Deferasirox therapy is associated with reduced mortality risk in a medicare population with myelodysplastic syndromes.
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ABSTRACT:
SUBMITTER: Zeidan AM
PROVIDER: S-EPMC5549705 | biostudies-other | 2015 Aug
REPOSITORIES: biostudies-other
Publications
Deferasirox therapy is associated with reduced mortality risk in a medicare population with myelodysplastic syndromes.
Zeidan Amer M AM Hendrick Franklin F Friedmann Erika E Baer Maria R MR Gore Steven D SD Sasane Medha M Paley Carole C Davidoff Amy J AJ
Journal of comparative effectiveness research 20150801 4
<h4>Aims</h4>Iron overload adversely affects patients with myelodysplastic syndromes (MDS), but benefits of iron chelation therapy have not been clearly demonstrated. We examined the association between deferasirox (DFX) therapy and mortality in transfusion-receiving Medicare patients.<h4>Patients & methods</h4>MDS patients from 2005 to 2008 were identified using ICD-9 codes from 100% Medicare claims. Patients receiving ≥20 blood units were observed until death or end of study. Marginal structur ...[more]
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| S-EPMC8425516 | biostudies-literature
Project description:After being a neglected and poorly-understood disorder for many years, there has been a recent explosion of data regarding the complex pathogenesis of myelodysplastic syndromes (MDS). On the therapeutic front, the approval of azacitidine, decitabine, and lenalidomide in the last decade was a major breakthrough. Nonetheless, the responses to these agents are limited and most patients progress within 2 years. Allogeneic stem cell transplantation remains the only potentially curative therapy, but it is associated with significant toxicity and limited efficacy. Lack or loss of response after standard therapies is associated with dismal outcomes. Many unanswered questions remain regarding the optimal use of current therapies including patient selection, response prediction, therapy sequencing and combinations, and management of resistance. It is hoped that the improved understanding of the underpinnings of the complex mechanisms of pathogenesis will be translated into novel therapeutic approaches and better prognostic/predictive tools that would facilitate accurate risk-adaptive therapy.
| S-EPMC4124605 | biostudies-literature
Project description:Over recent decades we have been fortunate to witness the advent of new technologies and of an expanded knowledge and application of chelation therapies to the benefit of patients with iron overload. However, extrapolation of learnings from thalassemia to the myelodysplastic syndromes (MDS) has resulted in a fragmented and uncoordinated clinical evidence base. We're therefore forced to change our understanding of MDS, looking with other eyes to observational studies that inform us about the relationship between iron and tissue damage in these subjects. The available evidence suggests that iron accumulation is prognostically significant in MDS, but levels of accumulation historically associated with organ damage (based on data generated in the thalassemias) are infrequent. Emerging experimental data have provided some insight into this paradox, as our understanding of iron-induced tissue damage has evolved from a process of progressive bulking of organs through high-volumes iron deposition, to one of 'toxic' damage inflicted through multiple cellular pathways. Damage from iron may, therefore, occur prior to reaching reference thresholds, and similarly, chelation may be of benefit before overt iron overload is seen. In this review, we revisit the scientific and clinical evidence for iron overload in MDS to better characterize the iron overload phenotype in these patients, which differs from the classical transfusional and non-transfusional iron overload syndrome. We hope this will provide a conceptual framework to better understand the complex associations between anemia, iron and clinical outcomes, to accelerate progress in this area.
| S-EPMC5333736 | biostudies-literature
Project description:Genome-wide expression and methylation profiling identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes (MDSs). Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases. Low-risk MDS patients and age-matched controls without haematological malignancies were included in the study. Mononuclear cells were isolated from bone marrow samples of low-risk MDS patients and controls by density gradient (Ficoll). A cohort of 18 patients with low-risk MDS and seven controls were included in a simultaneous integrative study of methylation and expression, while the whole series was used as a control group of expression data.
2012-09-25 | E-GEOD-41130 | biostudies-arrayexpress
Project description:Genome-wide expression and methylation profiling identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes (MDSs). Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases. Low-risk MDS patients and age-matched controls without haematological malignancies were included in the study. Mononuclear cells were isolated from bone marrow samples of low-risk MDS patients and controls by density gradient (Ficoll). A cohort of 18 patients with low-risk MDS and seven controls were included in a simultaneous integrative study of methylation (using Methylated CpG Island Amplification and Microarrays, MCAM) and expression (using Affymetrix microarrays HG-U133 Plus 2), while the whole series was used as a control group of expression data.
2012-09-28 | E-GEOD-41215 | biostudies-arrayexpress
Project description:BACKGROUND: Interactions between genetic variants and risk factors in myelodysplastic syndromes are poorly understood. In this case-control study, we analyzed 1 421 single nucleotide polymorphisms in 408 genes involved in cancer-related pathways in 198 patients and 292 controls. METHODS: The Illumina SNP Cancer Panel was used for genotyping of samples. The chi-squared, p-values, odds ratios and upper and lower limits of the 95% confidence interval were calculated for all the SNPs that passed the quality control filtering. RESULTS: Gene-based analysis showed nine candidate single nucleotide polymorphisms significantly associated with the disease susceptibility (q-value<0.05). Four of these polymorphisms were located in oxidative damage/DNA repair genes (LIG1, RAD52, MSH3 and GPX3), which may play important roles in the pathobiology of myelodysplastic syndromes. Two of nine candidate polymorphisms were located in transmembrane transporters (ABCB1 and SLC4A2), contributing to individual variability in drug responses and patient prognoses. Moreover, the variations in the ROS1 and STK6 genes were associated with the overall survival of patients. CONCLUSIONS: Our association study identified genetic variants in Czech population that may serve as potential markers for myelodysplastic syndromes.
| S-EPMC3556100 | biostudies-literature
Project description:BackgroundLenalidomide is approved for the treatment of anemia with transfusion dependence (TD) in patients with lower-risk myelodysplastic syndrome (MDS) with 5q deletion (del5q-MDS), but its "real-life" use and effect on transfusion needs are unclear. In the current study, the authors examined its use in the Medicare population.MethodsPatients with MDS who were enrolled in Medicare Parts A, B, and D were identified using International Classification of Diseases 9-Clinical Modification (ICD-9) codes from 100% Medicare claims from 2006 through 2008. Patients were followed until the end of the study or death. Claims were used to determine time to initiation of lenalidomide, daily dose, duration, and other MDS therapies. Transfusion status was defined each week based on transfusion use in rolling 8-week period: TD, required transfusions during 2 weeks, separated by ≥ 3 weeks; transfusion user (TU), 1 transfusion; and transfusion independence (TI), no transfusions.ResultsA total of 753 of 23,855 patients (3.2%) received lenalidomide, including 31% of 470 patients with del5q-MDS. At the time of lenalidomide initiation, 33% of patients were TD, 31% were TU, and 36% were TI. The median time to lenalidomide initiation was shorter for patients with del5q-MDS than for other lower-risk patients (8 weeks vs 20 weeks; P < .01). The percentage of patients with del5q-MDS receiving lenalidomide increased over time. Lenalidomide initiation was found to be negatively associated with older age and baseline diabetes, stroke, and renal disease. During the observation period, 44% of TU/TD patients (53% of the patients with del5q-MDS) achieved reductions in transfusion use; among TD patients receiving ≥ 3 cycles, 77% reduced their transfusion use and 40% achieved TI.ConclusionsTo the authors' knowledge, the current study is the first report of lenalidomide use in a large Medicare-enrolled population with MDS. Reductions in transfusion rates were overall consistent with data from clinical trials. Response rates were higher when ≥ 3 lenalidomide cycles were received.
| S-EPMC3805757 | biostudies-literature
Project description:The majority of myelodysplastic syndrome (MDS) patients belong to the International Prognostic Scoring System (IPSS) and IPSS-revised (IPSS-R) lower-risk categories. Their precise diagnostics and prognostic stratification is often a challenge, but may ensure the optimization of therapy. The availability of diverse treatment options has significantly improved the quality of life and survival of this group of patients. Anemia is the most relevant cytopenia in terms of frequency and symptoms in lower-risk MDS, and may be treated successfully with erythropoietic stimulating agents, provided a careful selection is performed on the basis of IPSS-R, endogenous erythropoietin levels, and transfusion independence. Doses and duration of therapy of erythropoietic-stimulating agents (ESAs) are critical to determine efficacy. In case a patient fails ESA treatment, the available options may include lenalidomide (approved for del5q positive cases), hypomethylating agents, and a rather large number of experimental agents, whose clinical trials should be offered to a larger number of MDS patients. The choice for second-line treatment must take into account biologic, cytogenetic, and molecular-identified characteristics of individual patients, as well as frailty and comorbidities. Other cytopenias are less frequently presenting as isolated. Specific therapy for thrombocytopenia has been proposed in experimental clinical trials with thrombomimetic agents that have shown good efficacy, but raised some safety concern. Although neutropenia is targeted symptomatically with growth factor supportive care, the immunosuppressive treatments are indicated mainly for pancytopenic, hypoplastic lower-risk MDS; they are not widely used because of their toxicity, despite the fact that they may induce responses. Finally, hematopoietic stem cell transplant is the curative option also for lower-risk MDS and timing should be carefully evaluated, balancing toxicity and the possibility of survival advantage. Finally, even when considered suitable for lower-risk MDS, transplant application is limited to the rarer fit and younger MDS patient.
| S-EPMC6142510 | biostudies-literature
Project description:Genome-wide expression and methylation profiling identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes (MDSs). Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases.
2012-09-25 | GSE41130 | GEO
Project description:Genome-wide expression and methylation profiling identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes (MDSs). Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases.
2012-09-28 | GSE41215 | GEO