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Variable selection methods for predicting clinical outcomes following allogeneic hematopoietic cell transplantation.

ABSTRACT: Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative procedure for a large number of diseases. However, the greatest barriers to the success of allo-HCT are relapse and graft-versus-host-disease (GVHD). Many studies have examined the reconstitution of the immune system after allo-HCT and searched for factors associated with clinical outcome. Serum biomarkers have also been studied to predict the incidence and prognosis of GVHD. However, the use of multiparametric immunophenotyping has been less extensively explored: studies usually focus on preselected and predefined cell phenotypes and so do not fully exploit the richness of flow cytometry data. Here we aimed to identify cell phenotypes present 30 days after allo-HCT that are associated with clinical outcomes in 37 patients participating in a trial relating to the prevention of GVHD, derived from 82 flow cytometry markers and 13 clinical variables. To do this we applied variable selection methods in a competing risks modeling framework, and identified specific subsets of T, B, and NK cells associated with relapse. Our study demonstrates the value of variable selection methods for mining rich, high dimensional clinical data and identifying potentially unexplored cell subpopulations of interest.

SUBMITTER: Pasin C

PROVIDER: S-EPMC7865009 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Associations of minor histocompatibility antigens with outcomes following allogeneic hematopoietic cell transplantation.

Project description:The role of minor histocompatibility antigens (mHAs) in mediating graft versus leukemia and graft versus host disease (GvHD) following allogeneic hematopoietic cell transplantation (alloHCT) is recognized but not well-characterized. By implementing improved methods for mHA prediction in two large patient cohorts, this study aimed to comprehensively explore the role of mHAs in alloHCT by analyzing whether (1) the number of predicted mHAs, or (2) individual mHAs are associated with clinical outcomes. The study population consisted of 2249 donor-recipient pairs treated for acute myeloid leukemia and myelodysplastic syndrome with alloHCT. A Cox proportional hazard model showed that patients with a class I mHA count greater than the population median had an increased hazard of GvHD mortality (hazard ratio [HR] = 1.39, 95% confidence interval [CI] = 1.01, 1.77, p = .046). Competing risk analyses identified the class I mHAs DLRCKYISL (GSTP), WEHGPTSLL (CRISPLD2), and STSPTTNVL (SERPINF2) were associated with increased GVHD mortality (HR = 2.84, 95% CI = 1.52, 5.31, p = .01), decreased leukemia-free survival (LFS) (HR = 1.94, 95% CI = 1.27, 2.95, p = .044), and increased disease-related mortality (DRM) (HR = 2.32, 95% CI = 1.5, 3.6, p = .008), respectively. One class II mHA YQEIAAIPSAGRERQ (TACC2) was associated with increased risk of treatment-related mortality (TRM) (HR = 3.05, 95% CI = 1.75, 5.31, p = .02). WEHGPTSLL and STSPTTNVL were both present within HLA haplotype B*40:01-C*03:04 and showed a positive dose-response relationship with increased all-cause mortality and DRM and decreased LFS, indicating these two mHAs contribute to the risk of mortality in an additive manner. Our study reports the first large-scale investigation of the associations of predicted mHA peptides with clinical outcomes following alloHCT.

| S-EPMC10368187 | biostudies-literature

Sleep Disruption, Fatigue, and Depression as Predictors of 6-Year Clinical Outcomes Following Allogeneic Hematopoietic Cell Transplantation.

Project description:BackgroundAllogeneic hematopoietic cell transplantation (HCT) is a widely used treatment for hematologic cancers, with survival rates ranging from 25% to 78%. Known risk factors for chronic graft-versus-host disease (cGVHD), a serious and common long-term complication, disease relapse, and mortality following HCT have been identified, but much of the variability in HCT outcomes is unexplained. Biobehavioral symptoms including depression, sleep disruption, and fatigue are some of the most prevalent and distressing for patients; yet research on biobehavioral risk factors for HCT outcomes is limited. This study evaluated patient-reported depression, sleep disruption, and fatigue as risk factors for cGVHD, disease relapse, and mortality.MethodsAdults receiving allogeneic HCT for a hematologic malignancy (N = 241) completed self-report measures of depression symptoms, sleep quality, and fatigue (severity, interference) pre-HCT and 100 days post-HCT. Clinical outcomes were monitored for up to 6 years.ResultsCox proportional hazard models (2-tailed) adjusting for patient demographic and medical characteristics revealed that high pre-HCT sleep disruption (Pittsburgh Sleep Quality Index >9; hazard ratio [HR] = 2.74, 95% confidence interval [CI] = 1.27 to 5.92) and greater post-HCT fatigue interference (HR = 1.32, 95% CI = 1.05 to 1.66) uniquely predicted increased risk of mortality. Moderate pre-HCT sleep disruption (Pittsburgh Sleep Quality Index 6-9) predicted increased risk of relapse (HR = 1.99, 95% CI = 1.02 to 3.87). Biobehavioral symptoms did not predict cGVHD incidence.ConclusionsBiobehavioral symptoms, particularly sleep disruption and fatigue interference, predicted an increased risk for 6-year relapse and mortality after HCT. Because these symptoms are amenable to treatment, they offer specific targets for intervention to improve HCT outcomes.

| S-EPMC8633423 | biostudies-literature

Tolerance associated gene expression following allogeneic hematopoietic cell transplantation.

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.

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Early antibiotic use is associated with CMV risk and outcomes following allogeneic hematopoietic cell transplantation.

Project description: Not available

| S-EPMC7756990 | biostudies-literature

A gut microbiota score predicting acute graft-versus-host disease following myeloablative allogeneic hematopoietic stem cell transplantation.

Project description:Although studies have reported that intestinal microbiota are associated with acute graft-versus-host disease (aGVHD), they lacked a satisfactory method for predicting aGVHD. We collected stool and blood samples at day 15 posttransplant from 150 patients from two centers who underwent myeloablative conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT). Stool microbiota were detected by 16S ribosomal RNA gene sequencing; inflammatory factors and T lymphocytes were detected by multiplex immunoassays and flow cytometry, respectively. A gut microbiota score (GMS) from a LASSO (least absolute shrinkage and selection operator) model was developed and validated to predict aGVHD. In the discovery cohort, the GMS could predict II-IV aGVHD (area under the receiver operating characteristic [ROC] curve [AUC] = 0.904, P < .0001). Furthermore, the validation model was consistent with the discovery set (AUC = 0.887, P < .0001). Regulatory T/T-helper 17 (Treg/Th17) cells ratio in the low GMS subgroup was higher compared with the high GMS (P = .012), and the validation set is consistent with the discovery set (P = .003). In addition, high cytokine levels were associated with high GMS. In conclusion, the GMS at neutrophil engraftment could predict aGVHD, and it was a potential and novel method. The GMS was associated with the inflammatory factor and Treg/Th17 balance.

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Tolerance associated gene expression following allogeneic hematopoietic cell transplantation

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. Samples were collected after allogeneic hematopoietic cell transplantation (HCT) or in healthy control subjects. 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).

2015-05-25 | E-GEOD-64300 | biostudies-arrayexpress

Steroid-dependent acute GVHD after allogeneic hematopoietic cell transplantation: risk factors and clinical outcomes.

Project description:Acute graft-versus-host disease (aGVHD) has various risk factors and outcomes. We defined distinct aGVHD treatment response groups based on response to first-line corticosteroids: steroid sensitive (SS), steroid resistant (SR), and the rarely studied steroid dependent (SD) aGVHD. In 1143 consecutive adult and pediatric allogeneic hematopoietic cell transplant recipients, 385 (34%) developed aGVHD, with 10% having SS aGVHD, 9% SD aGVHD, and 14% SR aGVHD. The only factor significantly associated with SD in comparison with SS was older age (odds ratio [OR], 3.9; 95% confidence interval [CI], 1.4-11.3, when comparing 18- to 60-year-olds with <18-year-olds). Factors significantly associated with SR in comparison with SS were unrelated donor (OR, 3.0; 95% CI, 1.2-7.4) and Minnesota high-risk aGVHD (OR, 2.4; 95% CI, 1.3-4.6). SR aGVHD was independently associated with higher risk for 2-year overall mortality (hazards ratio [HR], 1.8; 95% CI, 1.2-2.8) and nonrelapse mortality (NRM; HR, 2.1; 95% CI, 1.2-3.9). SS and SD GVHD groups had similar overall survival and NRM. The cumulative incidence of chronic GVHD was highest in the SD group, followed by the SR and SS groups (46%, 41%, and 29%, respectively). SD and SS GVHD had similar prognoses, both markedly better than those of the SR groups.

| S-EPMC7948274 | biostudies-literature

Reconstitution of T Cell Subsets Following Allogeneic Hematopoietic Cell Transplantation.

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

Tolerance associated gene expression following allogeneic hematopoietic cell transplantation

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.

2015-05-25 | GSE64300 | GEO

Cyclophosphamide followed by intravenous targeted busulfan for allogeneic hematopoietic cell transplantation: pharmacokinetics and clinical outcomes.

Project description:Targeted busulfan ((T)BU) and cyclophosphamide (CY) for allogeneic hematopoietic cell transplantation carries a high risk of sinusoidal obstruction syndrome (SOS) in patients undergoing transplantation for myelofibrosis. We tested the hypothesis that reversing the sequence of administration (from (T)BU/CY to CY/(T)BU) would reduce SOS and day +100 nonrelapse mortality. We enrolled 51 patients with myelofibrosis (n = 20), acute myelogenous leukemia (n = 20), or myelodysplastic syndrome (n = 11) in a prospective trial of CY/(T)BU conditioning for allogeneic hematopoietic cell transplantation. CY 60 mg/kg/day i.v. for 2 days was followed by daily i.v. BU for 4 days, targeted to a concentration at steady state (Css) of 800-900 ng/mL. Compared with (T)BU/CY-conditioned patients, CY/(T)BU-conditioned patients had greater exposure to CY (P < .0001) and less exposure to 4-hydroxycyclophosphamide (P < .0001). Clinical outcomes were compared between cases and controls (n = 271) conditioned with (T)BU/CY for the same indications. In patients with myelofibrosis, CY/(T)BU conditioning was associated with a significantly reduced incidence of SOS (0% versus 30% after (T)BU/CY; P = .006), whereas the incidence of SOS was low in both cohorts with acute myelogenous leukemia/myelodysplastic syndrome. Day +100 mortality was significantly lower in the CY/(T)BU cohort (2% versus 13%; P = .01). CY/(T)BU conditioning had a marked affect on the pharmacokinetics of CY and was associated with significantly lower incidence of SOS and day +100 mortality, suggesting that CY/(T)BU is superior to (T)BU/CY as conditioning for patients with myelofibrosis.

| S-EPMC3898851 | biostudies-literature

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