Occurrence of Neoplastic Diseases in a Large Cohort of Thalassemic Patients in Greece

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3264-3264
Author(s):  
Alexandra Kouraklis ◽  
Antonia Chatziliami ◽  
Antonis Kattamis ◽  
Efthimia Vlachaki ◽  
Evangelos Briasoulis ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Cell Lymphoma ◽  
Iron Chelation ◽  
Beta Thalassemia ◽  
Thalassemia Intermedia ◽  
Neoplastic Diseases ◽  
Median Serum ◽  
Neoplastic Disorders

Abstract Abstract 3264 Life expectancy of thalassemic patients, appropriately transfused and adequately iron-chelated, has been substantially extended the last decades. However, these patients are subjected to particular risks which might favor the development of neoplasia, such as transfusional iron overload, high prevalence of viral diseases, particularly HCV infection, and transfusion-associated alteration of their immune status. The occurrence of neoplastic diseases has not been extensively investigated in this patient population. We sought to investigate the occurrence of neoplastic diseases during a 16.5 year-period, in a large cohort of 1972 thalassemic patients (homozygous beta-thalassemia N=1448, thalassemia intermedia N=352 and sickle-cell/beta thalassemia N=172), followed-up in 6 large Greek Thalassemic Units. All documented cases of neoplastic diseases, diagnosed during the period between 1.1.1996 and 30.6.2012 were collected and analyzed. The frequency of each type of neoplasia was then correlated with specific factors, potentially influencing the occurrence of these disorders, and particularly age at first transfusion, frequency of transfusions, previous splenectomy, smoking, use of hydroxyurea, previous autoimmune disorders, presence of HBV, HCV and HIV infection, adequacy of iron chelation and the degree of hepatic siderosis. Totally 38 cases of neoplastic disorders were documented among the 1972 patients. These were Hepatocellular carcinoma (10 cases), non-Hodgkin's Lymphoma (6 cases in total: Marginal-zone lymphoma N=2, Mantle-cell lymphoma N=1, Diffuse large B-cell lymphoma N=1, Burkitt's lymphoma N=1, T-cell lymphoblastic lymphoma N=1), Thyroid carcinoma (3 cases in total: papillary N=2, follicular N=1), Hodgkin's lymphoma (3 cases in total, classical N=2, LPHD N=1), Renal cell cancer (N=3), Colon cancer (N=3), Breast cancer (N=2), Cholangiocarcinoma (N=2), Pre-B Acute Lymphoblastic Leukemia (N=2), Testicular cancer (2 cases in total, seminoma N=1, teratoma N=1), melanoma (N=1), and Renal oncocytoma (N=1). Twenty-eight cases were diagnosed among patients with homozygous beta-thalassemia, 6 among patients with thalassemia intermedia and 4 among patients with sickle-cell/beta thalassemia. Median age at diagnosis of the neoplastic disease was 39 years (age range 21 to 63 years). Twenty-nine cases (76.3%) were diagnosed among previously splenectomized patients, although splenectomy had been performed in 41% of the total cohort of patients. All patients were HIV-negative, 3/31 (9.7%) were HBsAg-positive, whereas 22/37 (59.5%) had HCV infection. Patients were then classified according to the level of liver siderosis and the effectiveness of their iron chelation treatment, estimated by their annual median serum ferritin levels. Eleven patients were found to be adequately chelated (median serum ferritin 310 ng/ml), 16 were moderately-effectively chelated (median serum ferritin 1240 ng/ml) and 11 were inadequately chelated (median serum ferritin 2552 ng/ml). There was no difference in patient's age or in the type of neoplastic disorders occurred in each of the 3 categories, however 3/11 poorly chelated patients were long term survivors, versus 8/16 moderately chelated and 9/11 adequately chelated patients. In conclusion, the prolongation of overall survival of thalassemic patients results in increasing occurrence of neoplastic diseases among this patient population. Splenectomized and HCV-infected patients appear to represent higher-risk groups, whereas the role of iron overload appears not to influence the occurrence of neoplastic diseases but may have an impact on the long-term outcome and clearly deserves further investigation. Disclosures: No relevant conflicts of interest to declare.

The Correlation Of Hepatic Iron Loading Determined By Magnetic Resonance Image and Serum Ferritin In Patients With Beta-Thalassemia Intermedia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2203-2203
Author(s):  
Ampaiwan Chuansumrit ◽  
Jiraporn Laothamathat ◽  
Nongnuch Sirachainan ◽  
Pakawan Wongwerawattanakoon ◽  
Praguywan Kadekasem ◽  
...  
Keyword(s):  
Blood Transfusion ◽  
Serum Ferritin ◽  
Iron Chelation ◽  
Dry Weight ◽  
Beta Thalassemia ◽  
Hepatic Iron ◽  
Iron Loading ◽  
Thalassemia Intermedia ◽  
The Mean ◽  
Mri Study

Abstract Background Current practice of starting iron chelation when ferritin values reach 1,000 mcg/l has been given to patients with thalassemia disease. The body iron load in patients with thalassemia intemedia can be different from other severe thalassemia disease due to the increased intestinal iron absorption. Objective The correlation of hepatic iron loading determined by magnetic resonance image study (MRI) and various parameters was calculated. Materials and Methods MRI study, using CRMtool to determine the myocardial and hepatic iron loading, was performed in pediatric patients with beta-thalassemia intermedia. The amount of blood transfusion and duration of iron chelation were recorded. The levels of serum ferritin as well as the transfusion-transmitted diseases were checked twice yearly. Results In all, 40 patients (19 males, 23 females) manifested as beta-thalassemia intermedia were enrolled in the study. They included beta thalassemia/HbE disease (n=37) and beta thalassemia major (n=3) with the mean age of 14.9±3.6 years. Three patients with beta-thalassemia major behaved as beta-thalassemia intermedia since two patients carried the combination of beta-thalassemia0 and beta-thalassemia+ genes while another patient had an additional alpha-thalassemia gene. The remaining patients possessed the combination of beta-thalassemia genes at codon 41/42 (4 base pair deletion) and HbE gene at codon 26 (GAG>AAG). All patients received routine hepatitis B vaccination. None had positive serological testing for HBsAg, antiHCV or antiHIV. They required regular transfusion to maintain their pre-transfusion hematocrit at 24% starting at the mean age of 4.1±3.3 years with the mean duration of 10.1±4.6 years. Nineteen were splenectomized at the mean age of 8.0±3.1 years. They all received iron chelation of 10-12 hours of desferrioxamine subcutaneous injection, oral deferiprone ingestion or the combination of desferrioxamine and deferiprone starting at the mean age of 9.1±3.8 years with the mean duration of 6.2 ±4.3 years. At the mean age of 14.9±3.6 years, they underwent MRI study and revealed that the mean T2* of myocardium was 38.6±8.1 milliseconds (ms) and mean T2* of liver was 3.2±2.0 ms. Neither patients had myocardial iron loading while 36 patients had hepatic iron loading varying from severe degree of <1.4 ms (iron >10 mg/g dry weight, n=4), moderate degree of >1.4-2.7 ms (iron >5-10 mg/g dry weight, n=16) and mild degree of >2.7-6.3 ms (iron 2-5 mg/g dry weight, n=16). The results revealed no correlation of the hepatic T2* and the duration of blood transfusion (p=0.157), duration of iron chelation (p=0.071), total blood transfusion and total iron loading from transfusion (p=0.471) one-year blood transfusion and one-year iron loading from transfusion (p=0.321) except for the serum ferritin (p=0.001). The geographic mean of ferritin was 1584.9 mcg/l. The hepatic iron loading by MRI was shown in the equation of T2*(ms) = 4.663-0.001ferritin (mcg/l) (r=-0.503, p=0.001). Patients with serum ferritin ≥1,000 mcg/l risked hepatic iron loading (T2*<2.7 ms, iron 5-10 mcg/g dry weight) with an odds ratio of 5.07 (95% CI 1.09-23.44). Therefore, patients with beta-thalassemia intermedia were at risk of hepatic iron overloading if the initiation of iron chelation started at the serum ferritin of 1,000 mcg/l. Conclusion The current practice of starting iron chelation when ferritin values reach 1,000 mcg/l risks hepatic iron loading in patients with beta-thalassemia intermedia. Advanced technology for evaluating hepatic iron loading is suggested. Thus, where MRI study is not feasible, serum ferritin can be used to estimate the hepatic T2*. Disclosures: No relevant conflicts of interest to declare.

Correlation of Serum Ferritin Levels and Liver Iron Concentration Determined by R2* MRI in Patients with Thalassemia Intermedia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3818-3818
Author(s):  
Ali Taher ◽  
F. El Rassi ◽  
H. Ismaeel ◽  
S. Koussa ◽  
A. Inati
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Care Center ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Thalassemia Intermedia ◽  
Liver Iron Concentration ◽  
Liver Iron ◽  
Cross Sectional ◽  
Transfusion Therapy

Abstract Background: Unlike patients with thalassemia major (TM), those with thalassemia intermedia (TI) do not require regular blood transfusion therapy but remain susceptible to iron overload due to increased intestinal iron uptake triggered by ineffective erythropoiesis. TI patients can accumulate 1–3.5 g of excess iron per year, and effective monitoring of iron burden is an important element of patient management. Assessment of serum ferritin (SF) levels is a convenient and widely used method, and a correlation between SF and liver iron concentration (LIC) has been demonstrated in patients with TM. SF levels may, however, be a poor indicator of LIC in patients with TI and the limited data available on the SF:LIC correlation prove equivocal; in fact, reports suggest a discrepancy between LIC and SF in patients with TI. This is the largest study to use R2* MRI to evaluate the SF:LIC correlation in patients with TI. Methods: This was a cross-sectional study of randomly selected, infrequently/non-transfused TI patients treated at a chronic care center in Hazmieh, Lebanon. Patient charts were reviewed and a medical history was compiled. Blood samples were taken for SF assessment, and LIC was determined by R2* MRI. Results: Data from 74 TI patients were included in this analysis (33 male, 41 female; mean age 26.5 ± 11.5 years). Of this group, 59 (79.7%) patients were splenectomized, 20 were transfusion-naive, 45 had received several transfusions in their lifetime but none in the past year, and 9 patients were regularly transfused 2–4 times per year. Overall mean SF values were 1023 ± 780 ng/mL (range 15–4140); mean LIC levels were 9.0 ± 7.4 mg Fe/g dry weight [dw] (range 0.5–32.1). In contrast to previous findings, a significant positive correlation between mean LIC and SF values was seen in the whole group (R=0.64; P&lt;0.001), and in a subset of splenectomized patients (R=0.62; P&lt;0.001). In comparison with data obtained from a randomly selected group of patients with TM treated at the center, SF levels in TI were seen to be significantly lower, while the mean LIC values were similar in both groups of TI and TM. For a given LIC, SF values were lower in patients with TI than those with TM (Figure). Conclusions: Evaluation of iron levels shows that many patients with TI have SF and LIC levels above the recommended threshold levels, indicating a risk of significant morbidity/mortality. Similar to TM, a significant correlation between SF and LIC was observed in patients with TI; however, the relationship between SF and LIC was different between TI and TM (for the same LIC, the SF values in TI were lower than those in TM). Therefore, use of the current threshold for iron overload based on SF values in TM will lead to significant underestimation of the severity of iron overload in patients with TI. This may result in delayed chelation therapy, and expose patients to morbidity and mortality risks associated with iron overload. Disease-specific management approaches are therefore required in patients with TI. This includes either regular assessments of LIC, ideally by non-invasive R2* MRI, or lowering the SF threshold for initiating iron chelation in patients with TI. Figure Figure

Treatment with Deferasirox Effectively Decreases Iron Burden in Patients with Sickle Cell Disease and Thalassemia Intermedia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1517-1517
Author(s):  
Ersi Voskaridou ◽  
Eleni Plata ◽  
Panagiota Stefanitsi ◽  
Marousa Douskou ◽  
Dimitrios Christoulas ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Renal Impairment ◽  
Serum Creatinine ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Thalassemia Intermedia ◽  
Cell Disease ◽  
Liver Iron

Abstract Abstract 1517 Poster Board I-540 Iron overload was not thought to be an important issue in sickle cell disease (SCD) in the past because of the short life-span of SCD patients. However, the increase in longevity during the recent years has been associated with clinical evidence of iron overload in some SCD patients due to accumulation of transfusional iron, increased absorption associated with intensive erythropoiesis and iron deposition as a result of continuous hemolysis. Therefore, iron overload may play an important role in the severity of SCD and iron chelation has a definite indication in several SCD cases. Thalassemia intermedia (TI) encompasses a wide clinical spectrum of beta-thalassemia phenotypes. Iron overload is alsofrequently present in TI patients as a result of increased intestinal iron absorption secondary to chronic anemia and to sporadic blood transfusion therapy, which may be administered intermittently when hemoglobin (Hb) levels fall <7 g/dL. Thus, a variable rate of iron loading, reaching toxic levels in some patients, was seen in a series of intermittently transfused TI patients who need adequate chelation therapy. Deferasirox (Exjade®) is a once-daily orally administered iron chelator approved for the treatment of transfusional iron overload in patients with transfusion-dependent anemia. Here, we report on the efficacy and safety of deferasirox in iron-overloaded patients with SCD and TI. We evaluated 18 adult patients with SCD (8M/10F; mean age 41.3 ± 8.5 years) and 11 with TI (5M/6F; mean age 41.2 ± 6.5 years) who had serum ferritin levels >1000 ng/mL and who were sporadically transfused with <20 units of red blood cells before starting deferasirox treatment for up to 12 months. Twenty-four patients (15 with SCD and 9 with TI) and 5 (3 with SCD and 2 with TI) patients were initially treated with deferasirox at 10 and 20 mg/kg/day, respectively, based on the number of blood transfusions received before the initiation of treatment. After 3 months, dose adjustments (increases) were allowed in increments of 5 mg/kg/day every 3 months as required to reduce markers of iron overload. Total iron burden was monitored by measuring serum ferritin levels before and monthly after starting deferasirox, while liver iron concentration and cardiac iron burden were measured by magnetic resonance imaging (MRI) T2 and T2* parameters at baseline and 12 months after deferasirox treatment. Left ventricular ejection fraction (LVEF) by MRI, and 24-hour proteinurea (Prot 24h) before and after treatment, were also measured. Hb levels, serum creatinine, cystatin-C (a sensitive marker of renal impairment), alanine (ALT) and aspartate aminotransferase (AST) were measured before and every month during deferasirox treatment. Serum ferritin level was significantly reduced after 12 months of deferasirox treatment in both SCD (mean±SD: from 1993±997 ng/ml to 1106±1016 ng/ml, p<0.001) and TI patients (from 2030±1040 ng/ml to 1165±684 ng/ml, p=0.02). Similarly baseline liver T2 and T2* significantly increased following 12 months of therapy in SCD (from 21.1±5.7 ms to 27.4±8.0 ms, p=0.001 and from 4.1±3.8 ms to 6.0±3.4 ms, p=0.013, for T2 and T2* respectively) and TI patients (from 20.1±4.1 ms to 23.7±6.2 ms, p=0.01 and from 3.4±3.0 ms to 4.4±3.0 ms, p=0.02, for T2 and T2* respectively). Mean cardiac T2* and LVEF were normal at baseline and did not significantly change after 12 months of treatment in SCD and TI patients. There were also no significant changes in mean serum creatinine, Hb or Prot 24h levels after 12 months of deferasirox treatment, while mean ALT and AST levels significantly decreased over 12 months in both groups of patients (p<0.02 and p<0.04 for SCD and TI, respectively). In terms of cystatin-C, there was a significant increase after 12 months of treatment in SCD patients (from 0.97±0.32 mg/l to 1.12±0.4 mg/l, p<0.001) but not in TI patients, in whom the increase was of borderline significance (from 0.98±0.23 mg/l to 1.13±0.27 mg/l, p=0.094). These data indicate that, over 12 months, deferasirox significantly reduced liver iron burden and serum ferritin levels in these iron-overloaded patients with SCD and TI. The decreases in ALT and AST are suggestive of an improvement in liver function, while there must be some caution for renal impairment, mainly in SCD. This study indicates that deferasirox provides effective iron chelation therapy in these patients without any significant adverse effects. Disclosures No relevant conflicts of interest to declare.

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 ◽  
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.

Phlebotomy and Hydroxyurea for Non-Transfusion Dependent Iron Overload in Beta-Thalassemia Intermedia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4031-4031
Author(s):  
Oscar Boutros Lahoud ◽  
Velta Willis ◽  
William B. Solomon
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Chelating Agents ◽  
Iron Deposition ◽  
Beta Thalassemia ◽  
Thalassemia Intermedia ◽  
Ineffective Erythropoiesis ◽  
Clinically Significant ◽  
Iron Chelating Agents ◽  
T2 Mri

Abstract Background: Patients with beta-thalassemia intermedia are at increased risk of developing clinically relevant iron overload independent of blood transfusions, which can result in serious sequelae, including liver, myocardial and endocrine dysfunction. This is thought to be modulated by downregulation of hepcidin and upregulation of ferroportin1. Standard of care in these patients has essentially consisted of iron-chelating agents such as deferasirox, presumably based on the hypothesis that phlebotomy would worsen clinical anemia and potentially exacerbate further ineffective erythropoeisis2. We present the cases of two patients with non-transfusion dependent iron overload secondary to beta-thalassemia intermedia, who were treated with serial phlebotomies as well as hydroxyurea. Case #1: Patient A was heterozygous for the Gln39X beta zero thalassemic allele as well as heterozygous for the H63D HFE-1 allele, and presented with a serum ferritin of 1928 ng/ml. T2* MRI of liver and myocardium demonstrated mild iron deposition in the liver and none in the heart. During a period of 18 months Patient A received serial phlebotomies and hydroxyurea 500 mg daily with decrease in serum ferritin to 770 ng/ml with no change in her baseline Hb and an increase in Hb F from 7% to 15%. Repeat T2*MRI of the liver and myocardium demonstrated no clinically significant iron deposition. Patient A continues to be phlebotomized every one to two months. Case #2: Patient B was heterozygous for the Gln39X beta zero allele with no mutant HFE-1 alleles, and presented with a serum ferritin of 1230 ng/ml. T2* MRI of the liver and myocardium demonstrated iron deposition in the liver and none in the heart. Over a period of twelve months patient B received serial phlebotomies and hydroxyurea 500 mg daily with decrease in his serum ferritin to 450 ng/mL, with no change in baseline Hb and no increase in Hb F. Repeat T2* MRI demonstrated no cardiac iron overload and slight improvement in the liver T2* relaxation time. Patient B continues to be phlebotomized every one to two months. Discussion: We presented two cases of non-transfusion dependent iron overload secondary to beta thalassemia intermedia managed with the combination of phlebotomy and low dose hydroxyurea, which resulted in clinically significant decrease in serum ferritin. In both patients the decrease in serum ferritin averaged ~65 ng/ml/month. As a reference, the higher dose regimen of deferasirox 10 mg/kg/d has a reported average decrease in serum ferritin of around 222 ng/mL/year, corresponding to an estimated 18.5 ng/mL/month2. There was no change in either patient’s Hb/Hct or markers of ineffective erythropoiesis such as LDH, indirect bilirubin and reticulocyte count. This could be due to a somewhat protective effect from hydroxyurea, which may decrease unbound alpha-globin chains, thereby permitting phlebotomy while maintaining adequate counts. Conclusion: These two cases suggest that in some non-transfusion dependent patients, the combination of phlebotomy and hydroxyurea may be an appropriate first-line treatment of iron overload due to beta-thalassemia. It appears to potentially offer enhanced efficacy with presumably less toxicity than standard iron-chelating agents in selected patients. Further investigation is needed to determine the specific population that would benefit most from this combination. The optimal treatment modality/combination in those patients has yet to be determined. Additional studies about treatment effect on iron-regulatory pathways are warranted. References: (1) Gardenghi S, et al. Ineffective erythropoiesis in beta-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. Blood 2007: 109(11):5027-5035. (2) Taher AT, et al. Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study. Blood 2012; 120(5): 970-977. Disclosures No relevant conflicts of interest to declare.

Cardioprotection by Deferiprone[L1] Inspite of Rising Serum Ferritin in Beta Thalassemia Major Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3816-3816
Author(s):  
Anil Pathare ◽  
Shahina Daar ◽  
Salam Alkindi ◽  
J.David Dennison
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Myocardial Performance ◽  
Beta Thalassemia Major ◽  
One Year ◽  
Fractional Shortening ◽  
Paired T Test

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 therefore 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 in achieving optimal therapeutic results. The availability of oral iron chelation with deferiprone (L1) is useful but shows poor efficacy when used alone as compared to DFX. We observed that inspite of rising serum ferritin, these patients benefit by an improvement in the myocardial performance parameters indicating a cardioprotective effect of L1 inspite of worsening of transfusional iron overload. Aim: To study the cardioprotective efficacy of L1 in a prospective study over one year in beta thalassemia major patients with transfusional overload by echocardiography. Methods: We studied 23 patients [M:F;12:11] with beta thalassemia major (Mean age + SD, 19.48 + 5.02; Range 13–32 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 had been 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, due to various reasons, they had developed considerable transfusional iron overload and could not continue to use DFX owing to poor compliance. These patients were allocated to prospectively receive therapy with oral iron chelator L1 [Deferiprox-APOTEX] at 75mg/kg body weight in three divided doses with food after informed consent. They were observed and examined regularly at monthly intervals when they came for regular blood transfusions. Cardiac evaluation was performed with a yearly assessment of ECG and echocardiography. Iron overload assessment was performed by serial serum ferritin levels every two months. It being an acute phase reactant, ESR and C-reactive protein were also estimated whenever needed to validate the utility of ferritin levels as a marker of iron overload. Results: Over the one year study period, the mean serum ferritin rose dramatically from 5209 ng/ml to 6792 ng/ml (p&lt;0.004;paired t test). Interestingly, over the same period there was a significant improvement in the myocardial function as assessed by the Ejection fraction which improved from 68.22% to 73.87% (p&lt;0.0001) and Fractional shortening which also rose from 33.45% to 37.44% (p&lt;0.0001). Improved myocardial performance inspite of progressive worsening of iron overload with Deferiprone therapy for one year[n=23] SF Pre L 1 SF After one year EF Pre L 1 EF After one year FS Pre L 1 FS After one year SF-Serum Ferritin ng/ml;EF-Ejection Fraction%;FS-Fractional Shortening% Mean 5209 6791 68.22 73.87 33.45 37.45 ±SD 2638 4271 5.3 4.8 4.06 4.42 Range - Min 2006 3395 58 62 25.2 29.9 Range - Max 14000 20000 75 88 42 51.1 Students paired ‘t’ test p&lt;0.004 p&lt;0.0001 p&lt;0.0001 Summary/Conclusion: The study emphasizes that beta thalassemia major patients with transfusional iron overload who receive L1 at 75 mg/kg/day as their main chelation therapy show progressive iron overloading. However, inspite of this there is a silver lining is as much as that this treatment has a significant cardio protective effect as shown by the improvement in the echocardiographic parameters of myocardial performance in these patients under study.

Long Term Erythrocytapheresis Is Associated with Reduced Liver Iron Concentration in Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4867-4867
Author(s):  
Scott N. Myers ◽  
Ryan Eid ◽  
John Myers ◽  
Salvatore J. Bertolone ◽  
Ashok B. Raj
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Cell Disease ◽  
Liver Iron ◽  
Serial Serum ◽  
Low Levels ◽  
The Impact

Abstract Background: Observational studies and randomized clinical trials have demonstrated that RBC transfusions can alleviate or prevent many complications of sickle cell disease (SCD). Obligatory iron loading is most problematic for those receiving chronic simple transfusions and is managed with chelation therapy to prevent hepatic, cardiac, and endocrinologic complications. Erythrocytapheresis procedures are increasingly used in SCD as they achieve dilution of hemoglobin S without significantly raising the total hematocrit. Some guidelines for the management of iron overload use serum ferritin levels, but non-invasive measurements of liver iron concentration (LIC) using validated and widely available MRI techniques have been described. There is a paucity of data elucidating the impact of long-term erythrocytapheresis (LTE) on LIC. We evaluated LIC with MRI and serial serum ferritin measurements among a population of SCD patients maintained on LTE at a single institution. Methods: Subjects with SCD maintained on the LTE program included those with elevated TCD, history of stroke, recurrent acute chest syndrome, or frequent pain crises unresponsive to hydroxyurea therapy. Serial serum ferritin measurements were followed and chelation with deferasirox was initiated for consistent ferritin level >1000 ng/mL. MRI of liver and cardiac iron was measured on all LTE subjects with non-contrast MRI techniques. A total of n=31 subjects maintained on LTE were enrolled and stratified into two groups: high LIC, ≥5mg/g of dry tissue (n=4, 12.9%) and low LIC, <5mg/g (n=27, 87.1%). Chi-squared and t-test were used to test for differences between the two groups. Logistic regression was used to test what impacted the odds of having a high LIC, while generalized linear mixed-effects modeling was used to test what impacted LIC. Results: None of the subjects had high cardiac iron concentration. Subjects with high LIC were significantly older (17.8 vs. 13.1, p=0.032) and were more likely to be female (100% vs. 44.4%, p=0.038). The duration of LTE was not associated with high and low levels of LIC (8.25 vs. 6.15, p=0.240, Figure 1), levels of LIC (r=0.247, p=0.188, Figure 2), or serum ferritin (r=0.077, p=0.680). The total number of simple of transfusions was not associated with serum ferritin (r=-0.177, p=0.558) or LIC (r=-0.022, p=0.910). Serum ferritin was not significantly associated with LIC (r=0.296, p=0.112, Figure 3). One of the 4 patients with high LIC required chelation with deferasirox for ferritin >1000 ng/mL. Three of the 31 subjects required iron chelation with deferasirox. Conclusions: There was no significant correlation between duration of LTE and LIC. The impact of cumulative simple transfusions on LIC was obviated by maintenance LTE. These findings are consistent with reports that LTE is associated with reduced transfusional iron overload. The lack of significant association between serum ferritin and LIC suggest that validated MRI measurements of LIC may have greater sensitivity for identifying patients with iron overload and guidelines for iron chelation should consider LIC rather than serum ferritin alone. Figure 1. Duration of LTE (years) was not associated with high and low levels of LIC. Figure 1. Duration of LTE (years) was not associated with high and low levels of LIC. Figure 2. Duration of LTE was not associated with levels of LIC. Figure 2. Duration of LTE was not associated with levels of LIC. Figure 3. Serum ferritin was not significantly associated with LIC. Figure 3. Serum ferritin was not significantly associated with LIC. Disclosures No relevant conflicts of interest to declare.

scholarly journals SEVERE LIVER IRON CONCENTRATIONS (LIC) IN 24 PATIENTS WITH Β-THALASSEMIA MAJOR: CORRELATIONS WITH SERUM FERRITIN, LIVER ENZYMES AND ENDOCRINE COMPLICATIONS

2018 ◽  
Vol 10 ◽  
pp. e2018062 ◽  
Author(s):  
Vincenzo De Sanctis
Keyword(s):  
Iron Overload ◽  
Adrenal Insufficiency ◽  
Serum Ferritin ◽  
Chelation Therapy ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Dry Weight ◽  
Thalassemia Major ◽  
Liver Iron

Abstract. Introduction: Chronic blood transfusion is the mainstay of care for individuals with β-thalassemia major (BTM). However, it causes iron-overload that requires monitoring and management by long-term iron chelation therapy in order to prevent endocrinopathies and cardiomyopathies, that can be fatal. Hepatic R2 MRI method (FerriScan®) has been validated as the gold standard for evaluation and monitoring liver iron concentration (LIC) that reflects the total body iron-overload. Although adequate oral iron chelation therapy (OIC) is promising for the treatment of transfusional iron-overload, some patients are less compliant with it and others suffer from long-term effects of iron overload. Objective: The aim of our study was to evaluate the prevalence of endocrinopathies and liver dysfunction, in relation to LIC and serum ferritin level, in a selected group of adolescents and young adult BTM patients with severe hepatic iron overload (LIC from 15 to 43 mg Fe/g dry weight). Patients and Methods: Twenty-four selected BTM patients with severe LIC, due to transfusion-related iron-overload, followed at the Hematology Section, National Center for Cancer Care and Research, Hamad Medical Corporation of Doha (Qatar), from April 2015 to July 2017, were retrospectively evaluated. The prevalence of short stature, hypogonadism, hypothyroidism, hypoparathyroidism, impaired fasting glucose (IFG), diabetes, and adrenal insufficiency was defined and assessed according to the International Network of Clinicians for Endocrinopathies in Thalassemia (ICET) and American Diabetes Association criteria. Results: Patients have been transfused over the past 19.75 ± 8.05 years (ranging from 7 to 33 years). The most common transfusion frequency was every 3 weeks (70.8%).  At the time of LIC measurements, the mean age of patients was 21.75 ± 8.05 years, mean LIC was 32.05 ± 10.53 mg Fe/g dry weight (range: 15 to 43 mg Fe/g dry weight). Their mean serum ferritin level was 4,488.6 ± 2,779 µg/L. The overall prevalence of growth failure was 26.1% (6/23), IFG was 16.7% (4/24), sub-clinical hypothyroidism was 14.3% (3/21), hypogonadism was 14.3% (2/14), diabetes mellitus was 12.5% (3/24), and biochemical adrenal insufficiency was 6.7% (1/15). The prevalence of hepatitis C positivity was 20.8% (5/24). No case of clinical hypothyroidism, adrenal insufficiency or hypoparathyroidism was detected in this cohort of patients. The prevalence of IFG impaired fasting glucose was significantly higher in BTM patients with very high LIC (>30 mg Fe/g dry liver) versus those with lower LIC (p = 0.044). LIC was correlated significantly with serum ferritin levels (r = 0.512; p = 0.011), lactate dehydrogenase (r = 0.744; p = 0.022) and total bilirubin (r = 0.432; p = 0.035). Conclusions: A significant number of BTM patients, with high LIC and endocrine disorders, still exist despite the recent developments of new oral iron chelating agents. Therefore, physicians’ strategies shall optimize early identification of those patients in order to optimise their chelation therapy and to avoid iron-induced organ damage. We believe that further studies are needed to evaluate if serial measurements of quantitative LIC may predict the risk for endocrine complications. Until these data are available, we recommend a close monitoring of endocrine and other complications, according to the international guidelines.  

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

Blood ◽  
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.

Lack of Correlation between Serum Ferritin and Liver Iron Concentration in Beta-Zero Thalassemia Intermedia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3620-3620 ◽  
Author(s):  
Renzo Galanello ◽  
Nicolina Giagu ◽  
Susanna Barella ◽  
Liliana Maccioni ◽  
Raffaella Origa
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Regulatory Protein ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Dry Weight ◽  
Thalassemia Major ◽  
Thalassemia Intermedia ◽  
Liver Iron Concentration ◽  
Liver Iron

Abstract Serum ferritin and liver iron concentration (LIC) are the most commonly used methods for assessment of iron overload in thalassemia. While in patients with thalassemia major a significant correlation has been found between these two parameters, data are lacking in patients with thalassemia intermedia. In this study we measured the serum ferritin and LIC in 22 adult patients with beta-zero thalassemia intermedia never transfused (14 patients) or sporadically transfused, i.e. less than 10 units in total (8 patients), who maintained a mean hemoglobin of 8.8 ± 1.1 g/dl. Serum ferritin levels were measured by an automated chemiluminescence immunoassay analyzer, whereas LIC was determined by atomic absorption in liver biopsies. We compared the results obtained in those patients with those obtained in 22 regularly transfused (mean annual Hb = 11.3 ± 0.3 g/dl) and iron chelated thalassemia major patients, matched by sex, age and liver iron concentration. We also determined serum erythropoietin (s-epo) and serum transferrin receptor (s-TfR) in a cohort of the two patient groups (12 thalassemia intermedia; 15 thalassemia major). Mean LIC was 11.3 ± 6 mg/g dry weight tissue in thalassemia intermedia, and 11.8 ± 7 mg/g d.w. in thalassemia major group. Mean serum ferritin (at least 2 determinations from each patient within ± 2 months of liver biopsy) was 627 ± 309 ng/ml in thalassemia intermedia and 2748 ± 2510 ng/ml in thalassemia major. The difference was statistically significant (p = 0.0001). LIC was weakly correlated with serum ferritin in thalassemia major patients (r2=0.46; p=0.001) and uncorrelated in patients with thalassemia intermedia (r2=0.04; p=0.37) (Figure). S-epo and s-TfR were significantly higher in thalassemia intermedia than in thalassemia major [s-epo 467 ± 454 mU/ml versus 71 ± 44 mU/ml (p<0.001); s-TfR 43 ± 13 mU/ ml versus 13 ± 6 mU/ml (p<0.0001)]. The discrepancy between LIC and serum ferritin in thalassemia intermedia patients may be due to the higher levels of s-epo (secondary to anemia) in those patients, which through the iron regulatory protein 1 determine an up-regulation of s-TfR and a repression of ferritin translation (Weiss et al 1997). The mechanism of iron overload may also be mediated by hepcidin, whose synthesis could be suppressed as a consequence of anemia. The observation reported has important implications for iron chelation in patients with thalassemia intermedia. In such patients serum ferritin levels have little value for the monitoring of iron overload. Figure Figure

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