Role of iron chelation in improving survival: An integral part of current therapy for myelodysplastic syndromes.
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ABSTRACT:
SUBMITTER: Taran SJ
PROVIDER: S-EPMC4772398 | biostudies-literature | 2015 Oct-Dec
REPOSITORIES: biostudies-literature
Publications
Role of iron chelation in improving survival: An integral part of current therapy for myelodysplastic syndromes.
Taran Sachi Jain SJ Taran Rakesh R
South Asian journal of cancer 20151001 4
This review article highlights the current role of iron chelation in MDS to optimize survival and quality of life. Its role in specific subtypes of MDS is also discussed. ...[more]
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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.
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Project description:Anemia leading to transfusion dependency (TD) and iron overload (IO) is commonly observed in patients with myelodysplastic syndromes (MDS). In MDS, TD and IO have been retrospectively associated with inferior survival and worse clinical outcomes, including cardiac, hepatic and endocrine dysfunction, and, in some analyses, with leukemic progression and infectious complications. Although suggested by retrospective analyses, clear prospective documentation of the beneficial effects of iron chelation therapy (ICT) on organ function and survival in MDS patients with TD and IO is currently lacking. Consequently, the role of ICT in MDS patients with TD and IO remains a very controversial aspect in the management of MDS. In this review, the authors summarize the current knowledge regarding IO in MDS and the role of ICT.
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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.
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Project description:Myelodysplastic syndromes (MDS), a heterogeneous group of blood diseases, are usually diagnosed in older individuals, with a median age at diagnosis of more than 70 years. Anemia is a common symptom in patients with MDS and may require frequent red blood cell transfusions, which can lead to iron overload. Iron chelation therapy is recommended to decrease iron concentrations in tissue and minimize organ dysfunction. However, the currently available iron chelation therapies are associated with side effects, financial constraints, and dosing issues, which may affect patient adherence. Moreover, many patients with MDS lack an understanding of the disease and their prognosis and treatments. This review can be used in the advanced practice setting to discuss the importance of communicating with patients about MDS from the time of diagnosis and will explore strategies to enhance adherence to iron chelation therapy. An individualized approach that weighs the risks and benefits of treatment for older patients with MDS will allow advanced practitioners to set expectations while developing adherence strategies to optimize outcomes. This approach provides a platform for advanced practitioners to communicate with patients to ensure they understand the natural history of MDS, their individual prognoses, and the goals of both active treatment and supportive care.
| S-EPMC5902151 | biostudies-literature
Project description:Myelodysplastic syndromes (MDS) include a group of clonal myeloid neoplasms characterized by cytopenias due to ineffective hematopoiesis, abnormal blood and marrow cell morphology, and a risk of clonal evolution and progression to acute myeloid leukemia (AML). Because outcomes for patients with MDS are heterogeneous, individual risk stratification using tools such as the revised International Prognostic Scoring System (IPSS-R) is important in managing patients-including selecting candidates for allogeneic hematopoietic stem cell transplantation (ASCT), the only potentially curative therapy for MDS. The IPSS-R can be supplemented by molecular genetic testing, since certain gene mutations such as TP53 influence risk independent of established clinicopathological variables. For lower risk patients with symptomatic anemia, treatment with erythropoiesis-stimulating agents (ESAs) or lenalidomide (especially for those with deletion of chromosome 5q) can ameliorate symptoms. Some lower risk patients may be candidates for immunosuppressive therapy, thrombopoiesis-stimulating agents, or a DNA hypomethylating agent (HMA; azacitidine or decitabine). Among higher risk patients, transplant candidates should undergo ASCT as soon as possible, with HMAs useful as a bridge to transplant. Non-transplant candidates should initiate HMA therapy and continue if tolerated until disease progression. Supportive care with transfusions and antimicrobial drugs as needed remains important in all groups.
| S-EPMC5967332 | biostudies-literature
Project description:Red blood cell transfusions remain one of the cornerstones in supportive care of lower-risk patients with myelodysplastic syndromes. We hypothesized that patients develop oxidant-mediated tissue injury through the formation of toxic iron species, caused either by red blood cell transfusions or by ineffective erythropoiesis. We analyzed serum samples from 100 lower-risk patients with myelodysplastic syndromes at six-month intervals for transferrin saturation, hepcidin-25, growth differentiation factor 15, soluble transferrin receptor, non-transferrin bound iron and labile plasma iron in order to evaluate temporal changes in iron metabolism and the presence of potentially toxic iron species and their impact on survival. Hepcidin levels were low in 34 patients with ringed sideroblasts compared to 66 patients without. Increases of hepcidin and non-transferrin bound iron levels were visible early in follow-up of all transfusion-dependent patient groups. Hepcidin levels significantly decreased over time in transfusion-independent patients with ringed sideroblasts. Increased soluble transferrin receptor levels in transfusion-independent patients with ringed sideroblasts confirmed the presence of ineffective erythropoiesis and suppression of hepcidin production in these patients. Detectable labile plasma iron levels in combination with high transferrin saturation levels occurred almost exclusively in patients with ringed sideroblasts and all transfusion-dependent patient groups. Detectable labile plasma iron levels in transfusion-dependent patients without ringed sideroblasts were associated with decreased survival. In conclusion, toxic iron species occurred in all transfusion-dependent patients and in transfusion-independent patients with ringed sideroblasts. Labile plasma iron appeared to be a clinically relevant measure for potential iron toxicity and a prognostic factor for survival in transfusion-dependent patients. clinicaltrials.gov Identifier: 00600860.
| S-EPMC5777192 | biostudies-literature
Project description:Transfusional iron overload is a major target in the care of patients with transfusion-dependent thalassemia (TDT) and other refractory anemias. Iron accumulates in the liver, heart, and endocrine organs leading to a wide array of complications. In this review, we summarize the characteristics of the approved iron chelators, deferoxamine, deferiprone, and deferasirox, and the evidence behind the use of each, as monotherapy or as part of combination therapy. We also review the different guidelines on iron chelation in TDT. This review also discusses future prospects and directions in the treatment of transfusional iron overload in TDT whether through innovation in chelation or other therapies, such as novel agents that improve transfusion dependence.
| S-EPMC4476479 | biostudies-literature
Project description:PurposeThe current classification systems of myelodysplastic syndromes (MDS), including the International Prognostic Scoring System (IPSS), do not fully reflect the molecular heterogeneity of the disease. Molecular characterization may predict clinical outcome and help stratify patients for targeted therapies. Epigenetic therapy using decitabine, a DNA hypomethylating agent, is clinically effective for the treatment of MDS. Therefore, we investigated the association between DNA methylation and clinical outcome in MDS.Patients and methodsWe screened 24 patients with MDS for promoter CpG island methylation of 24 genes and identified aberrant hypermethylation at 10 genes. We then performed quantitative methylation analyses by bisulfite pyrosequencing of the identified genes in 317 patient samples from three independent studies and assessed relations between methylation and clinical outcome.ResultsIn an initial training cohort of 89 patients with MDS, methylation frequencies of individual genes ranged from 7% to 70% and were highly concordant. Therefore, we defined a methylation z score based on all genes for each patient. We found that patients with higher levels of methylation, compared with patients with lower levels, had a shorter median overall survival (12.3 v 17.5 months, respectively; P = .04) and shorter median progression-free survival (6.4 v 14.9 months, respectively; P = .009). This methylation prognostic model was independent of age, sex, and IPSS group. Applied to two validation cohorts (228 patients), this model was confirmed as an independent prognostic predictor for survival. Although methylation at baseline did not correlate with clinical response to decitabine, we observed a significant correlation between reduced methylation over time and clinical responses.ConclusionDNA methylation predicts overall and progression-free survival in MDS.
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Project description:Although iron overload is a clinical challenge, little is known about the clinical impact of HFE-variants in myelodysplastic syndromes (MDS) to date. We analyzed the HFE status in 167 MDS patients and 494 healthy controls. One or more of the 3 HFE-variants (H63D, C282Y, S65C) were found in 65/167 (38.9%) MDS patients and in 164/494 (33.2%) controls. At diagnosis, the median serum ferritin levels were higher in MDS patients with HFE-variants (409 µg/L; range: 23-7415) compared to those without HFE-variants (346.5 µg/L; range: 10-5450) (P=0.62). Moreover, 'HFE-mutated' patients had a slightly faster increase in serum ferritin in follow up examinations. The percentage of patients with HFE-variants was higher in refractory anemia (RA) (22/53=41.5%) or RA with ring sideroblasts (RARS) (17/39=43.6%) compared to RA with excess of blasts (RAEB) (16/46=34.8%) or RAEB in transformation (RAEB-T) (5/17=29.4%). Differences were also detectable when comparing low- and high-risk MDS variants defined by the World Health Organization classification. There was no significant correlation between HFE-variants and MDS-related somatic mutations. Progression-free survival was substantially longer in patients with HFE-variants compared to those without HFE-variants H63D and C282Y (P=0.089). Together, the HFE-variants H63D and C282Y are frequently detected in Austrian MDS patients. These patients have substantially higher ferritin levels at diagnosis, accumulate iron slightly faster and have a better progression-free survival than non-mutated patients.
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Project description:Myelodysplastic syndromes (MDS) represent a heterogeneous group of myeloid neoplasms that are characterized by ineffective hematopoiesis, variable cytopenias, and a risk of progression to acute myeloid leukemia. Most patients with MDS are affected by anemia and anemia-related symptoms, which negatively impact their quality of life. While many patients with MDS have lower-risk disease and are managed by existing treatments, there currently is no clear standard of care for many patients. For patients with higher-risk disease, the treatment priority is changing the natural history of the disease by delaying disease progression to acute myeloid leukemia and improving overall survival. However, existing treatments for MDS are generally not curative and many patients experience relapse or resistance to first-line treatment. Thus, there remains an unmet need for new, more effective but tolerable strategies to manage MDS. Recent advances in molecular diagnostics have improved our understanding of the pathogenesis of MDS, and it is becoming clear that the diverse nature of genetic abnormalities that drive MDS demands a complex and personalized treatment approach. This review will discuss some of the challenges related to the current MDS treatment landscape, as well as new approaches currently in development.
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