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Risky Health Behaviors and Subsequent Late Mortality after Blood or Marrow Transplantation: a BMTSS Report
Balas, N., Richman, J., Landier, W., Shrestha, S., Bruxvoort, K., Hageman, L., Meng, Q., Ross, E. S., Bosworth, A. K., Te, H. S., et al
Blood advances. 2023
Abstract
We examined the association between risky healthy behaviors (smoking, heavy-alcohol consumption, and lack of vigorous-physical activity) and all-cause and cause-specific late mortality after blood or marrow transplantation (BMT) to understand the role played by potentially modifiable risk factors. Study participants were drawn from the BMT Survivor Study (BMTSS), and included patients transplanted between 1974 and 2014, who had survived ≥2 years post BMT and were age ≥18 at study cohort entry. Survivors provided information on sociodemographic characteristics, chronic health conditions and health-behaviors. National Death Index was used to determine survival and cause of death. Multivariable regression analyses determined the association between risky health behaviors and all-cause mortality (Cox regression) and non-recurrence related mortality [NRM] (sub-distribution hazard regression) after adjusting for relevant sociodemographic, clinical variables and therapeutic exposures. Overall, 3,866 participants completed the BMTSS survey and were followed for a median of 5 years to death or December 31, 2021; 856 participants died (22.1%) after survey completion. Risky health behaviors were associated with increased hazard of all-cause mortality (adjusted hazard ratio [aHR] former smoker=1.2, aHR current smoker=1.7, ref: non-smoker; aHR heavy drinker=1.4; ref: non-heavy drinker; and aHR no vigorous activity=1.2, ref: vigorous activity) and NRM (aHR former smoker=1.3, aHR current smoker=1.6, ref: non-smoker; aHR heavy drinker=1.4; ref: non-heavy drinker; and aHR no vigorous activity=1.2, ref: vigorous activity). The association between potentially modifiable risky health behaviors and late mortality offers opportunities for development of interventions to improve both the quality and quantity of life after BMT.
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Genome-wide variants and polygenic risk scores for cognitive impairment following blood or marrow transplantation
Sharafeldin, N., Zhang, J., Singh, P., Bosworth, A., Chen, Y., Patel, S. K., Wang, X., Francisco, L., Forman, S. J., Wong, F. L., et al
Bone marrow transplantation. 2022
Abstract
Cognitive impairment is prevalent in blood or marrow transplantation (BMT) recipients, albeit with inter-individual variability. We conducted a genome-wide association study of objective cognitive function assessed longitudinally in 239 adult BMT recipients for discovery and replicated in an independent cohort of 540 BMT survivors. Weighted genome-wide polygenic risk scores (PRS) were constructed using linkage disequilibrium pruned significant SNPs. Forty-four genome-wide significant SNPs were identified using additive (n = 3); codominant (n = 20) and genotype models (n = 21). Each additional copy of a risk allele was associated with a 0.28-point (p = 1.07 × 10(-8)) to a 1.82-point (p = 6.7 × 10(-12)) increase in a global deficit score. We replicated two SNPs (rs11634183 and rs12486041) with links to neural integrity. Patients in the top PRS quintile were at increased risk of cognitive impairment in discovery (RR = 1.95, 95%CI: 1.28-2.96, p = 0.002) and replication cohorts (OR = 1.84, 95%CI, 1.02-3.32, p = 0.043). Associations were stronger among individuals with lowest clinical risk for cognitive impairment. These findings support potential utility of PRS-based risk classification in the development of targeted interventions aimed at improving cognitive outcomes in BMT survivors.
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Clinical and Genetic Risk Prediction of Cognitive Impairment After Blood or Marrow Transplantation for Hematologic Malignancy
Sharafeldin, N., Richman, J., Bosworth, A., Chen, Y., Singh, P., Patel, S. K., Wang, X., Francisco, L., Forman, S. J., Wong, F. L., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020;:Jco1901085
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Abstract
PURPOSE Using a candidate gene approach, we tested the hypothesis that individual single nucleotide polymorphisms (SNPs) and gene-level variants are associated with cognitive impairment in patients with hematologic malignancies treated with blood or marrow transplantation (BMT) and that inclusion of these SNPs improves risk prediction beyond that offered by clinical and demographic characteristics. PATIENTS AND METHODS In the discovery cohort, BMT recipients underwent a standardized battery of neuropsychological tests pre-BMT and at 6 months, 1 year, 2 years, and 3 years post-BMT. Associations between 68 candidate genes and cognitive impairment were assessed using generalized estimating equation models. Elastic-Net regression was used to build Base (sociodemographic), Clinical, and Combined (Base plus Clinical plus genetic) risk prediction models of post-BMT impairment. An independent nonoverlapping cohort from the BMT Survivor Study with self-report of learning/memory problems (as identified by their health care provider) was used for model replication. RESULTS The discovery cohort included 277 participants (58.5% males; 68.6% non-Hispanic whites; and 46.6% allogeneic BMT recipients). Adjusting for BMT type, age at BMT, sex, race/ethnicity, and cognitive reserve, SNPs in the blood-brain barrier, telomere homeostasis, and DNA repair genes were significantly associated with cognitive impairment. Compared with the Clinical Model, the Combined Model had higher predictive power in both the discovery cohort (mean area under the receiver operating characteristic curve [AUC], 0.89; 95% CI, 0.85 to 0.93 v 0.77; 95% CI, 0.71 to 0.83; P = 1.24 x 10(-9)) and the replication cohort (AUC, 0.71; 95% CI, 0.66 to 0.76 v 0.63; 95% CI, 0.57 to 0.68; P = .004). CONCLUSION Inclusion of candidate genetic variants enhanced the prediction of risk of post-BMT cognitive impairment beyond that offered by demographic/clinical characteristics and represents a step toward a personalized approach to managing patients at high risk for cognitive impairment after BMT.
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Self-endorsed cognitive problems versus objectively assessed cognitive impairment in blood or bone marrow transplantation recipients: A longitudinal study
Murdaugh, D. L., Bosworth, A., Patel, S. K., Sharafeldin, N., Chen, Y., Francisco, L., Forman, S. J., Wong, F. L., Bhatia, S.
Cancer. 2020
Abstract
BACKGROUND Cognitive impairment in survivors of blood or bone marrow transplantation (BMT) is well documented. However, to the authors' knowledge, the clinical relevance of self-endorsed cognitive problems and their relation to objectively assessed cognitive impairment is not known. METHODS The authors assessed cognitive impairment in 378 BMT recipients (median age, 52.2 years, 40% of whom were female and 68% of whom were non-Hispanic white) and 98 healthy controls at 5 predetermined time points: at baseline (before BMT) and at 6 months, 1 year, 2 years, and 3 years after BMT. Self-endorsed cognitive problems were evaluated using the Neuropsychological Impairment Scale (NIS) and correlated with a standardized 2-hour battery of objective cognitive testing at each time point. The authors examined the magnitude of difference in self-endorsed cognitive problems between BMT recipients and healthy controls, and the rate of change in scores over time. Multivariable analyses were used to identify clinical and/or demographic variables associated with self-endorsed cognitive problems. The authors also examined the association between cognitive impairment and returning to work after BMT. RESULTS Compared with healthy controls, BMT recipients endorsed more cognitive problems (P < .001) at all time points, and the rate of change in NIS scores was found to be significantly greater in BMT recipients. Fatigue was associated with greater endorsement of cognitive problems at 1 year after BMT (odds ratio, 4.23; 95% CI, 2.1-8.3 [P < .001]). Overall, there was a statistically significant, modest correlation noted between self-endorsed cognitive problems and objective cognitive impairment (range, 0.401-0.445 [P ≤ .01]). Higher self-endorsed cognitive problems were associated with a 3.7-fold (P = .02) higher odds of not returning to work at 3 years after BMT. CONCLUSIONS The results of the current study demonstrated that self-endorsed cognitive problems can help to identify vulnerable patient subpopulations for detailed cognitive assessment and possible cognitive remediation.
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Cognitive Functioning After Hematopoietic Cell Transplantation for Hematologic Malignancy: Results From a Prospective Longitudinal Study
Sharafeldin, N., Bosworth, A., Patel, S. K., Chen, Y., Morse, E., Mather, M., Sun, C., Francisco, L., Forman, S. J., Wong, F. L., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2018;36(5):463-475
Abstract
Purpose Cognitive impairment is well-recognized after myeloablative allogeneic hematopoietic cell transplantation (HCT). However, cognitive functioning after reduced-intensity allogeneic or autologous HCT remains unclear. Methods A total of 477 HCT recipients (236 autologous, 128 reduced-intensity allogeneic, 113 myeloablative allogeneic) underwent standardized neuropsychologic testing before HCT and at 6 months and 1, 2, and 3 years after HCT. Ninety-nine frequency-matched healthy controls underwent testing at commensurate time points. Primary outcomes of the study were practice effect-adjusted domain-specific T scores and global deficit scores. Piecewise generalized estimating equation models were used to compare groups and to identify associated variables and post-HCT trends of cognitive impairment. Results Median age was 52 years (range, 18 to 74 years) for HCT recipients and 55 years (range, 19 to 73 years) for controls. Post-HCT scores were comparable between controls and autologous and reduced-intensity HCT recipients. Myeloablative HCT recipients had significantly lower ( P < .001) post-HCT scores than controls for executive function, verbal speed, processing speed, auditory memory, and fine motor dexterity. Pre-HCT to 6 months post-HCT scores did not change after reduced-intensity HCT but declined significantly for fine motor dexterity ( P < .001) after myeloablative HCT. However, pre-HCT to 3 years post-HCT scores declined significantly ( P < .003) in reduced-intensity HCT recipients for executive function, verbal fluency, and working memory. Older age, male sex, and lower education, income, and cognitive reserve were associated with post-HCT cognitive impairment. At 3 years post-HCT, global cognitive impairment was present in 18.7% of autologous and 35.7% of allogeneic HCT recipients. Conclusion Myeloablative allogeneic HCT recipients showed significant cognitive decline compared with healthy controls. Reduced-intensity allogeneic HCT recipients showed evidence of delayed decline. Cognitive functioning in autologous HCT recipients generally was spared. The study identified vulnerable subpopulations that could benefit from targeted interventions.