Latin American Registry of Patients (Pts) with Transfusional Hemosiderosis (Th): The RELATH Study.

Abstract In Latin America (LA), miscegenation of populations of Mediterranean and African ancestry has occurred for several centuries, thus facilitating the spread of hemoglobin variants. The prevalence of thalassemias, sickle-cell disease (SCD) and other hemoglobinopathies, as well as of myelodysplastic syndromes (MDS) and other diseases associated with TH is largely unknown in LA. As a retrospective registry of pts with TH in LA, the RELATH Study provides a unique opportunity to gain insight about the prevalence of TH and the patterns of care for these pts in LA. Participating countries include Brazil, Colombia, Mexico, Peru, and Venezuela. Target accrual is approximately 1,000 patients. Cases are accrued by large-volume, tertiary-care hematology centers located in large cities through a CRF designed for the study. Treatment and pt evaluation are not influenced by the study. Eligible pts have age >2 yr, consultation in the participating institutions at least once since 01/04, any disorder requiring chronic red-blood-cell (RBC) transfusion, receipt of >9 RBC units, at least one value of serum ferritin >1000 mcg/L, and/or a liver iron content (LIC) >2 mg/g dry weight (pts. with leukemia are excluded). Between Jan/06 and May/07, 239 pts have been accrued, 236 of which are evaluable. The mean age was 29.2 +/− 20.4 (range, 2 to 92), and 53.8% of pts were female. Ethnic distribution was Hispanic (41.0%), African (34.6%), and Caucasian ancestry (24.4%). The most frequent diagnoses were SCD (43.6%), beta-thalassemia major (17.4%), aplastic anemia (13.6%), and MDS (7.2%, 53.3% of which had refractory anemia). RBC transfusion was > 9 in 100% and >19 in 89.8% of pts, and mean ferritin was 2564 +/− 1834 mcg/L. LIC determination was not available or not done in 90.6% of cases. The level of hemoglobin at which transfusion was indicated was 7 to 10 g/dL in 60.7%, and 6 g/dL or less in 38.1% (N/A in 1.3%). The mean number of transfusions received was 12.2 +/− 8.8/yr (range, 1 to 80). Iron overload was assessed using ferritin (93.2%), and TH related complications were evaluated with echocardiogram (42.8%), and liver US (27.5%). TH-related complications were reported in 82.2% of cases (66.5% of pts had hepatic complications, 32.6% endocrine, 16.1% cardiac). Iron-chelation therapy was given to 39.8% of pts, more frequently on the basis of ferritin (27.5%), number of transfusions (18.2%), and complication from iron overload (5.5%). Deferoxamine (93.6%) and deferasirox (6.4%) were the most frequent chelators. In most cases, treatment was still ongoing, but reasons for discontinuation were pt refusal (4.7%), drug no longer available (4.2%), and poor compliance (3.8%). In conclusion, this preliminary report from the ongoing RELATH study shows that a registry is feasible and may provide valuable information regarding TH in various countries of LA. In addition, the study suggests so far that most LA patients undergoing chronic transfusion develop TH, whose complications could be prevented by more effective use of iron chelation, which was relatively low in this sample.

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

Blood ◽

10.1182/blood.v118.21.5283.5283 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5283-5283

Author(s):

Nicole Hugel ◽

Cyrus C. Hsia

Keyword(s):

Iron Overload ◽

Bone Marrow Failure ◽

Tertiary Care ◽

Iron Chelation ◽

Care Centre ◽

Tertiary Care Centre ◽

Bone Marrow Failure Syndromes ◽

London Health ◽

Transfusion Dependency ◽

Rbc Transfusion

Abstract Abstract 5283 Awareness 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.

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Effective and Safe Deferasirox Treatment of Patients with Various anemia's and Transfusional Iron-Overload in the Medical Practice: Results From Two German Observational Studies

Blood ◽

10.1182/blood.v118.21.5165.5165 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5165-5165

Author(s):

Christian Junghanss ◽

Rudolf Schlag ◽

Bernd Gaede ◽

Matthias Moelle ◽

Steffen Doerfel ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Observational Studies ◽

Chelation Therapy ◽

Iron Chelation ◽

Iron Chelator ◽

Beta Thalassemia ◽

Final Visit ◽

Iron Chelation Therapy ◽

The Mean

Abstract Abstract 5165 Background: Progressive anaemia is highly prevalent amongst many malignant diseases leading to RBC transfusion-dependency. Therefore transfusion-related iron overload (IOL) is common in these patients (pts) and can result in multiple organ failure. Iron chelation therapy prevents organ failure, reduces the risk of infections and can improve hematopoesis in some diseases. The once-daily oral iron chelator deferasirox has been shown to reduce iron overload in pts with various transfusion-dependent anaemias assessed by serum ferritin (SF). Despite extensive knowledge of iron chelation in MDS or beta-thalassemia pts, data in pts with other anaemias is limited. Here, we present data from a subgroup of transfusion-related IOL pts that were included two non-interventional studies (EXTEND, EXJANGE) performed in Germany and who suffered from diseases other than MDS or beta thalassemia. Methods: 130 pts with various malignant diseases such as myeloproliferative disorders (43 pts, including 31 pts particular specified as myelofibrosis), acute myeloid leukaemia (14 pts), sickle cell anaemia (6 pts), aplastic anaemia (11), congenital aplastic anaemia (5) or Non-Hodgkin's lymphoma (6 pts) were treated with deferasirox in the daily-routine setting of office-based physicians and included in either the EXTEND or EXJANGE study. Patient with MDS or beta-thalassemia were also included in the studies, but are excluded from this analysis. Analysis is based on 1-year pooled data of these two, multicenter, non-interventional observational studies. Transfusion-dependent pts with IOL with or without prior chelation were enrolled and received the iron chelator deferasirox. Prescription of deferasirox, just as inclusion and exclusion criteria was in accordance with the terms of Exjade marketing authorization in the EU. Efficacy and safety parameters, including serum ferritin and adverse events (AEs), were collected in 2-monthly intervals. Results: 98 pts had no prior chelation therapy (51 M, 45 F, 2 missing; mean age 63.3, range 3.2–91.9 yrs) and a median baseline SF of 2,968 (range 561–11, 423) ng/mL. 32 pts had prior received prior chelation therapy (mainly with desferal; 17 M, 15 F; mean age 50.1, range 3.5–80.9 yrs) and a median baseline SF of 2,635 (range 539–19, 540) ng/mL. The mean number of prior red blood cell transfusions was 55. The mean prescribed daily dose of deferasirox at the first visit was 16.3 mg/kg/d rising up to 18.1 mg/kg/d after 12 months. During treatment, median SF levels clearly decreased from first to final visit [-806 ng/mL; p<0.0001 (explorative analysis)] in the chelation-naïve and also in the pre-chelated population [-300 ng/ml; p = 0.1705 (explorative analysis)]. The median observation period and days on therapy was 349 and 343 days, respectively. At final visit 74 pts (56.9%) were still on deferasirox therapy. Reasons for discontinuation by the final visit included 19 AEs (35.2%). 45 pts (34.6%) experienced an investigator assessed drug-related AE. The most common drug-related AEs were diarrhea (n=17; 37.8%), nausea (n=11; 24.4%) and blood creatinine increased (n=6; 13.3%). As in previous clinical trials, serum creatinine clearances showed a minor decrease over the study period (median decrease until final visit: 4 ml/min). Conclusion: Our analysis confirmed that deferasirox is effective and well tolerated in chelation-naïve as well as in previously chelated pts with transfusion-related IOL and diseases other than MDS or beta thalassemia. As baseline serum ferritin values were >2,500 ng/mL even in pts with prior chelation therapy, adequate chelation treatment should be considered earlier at a serum ferritin >1,000 ng/mL in pts with transfusion-dependent IOL for adequate iron chelation therapy. Disclosures: Junghanss: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Haus:Novartis Pharma: Employment. Junkes:Novartis: Employment. Leismann:Novartis: Employment.

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PATTERN AND CLINICAL PROFILE OF PATIENTS WITH Β- THALASSEMIA IN REPEATED BLOOD TRANSFUSION

10.36106/ijar/7211096 ◽

2020 ◽

pp. 32-34

Author(s):

Ashok Badakali ◽

Deepti Shetty ◽

Manohar MR

Keyword(s):

Blood Transfusion ◽

Iron Overload ◽

Serum Calcium ◽

Chelation Therapy ◽

Iron Chelation ◽

Serum Phosphate ◽

Clinical Profile ◽

Beta Thalassemia ◽

Serum Phosphate Level ◽

The Mean

Chronic transfusions inevitably lead to iron overload as humans cannot actively remove excess iron. The cumulative effects of iron overload lead to significant morbidity and mortality, if untreated. The combination of transfusion and chelation therapy has dramatically extended the life expectancy of thalassemia patients, but with complications like hypocalcaemia. Hence, present study was undertaken to determine pattern and clinical profile of patients with β- thalassemia who are receiving repeated blood transfusion Methods: Hospital based study conducted at S. Nijalingappa Medical College and Hanagal Shri Kumareshwar hospital, Bagalkot. The study period was one and half year from 2015 to 2016. 53 beta thalassemia major cases fulfilling inclusion criteria were investigated after an informed consent, for serum calcium, serum phosphorous, serum ALP and paratharmone levels. Result: Among 53 transfusion dependent children studied, the mean age is 5.249 years. The study consisted of 32 (60.4%) males and 21 (39.6%) females. Maximum number of cases i.e. 29 (54.7%) were diagnosed at the age of 4-6 months. 50 (94.3%) were on iron chelation therapy. The mean serum calcium is 8.28 + 0.89 mg/dl. The mean serum phosphate is 6.40 + 0.80mg/dl, mean PTH is 14.96 + 15.49ng/L. The mean value of serum phosphate level is 14.96 + 15.49 ng/L. The mean ALP is 166.789 U/L. Conclusion: To get better results, regular testing is needed to detect the complications of the early stages with proper treatment of the factors and complications. Therefore, should be monitored to avoid complication related to hypocalcemia.

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Monitoring Cardiac Siderosis in Patients with Beta-Thalassemia Major on Various Chelation Regimens,

Blood ◽

10.1182/blood.v118.21.3177.3177 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3177-3177

Author(s):

Srikanth R. Ambati ◽

Rachel Randolph ◽

Kevin Mennitt ◽

Dorothy A Kleinert ◽

Patricia Giardina

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Iron Concentration ◽

Iron Chelation ◽

Thalassemia Major ◽

Beta Thalassemia ◽

Liver Iron ◽

Beta Thalassemia Major ◽

Cardiac Siderosis ◽

Hepatic Iron Overload

Abstract Abstract 3177 Background: Patients with Beta-thalassemia major develop progressive iron overload in various organs. Cardiac siderosis is a major cause of mortality and morbidity in these patients, and also poses a significant treatment challenge. Methods: We have reviewed 101 beta-thalassemia major patients 39 Male (M) 62 Female (F) with a mean age of 27.9 (range: 2 to 60 years). All received regular transfusions to maintain pre transfusion Hb levels of 9 to10 gm/dl and all received iron chelation initially with deferoxamine (DFO) and subsequently treated with deferasirox (DFX) or deferiprone (DFP) in combination with DFO. Each patient was monitored yearly for iron excess by hepatic and cardiac magnetic resonance imaging (MRI) T2*. They were also assessed with monthly evaluations for liver and renal function (Bili, AST, ALT, BUN, Creatinine), serum ferritin, CBC (or weekly if on DFP), and urinalysis. Annual EKG, ECHO, hearing and vision testing and endocrine evaluations were also performed. The patients were grouped according to the severity of cardiac siderosis. Mild to moderate cardiac siderosis was defined as a T2* 12–20 msec and severe cardiac siderosis T2*≤ 11 msec. Annual studies were compared using paired student T test and repeated measures Analysis Of Variance (ANOVA) when necessary. Patient population: Twenty one of the 101 patients (7M and 14F) with a mean age of 30.6 yr, age range 15 to 56 yr, had abnormal cardiac T2* of <20 msec and three or more subsequent annual cardiac T2* measurements. Thirteen patients, 3 M 10 F with a mean age of 33 (range: 19 to 60), had severe cardiac siderosis and 8 patients, 3 M 5 F with mean age of 38 (range: 25 to 49), had mild-moderate cardiac siderosis. During the course of the observation their iron chelation therapy was optimized to reduce serum ferritin levels < 1500 μg/dl and to reduce or maintain liver iron concentration (LIC) ≤ 7 mg/gm dw. Data analysis: At the time of their first annual MRI study (baseline), 8 patients were on DFO of which 6 were switched to DFX, 13 patients were on DFX, 11 patients were dose escalated on DFX, and 4 patients were switched to combination chelation with DFO and DFP. At baseline, patients with severe cardiac siderosis had a mean cardiac T2* level = 7.4 ± 0.47 SEM (range: 4.6 to 11msec). Over the treatment course of 6 years annual cardiac T2* levels consistently improved and by 6 years cardiac T2* reached a mean level =14.3 ±1.5 SEM (range: 12 to 17 ms) (Fig 1). Those patients who at baseline had a mild to moderate cardiac siderosis with mean cardiac T2* of 14.6 ± 1.02 SEM (range: 12 to 19 msec) improved by 3 years of treatment when they achieved a mean cardiac T2* of 26.3 ± 3.4 SEM (range of 16 to 42 msec) (Fig 2). Liver iron concentration (LIC) was measured annually by MRI. Initially the majority, 16 out of 21 of patients, had hepatic iron overload LIC ≤ 10 mg/ gm dw of whom 56% (9 of the 16) had severe cardiac siderosis. 5 of 21 patients had a LIC > 15 mg/ gm dw of whom 80% (4 out of 5) patients had severe cardiac siderosis (Fig 3). Patients with LIC ≤10 mg/ gm dw had ferritin levels ranging from 166 to 3240 μg/ dl and patients with LIC >15 mg/ gm dw had elevated serum ferritin levels of 1180 to 17,000 μg/ dl. Patients with severe cardiac siderosis had mean MRI ejection fraction (EF)= 55.8% (range: 31 to 70%) while patients with mild to moderate cardiac siderosis had mean MRI EF= 60% (range: 53 to 66%). One patient with severe cardiac siderosis was recovering from symptomatic congestive heart failure. Conclusion: Cardiac siderosis can be noninvasively diagnosed utilizing MRI T2* techniques and subsequently to monitor treatment. The majority of patients improve cardiac T2* over time with optimal chelation therapy. Severe cardiac siderosis occurs even with mild to moderate hepatic iron overload. Left ventricular EF may not predict severe cardiac siderosis. Therefore it is important to annually monitor cardiac siderosis with MRI T2*. Disclosures: No relevant conflicts of interest to declare.

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Efficient Iron Chelation Resulting in Improved Myocardial Performance with Combined Desferrioxamine and Deferiprone in Beta Thalassemia Major Patients.

Blood ◽

10.1182/blood.v104.11.3766.3766 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3766-3766 ◽

Cited By ~ 2

Author(s):

Anil V. Pathare ◽

Shahina Daar ◽

Salam Al Kindi ◽

J. David Dennison

Keyword(s):

Combination Therapy ◽

Iron Overload ◽

Serum Ferritin ◽

Iron Chelation ◽

Thalassemia Major ◽

Beta Thalassemia ◽

Myocardial Performance ◽

Beta Thalassemia Major ◽

The Mean ◽

To Receive

Abstract Background: Iron overload is the main cause of morbidity and mortality especially from heart failure in patients with beta thalassemia major [TM]. Successful iron chelation is thus essential for the optimal management of TM. Although desferrioxamine [DFX] has been the major iron-chelating treatment of transfusional iron overload, compliance is a major hindrance. The availability of oral iron chelation with deferiprone [L1] since 1987 was welcome but showed poor efficacy when used alone as compared to DFX. Aim: To compare DFX and prospective combined therapy with DFX and L1 in beta thalassemia major patients with iron overload. Methods: We studied 69 patients with beta thalassemia major (Mean age ± SD, 15.02± 5.8; Range 4–28 years) attending the Day Care unit for regular transfusional support. They received packed red cells every 3–4 weeks to maintain pre-transfusion hemoglobin concentration above 9 g/dl. They were receiving DFX at a daily dose of 40mg/kg/day by subcutaneous infusion for 8–10 hrs on 4–5 nights each week for past several years. However, owing to various reasons, they developed considerable transfusional iron overload. These patients were enrolled prospectively to receive additional therapy with oral iron chelator L1 at 75 mg/kg body weight in three divided doses with food after informed consent and also continued to receive treatment with DFX as per the above dosage. Results: Of the 69 patients, 6 developed severe GI upset, 2 developed persistently raised liver enzymes, 2 died [sepsis], two underwent bone marrow transplantation and 2 developed agranulocytosis and so did not continue in the study. In the remaining 55 evaluable patients, [3–48 months on combination therapy; mean(±SD) 22±12 months] the mean serum ferritin(±SD) fell dramatically from 3088(±1299) [DFX alone] to 2051(±935)ng/ml [DFX+L1; p<0.001], with the mean of lowest serum ferritin being 1731(±828) ng/ml in this group. Interestingly, there was also a significant improvement in the Ejection fraction [p<0.004]and Fractional shortening[p<0.0436] in these patients. Sustained successful iron chelation on combination therapy Ferritin pretherapy[DFX] 6mths[DXF+L1] 12 mths [DXF+L1] 18mths [DXF+L1] 24mths [DXF+L1] 36mths [DXF+L1] 48 mths [DXF+L1] No of Patients n=55 n=54 n=42 n=32 n=24 n=12 n=7 Mean± SD 3088±1299 2530±1221 2495±1175 2433±1154 2165±889 1686±917 997±318 Range-Max 7534 6070 5559 5126 4130 3172 1471 Range-Min 1072 599 776 408 712 473 559 Students t test[DFX v/s DFX+L1] p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 Improved myocardial performance on combination therapy Pretherapy [DFX] Combination Therapy [DFX+L1] p value Ejection Fraction [%] 69.04±5.182 72.99±5.54 p<0.0004 Fractional Shortening [%] 32.19±4.32 34.89±5.4 p<0.0436 Summary/Conclusion: The study emphasizes that beta thalassemia major patients with transfusional iron overload can be successfully treated with a combination of DFX and L1. The results also demonstrate significant statistical improvement as early as 6 months of combination therapy. Furthermore, this improvement was sustained leading to a progressive fall in the mean serum ferritin. Lastly, the study also demonstrates significant improvement in echocardiographic parameters of myocardial performance in these patients receiving combination therapy.

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The study of severe asthma in Latin America and Spain (1994-2004): characteristics of patients hospitalized with acute severe asthma

Jornal Brasileiro de Pneumologia ◽

10.1590/s1806-37132009000700004 ◽

2009 ◽

Vol 35 (7) ◽

pp. 635-644 ◽

Cited By ~ 11

Author(s):

Gustavo Javier Rodrigo ◽

Vicente Plaza ◽

Jesús Bellido-Casado ◽

Hugo Neffen ◽

María Teresa Bazús ◽

...

Keyword(s):

Latin America ◽

Severe Asthma ◽

Latin American ◽

Inhaled Corticosteroids ◽

Pulmonary Function Tests ◽

Tertiary Care ◽

Asthma Management ◽

Case Series ◽

Acute Severe Asthma ◽

The Mean

OBJECTIVE: Studies assessing the characteristics and management of patients hospitalized with asthma have been limited to a small number of facilities and have evaluated short time periods. The present study evaluated long-term changes among hospitalized asthma patients at a large number of facilities. METHODS: This was a retrospective, hospital-based observational case series, designated the Study of Severe Asthma in Latin America and Spain, which was conducted in Spain and in eight Latin-American countries. We reviewed the hospital records of 3,038 patients (age range, 15-69 years) hospitalized with acute severe asthma at one of nineteen tertiary-care hospitals in 1994, 1999 and 2004. RESULTS: Over time, the use of inhaled corticosteroids and long-acting β2 agonists increased significantly, whereas the use of theophylline as a controller medication decreased. The utilization of pulmonary function tests also increased. There was a significant reduction in the mean hospital stay (8.5 days, 7.4 days and 7.1 days in 1994, 1999 and 2004, respectively, p = 0.0001) and a significant increase in the mean of the lowest arterial pH at hospital admission. In contrast, there was a significant decrease in the proportion of cases in which PEF was determined in the emergency room (48.6% in 1994 vs. 43.5% in 2004, p = 0.0001). We found the quality of asthma management and care to be generally better in Spain than in Latin America. CONCLUSIONS: Although there have been certain improvements in the management of asthma between severe exacerbations and during hospitalization, asthma management remains suboptimal in Spain and, especially, in Latin America.

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Hepatocellular Carcinoma in β-Thalassemia Patients: Review of the Literature with Molecular Insight into Liver Carcinogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms19124070 ◽

2018 ◽

Vol 19 (12) ◽

pp. 4070 ◽

Cited By ~ 4

Author(s):

Antoine Finianos ◽

Charbel Matar ◽

Ali Taher

Keyword(s):

Hepatocellular Carcinoma ◽

Iron Overload ◽

Treatment Success ◽

Iron Concentration ◽

Iron Chelation ◽

Multicenter Studies ◽

Major Life ◽

Liver Iron ◽

Magnetic Resonance Imaging Mri ◽

Personalized Approach

With the continuing progress in managing patients with thalassemia, especially in the setting of iron overload and iron chelation, the life span of these patients is increasing, while concomitantly increasing incidences of many diseases that were less likely to show when survival was rather limited. Hepatocellular carcinoma (HCC) is a major life-threatening cancer that is becoming more frequently identified in this population of patients. The two established risk factors for the development of HCC in thalassemia include iron overload and viral hepatitis with or without cirrhosis. Increased iron burden is becoming a major HCC risk factor in this patient population, especially in those in the older age group. As such, screening thalassemia patients using liver iron concentration (LIC) measurement by means of magnetic resonance imaging (MRI) and liver ultrasound is strongly recommended for the early detection of iron overload and for implementation of early iron chelation in an attempt to prevent organ-damaging iron overload and possibly HCC. There remain lacking data on HCC treatment outcomes in patients who have thalassemia. However, a personalized approach tailored to each patient’s comorbidities is essential to treatment success. Multicenter studies investigating the long-term outcomes of currently available therapeutic options in the thalassemia realm, in addition to novel HCC therapeutic targets, are needed to further improve the prognosis of these patients.

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Durable Red Blood Cell Transfusion Independence in a Patient with an MDS/MPN Overlap Syndrome Following Discontinuation of Iron Chelation Therapy

Case Reports in Hematology ◽

10.1155/2015/253294 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Harpreet Kochhar ◽

Chantal S. Leger ◽

Heather A. Leitch

Keyword(s):

Blood Cell ◽

Iron Overload ◽

Red Blood Cell ◽

Chelation Therapy ◽

Iron Chelation ◽

Red Blood Cell Transfusion ◽

Favorable Effect ◽

Iron Chelation Therapy ◽

Transfusion Independence ◽

Rbc Transfusion

Background. Hematologic improvement (HI) occurs in some patients with acquired anemias and transfusional iron overload receiving iron chelation therapy (ICT) but there is little information on transfusion status after stopping chelation.Case Report. A patient with low IPSS risk RARS-T evolved to myelofibrosis developed a regular red blood cell (RBC) transfusion requirement. There was no response to a six-month course of study medication or to erythropoietin for three months. At 27 months of transfusion dependence, she started deferasirox and within 6 weeks became RBC transfusion independent, with the hemoglobin normalizing by 10 weeks of chelation. After 12 months of chelation, deferasirox was stopped; she remains RBC transfusion independent with a normal hemoglobin 17 months later. We report the patient’s course in detail and review the literature on HI with chelation.Discussion. There are reports of transfusion independence with ICT, but that transfusion independence may be sustained long term after stopping chelation deserves emphasis. This observation suggests that reduction of iron overload may have a lasting favorable effect on bone marrow failure in at least some patients with acquired anemias.

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Does Gene Therapy in Beta Thalassemia Normalize Novel Markers of Ineffective Erythropoiesis and Iron Homeostasis?

Blood ◽

10.1182/blood-2019-129658 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 816-816 ◽

Cited By ~ 1

Author(s):

Alexis A. Thompson ◽

Tomas Ganz ◽

Mary Therese Forsyth ◽

Elizabeta Nemeth ◽

Sherif M. Badawy

Keyword(s):

Gene Therapy ◽

Stem Cell ◽

Iron Overload ◽

Serum Ferritin ◽

Research Funding ◽

Iron Homeostasis ◽

Beta Thalassemia ◽

Ineffective Erythropoiesis ◽

Liver Iron ◽

Equity Ownership

BACKGROUND: Ineffective erythropoiesis in thalassemia alters iron homeostasis, predisposing to systemic iron overload. Successful allogeneic hematopoietic stem cell transplantation (HSCT) in thalassemia major corrects anemia, should eliminate ineffective erythropoiesis (IE) and normalize iron homeostasis (IH). Whether gene therapy (GT) will fully correct IE and IH is not known. This cross-sectional observational study evaluated the iron status of patients with beta thalassemia following HSCT or GT, and compared them with cohorts of patients with thalassemia intermedia (TI) or transfusion-dependent thalassemia (TDT) using recently introduced biomarkers along with imaging studies and other clinical assessments to better understand and characterize IE and IH across groups. METHODS: We evaluated a convenience sample of 29 participants with beta thalassemia (median age 25 years, IQR 21-35; females 55%; Asian 52%). Participants in the HSCT (n=6) and GT (n=10) groups were evaluated on average 116.5 and 46.9 months following cell infusion, respectively. TDT patients (n= 9) were evaluated pre-transfusion and off iron chelation for at least 7 days, and TI (n=4) were un-transfused or not transfused in >3 years. Clinical lab assessments and MRI R2*/ T2* to assess heart and liver iron burden including post-processing, were performed using local clinical protocols. ELISAs for hepcidin, erythroferrone (Erfe) and GDF-15 were performed in a blinded manner. RESULTS: Median values for all IE and IH parameters tested were normal in the HSCT group, and were significantly lower than in all other groups. There were significant differences among all groups for hemoglobin (p=0.003), erythropoietin (Epo) (p=0.03), serum ferritin (SF) (p=0.01), transferrin (p=0.006), soluble transferrin receptor (sTfR) (p=0.02), serum hepcidin: serum ferritin (H:F) ratio (p=0.006), Erfe (p=0.001), GDF15 (p=0.003), and liver iron content (LIC) by MRI R2* (p=0.02). H:F ratio, a surrogate for predisposition to systemic iron loading, inversely correlated with Erfe (rs= -0.85, p<0.0001), GDF15 (rs= -0.69, p=0.0001) and liver R2* (rs= -0.66, p=0.0004). In a multivariate analysis, adjusted for gender and race, H:F ratio and Epo levels predicted Erfe and GDF15 (p=0.05 and p=0.06; p=0.01 and p=0.05), respectively. Even after excluding GT patients that are not transfusion independent (N=2), SF, Epo, sTfR and hepcidin remain abnormal in the GT group, and there were no significant differences in these parameters between GT and TDT. However, novel biomarkers of IH and IE suggested lower ineffective erythropoiesis in GT compared to TDT (median (IQR) Erfe, 12 (11.6-25.2) vs. 39.6 (24.5-54.7), p=0.03; GDF15, 1909.9 (1389-4431) vs. 8906 (4421-12331), p=0.02), respectively. Erfe and GDF15 were also lower in GT compared to TI, however these differences did not reach statistical significance. There were no differences in hepcidin, ferritin, or H:F by race, however Erfe and GDF15 were significantly lower in Asians compared to non-Asians (p=0.006 and p=0.02, respectively). CONCLUSION: Nearly 4 years post infusion, most subjects with TDT treated with GT are transfusion independent with near normal hemoglobin, however, studies in this limited cohort using conventional measures suggest IE and IH improve, particularly when transfusion support is no longer needed, however they remain abnormal compared to HSCT recipients, who using these parameters appear to be cured. STfR did not detect differences, however GDF15 and Erfe were more sensitive assays that could demonstrate significant improvement in IE and IH with GT compared to TDT. Contribution to IE by uncorrected stem cell populations post GT cannot be determined. Transduction enhancement and other recent improvements to GT may yield different results. Longitudinal studies are needed to determine if thalassemia patients treated with GT will have ongoing IE predisposing to systemic iron overload. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Ganz:Intrinsic LifeSciences: Consultancy, Equity Ownership. Nemeth:Intrinsic LifeSciences: Consultancy, Equity Ownership; Silarus Therapeutics: Consultancy, Equity Ownership; Keryx: Consultancy; Ionis Pharmaceuticals: Consultancy; La Jolla Pharma: Consultancy; Protagonist: Consultancy.

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Magnetic Ressonance Imaging (MRI) in the Evaluation of Iron Overload in Patients with Beta Thalassaemia. The Brazilian National Program Preliminary Results.

Blood ◽

10.1182/blood.v106.11.3825.3825 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3825-3825

Author(s):

Nelson Hamerschlak ◽

Laercio Rosemberg ◽

Alexandre Parma ◽

Fernanda F. Assir ◽

Frederico R. Moreira ◽

...

Keyword(s):

Iron Overload ◽

Ventricular Function ◽

Iron Content ◽

Chelation Therapy ◽

Iron Concentration ◽

Iron Chelation ◽

Inverse Correlation ◽

Liver Iron ◽

Liver Iron Content ◽

Cooperative Program

Abstract Magnetic Ressonance Imaging (MRI) using T2 star (T2*) tecnique appears to be a very useful method for monitoring iron overload and iron chelation therapy in thalassaemia. In Brazil, we have around 400 thalassaemic major patients all over the country. They were treated with hipertransfusion protocols and desferroxamine and/or deferiprone chelation. We developed a cooperative program with the Brazilian Thalassaemic Patients Association (ABRASTA) in order to developT2* tecnique in Brazil to submit brazilian patients to an annual iron overload monitoring process with MRI.. We performed the magnetic ressonance T2* using GE equipment (GE, Milwaukee USA), with validation to chemical estimation of iron in patients undergoing liver biopsy. Until now, 60 patients were scanned, median age=23,2 (12–54); gender: 18 male (30%) and 42 female (70%). The median ferritin levels were 2030 ng/ml (Q1=1466; Q3=3296). As other authors described before, there was a curvilinear inverse correlation between iron concentration by biopsy, liver T2*(r=0,92) and also there were a correlation with ferritin levels. We also correlated myocardial iron measured by T2* with ventricular function.. As miocardial iron increased, there was a progressive decline in ejection fraction and no significant correlation was found between miocardial T2* and the ferritin levels. Liver iron content can be predicted by ferritin levels. On the other hand, cardiac disfunction is the most important cause of mortality among thalassaemic patients. Since Miocardio iron content cannot be predicted from serum ferritin or liver iron, and ventricular function can only detect those with advance disease, intensification and combination of chelation therapy, guided by T2* MRI tecnique should reduce mortality from the reversible cardiomyopathy among thalassaemic patients.

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