of deaths in the overall cohort and only 10% in 15-year survivors; the leading causes of nondisease-related mortality were subsequent malignancy (26.1%) and cardiopulmonary diseases (20.2%). We also identified the risk factors for nondisease-related mortality in 1- and 5-year survivors.ConclusionSurvival probability improves the longer patients survive after HCT. However, HCT recipients surviving 15 years or more remain at elevated mortality risk, largely because of health conditions other than their primary disease. Our study findings help inform preventive and interventional strategies to improve long-term outcomes after allogeneic HCT.
| S-EPMC7669225 | biostudies-literature
Project description:The authors sought to better understand the combined effects of pretransplant, transplant, and post-transplant factors in determining risks of serious cardiovascular disease after hematopoietic cell transplantation (HCT). Hospitalizations and deaths associated with serious cardiovascular outcomes were identified among 1379 Washington State residents who received HCT (57% allogeneic and 43% autologous) at a single center from 1985 to 2005, survived ≥ 2 years, and followed through 2008. Using a nested case-cohort design, relationships (hazard ratios [HRs]) between potential risk factors and outcomes were examined among affected survivors and a randomly selected subcohort (N = 509). After 7.0 years of median follow-up (range, 2.0 to 23.7), the 10-year cumulative incidence of ischemic heart disease, cardiomyopathy, stroke, and all-cause cardiovascular death was 3.8%, 6.0%, 3.5%, and 3.7%, respectively. In multivariable analysis, increased pretransplant anthracycline was associated with cardiomyopathy. Active chronic graft-versus-host disease was associated with cardiovascular death (HR, 4.0; 95% confidence interval, 1.1 to 14.7); risk was otherwise similar between autologous versus allogeneic HCT recipients. Independent of therapeutic exposures, pretransplant smoking, hypertension, dyslipidemia, diabetes, and obesity conferred additional risk of all outcomes except stroke (HR ≥ 1.5 for each additional risk factor, P < .03). Hypertension and dyslipidemia at 1 year with persistence of these conditions 2 or more years after HCT also were associated with independent risks of multiple outcomes. HCT survivors with preexisting or newly developed and persistent cardiovascular risk factors remain at greater risk of subsequent serious cardiovascular disease compared with other survivors, independent of chemo- and radiotherapy exposures. These survivors should receive appropriate follow-up and be considered for primary intervention.
| S-EPMC4019708 | biostudies-literature
Project description:Allogeneic (allo) hematopoietic cell transplantation (HCT) is the only curative treatment option for patients suffering from chemotherapy-refractory or relapsed hematological malignancies. The occurrence of morbidity and mortality after allo-HCT is still high. This is partly correlated with the immunological recovery of the T cell subsets, of which the dynamics and relations to complications are still poorly understood. Detailed information on T cell subset recovery is crucial to provide tools for better prediction and modulation of adverse events. Here, we review the current knowledge regarding CD4+ and CD8+ T cells, γδ T cells, iNKT cells, Treg cells, MAIT cells and naive and memory T cell reconstitution, as well as their relations to outcome, considering different cell sources and immunosuppressive therapies. We conclude that the T cell subsets reconstitute in different ways and are associated with distinct adverse and beneficial events; however, adequate reconstitution of all the subsets is associated with better overall survival. Although the exact mechanisms involved in the reconstitution of each T cell subset and their associations with allo-HCT outcome need to be further elucidated, the data and suggestions presented here point towards the development of individualized approaches to improve their reconstitution. This includes the modulation of immunotherapeutic interventions based on more detailed immune monitoring, aiming to improve overall survival changes.
| S-EPMC7409323 | biostudies-literature
Project description:Biologic markers of immune tolerance may facilitate tailoring of immune suppression duration after allogeneic hematopoietic cell transplantation (HCT). In a cross-sectional study, peripheral blood samples were obtained from tolerant (n = 15, median 38.5 months post-HCT) and non-tolerant (n = 17, median 39.5 post-HCT) HCT recipients and healthy control subjects (n = 10) for analysis of immune cell subsets and differential gene expression. There were no significant differences in immune subsets across groups. We identified 281 probe sets unique to the tolerant (TOL) group and 122 for non-tolerant (non-TOL). These were enriched for process networks including NK cell cytotoxicity, antigen presentation, lymphocyte proliferation, and cell cycle and apoptosis. Differential gene expression was enriched for CD56, CD66, and CD14 human lineage-specific gene expression. Differential expression of 20 probe sets between groups was sufficient to develop a classifier with > 90% accuracy, correctly classifying 14/15 TOL cases and 15/17 non-TOL cases. These data suggest that differential gene expression can be utilized to accurately classify tolerant patients following HCT. Prospective investigation of immune tolerance biologic markers is warranted.
| S-EPMC4361657 | biostudies-literature
Project description:BackgroundPediatric CML is very rare. Before the introduction of tyrosine kinase inhibitors (TKIs), allogeneic hematopoietic stem cell transplantation (HSCT) from a donor -if available- was the standard cure attempt. Data on the long-term outcome and health-related quality of life (HRQOL) in former pediatric CML patients undergoing HSCT are lacking.Study questionWe investigated long-term survivors' self-reporting to a questionnaire sent out to patients formerly enrolled in pediatric CML-HSCT trials.MethodsIndividuals with CML transplanted at age <18 years were identified from the German Childhood Cancer Registry database. Long-term survivors received a questionnaire based on the SF-36 and FACT-BMT asking them to self-report HRQOL issues. (Ethical vote #541_20 B, Medical Faculty, University of Erlangen-Nürnberg).Results111/171 (64.9%) individuals survived HSCT long-term and 86/111 (77.5%) fulfilled all inclusion criteria and received the questionnaire. 37/86 (43%) participants (24 female, 13 male, median age at HSCT 12 years [range 2-18], median age at the time of the survey 29 years [range 18-43]) responded after a median follow-up period of 19 years (range 4-27) after HSCT. 10/37 (27%) participants underwent no regular medical follow-up examinations. Self-reported symptoms like chronic graft-versus-host disease (cGvHD)-associated organ impairments and conditioning regimen consequences could causatively not sharply be separated in each case. Complains comprised hypothyroidism (N=11, 30%), infertility (N=9, 24%), lung problems, dry eyes (each N=7, 19%), skin alterations (N=6, 17%), hair problems (N=4, 11%), and sexual dysfunction (N=3, 9%). 10 (27%) participants experienced 13 CML relapses after a median interval from HSCT of 31 months (range 2-93). Only one patient underwent 2nd SCT after failure of relapse treatment with TKIs. Six secondary malignancies (dysplastic melanocytic nevus and ALL, basal cell carcinoma (N=2), rhabdomyosarcoma, and thyroid carcinoma developed in 5 (13%) participants. As assessed by the SF-36 questionnaire, impaired physical health was mainly associated with cGvHD. The mental component summary score showed that also participants without cGvHD scored significantly lower than the general population. When assessed by the FACT-BMT, participants with cGvHD scored significantly lower while participants without cGvHD scored even 5 points higher than the data from controls. 18 (49%) participants considered the sequelae of HSCT an obstacle to education. Out of the total cohort, N=20 (54%), N=7 (19%), N=5 (14%), and N=4 (11%) participants worked full time, part-time, were unemployed, or had not yet finalized their education, respectively. 20 (54%) participants lived as singles, 8 (22%) lived in a partnership, 6 (16%) were married, and 3 (8%) had been divorced. Four (11%) participants reported a total number of 7 children.ConclusionThis first assessment of HRQOL in former pediatric patients with CML surviving HSCT for more than two decades demonstrates self-reported satisfactory well-being only in the absence of cGvHD. Research-based on self-reported outcomes sheds light on former patients' perspectives and provides an additional layer of valuable knowledge for pediatric and adult hematologists. Regular follow-up examinations are mandatory helping to avoid that late secondary neoplasias, CML-relapse, and disorders forming the broad range of possible long-term consequences of HSCT are not detected too late.
| S-EPMC9580018 | biostudies-literature
Project description:PurposeAllogeneic hematopoietic cell transplantation (HCT) is curative but is associated with life-threatening complications. Most deaths occur within the first 2 years after transplantation. In this report, we examine long-term survival in 2-year survivors in the largest cohort ever studied.Patients and methodsRecords of 10,632 patients worldwide reported to the Center for International Blood and Marrow Transplant Research who were alive and disease free 2 years after receiving a myeloablative allogeneic HCT before 2004 for acute myelogenous or lymphoblastic leukemia, myelodysplastic syndrome, lymphoma, or severe aplastic anemia were reviewed.ResultsMedian follow-up was 9 years, and 3,788 patients had been observed for 10 or more years. The probability of being alive 10 years after HCT was 85%. The chief risk factors for late death included older age and chronic graft-versus-host disease (GVHD). For patients who underwent transplantation for malignancy, relapse was the most common cause of death. The greatest risk factor for late relapse was advanced disease at transplantation. Principal risk factors for nonrelapse deaths were older age and GVHD. When compared with age, sex, and nationality-matched general population, late deaths remained higher than expected for each disease, with the possible exception of lymphoma, although the relative risk generally receded over time.ConclusionThe prospect for long-term survival is excellent for 2-year survivors of allogeneic HCT. However, life expectancy remains lower than expected. Performance of HCT earlier in the course of disease, control of GVHD, enhancement of immune reconstitution, less toxic regimens, and prevention and early treatment of late complications are needed.
| S-EPMC3107742 | biostudies-literature
Project description:Purpose of reviewThis review explores what is known about the genetics of hematopoietic stem cell transplantation (HCT) and how genetic polymorphism affects risk of graft-versus-host disease (GVHD) and mortality.Recent findingsGenetic variation found across the human genome can impact HCT outcome by causing genetic disparity between patient and donor and modifying gene function. Single nucleotide polymorphism (SNP) and structural variation can result in mismatching for cellular peptides known as histocompatibility antigens. At least 25-30 polymorphic genes are known to encode functional histocompatibility antigens in mismatched individuals, but their individual contribution to clinical GVHD is unclear. HCT outcome may also be affected by polymorphism in donor or recipient. Association studies have implicated several genes associated with GVHD and mortality, however results have been inconsistent most likely due to limited sample size, and differences in racial diversity and clinical covariates. New technologies using DNA arrays genotyping for a million or more SNPs promise genome-wide discovery of HCT-associated genes, however adequate statistical power requires study populations of several thousand patient-donor pairs.SummaryAvailable data offers strong preliminary support for the impact that genetic variation has on risk of GVHD and mortality following HCT. Definitive results however await future genome-wide studies of large multicenter HCT cohorts.
| S-EPMC3177530 | biostudies-literature
Project description:BackgroundRelationships 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.MethodsThe 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.ResultsWe 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.ConclusionsPatterns 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.).
| S-EPMC7534690 | biostudies-literature