Strategies for managing transfusional iron overload: conventional treatments and novel strategies.

PURPOSE OF REVIEW: For individuals who have transfusion-dependent anemia, iron overload is the long-term complication, which results in significant morbidity. Ameliorating this is now the biggest unmet need. This review specifically addresses this issue. RECENT FINDINGS: Over the last decade or so, major advances in the treatment of these individuals, has resulted from novel strategies aimed at reducing transfusion requirement as well as optimizing chelation therapy. This review will summarize these advances and provide insights into some of the therapies in the pipeline. Strategies aimed at reducing transfusion requirement include modulation of erythropoietic regulation by reducing ineffective red cell production through activin trapping, as well as stem cell gene modification approaches, which aim for a cure, and transfusion independence. Refined means of assessing tissue iron and the introduction of oral chelators have facilitated tailoring chelation regimens with closer monitoring and improved compliance. Newer approaches to ameliorate iron toxicity have focused on the hepcidin pathway, all of which would result in increased hepcidin levels and reduction of iron absorption from the intestine, sequestration of iron in normal storage sites and reduced exposure of more susceptible organs, such as the heart and endocrine organs, to the toxic effects of increased iron. SUMMARY: These advances offer the promise of improved management of transfusion-dependent individuals.

International sentinel site surveillance of patients with transfusional hemosiderosis treated with deferasirox in actual practice setting.

OBJECTIVE: The study evaluates the long-term deferasirox treatment of adult and pediatric patients with chronic transfusional iron overload in clinical practice. METHODS: In this non-interventional study, patients were observed for up to 3 years from initiation of deferasirox treatment both prospectively and retrospectively for up to 1 year prior to enrollment. The primary end points were the proportion of patients with ≥1 notable increase in serum creatinine (SCr), and ≥1 notable increase in alanine aminotransferase (ALT). RESULTS: Overall, 120 patients were enrolled and 51 completed the study, with a limited 3-year dropout rate of 12.5% due to adverse events (AEs). Increase in SCr > 33% above baseline and the age-adjusted ULN (upper limit of normal) was observed in 14 patients (95%CI, 7.1-19.2). The ALT levels >5 × ULN was observed in 1 patient. Most frequent AEs reported during treatment with deferasirox include gastrointestinal disturbances. CONCLUSIONS: The long-term treatment with deferasirox was manageable in most transfusion-dependent patients with no unexpected safety findings. Regular monitoring and an adjusted deferasirox dosing strategy per local labels allowed continued iron chelation treatment and control of transfusional iron in the majority of patients on study.

Complications of a severe autoimmune hemolytic anemia crisis: transfusional iron overload and gangrenous cholecystitis.

BACKGROUND: Evans syndrome is a rare autoimmune disorder that is defined by the simultaneous or sequential presence of two or more cytopenias without an obvious underlying precipitating cause. Evans syndrome usually follows a chronic relapsing and remitting course and is quite rare, making it difficult to evaluate in clinical studies. CASE REPORT: A 66-year-old male patient with a 17-year history of Evans syndrome presented with fulminant autoimmune hemolytic anemia (AIHA). He presented with a markedly elevated C-reactive protein (CRP; 46 mg/L [normal, 0-5 mg/L]) before onset of a decrease in hemoglobin. He required the transfusion of 20 units of red blood cells while awaiting response to aggressive immunosuppressive therapy including high-dose corticosteroids, intravenous immunoglobin therapy, and rituximab. He achieved a complete hematologic response. RESULTS: His postdischarge course was complicated by acute cholecystitis requiring laparoscopic cholecystectomy. In addition, his transfusional iron overload requiring 16 phlebotomies to reduce his ferritin level from 4933 µg/L to 326 µg/L, with phlebotomies ongoing every 2 weeks to achieve a ferritin level of less than 100 µg/L. CONCLUSION: Neither transfusional iron overload nor acute cholecystitis are well-recognized complications of a severe episode of AIHA. An elevated CRP has been recently recognized as an important prognostic marker in patients with immune thrombocytopenic purpura and this case suggests a need to evaluate its utility in AIHA.

Clinical consequences of iron overload in patients with myelodysplastic syndromes: the case for iron chelation therapy.

INTRODUCTION: Patients with myelodysplastic syndromes (MDS) are at increased risk of iron overload due to ineffective erythropoiesis and chronic transfusion therapy. The clinical consequences of iron overload include cardiac and/or hepatic failure, endocrinopathies, and infection risk. Areas covered: Iron chelation therapy (ICT) can help remove excess iron and ultimately reduce the clinical consequences of iron overload. The authors reviewed recent (last five years) English-language articles from PubMed on the topic of iron overload-related complications and the use of ICT (primarily deferasirox) to improve outcomes in patients with MDS. Expert commentary: While a benefit of ICT has been more firmly established in other transfusion-dependent conditions, such as thalassemia, its role in reducing iron overload in MDS remains controversial due to the lack of prospective controlled data demonstrating a survival benefit. Orally administered chelation agents (e.g. deferasirox) are now available, and observational and/or retrospective data support a survival benefit of using ICT in MDS. The placebo-controlled TELESTO trial (NCT00940602) is currently examining the use of deferasirox in MDS patients with iron overload, and is evaluating specifically whether use of ICT to alleviate iron overload can also reduce iron overload-related complications in MDS and improve survival.