Survival In Transfusion-dependent Patients Research Articles

The effect of iron chelation therapy on overall survival in sickle cell disease and β-thalassemia: A systematic review.

Red blood cell transfusions have become standard of care for the prevention of life-threatening anemia in patients with β-thalassemia and sickle cell disease (SCD). However, frequent transfusions can lead to accumulation of iron that can result in liver cirrhosis, diabetes mellitus, arthritis, arrhythmias, cardiomyopathy, heart failure, and hypogonadotropic hypogonadism. Iron chelation therapy has been shown to reduce serum ferritin levels and liver iron content, but limitations of trial design have prevented any demonstration of improved survival. The objective of this systematic review was to investigate the impact of iron chelation therapy on overall and event-free survival in patients with β-thalassemia and SCD. Eighteen articles discussing survival in β-thalassemia and 3 in SCD were identified. Overall iron chelation therapy resulted in better overall survival, especially if it is instituted early and compliance is maintained. Comparative studies did not show any significant differences between available iron chelation agents, although there is evidence that deferiprone is better tolerated than deferoxamine and that compliance is more readily maintained with the newer oral drugs, deferiprone and deferasirox. Iron chelation therapy, particularly the second-generation oral agents, appears to be associated with improved overall and event-free survival in transfusion-dependent patients with β-thalassemia and patients with SCD.

Labile plasma iron levels predict survival in patients with lower-risk myelodysplastic syndromes

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.

A significant proportion of thalassemia major patients have adrenal insufficiency detectable on provocative testing.

Advances in chelation therapy and noninvasive monitoring of iron overload have resulted in substantial improvements in the survival of transfusion-dependent patients with thalassemia major. Myocardial decompensation and sepsis remain the major causes of death. Although endocrine abnormalities are a well-recognized problem in these iron-overloaded patients, adrenal insufficiency and its consequences are underappreciated by the hematology community. The aims of this study were to determine the prevalence of adrenal insufficiency in thalassemia major subjects, to identify risk factors for adrenal insufficiency, and to localize the origin of the adrenal insufficiency within the hypothalamic-pituitary-adrenal axis. Eighteen subjects with thalassemia major (18.9±9.3 y old, 7 female) were tested for adrenal insufficiency using a glucagon stimulation test. Those found to have adrenal insufficiency (stimulated cortisol <18 µg/dL) subsequently underwent an ovine corticotropin-releasing hormone (oCRH) stimulation test to define the physiological basis for the adrenal insufficiency. The prevalence of adrenal insufficiency was 61%, with an increased prevalence in males over females (92% vs. 29%, P=0.049). Ten of 11 subjects who failed the glucagon stimulation test subsequently demonstrated normal ACTH and cortisol responses to oCRH, indicating a possible hypothalamic origin to their adrenal insufficiency.

Adequate iron chelation therapy for at least six months improves survival in transfusion-dependent patients with lower risk myelodysplastic syndromes

Most patients with myelodysplastic syndromes (MDS) require transfusions at the risk of iron overload and associated organ damage, and death. Emerging evidence indicates that iron chelation therapy (ICT) could reduce mortality and improve survival in transfusion-dependent MDS patients, especially those classified as International Prognostic Scoring System (IPSS) Low or Intermediate-1 (Low/Int-1). Follow-up of a retrospective study. Sample included 127 Low/Int-1 MDS patients from 28 centers in Belgium. Statistical analysis stratified by duration (≥6 versus <6 months) and quality of chelation (adequate versus weak). Crude chelation rate was 63% but 88% among patients with serum ferritin ≥1000 μg/L. Of the 80 chelated patients, 70% were chelated adequately mainly with deferasirox (26%) or deferasirox following deferoxamine (39%). Mortality was 70% among non-chelated, 40% among chelated, 32% among patients chelated ≥6 m, and 30% among patients chelated adequately; with a trend toward reduced cardiac mortality in chelated patients. Overall, median overall survival (OS) was 10.2 years for chelated and 3.1 years for non-chelated patients (p<0.001). For patients chelated ≥6 m or patients classified as adequately chelated, median OS was 10.5 years. Mortality increased as a function of average monthly transfusion intensity (HR=1.08, p=0.04) but was lower in patients receiving adequate chelation or chelation ≥6 m (HR=0.24, p<0.001). Six or more months of adequate ICT is associated with markedly better overall survival. This suggests a possible survival benefit of ICT in transfusion-dependent patients with lower-risk MDS.

Red Bood Cell Transfusion Therapy and Iron Chelation in Patients With Myelodysplastic Syndromes

Anemia is the most frequent peripheral cytopenia observed in myelodysplastic syndromes (MDS) and has been recognized among the most important factors affecting the outcome of patients with MDS. In patients who are not candidates for potentially curative approaches, therapeutic options for symptomatic anemia include red blood cell (RBC) transfusion and iron chelation, hematopoietic growth factors, immunosuppression, immune-modulatory drugs, and hypomethylating agents. In about 40% of patients, regular RBC transfusions are the only therapeutic option that can be offered. The onset of a regular transfusion requirement significantly worsens the survival of patients with MDS. Transfusion-dependent patients invariably develop secondary iron overload. Elevated serum ferritin was proven to be associated with worse survival in transfusion-dependent patients, and recent data obtained using magnetic resonance imaging show both hepatic and myocardial iron accumulation in heavily transfused patients. According to evidence-based guidelines, patients with sideroblastic anemia, 5q- syndrome, or other forms of refractory anemia, in whom long-term transfusion therapy is likely, are recognized as the best candidates to receive iron chelation therapy. In addition, patients who are candidates for allogeneic stem cell transplantation might also benefit from chelation therapy because iron overload is associated with increased transplantation-related mortality. RBC transfusions and iron chelation are the mainstay of therapy for many individuals with MDS. However, critical issues remain to be clarified in order to optimize treatment, including the identification of target hemoglobin levels to prevent anemia-related morbidity and more accurate information on the effect of iron-mediated organ damage on the outcome of patients with MDS.

Satisfaction and Convenience of Chelation Therapy in Patients with Sickle Cell Disease (SCD): Comparison between Deferasirox (Exjade®, ICL670) and Deferoxamine (DFO).

Introduction: Frequently transfused patients with SCD develop hemosiderosis, which, if untreated, results in multi-organ damage and early death. DFO is the only iron chelator (IC) approved by the FDA and is injected subcutaneously over 8–12 hours/day, 5–7 days/week. However, adherence to this therapy is difficult for patients. This report summarises patient satisfaction with deferasirox (DSX), an oral IC in development, compared to DFO in an open-label Phase II trial.Methods: A total of 195 patients with SCD were randomized and treated with DSX (n=132) or DFO (n=63). Seventy-four patients had not received IC at baseline, of whom 25 were randomized to DFO and 49 to DSX. DSX was taken orally once/day while DFO was infused via a portable pump over 8–12 hours/day, 5–7 days/week. Patient reported outcome data were documented, including satisfaction and convenience with treatment, and number of hours lost/month for taking IC. Patients with previous experiences of DFO reported preferences for DSX, DFO, or neither. At end-of-study (EOS), patients reported their willingness to continue taking the drug they were on.Results: At baseline, only 21% of patients previously treated with DFO reported that they were ‘very satisfied' or ‘satisfied' with DFO taken prior to the study, and only 16.5% reported that DFO was ‘very convenient' or ‘convenient'. Further, 77.1% of them preferred DSX. Reasons included: more convenient to take (38.6%), less disruptive to their day (18.1%), less sore (15.7%) and less disruptive to sleep (6.0%). Table 1 indicates the greater satisfaction and convenience experienced by those on DSX versus DFO regardless of chelation status at baseline. At EOS, significantly more patients on DSX (84.3%) indicated they would be willing to continue DSX, compared to 10.5% of patients on DFO. Similarly, patients reported that time lost due to taking DSX ranged from 0.2–2.9 hours/month, while time lost due to taking DFO ranged from 3.2–37.4 hours/month.Table 1Satisfaction and Convenience in Patients Previously Treated with DFO versus Treatment Naïve PatientsDSXDFOPrevious DFOTreatment naïvePrevious DFOTreatment naïveVery Satisfied or Satisfied, %Wk 285.573.523.724.0Wk 1289.263.342.136.0Wk 2486.769.439.832.0EOS84.359.223.724.0Very Convenient or Convenient, %Wk 279.573.515.832.0Wk 1283.171.436.824.0Wk 2479.571.434.224.0EOS79.563.318.420.0Conclusions: Results suggest satisfaction and convenience scores are significantly higher, and the impact on daily activities is less, for patients on DSX than those on DFO. Further studies are needed to explore whether higher satisfaction and convenience will lead to better adherence to DSX. As adherence to chelation therapy impacts on survival in transfusion-dependent patients with SCD, these data indicate that DSX may significantly improve the care of transfusion-dependent patients.

Patient Satisfaction with Deferasirox (Exjade®, ICL670) an Oral Form of Chelation Therapy Versus Deferoxamine an Infused Chelation Therapy.

Frequent blood transfusions result in iron overload and lead to life-threatening complications and early mortality if regular chelation therapy (CT) is not implemented. Deferoxamine (DFO), the most common form of CT, requires infusions of 8–12 hours, 5–7 days per week. Deferasirox (DSX) is an oral CT under development. A randomised clinical trial was conducted to compare the safety and efficacy of DFO and DSX. The study demonstrated that at therapeutic doses, DSX is able to maintain/reduce iron burden comparably to DFO. Patient-reported outcomes (PRO) were also collected and are the focus of this analysis. 296 and 290 patients with β-thalassemia were randomised and treated with DSX and DFO, respectively. At baseline, 15 patients had not been treated previously with DFO; these results focus on the 571 patients who had taken DFO previously. DSX was taken orally once per day while DFO was infused via pump for 8–12 hours, 5–7 days per week. Patients who had previously taken DFO were asked at baseline, Week 4, 24 and at the end of the study (EOS) to rate satisfaction with and convenience of DFO or DSX on five-point scales, and indicate the number of hours lost per month while taking CT. At Week 4, patients provided their preferences for either DSX, DFO, or neither. At EOS patients reported whether they would be willing to take the study drug they were on. At baseline, 45% of patients reported that they were either very satisfied or satisfied with DFO taken prior to the study start and 68% reported that DFO was inconvenient or very inconvenient. DFO treatment took approximately 18 hours out of the previous month. At Weeks 4, 24 and EOS, significantly more patients on DSX (92.0%, 89.6%, 85.1%, respectively) reported being very satisfied or satisfied with treatment than patients on DFO (50.4%, 44.0%, 38.7%; p<0.0001). The majority of the DSX group reported that DSX was very convenient or convenient (>90%), whereas the majority of the DFO group reported DFO to be inconvenient (>60%). Similarly, patients reported 1.3–2.8 hours lost per month due to taking DSX, compared with 3.1–11.7 lost due to taking DFO during the study. 96.9% reported that they preferred DSX to the treatment they were on prior to the study (DFO). The primary reasons for preferring DSX were: more convenient to take (37.4%), less sore than DFO (25.3%), less disruptive to their day (22.8%), less disruptive to their sleep (6.2%) and to their family (4.2%). At EOS, significantly more patients on DSX (85.8%) previously treated with DFO indicated they would be willing to continue DSX, compared with 13.8% of patients on DFO who would be willing to continue DFO. Results suggest that satisfaction and convenience are far superior and the impact on daily activities is less for those on DSX, compared to those on DFO. This has direct implications on patients' preferences and willingness to continue taking treatments. As compliance to CT has historically been shown to impact survival in transfusion-dependent patients with β-thalassemia major, these data suggest that DSX may significantly improve thalassemia care.