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Comorbidities predict worse prognosis in patients with primary myelofibrosis.

ABSTRACT: Comorbidities have been shown to play an important role in the prognostic assessment of several hematologic conditions; however, the role of comorbidities in primary myelofibrosis has not been studied. The objective of the current study was to evaluate the prevalence and impact of comorbidities in patients with primary myelofibrosis (PMF) using the Adult Comorbidity Evaluation-27 (ACE-27).In this retrospective observational cohort study, a total of 349 consecutive patients with a confirmed diagnosis of PMF who presented to the study institution from 2000 to 2008 were evaluated. The authors evaluated the frequency and severity of comorbidities in these patients and assessed their impact on survival in a bivariable model that included the ACE-27 and Dynamic International Prognostic Scoring System scores as covariates.Approximately 64% of patients had at least 1 comorbid condition, and diseases of the cardiovascular system (63%) were most common. Comorbidities had a significant negative impact on survival (P

SUBMITTER: Newberry KJ

PROVIDER: S-EPMC4838182 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Comorbidities predict worse prognosis in patients with primary myelofibrosis.

Newberry Kate J KJ Naqvi Kiran K Nguyen Khanh T KT Cardenas-Turanzas Marylou M Florencia Tanaka Maria M Pierce Sherry S Verstovsek Srdan S

Cancer 20140610 19

<h4>Background</h4>Comorbidities have been shown to play an important role in the prognostic assessment of several hematologic conditions; however, the role of comorbidities in primary myelofibrosis has not been studied. The objective of the current study was to evaluate the prevalence and impact of comorbidities in patients with primary myelofibrosis (PMF) using the Adult Comorbidity Evaluation-27 (ACE-27).<h4>Methods</h4>In this retrospective observational cohort study, a total of 349 consecut ...[more]

PMID: 24917509

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Project description:Treatment decisions in primary myelofibrosis (PMF) are guided by numerous prognostic systems. Patient-specific comorbidities have influence on treatment-related survival and are considered in clinical contexts but have not been routinely incorporated into current prognostic models. We hypothesized that patient-specific comorbidities would inform prognosis and could be incorporated into a quantitative score. All patients with PMF or secondary myelofibrosis with available DNA and comprehensive electronic health record (EHR) data treated at Vanderbilt University Medical Center between 1995 and 2016 were identified within Vanderbilt's Synthetic Derivative and BioVU Biobank. We recapitulated established PMF risk scores (eg, Dynamic International Prognostic Scoring System [DIPSS], DIPSS plus, Genetics-Based Prognostic Scoring System, Mutation-Enhanced International Prognostic Scoring System 70+) and comorbidities through EHR chart extraction and next-generation sequencing on biobanked peripheral blood DNA. The impact of comorbidities was assessed via DIPSS-adjusted overall survival using Bonferroni correction. Comorbidities associated with inferior survival include renal failure/dysfunction (hazard ratio [HR], 4.3; 95% confidence interval [95% CI], 2.1-8.9; P = .0001), intracranial hemorrhage (HR, 28.7; 95% CI, 7.0-116.8; P = 2.83e-06), invasive fungal infection (HR, 41.2; 95% CI, 7.2-235.2; P = 2.90e-05), and chronic encephalopathy (HR, 15.1; 95% CI, 3.8-59.4; P = .0001). The extended DIPSS model including all 4 significant comorbidities showed a significantly higher discriminating power (C-index 0.81; 95% CI, 0.78-0.84) than the original DIPSS model (C-index 0.73; 95% CI, 0.70-0.77). In summary, we repurposed an institutional biobank to identify and risk-classify an uncommon hematologic malignancy by established (eg, DIPSS) and other clinical and pathologic factors (eg, comorbidities) in an unbiased fashion. The inclusion of comorbidities into risk evaluation may augment prognostic capability of future genetics-based scoring systems.

Project description:Toll-like receptor (TLR) family members are key players in inflammation. TLR10 has been poorly studied in chronic inflammatory disorders, and its clinical relevance in rheumatoid arthritis (RA) is as yet unknown. We aimed at identifying TLR10 variants within all coding regions of the gene in patients with RA as well as studying their functional and clinical significance.TLR10 gene variants were studied by performing sequencing of 66 patients with RA and 30 control subjects. A selected variant, I473T, was then analyzed in 1654 patients and 1702 healthy control subjects. The capacity of this TLR10 variant to modify the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) was determined by using a luciferase reporter assay and analyzing the expression of NFkB target genes by quantitative polymerase chain reaction. Differences between groups were analyzed by using the Mann-Whitney U test and the unpaired two-tailed Student's t test.We detected ten missense variants in the TLR10 gene and focused on the I473T substitution based on allele frequencies and the predicted functional impact. I473T variant is not associated with susceptibility to RA, but it significantly correlates with erosive disease in patients seropositive for antibodies to citrullinated protein antigens (p?=?0.017 in the total cohort and p?=?0.0049 in female patients) and with a lower response to infliximab treatment as measured by the change in Disease Activity Score in 28 joints (p?=?0.012) and by the European League Against Rheumatism criteria (p?=?0.049). Functional studies showed that TLR10 reduced activation of the NFkB inflammatory pathway in hematopoietic cells, whereas the I473T variant lacked this inhibitory capacity. Consistently, after exposure to infliximab, cells expressing the I437T variant showed higher NFkB activity than cells carrying wild-type TLR10.A TLR10 allelic variant, I473T, has impaired NFkB inhibitory activity and is highly associated with disease severity and low response to infliximab in patients with RA.

Dataset Information

Comorbidities predict worse prognosis in patients with primary myelofibrosis.

Publications

Comorbidities predict worse prognosis in patients with primary myelofibrosis.

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