Iron Overload In Transfusion-dependent Patients Research Articles

Effect of Eculizumab on Iron Metabolism in Transfusion-independent Patients With Paroxysmal Nocturnal Hemoglobinuria

Effect of Eculizumab on Iron Metabolism in Transfusion-independent Patients With Paroxysmal Nocturnal Hemoglobinuria

5610224 THE USE OF LUSPATERCEPT IN PATIENTS WITH β -THALASSAEMIA AND MULTIPLE SYSTEMIC COMPLICATIONS INCREASES HEMOGLOBIN LEVEL, DECREASES TRANSFUSION BURDEN, AND IS UNAFFECTED BY COMPLICATIONS. SINGLE THALASSEMIA AND SICKLE CELL DEPARTEMENT’S EXPERIENCE.

Introduction: Luspatercept is a novel recombinant protein that improves erythroid maturation and has been shown to reduce the transfusion burden in transfusion dependent β -thalassemia patients. The aim of this study is to evaluate transfusion needs, biochemical markers, and biomarkers of tissue iron overload in transfusion-dependent patients with -thalassemia and comorbidities following Luspatercept administration. Methods: In a single department of thalassemia and sickle cell disease over a 9-month period, 17 patients (Women/Men: 9/8, mean age: 50.61 years)with transfusion-dependent β-thalassemia were evaluated 12 weeks before Luspatercept administration and 12 and 24 weeks after Luspatercept administration, respectively. (image1:genotypes and cormobidities)The authors evaluated hemoglobin levels, transfusion demands, transfusion intervals, and biochemical markers. In parallel, they evaluated clinical comorbidities, liver iron content (LIC), liver fibrosis by Fibroscan, and left ventricular ejection fraction. Other treatments were provided to patients according to standard clinical practice. SPSS was used to perform statistical analysis of the results. p0.05 indicates statistical significance. Results: In three patients, the dose was increased from 1 mg to 1.25 mg/kg after three cycles of luspatercept, while in one patient there was no response and treatment discontinued. Five of the seventeen patients terminated treatment due to fatigue (4/5) and lower extremity edema (1/5). A non-statistically significant improvement in liver fibrosis and LIC was reported 24 weeks following the onset of treatment, whereas the ejection fraction improved. At 12 weeks, there was a statistically significant increase in hemoglobin levels, a decrease in blood needs, and longer intervals between transfusions. Patients continue to demonstrate statistically significant improvement in terms of improved transfusion intervals and hemoglobin levels 24 weeks after initiating therapy. Except for the increase in uric acid and LDH, the remaining biomarkers continue to improve without a statistically significant effect at 24 weeks. Ferritin levels decreased over a period of 12 to 24 weeks. There was no statistical correlation among comorbidities (pulmonary hypertension, atrial fibrillation, hypogonadism, osteoporosis, albuminuria, thrombophilia, hepatitis C, extramedullary foci) and genotypes in luspatercept response (Detailed results in table 1). Conclusions: Treatment with Luspatercept in TD patients with beta-thalassemia major and severe comorbidities has a positive effect on therapeutic efficacy. Table - of the results displaying different parameters in 17 patients pre- and post- Luspatercept administration parameter baseline 12 wks 0 to 12 wks (p<0.05) 24 wks 0 to 24 wks(p<0.05) 12 to 24 wks(p<0.05) Hb (g/dl) 10.11 11.4 <0.001 10.50 0.150 <0.001 transfused blood volume 3227 2427 <0.001 2320 0.054 <0.001 transfusion interval 15.58 21.76 <0.001 22.53 <0.001 <0.001 LIC 6.31 5.51 0,089 Fibroscan 7.57 6.82 0.093 E.F 56.59 59.53 0.011 Ferritin 1704 1204 0.139 816 0.234 0.014 LDH 311 328 0.720 412 0.263 <0.001 Uric Acid 5.5 5.7 0.421 6.38 0.28 <0.001

MRI Measurements of Iron Load in Transfusion-Dependent Patients: Implementation, Challenges, and Pitfalls.

Magnetic resonance imaging (MRI) has played a key role in studies of iron overload in transfusion‐dependent patients, providing insights into the relations among liver and cardiac iron loading, iron chelator dose, and morbidity. Currently, there is rapid uptake of these methods into routine clinical practice as part of the management strategy for iron overload in regularly transfused patients. Given the manifold methods of data acquisition and analysis, there are several potential pitfalls that may result in inappropriate decision making. Herein, we review the challenges of establishing suitable MRI techniques for tissue iron measurement in regularly transfused patients.

Deferasirox Decreases Liver Iron Concentration in Iron-Overloaded Patients with Myelodysplastic Syndromes, Aplastic Anemia and Other Rare Anemias

Iron overload in transfusion-dependent patients with rare anemias can be managed with chelation therapy. This study evaluated deferasirox efficacy and safety in patients with myelodysplastic syndromes (MDS), aplastic anemia (AA) or other rare anemias. A 1-year, open-label, multicenter, single-arm, phase II trial was performed with deferasirox (10-40 mg/kg/day, based on transfusion frequency and therapeutic goals), including an optional 1-year extension. The primary end point was a change in liver iron concentration (LIC) after 1 year. Secondary end points included changes in efficacy and safety parameters (including ophthalmologic assessments) overall as well as in a Japanese subpopulation. Overall, 102 patients (42 with MDS, 29 with AA and 31 with other rare anemias) were enrolled; 57 continued into the extension. Mean absolute change in LIC was -10.9 mg Fe/g dry weight (d.w.) after 1 year (baseline: 24.5 mg Fe/g d.w.) and -13.5 mg Fe/g d.w. after 2 years. The most common drug-related adverse event was increased serum creatinine (23.5%), predominantly in MDS patients. Four patients had suspected drug-related ophthalmologic abnormalities. Outcomes in Japanese patients were generally consistent with the overall population. Results confirm deferasirox efficacy in patients with rare anemias, including a Japanese subpopulation. The safety profile was consistent with previous studies and ophthalmologic parameters generally agreed with baseline values (EUDRACT 2006-003337-32).

The IRON2 Study. A Retrospective Observational Study to Describe the Evolution of Iron Overload in Patients with Low-Risk Myelodysplastic Syndrome

AbstractAbstract 1723 Introduction and Objective:A large number of patients with low-risk myelodysplastic syndrome (MDS) need blood transfusions, being iron overload an inevitable consequence that may cause hepatic fibrosis and cirrhosis, diabetes or myocardiopathy unless it is not treated. The main objective of this study is to describe the evolution of iron overload in transfusion-dependent patients with low-risk MDS. Secondary objectives include the evaluation of the impact of iron chelation therapy on Event Free Survival (EFS) (including infections, arthropathy, diabetes mellitus, hepatic and cardiac complications), Overall Survival (OS) and Leukemia Free Survival (LFS). Methods and Patients:Retrospective observational study carried out in Haematology Departments of 47 Spanish hospitals between March 2010 and March 2011. Transfusion-dependent patients with low/intermediate-1 IPSS risk who had received ≥10 red blood cell (RBC) transfusion during at least 12 months previous to study entry were eligible. Results:A total of 263 patients were evaluated [age at diagnosis, 74 ± 10.5 years]. IPSS classification was available in 82.9% included patients (lack of cytogenetics in 37 patients), classified as low risk (86%) and int-1 risk (14%). At diagnosis, 25.5% of patients had serum ferritin (SF) levels >500ng/ml, 8.7% SF>1,000ng/ml, and 22% TSI>50%. The median number of RBC transfusions per month was 2.35 RBC/month; during the course of the disease, 82.4% of patients reached SF levels >1,000ng/ml. Cardiac complications worsened/appeared in 24.4% of patients, having received a median RBC transfusions of 22 (7–92), and showing a median SF levels of 1,365 (735–3,025) ng/ml. One-hundred forty-seven (55.9%) patients started iron chelation therapy (85.5% with deferasirox) with a median number of RBC transfused of 23 (14–38) and a median SF levels of 1,570 (1,231.5–2,195) ng/ml. 71% of patients with SF>1,000ng/ml were on iron chelation therapy. Table 1 shows the results of univariate analysis of EFS, OS and LFS. As part of this study, we are currently performing a multivariate analysis whose results will be presented in forthcoming congress.Table 1Univariate analyses of EFS, OS and LFSNon chelatedChelated*p-valueMedian EFS arthropathy complications (months), n=236Not reachedNot reached0.794Median EFS diabetes complications (months), n=216Not reachedNot reached0.559Median EFS hepatic complications (months), n=236208Not reached0.303Median EFS cardiac complications (months), n=196901370.004Median OS (months), n=2281051330.009Median LFS (months), n=228Not reachedNot reached0.043*Analysis including patients with ≥3 months chelation (n=109) (of whom 73.4% received deferasirox as first option therapy with a mean dose of 18 mg/kg/day). Conclusions:The results of this study show that a high percentage of transfusion-dependent patients with low-risk MDS (82.4%) reach SF levels >1,000ng/ml during the course of their disease. Patients on iron chelation therapy show a higher cardiac EFS, OS and LFS compared with those not treated, being deferasirox the most frequently used chelating agent in clinical practice. Disclosures:Sanz:Novartis Farmaceutica S.A.: Employment.

Awareness of and Identifying Iron Overload in Transfusion-Dependent Patients Can Be Improved: A Retrospective Review At a Single Tertiary Care Centre

Abstract 5283Awareness of and Identifying Iron Overload in Transfusion-dependent Patients can be improved: A Retrospective Review at a Single Tertiary Care Centre Nicole Hugel, HBSc1 and Cyrus C. Hsia, HBSc, MD, FRCPC2. 1Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada, 2Schulich School of Medicine and Dentistry, University of Western Ontario, Division of Hematology, Department of Medicine, London Health Sciences Centre, London, ON, Canada. Introduction:Several patient populations, including those with thalassemia, sickle cell disease, and bone marrow failure syndromes, often require red blood cell (RBC) transfusions and are at risk of iron overload. Chronic RBC transfusions lead to an increase in morbidity and mortality, particularly as a result of iron overload, proven in patients with thalassemia major and implicated in certain bone marrow failure syndromes such as myelodysplasia. Guidelines currently recommend iron chelation in these various clinical settings, yet the true incidence of iron overload and physician awareness patterns remain unknown. Iron overload is likely under recognized and under managed. We aim to determine the incidence of iron overload in transfusion-dependent patients in a general tertiary care centre and to determine if physicians are adequately screening for and considering treatment for iron overload. Methods:All adult patients at a single tertiary care centre, London Health Sciences Centre (LHSC), who received at least one RBC transfusion between January 1, 2006 and December 31, 2008, were captured through the local Blood Transfusion Laboratory (BTL) database. Patients who were deemed transfusion-dependent, defined as having received a minimum of 12 units of RBCs in any 12 month period with at least one RBC transfusion every 8 weeks, were identified for further analysis. This was based on the World Health Organization (WHO) criteria for RBC transfusion dependency in patients with myelodysplastic syndrome (MDS), where RBC transfusion dependency was defined as having at least one RBC transfusion every 8 weeks over a period of 4 months. Full chart reviews for these patients from the beginning of the study period to up to 12 months after the last transfusion in the LHSC BTL database during the study period were performed. For these transfusion-dependent patients, the number who had ferritin levels checked was determined. Those who had a ferritin level >1000μg/L were considered to have iron overload. Finally, of these patients who were transfusion-dependent with iron overload, full chart reviews during the study period were undertaken to determine if treating physicians considered monitoring for and treating the iron overload. Results:The LHSC BTL database included a total of 67449 RBC transfusions administered to 12486 unique patients during the study period. 1200 patients (6.6%) received at least 12 units of RBCs during the study period and were evaluated further. 48 adult patients (0.4%) satisfied the criteria for RBC transfusion dependence.Of the 48 transfusion-dependent patients, 40 (83.3%) had a ferritin value measured during and/or up to 12 months following the end of the study period. 30 (75.0%) transfusion-dependent patients with a ferritin measurement were deemed to have iron overload, consisting of patients with MDS (n=13), myelofibrosis (n=4), beta thalassemia (n=3), red cell aplasia (n=3), aplastic anemia (n=1), and other diagnoses (n=6). In this smaller cohort of 30 patients, 24 patients (80.0%) had physicians that referred to the possibility of iron overload in the clinical notes and only 16 patients (53.3%) were treated with iron chelation at some point during the study period. Conclusions:In a general tertiary care centre the percentage of transfusion-dependent patients is low compared to the total number of patients who are transfused. The percentage of transfusion-dependent patients who treating physicians monitored for or identified iron overload and subsequently managed were slightly higher than previous published rates. However, awareness of and identifying iron overload in transfusion-dependent patients at a general tertiary care centre can be improved. Disclosures:Hugel:Novartis: Unspecified Educational Fund.

A European survey on the detection and management of iron overload in transfusion-dependent patients with MDS

To better understand the detection and management of iron overload in transfusion-dependent patients with myelodysplastic syndromes (MDS), a 15-min web- or paper-based survey was conducted among 338 European physicians from 27 countries. Respondents had a mean of 18 years of clinical experience. Forty-six percent and 27% of physicians noted that detecting and treating iron overload were either “very important” or “important,” respectively. The main reason for not actively exploring iron overload was related to poor patient prognosis, while the main reasons for not initiating iron chelation therapy were poor patient prognosis and older patient age. Thirty-seven percent and 31% of physicians believed that treating iron overload in these patients was “very important” or “important,” respectively. Ninety percent of physicians prescribed iron chelation therapy, and 38% of transfusion-dependent patients received iron chelation therapy. The key reasons for not initiating iron chelation therapy were related to poor patient prognosis (72%), patient age ≥85 years (50%), and comorbidities (34%). The views of these experienced MDS physicians reflect available international MDS treatment guidelines.

New treatments for myelodysplastic syndromes.

In the last decade, significant advances have been made in the treatment of patients with Myelodysplastic Syndromes (MDS). Although best supportive care continues to have an important role in the management of MDS, to date the therapeutic approach is diversified according to the IPSS risk group, karyotype, patient’s age, comorbidities, and compliance. Hematopoietic growth factors play a major role in lower risk MDS patients, and include high dose erithropoiesis stimulating agents and thrombopoietic receptor agonists. Standard supportive care should also include iron chelating therapy to reduce organ damage related to iron overload in transfusion-dependent patients. Biologic therapies have been introduced in MDS, as lenalidomide, which has been shown to induce transfusion independence in most lower risk MDS patients with del5q. Hypomethylating agents have shown efficacy in INT-2/high risk MDS patients, reducing the risk of leukemic transformation and increasing survival. Other agents under development for the treatment of MDS include histone deacetylase inhibitors, farnesyltransferase inhibitors, clofarabine and ezatiostat.

Erythropoietin-Assisted Phlebotomy in Stem Cell Transplant Patients with Iron Overload.

Abstract 4296▪ BackgroundStem cell transplantation is a potential curative treatment for hematologic malignancies. This treatment often requires repeated packed red blood cell (PRBC) transfusion requirements raising the risk of secondary hemochromatosis with each successive unit transfused. Erythropoietin-assisted phlebotomy is a potential treatment to alleviate iron overload in transfusion-dependent patients. MethodsWe carried out a retrospective review from 2000 to 2008 of records of both allogeneic and autologous stem cell transplant recipients treated at San Antonio Military Medical Center South for a total of 372 patients. We evaluated the maximum level of ferritin recorded for each patient and used an upper level of 1,000 ug/mL (approx 2.5x upper level of normal) to identify those patients at increased risk for complications of iron overload. 65 patients had ferritin levels <1,000ng/mL and served as a control group. There were 56 patients who met our criteria for iron overload. Their transfusion records were reviewed and further subdivided into those who received therapeutic erythropoietin-assisted phlebotomy and those who did not. They were also reviewed for evidence of any opportunistic infection during their treatment course. ResultsOf the 56 patients with documented ferritin levels over 1,000ug/mL, the average ferritin level was 2,965ug/mL. The transfusion records for these patients were obtained and showed that they received an average of 26.6 units of transfused PRBCs during their transplant course. Ten of these patients underwent therapeutic erythropoietin-assisted phlebotomy of 500cc of whole blood approximately once every two weeks to decrease their ferritin levels with a stated goal of <500ugmL. All records were then reviewed for evidence of opportunistic infections complicating treatment and corresponding mortality. The non-phlebotomized group had an increased rate of infections and trended toward a higher mortality rate. Overall infections were significantly different, with the hyperferritinemia group who did not receive phlebotomy having the highest rates within our three groups at both the three and six month intervals (p<0.004 and p<0.008). These differences were not significant at one year (p<0.086). When we compared the two main groups (ferritin <1,000 ng/ml and >1,000 ng/ml), infection rate results were higher in the hyperferritinemia group at all three time intervals (p<0.003, p<0.008 and p<0.049). There was no significant difference between infection rates in the erythropoietin-assisted-phlebotomy group and the control group at either the 3 or 6 month intervals. (p<0.17 and p<0.107) Mortality differences between the two main groups (ferritin >1,000ng/ml and ferritin <1,000 ng/ml) were significant at both six months and one year (p<0.0004 and p<0.005 respectively). There was also a significant difference noted between the hyperferritinemia group who did not receive phlebotomy and the ferritin <1,000 ng/ml group at both six months and one year (p<0.00002 and p<0.0004 respectively). Two-tailed Fishers exact test showed that the mortality rate between the two subsets in the hyperferritinemia group was significant at six months (p=0.009 two sided; p=0.005 one sided) but not at one year (p=0.34, two-sided; p=0.19 one sided). There was no significant difference in mortality rates between the erythropoietin-assisted-phlebotomy group and the control group. ConclusionsIron overload can be insidious. Multiple transfusions raise the risk for ferritin levels ≥1,000 ug/mL and predispose patients to secondary hemochromatosis which is a risk factor for opportunistic fungal and bacterial infections and may lead to increased mortality rates. Erythropoietin-assisted phlebotomy is a potential treatment to prevent the complications of iron overload in HSCT patients. Disclosures:No relevant conflicts of interest to declare.

Japanese epidemiological survey with consensus statement on Japanese guidelines for treatment of iron overload in bone marrow failure syndromes

Many patients with bone marrow failure syndromes need frequent transfusions of red blood cells, and most of them eventually suffer from organ dysfunction induced by excessively accumulated iron. The only way to treat transfusion-induced iron overload is iron chelating therapy. However, most patients have not been treated effectively because daily/continuous administration of deferoxamine is difficult for outpatients. Recently, a novel oral iron chelator, deferasirox, has been developed, and introduction of the drug may help many patients benefit from iron chelation therapy. In this review, we will discuss the current status of iron overload in transfusion-dependent patients, and the development of Japanese guidelines for the treatment of iron overload in Japan, which were established by the National Research Group on Idiopathic Bone Marrow Failure Syndromes in Japan.

Quantification of siderophages in bronchoalveolar fluid in transfusional and primary pulmonary hemosiderosis

Transfusional iron overload may occur in the lungs. We hypothesized that quantitating siderophages in the bronchoalveolar fluid (BALF) of heavily transfused patients may prove to be a useful tool in determining lung iron overload in transfusion-dependent patients. The study included six patients (7-20 years) with thalassemia major (TM) who had received multiple blood transfusions, one with hereditary spherocytosis (four blood transfusions) and one with sickle cell disease (never transfused); they were compared to three children with idiopathic pulmonary hemosiderosis (IPH) (2.5-7.0 years) as positive controls. Fiberoptic bronchoscopy with bronchoalveolar lavage was performed in seven patients under general anesthesia for elective surgery and the rest were bronchoscoped electively under sedation. Spirometry was also performed in eight patients. There was no significant difference between children with TM and IPH in siderophages as percentage of total count (95% CI -31.0 to 1.5, P = 0.068). There were positive relationships between both mean serum ferritin values during the preceding year and the total number of units of transfused blood, and percent siderophage count among multiply transfused patients (P = 0.010, P = 0.052, respectively); similar findings were noted for the Golde score (P = 0.001, P = 0.031, respectively). None of the patients showed lung function impairment. In conclusion, in this small study, we found that the BALF of multiply transfused patients with benign hematological disorders contain similar numbers of siderophages to that of patients with IPH; this is strongly suggestive of secondary pulmonary hemosiderosis. The correlation between the patients' serum ferritin, and the BALF siderophages suggests that the later may serve as a marker of pulmonary iron overload in patients requiring blood transfusion and appear to be more sensitive than standard pulmonary function tests.

MR marrow signs of iron overload in transfusion-dependent patients with sickle cell disease.

Magnetic resonance (MR) marrow signal in the axial and appendicular skeleton of 13 transfusion-dependent and chelated pediatric patients with sickle cell anemia (SSD) was compared with marrow signal in six non-transfusion-dependent patients with SSD. Hepatic, pancreatic, and renal MR signal were also evaluated. Indication for hypertransfusion therapy was primarily prior history of stroke. Transfusion-dependent patients had evidence of iron deposition throughout the imaged marrow and the liver, despite deferoxamine chelation therapy. Non-transfusion-dependent patients did not demonstrate grossly apparent signs of iron overload. Red marrow restoration was present in the spine, pelvis, and long bones and, in some patients, within the epiphyses. Marrow edema secondary to vaso-occlusive crises was evident in the metaphyses and diaphyses of long bones in areas of both red and fatty marrow and was best seen using fat-saturated T2-weighted imaging techniques.