Iron Overload Occurs Very Early In Newly-Diagnosed Patients With Congenital, Transfusion-Dependent Anemias

Systematic transfusions are lifesaving for patients with severe congenital anemias, but they eventually lead to iron overload and the indispensable necessity of iron chelation therapy. Current official guidelines for the starting time of chelation therapy derives from data obtained with the use of desferrioxamine, which has been shown to have significant toxicity in very young patients, especially when used in low iron burden. No data exist on the use of the oral iron chelators in this setting. The purpose of this study was to evaluate the changes of iron parameters at the initial period of transfusion therapy in newly diagnosed patients with congenital anemias Methods Nine patients participated in this study. One patient was diagnosed with Diamond-Blackfan anemia, one patient with severe alpha-thalassemia, while 7 had beta-thalassemia. Three of the beta-thalassemia started transfusions at 1.5, 2 and 5 years, respectively. All others started transfusions between 2-4 months of age. Iron, transferrin saturation, ferritin levels. serum transferrin receptors (sTfR), were estimated by standard methods, while labile plasma iron (LPI) by the FeROS LPI kit (Aferrix, Ltd, Israel). The main results of the study show that: 1) transferrin saturation increases rapidly with transfusions (mean levels after 4 transfusions 49.2% (range: 23.8-90.5%), mean after 6 transfusions 69.1% (range: 39.5-112%)), though it has significant diversity in between patients, as indicated also by one patient that continued to have transferrin saturation at 65% even after 12 sessions. Transferrin saturation significantly correlates with ferritin levels (r=0.763, p<0.0001), with the number of previous transfusions (r=0.486, p=0.002) and with the levels of sTfR, which is also an index of the degree of erythropoiesis (r=0.550, p<0.001). The increase of ferritin correlates also with the sTfR levels (r=0.697, p<0.0001), while the rate of increasing transferrin saturation per transfusion correlates to sTfR levels (r=0.486, p=0.002). LPI levels appears early in the transfusion history and correlates with transfusion saturation. Discussion The results of the study indicate that iron overload starts early in the transfusion history of young patients with transfusion-dependent anemias. These findings dispute current guidelines suggesting starting chelation therapy, when the patients have already received 10 transfusions or when ferritin levels reach more than 1000ug/dl. Disclosures: No relevant conflicts of interest to declare.

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Plasma Biomarkers of Iron Regulation, Overload, and Inflammation in Sickle Cell Disease

Blood ◽

10.1182/blood.v124.21.1380.1380 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1380-1380

Author(s):

Abhishek Mangaonkar ◽

Niren Patel ◽

Hongyan Xu ◽

Kavita Natrajan ◽

Betsy Clair ◽

...

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Inflammatory Markers ◽

Conflicts Of Interest ◽

Plasma Concentrations ◽

Transferrin Saturation ◽

Iron Regulation ◽

Cell Disease ◽

Transfusion History

Abstract Transfusional iron overload has been increasingly recognized among patients with sickle cell disease (SCD) over the past two decades. We recently reported on the prevalence of iron overload among 635 adult SCD patients followed at our center and found that 80 patients (12%) had developed iron overload as a result of repeated blood transfusions. Fifty six (70%) of these subjects developed iron overload as a result of episodic, mostly unnecessary transfusions at outlying hospitals. There have been reports of association of increased morbidity and mortality among iron overloaded SCD patients; it has also been hypothesized that SCD patients tend to develop fewer complications of iron overload, compared to transfusion dependent beta thalassemia, primarily due to the chronic inflammatory state with resultant upregulation of hepcidin, and lower extra-hepatic iron loading. We studied biomarkers of iron metabolism, iron regulation, and inflammatory markers in 22 patients with SCD (SS) and iron overload (two consecutive ferritin levels of >1000 ng/ml and significant transfusion history) and compared these with 14 SCD patients without iron overload (ferritin <1000 ng/ml, and no significant transfusion history). Serum Fe, ferritin, %transferrin saturation (Tf) and total iron binding capacity, as well as high sensitivity C reactive protein (hsCRP) were performed by routine laboratory methods. Plasma concentrations of soluble transferrin receptor (sTfR), interleukin-6 (IL-6), Growth Differentiation Factor-15 (GDF-15) were measured using commercially available ELISA kits (R&D Systems, Minneapolis, USA). Plasma hepcidin was measured using a commercially available kit from DRG Diagnostics (Marburg, Germany). The results are summarized below: Abstract 1380. TableAgeyearsFerritin ng/ml% sathsCRPmg/dLHepcidinng/mlsTfRnmol/LGDF-15pg/mlIL-6pg/mlCases (n=22)33.42083.560.40.8829.872.21201.55.2Controls (n=14)29.0401.840.40.9512.477.11115.34.1p-value0.236.14E-050.020.80.0020.20.550.24 As expected, ferritin and % Tf saturation were significantly higher in the iron overloaded group. Hepcidin levels were also significantly higher in cases vs. controls, indicative of appropriate upregulation of hepcidin in Fe overload. sTfR and GDF-15 levels, as well as the inflammatory markers (hsCRP and IL-6) did not differ significantly between Fe overloaded and non-iron overloaded SCD patients. The two groups did not differ significantly in terms of the measures of disease severity (number of pain crises/year and number of hospitalizations/year). We further looked at the ratio of hepcidin/ferritin, sTfR/log ferritin, GDF-15/hepcidin, and tested the correlation between GDF-15 and hepcidin levels and ferritin and hepcidin levels; the ratio of hepcidin to ferritin was not different between cases and controls (0.019 and 0.021, respectively, p=0.73). sTfR to log ferritin ratio was significantly lower in cases compared to controls (22.3 vs 33.24, p=0.0004). GDF-15/hepcidin ratio was also found to be significantly lower in cases (262.1 vs 1896.7, p=0.01). Additionally, GDF-15 and hepcidin levels correlated significantly in controls but not iron overloaded SCD patients (p=0.04 vs p=0.7). Similarly, hepcidin and ferritin levels were significantly correlated in controls (p=0.03) but not in cases (p=0.8). Our results suggest that i) hepcidin levels are appropriately upregulated in iron overloaded SCD patients, ii) inflammatory markers (hsCRP and IL-6) were not significantly different between iron overloaded and non-iron overloaded patients, suggesting that systemic inflammation is not the driving factor behind hepcidin upregulation in iron overloaded SCD patients; however, a local/paracrine effect of IL-6 on hepatocytes secondary to Fe related inflammation in the liver cannot be excluded; and iii) GDF-15 and sTfR levels are not different between cases and controls, indicating that erythropoiesis does not differ between Fe overloaded and non-iron overloaded SCD patients. The observation that the correlation between GDF-15 and hepcidin levels is lost in iron overloaded SCD patients suggests that erythropoiesis does not contribute to hepcidin regulation in these subjects. This can further be clarified by studying the role of the newly described erythroid regulator of hepcidin, erythroferrone in SCD with and without iron overload. Disclosures No relevant conflicts of interest to declare.

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A Randomized Trial on the Safety and Efficacy of Early Start of Iron Chelation Therapy with Deferiprone in Newly Diagnosed Children with Transfusion Dependent Thalassemia

Blood ◽

10.1182/blood.v128.22.1286.1286 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1286-1286

Author(s):

Mohsen Saleh Elalfy ◽

Vasilios Berdoukas ◽

Fernando Tricta ◽

Amira Adly ◽

Nyeria Hazza ◽

...

Keyword(s):

Adverse Events ◽

Iron Overload ◽

Chelation Therapy ◽

Transferrin Saturation ◽

Iron Chelation ◽

Iron Accumulation ◽

Iron Chelation Therapy ◽

Newly Diagnosed ◽

Abdominal Colic

Abstract Iron toxicity is the main risk factor for morbidity and mortality in patients with transfusion-dependent thalassemia. Current practice is to start chelation therapy only after 10-20 transfusions, or when the serum ferritin (SF) level rises above 1,000 μg/L. This delay is aimed at minimizing the risk of chelation toxicity that was observed with the use of deferoxamine in children with low iron stores. Deferiprone has lower affinity for iron than deferoxamine and data from clinical trials on its use in patients without systemic iron overload indicate a safety profile for its use in those conditions. The current trial was designed to evaluate the safety of the early use of low-dose deferiprone in newly diagnosed pediatric thalassemia and to evaluate if it can postpone iron overload. Sixty-four children recently diagnosed with thalassemia major who had begun receiving blood transfusions every 3-4 weeks to keep pre-transfusion Hb above 10 gm/dl, had not yet started iron chelation therapy and had SF ≥ 400 μg/L or transferrin saturation (TSAT) ≥ 70% or labile plasma iron (LPI) ≥ 0.2 µM were randomized to start deferiprone (DFP) at a dose normally considered to be sub-therapeutic (50 mg/kg/day) or no chelation (NC). Age at 1st transfusion was 8.1 ± 1.7 for DFP-treated and 8.1 ± 1.6 months for NC children. The percentage of patients with LPI ≥ 0.6 µM, SF ≥ 1000 μg/L or TSAT ≥ 70% in each study arm was assessed at 6 months and 12 months. Patients with confirmed SF ≥1000 ng/mL were withdrawn from the study and placed on a standard chelation regimen. Results. Two patients (DFP) were lost to follow after baseline measurements, 1 patient (NC) withdrew consent at baseline, and 10 patients (5 DFP, 5 NC) have yet to complete all follow up visits. All NC patients had been removed from the trial prior to completing 7 months of follow-up 12 due to confirmed SF ≥ 1000 μg/L. Mean ± SD time of follow up was 10.4± 4.9 and 5.9 ± 2.5 months for DFP and NC, respectively. Most common adverse events in patients on DFP versus NC were diarrhoea (19% vs 13%, p= 0.73), vomiting (13% vs 13%, p=1.00), abdominal colic (13% vs 13%), increased liver enzymes (6% vs 3%, p=1.00) and neutropenia (neutrophil count between 1,000-1,500 x 109/L) (6% vs 6%). All adverse events were mild in severity and did not require interruption of DFP use. There were no cases of agranulocytosis or of moderate neutropenia, no arthralgia and no serious infections in DFP-treated patients. Preliminary efficacy results are presented in the table. DFP therapy was associated with a significant reduction in the rate of iron accumulation as measured by SF (P<0.0001) (Figure 1), LPI (P<0.001) (Figure 2) and TSAT (P<0.001). LPI ≥ 0.6 µM appeared as early as after 5 transfusions in NC children and was delayed to at least 10 transfusions with DFP therapy. TSAT ≥ 70% appeared after 10 transfusions in NC children and was delayed to at least 17 transfusions with DFP therapy. The results of this study show that LPI and TSAT may reach values ≥ 0.6 µM and ≥ 70%, respectively, after 5 -10 transfusions in children with TM and all NC children had SF ≥ 1000 μg/L after 8-9 transfusions. A sub-therapeutic dose regimen of deferiprone for a mean of 10 months in children with TM and low iron overload was not associated with safety concerns and able to significantly reduce the rate of iron accumulation as measured by SF and the appearance of high levels of LPI and of TSAT. Table Table. Disclosures Berdoukas: ApoPharma Inc: Consultancy. Tricta:ApoPharma Inc: Employment.

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Time to Start Delivering Iron Chelation Therapy in Newly Diagnosed Severe β-Thalassemia

BioMed Research International ◽

10.1155/2020/8185016 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Susi Susanah ◽

Ponpon S. Idjradinata ◽

Nur M. Sari ◽

Lulu E. Rakhmilla ◽

Yunia Sribudiani ◽

...

Keyword(s):

Iron Overload ◽

Chelation Therapy ◽

Iron Status ◽

Transferrin Saturation ◽

Iron Chelation ◽

Normal Diet ◽

Iron Chelation Therapy ◽

Newly Diagnosed ◽

Hepcidin Level ◽

Significant Difference

Background. Iron overload is still a major complication of severe β-thalassemia. Indication to start iron chelation therapy is based on serum ferritin (SF) or transferrin saturation (TS) level or the amount of transfusion. The goal of this study is to analyse the pattern of iron status, the amount of transfusion regarding the time to start iron chelator, and serum hepcidin levels in newly diagnosed severe β-thalassemia. Methods. A prospective cohort study was performed at Hasan Sadikin General Hospital on newly diagnosed severe β-thalassemia patients. Subjects had not received any blood transfusion with normal liver function test, CRP, and IL-6 levels who consumed normal diet according to age. The SF and TS levels indicate iron status, while hepcidin level indicates iron regulator status. Main indicator to start iron chelation therapy when SF level ≥1.000 ng/mL, TS level ≥70%, or after receiving transfusion at least 10 times. Statistical analysis used Mann–Whitney and Spearman. Results. Forty-two newly severe β-thalassemia, 30 (71.4%), were diagnosed before 1 year old, mean 9.9 ± 6.4 months, range 2–24 months. Range amount of transfusion until SF level reached ≥1,000 ng/mL were 4-12 times, mean 7 ± 2 times. Mean SF and TS level at diagnosis were 365.6 ± 194.9 ng / mL and 67.3 ± 22.5 % , while hepcidin level was normal, mean 242.6 ± 58 ng / mL . 36/42 patients have reached SF >1000 ng/mL with amount of transfusion less than 10 times. There was no significant difference of SF, TS, and hepcidin levels when SF >1000 ng/mL in the group with amount of transfusion 7–12 and less than 7 ( p = 0.454 , p = 0.084 , p = 0.765 ), respectively. A significant positive correlation between SF and amount of transfusion was observed ( p < 0.001 ; r = 0.781 ). Conclusion. Iron overload in severe β-thalassemia patients might occur earlier even before they received 10 times transfusion. Hepcidin serum level tends to increase when iron overload just started.

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Hepcidin Levels and Their Determinants In Different Types of Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v116.21.4250.4250 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4250-4250

Author(s):

Valeria Santini ◽

Domenico Girelli ◽

Alessandro Sanna ◽

Nicola Martinelli ◽

Lorena Duca ◽

...

Keyword(s):

Iron Overload ◽

Myelodysplastic Syndromes ◽

Iron Homeostasis ◽

Conflicts Of Interest ◽

Iron Status ◽

Transferrin Saturation ◽

Ineffective Erythropoiesis ◽

Transfusion Therapy ◽

Different Types ◽

Serum Hepcidin

Abstract Abstract 4250 Background and Aims. Iron overload is frequently occurring in patients with myelodysplastic syndromes (MDS), with recent data suggesting an impact on both overall and leukemia-free survival1,2. Though prolonged RBC transfusion therapy appears the main contributor, many patients develop iron overload at an early stage of the disease, before the onset of transfusion dependency. It has been postulated that an altered production of hepcidin, the key hormone regulating iron homeostasis, may play a role at this regard. Until recently, studies have been hampered by problems in the development of reliable hepcidin assays, so that only scanty and conflicting data based on semi-quantitative measurement of urinary hepcidin have been reported3,4. This study mainly focused on analyzing serum hepcidin levels in MDS patients by means of a recently validated and improved Mass-Spectrometry based method5. Patients and Methods. One hundred and thirteen consecutive patients (mean age 72.8 ± 9.2 years; 68.1% males) with different types of MDS according to the WHO classification were included in this study. To be enrolled, patients had to be previously untreated or treated only with transfusions. Besides hepcidin, in all subjects we determined serum ferritin, transferrin saturation (TS), non-transferrin-bound-iron (NTBI), along with some putative determinants of hepcidin, like GDF-156 known to be associated with ineffective erythropoiesis, and C-Reactive Protein (CRP) as a surrogate of systemic IL-6 production. Fifty-four healthy individuals (61.1% males) with rigorous definition of normal iron status were used as controls. Main Results. Biochemical markers of iron overload (ferritin and TS), but also CRP and GDF-15 were significantly higher in MDS patients than in controls, even when considering only non-transfused patients. Patients with RARS and the 5q- syndrome appeared as the most iron overloaded, having the highest levels of ferritin, TS, and NTBI. In the whole MDS population, serum hepcidin levels showed a considerable variability, with overall mean values not significantly different from controls [geometric means (gm) with 95% CIs: 5.31 (3.98-7.08) versus 4.2 (3.53-5.0) nM, P=0.28], while the hepcidin/ferritin ratio was significantly lower than in controls [10.1 (7.53-13.53) versus 52.9 (43.6-64.3), P<0.001]. After stratification according to WHO subtypes, hepcidin levels showed significant differences, with the lowest levels in patients with RARS (gm 1.43 nM) and the highest levels in patients with RAEB 1–2 (gm 11.3 nM) and with CMML (gm 10.04 nM) (P=0.003 by ANOVA). The latter groups had substantial elevation of CRP as compared to other MDS subtypes (P=0.008 by ANOVA), while GDF-15 was consistently but uniformly elevated in all MDS subtypes (P=0.97 by ANOVA). Multivariate linear regression models adjusted also for age, sex, and history of RBC transfusions, showed ferritin (β-coefficient 0.45, P=0.002), CRP (β-coefficient 0.21, P=0.02), and different MDS subtypes as the main independent predictors of hepcidin levels. The different degree of correlation between hepcidin and ferritin among the MDS subtypes were analyzed in a general linear model using the F test for slopes. Hepcidin regulation by iron appeared conserved, though relatively blunted in RA, RARS, and 5q- patients, while it was lost in RAEB 1–2 and CMML. Conclusions. Hepcidin levels are consistently heterogeneous in MDS according to different subtypes, likely as the result of the relative strength of competing stimuli. Relative inhibition by ineffective erythropoiesis (but not mediated by GDF-15) seems to prevail particularly in RARS and 5q- syndrome, and is likely to increase the risk of iron overload in these subgroups. On the other hand, patients with RAEB 1–2 and CMML appears to have hepcidin induction that could be driven by cytokines. If confirmed, these results may be relevant not only for a better understanding of iron pathophysiology in MDS, but also for possible future approach with hepcidin modulators7. References: 1) Sanz G, et al. Blood 2008;112: abs 640. 2) Alessandrino EP, et al. Haematologica 2010;95:476-84. 3) Winder A, et al. Br J Haematol 2008;142:669-71. 4) Murphy PT, et al. Br J Haematol 2009;144:451-2. 5) Campostrini N, et al. J Biomed Biotechnol 2010;2010:329646. 6) Tanno T, et al. Nat Med 2007;13:1096-101. 7) Sasu BJ, et al. Blood 2010;115:3616-24. Disclosures: No relevant conflicts of interest to declare.

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Liver Enzymes in Children with beta-Thalassemia Major: Correlation with Iron Overload and Viral Hepatitis

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2015.059 ◽

2015 ◽

Vol 3 (2) ◽

pp. 287-292 ◽

Cited By ~ 7

Author(s):

Khaled M. Salama ◽

Ola M. Ibrahim ◽

Ahmed M. Kaddah ◽

Samia Boseila ◽

Leila Abu Ismail ◽

...

Keyword(s):

Blood Transfusion ◽

Iron Overload ◽

Viral Hepatitis ◽

Serum Ferritin ◽

Liver Enzymes ◽

Transferrin Saturation ◽

Thalassemia Major ◽

Beta Thalassemia ◽

Elevated Liver Enzymes ◽

Hcv Antibody

BACKGROUND: Beta Thalassemia is the most common chronic hemolytic anemia in Egypt (85.1%) with an estimated carrier rate of 9-10.2%. Injury to the liver, whether acute or chronic, eventually results in an increase in serum concentrations of Alanine transaminase (ALT) and Aspartate transaminase (AST).AIM: Evaluating the potentiating effect of iron overload & viral hepatitis infection on the liver enzymes.PATIENTS AND METHODS: Eighty (80) thalassemia major patients were studied with respect to liver enzymes, ferritin, transferrin saturation, HBsAg, anti-HCV antibody and HCV-PCR for anti-HCV positive patients.RESULTS: Fifty % of the patients were anti-HCV positive and 55% of them were HCV-PCR positive. Patients with elevated ALT and AST levels had significantly higher mean serum ferritin than those with normal levels. Anti-HCV positive patients had higher mean serum ferritin, serum ALT, AST and GGT levels and higher age and duration of blood transfusion than the negative group. HCV-PCR positive patients had higher mean serum ferritin and serum ALT and also higher age and duration of blood transfusion than the negative group.CONCLUSION: Iron overload is a main leading cause of elevated liver enzymes, and presence of HCV infection is significantly related to the increased iron overload.

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Growth Differentiation Factor 15 (GDF15) and Erythropoietin (EPO) Levels in Beta Talassemia Major Patients.

Blood ◽

10.1182/blood.v112.11.1881.1881 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1881-1881

Author(s):

Ilaria Salussoglia ◽

Gisella Volpe ◽

Silvia Fracchia ◽

Simona Roggero ◽

Filomena Longo ◽

...

Keyword(s):

Iron Status ◽

Clinical Status ◽

Transferrin Saturation ◽

Iron Chelation ◽

Serum Levels ◽

Thalassemia Major ◽

Beta Thalassemia ◽

Transfusion Therapy ◽

Beta Thalassemia Major ◽

The Mean

Abstract Background: The serum level of GDF15 has been recently indicated as a possible marker of erythropoiesis (Tanno et al., Nature 2007) suggesting a role of its over-expression in contributing to iron overload in thalassemia syndromes by inhibiting hepcidin expression. The aim of present study has been to evaluate GDF15 serum levels in a homogeneous series of thalassemia patients and the relationship with transfusional parameters and iron status markers. Methods: A group of consecutive patients with beta thalassemia major followed at our institution were included in the study. All patients were on regular transfusion and iron chelation treatment. Quantification of GDF15 on serum samples was performed with DuoSet ELISA for human GDF15 (R&D Systems) following the manufacturer’s protocol (Tanno et al., Nature 2007). Each patient had also a blood test for haemoglobin (Hb), serum iron, ferritin, transferrin, transferrin saturation and EPO levels. Liver Iron Concentration by SQUID and cardiac iron by MRI T2* have been assessed. The mean hemoglobin levels of the previous year (pre-transfusional, post-transfusional and mean) have been calculated for each individual. The presence of mild thalassemic mutations was used to classify mild or severe genotype. Clinical status has been assessed on the presence/absence of main complications (heart disease, liver disease, diabetes, hypothyroidism). Statistical analysis was performed using the software Statistica (StatSoft). Results: One hundred-forty patients (73 male, 67 females) were studied. The mean age was 27.9 ± 9.0 years (range: 3.5–42). One hundred (71%) were splenectomised. Betathalassemia major patients had elevated GDF15 serum levels (mean 6892 ± 6894 pg/mL; range 720–52521) in comparison with healthy volunteers (273 ± 104 pg/mL; range 129–401). GDF 15 levels were strongly related to EPO levels (r=0,81; p<0,001). GDF15 levels were not related with age, gender, spleen, clinical status and iron markers. Patients with a severe genotype had higher GDF15 levels than mild genotype patients. GDF15 levels had a negative correlation with Hbs (p<0,05 for actual Hb and pre-transfusional Hb; p<0,001 for post-transfusional Hb and mean Hb). In thalassemia major patients with a severe genotype, GDF15 levels within thrice the normal range have been observed only in patients with pre-transfusional Hb above 9,6, post-transfusional Hb above 12,5 and a mean Hb above 11,3. Conclusions: In beta thalassemia major patients on regular transfusion and iron chelation, serum GDF15 levels are high, inversely related to the haemoglobin levels maintained. Further studies of this marker may lead to a rethinking of the optimal transfusion therapy in these conditions.

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Comparing the Value of Serum Ferritin, Transfusion History and Magnetic Resonance Imaging for the Prediction of Iron Overload In MDS and AML Patients Undergoing Allogeneic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v116.21.3493.3493 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3493-3493

Author(s):

Martin Wermke ◽

Jan Moritz Middeke ◽

Nona Shayegi ◽

Verena Plodeck ◽

Michael Laniado ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Iron Content ◽

Iron Concentration ◽

Transferrin Saturation ◽

Resonance Imaging ◽

Liver Iron Concentration ◽

Liver Iron ◽

Liver Iron Content ◽

Transfusion History

Abstract Abstract 3493 An increased risk for GvHD, infections and liver toxicity after transplant has been attributed to iron overload (defined by serum ferritin) of MDS and AML patients prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nevertheless, the reason for this observation is not very well defined. Consequently, there is a debate whether to use iron chelators in these patients prior to allo-HSCT. In fact, serum ferritin levels and transfusion history are commonly used to guide iron depletion strategies. Both parameters may inadequately reflect body iron stores in MDS and AML patients prior to allo-HSCT. Recently, quantitative magnetic resonance imaging (MRI) was introduced as a tool for direct measurement of liver iron. We therefore aimed at evaluating the accurateness of different strategies for determining iron overload in MDS and AML patients prior to allo-HSCT. Serologic parameters of iron overload (ferritin, iron, transferrin, transferrin saturation, soluble transferrin receptor) and transfusion history were obtained prospectively in MDS or AML patients prior to allo-SCT. In parallel, liver iron content was measured by MRI according to the method described by Gandon (Lancet 2004) and Rose (Eur J Haematol 2006), respectively. A total of 20 AML and 9 MDS patients (median age 59 years, range: 23–74 years) undergoing allo-HSCT have been evaluated so far. The median ferritin concentration was 2237 μg/l (range 572–6594 μg/l) and patients had received a median of 20 transfusions (range 6–127) before transplantation. Serum ferritin was not significantly correlated with transfusion burden (t = 0.207, p = 0.119) but as expected with the concentration of C-reactive protein (t = 0.385, p = 0.003). Median liver iron concentration measured by MRI was 150 μmol/g (range 40–300 μmol/g, normal: < 36 μmol/g). A weak but significant correlation was found between liver iron concentration and ferritin (t = 0.354; p = 0.008). The strength of the correlation was diminished by the influence of 5 outliers with high ferritin concentrations but rather low liver iron content (Figure 1). The same applied to transfusion history which was also only weakly associated with liver iron content (t = 0.365; p = 0.007). Levels of transferrin, transferrin saturation, total iron and soluble transferrin receptor did not predict for liver iron concentration. Our data suggest that serum ferritin or transfusion history cannot be regarded as robust surrogates for the actual iron overload in MDS or AML patients. Therefore we advocate caution when using one of these parameters as the only trigger for chelation therapy or as a risk-factor to predict outcome after allo-HSCT. Figure 1. Correlation of Liver iron content with Ferritin. Figure 1. Correlation of Liver iron content with Ferritin. Disclosures: No relevant conflicts of interest to declare.

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Deferiprone Oral Solution, An Alternative for Early Chelation Therapy In Young Children with Transfusional Iron Overload: A Preliminary Data From A 6-Month Study Period

Blood ◽

10.1182/blood.v118.21.2108.2108 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2108-2108

Author(s):

Duantida Songdej ◽

Nongnuch Sirachainan ◽

Pakawan Wongwerawattanakoon ◽

Praguywan Kadegasem ◽

Ampaiwan Chuansumrit

Keyword(s):

Young Children ◽

Iron Overload ◽

Chelation Therapy ◽

Conflicts Of Interest ◽

Ferritin Level ◽

Oral Solution ◽

Tablet Form ◽

Iron Load ◽

Short Period ◽

Hbh Disease

Abstract Abstract 2108 Introduction: The choice of chelation therapy is limited in young children with transfusional iron overload. Desferrioxamine can disturb bone growth especially in those younger than 6 years of age. Moreover, incooperation of young patients to subcutaneous overnight infusion of the medication causes none adherence. Deferasirox is an unaffordable chelation for many patients in developing countries. Deferiprone has been evaluated in several studies for its safety and efficacy in young children. However, the widely used large tablet form of deferiprone may not be suitable for this group of patients. Objective: To study efficacy, safety and tolerability of deferiprone oral solution for early chelation therapy in young children with transfusional iron overload. Inclusion criteria: Patients age <10 years with transfusional iron overload (ferritin >1,000 ng/mL or received >10 transfusions) at Pediatrics Department, Faculty of Medicine, Ramathibodi Hospital, Mahidol University that fail to accomplish adequate chelation by desferrioxamine or deferiprone tablet due to poor compliance. Methods: Deferiprone oral solution (Ferriprox®) was given at a dose of 75 mg/kg/day in three divided dose for patients who previously received tablet form of deferiprone and 50 mg/kg/day for others who never experienced deferiprone. Ferritin level, complete blood counts, alanine transferase, serum creatinine and spot urine protein were measured every 4 weeks. Complete history taking and physical examination were performed and compliance was recorded during monthly visit. Results: A total of 10 patients were enrolled with equal male and female. The median age was 4.8 years (range 2–9.8 years) whereas seven patients was ≤5 years of age. Seven out of 10 patients were diagnosed β thalassemia HbE disease and the rest were diagnosed β thalassemia major, HbH disease and hereditary spherocytosis respectively. Only one patient was splenectomized and none of them was seropositive for hepatitis B or C virus. All patients have received regular packed red cell transfusion for the median of 3.9 years (range 1.1–6.4 years) to maintain pretransfusion hematocrit of 27%. The median transfusional iron load was 0.39 mg/kg/day (range 0.29–0.48 mg/kg/day) whereas the median ferritin level at the beginning of the study was 1,598.2 ng/mL (range 654.4–3, 163.8 ng/mL). Two patients were previously chelated with desferrioxamine, three patients with deferiprone tablet and 1 with combined desferrioxamine and deferiprone tablet. The remaining four patients were naïve for deferiprone oral solution. Efficacy The median ferritin level at the end of 6 months was significantly lower than that of pretreatment period (median 1,445.8 ng/mL, range 114.6–2806.2 ng/mL, p=0.037). Four out of 10 patients had final ferritin level at 6 months <1,000 ng/mL and half of them had ferritin level <500 ng/mL. This group of four patients were ≤5 years old and had ferritin level between 654.4–1, 507.8 ng/mL at the beginning of study. However, the transfusional iron load was ranging from 0.36–0.48 mg/kg/day. They all received 50 mg/kg/day of deferiprone solution. One out of these four was a patient with HbH disease who was occasionally transfused. The ferritin level of the boy decreased from 654.4 ng/mL to 114.6 ng/mL and deferiprone oral solution could be stopped at the end of the third month. Safety No episode of neutropenia or agranulocytosis occurred. One patient had an episode of mild thrombocytopenia of 137,000/μL during the second month of treatment. However, deferiprone oral solution was continued and spontaneous recovery of platelet counts was observed on the following month. No transaminitis and renal impairment were found. Neither arthralgia nor GI discomfort occurred. Tolerability All patients tolerated well with deferiprone oral solution and excellent compliance of the treatment was achieved. Conclusion: Deferiprone oral solution is a safe and effective alternative for chelation therapy in transfusion-related iron overload especially those with younger age. Serum ferritin level decreased well in a short period of time with only as low dose of deferiprone as 50 mg/kg/day when given at earlier age with starting ferritin level ≤1,000 ng/mL. Better absorption of deferiprone in the form of solution may be a reason for such efficacy. Moreover, liquid formulation of the medication could be a solution to improve adherence to chelation treatment in young children. Disclosures: No relevant conflicts of interest to declare.

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Estimating Iron Burden in Simple Vs. Modified Manual Exchange Transfusions in Pediatric Sickle Cell Patients on Chronic Transfusions

Blood ◽

10.1182/blood.v118.21.4850.4850 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4850-4850

Author(s):

Mansi Lalwani ◽

Mary DeBarr ◽

Ann O'Riordan Mary ◽

Connie M Piccone ◽

Brian W Berman

Keyword(s):

Iron Overload ◽

Sickle Cell ◽

Exchange Transfusion ◽

Chelation Therapy ◽

Iron Chelation ◽

Red Cell ◽

Cell Disease ◽

Transfusion Therapy ◽

Packed Red Blood Cells ◽

Transfusion Protocol

Abstract Abstract 4850 Introduction: Nearly 100,000 Americans are affected by sickle cell disease (SCD), making it one of the most prevalent genetic disorders in the United States. Individuals with SCD exhibit significant morbidity and mortality related to chronic hemolysis, vasculopathy, and vascular occlusion by red cell sickling. Currently, red cell transfusions are a primary therapy for some of the acute and chronic complications of SCD, including prevention and treatment of stroke. The benefits of transfusion therapy are well known; however, transfusional iron overload is an inevitable consequence. Excess iron in the circulation leads to the formation of reactive oxygen species which ultimately causes end-organ damage. It is well established that adult SCD patients with significant iron overload have a higher mortality. As a result, exchange transfusion protocols are utilized to try to decrease overall iron overload. In our center, a modified manual exchange (MME) protocol is used which involves therapeutic phlebotomy of approximately 5–7.5ml/kg followed by the infusion of 15–20ml/kg packed red blood cells. MME is performed in the outpatient setting every 4–6 weeks with a goal hemoglobin S of less than 30%. Objective: The primary objective of our study was to describe the benefits of a MME protocol compared with a simple transfusion protocol in patients experiencing both. The effects of MME versus simple tranfusion on systemic iron overload were evaluated using serum ferritin levels, net transfusion volume, and need for iron chelation therapy. Study Design/Methods: A retrospective chart review was performed on patients with SCD (type SS) less than 18 years of age who were on chronic transfusions and transitioned from a simple to a MME protocol. All patients included were on chronic transfusions for primary/secondary stroke prevention. Exclusion criteria included all patients on automated exchange transfusion protocols and those patients who started iron chelation therapy after January 1, 2008. Demographic as well as clinical and laboratory data were collected on each patient. A simple transfusion was defined as 20ml/kg packed red blood cells transfused every 4–6 weeks. The MME protocol was defined as above. Iron overload was assessed using indicators including net volume of blood transfused, serum ferritin, and the need for iron chelation during both time periods, and differences were calculated. The Wilcoxon signed rank test was used for the change in amount of blood transfused. Slopes of ferritin levels over time were estimated for each transfusion protocol separately using mixed model methods. The need for chelation therapy was tabulated for each patient. Results: A total of six patients were included in the study, 4 boys and 2 girls. Ages ranged from 6–14 years. Four patients had been on chronic transfusions for more than 2 years prior to the start of our study. The mean net volume transfused during simple transfusion and MME was 400ml and 290ml, respectively (p=0.03). The slope of ferritin rise was 0.18 (CI: 0.11, 0.84) for MME and 1.37 (CI: 0.56, 2.17) for simple transfusion. One patient was taken off chelation therapy completely after transitioning to MME and another patient was maintained on low-dose chelation while on MME. Conclusions: MME appears to reduce the amount of blood transfused, slow the rise of ferritin, and potentially reduce the need for additional medication. MME may provide a safe and cost effective approach for delaying or preventing iron overload in patients with sickle cell disease who require long term transfusion therapy. Disclosures: No relevant conflicts of interest to declare.

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Role of Magnetic Ressonance Imaging – T2* in Hereditary Hemochromatosis.

Blood ◽

10.1182/blood.v120.21.2096.2096 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2096-2096

Author(s):

Reijane Alves de Assis ◽

Fernando Uliana Kay ◽

Paulo Vidal Campregher ◽

Gilberto Szarf ◽

Fabiana Mendes Conti ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Conflicts Of Interest ◽

Hereditary Hemochromatosis ◽

Transferrin Saturation ◽

Laboratory Data ◽

Surrogate Marker ◽

Control Group ◽

Double Mutation ◽

H63d Mutation

Abstract Abstract 2096 Introduction: Hereditary hemochromatosis (HH) is an autossomic recessive disorder characterized by increased iron absorption. Magnetic resonance imaging – T2* (MRI-T2*) has become a reliable and robust methodology to directly assess the iron burden, with better results in transfusional hemosiderosis compared to indirect methods, such as serum ferritin and transferrin saturation (TS). However, little is known about its role in HH. Objectives: Describe the demographic profile of HH type 1 patients as to the type of the HFE mutation and correlate laboratory parameters to MRI-T2*results. Methods: We collected data from patients with a positive HFE gene mutation who performed abdominal and/or cardiac MRI-T2* in our institution from 2004 to 2011. Images retrieved from the digital archive were analyzed by two blinded independent radiologists using the Thalassemia-Tools software (Cardiovascular Imaging Solutions, London, UK). Laboratory data available within 6 months before or after the MRI study were analyzed using the t-Student test, Exact Fisher's test analysis and multivariate analyses. Results: We analyzed 81 patients, 76 (93%) males and 5 (6.2%) females, with a median age of 48 years (21–80). Liver, pancreatic and splenic MRI-T2*values and LIC calculation were performed in 80 patients, and cardiac T2* assessment in 57 patients. The inter-observer T2* variation coefficient was 5%. Serum ferritin was abnormal in 70 patients (90.9%), while TS was abnormal in 34% of the tests. In our study sample, the H63D mutation was present in 70 patients (86.4%): 11 (13.6%) were homozygous, 59 (72.8%) heterozygous and 7 (8.6%) double heterozygous for C282Y/H63D. Only three patients (3.7%) were homozygous and 6 (7.4%) were heterozygous only for the C282Y mutation. The S65C mutation was detected in heterozygous state in 2 (2.5%) of cases. Two out 57 cases had a positive T2* result and were classified as light cardiac overload (T2*:18.98 e 19.14 ms). Both had the H63D mutation (1 homozygous and 1 heterozygous). Thirty seven out of 80 patients (46.3%) had liver overload in abdominal MRI (T2*: 3.8–11.4ms), being 33 (41.3%) light overload and four (5%) moderate overload (T2*:1.8–3.8ms). We found that 77.8% of patients with liver overload were C282Y carriers, of which 57.2% had double mutation and 40.3% had H63D mutation in hetero or homozigosity. Pancreatic overload was found in 20 patients (25.1%), while 30 patients (37.5%) had splenic overload. There was a slight correlation (r: 0.365) between liver T2* and splenic T2* (p=0.001). The presence of C282Y and H63D mutations was statistically associated with a higher frequency of abnormal liver T2* (p=0.017 and p=0.042, respectively). The H63D mutation was associated with iron accumulation in the liver (p=0,037) and homozygous carriers showed higher levels of liver overload (p=0,038). Conclusion: In our study, serum ferritin was a better surrogate marker for iron overload than ST. In addition, up to 40.3% of patients with H63D mutation had evidence of hepatic iron overload by MRI. These findings differ from the currente literature. The higher RMI positivity might be due to a higher sensitivity to detect lower levels of organic iron. Despite the lack of a control group and laboratory tests or MRI in all the cases studied, our results suggest that RMI-T2* is a promising methodology to guide the therapeutic management of HH patients. The clinical impact of this finding must be investigated in further studies. Disclosures: No relevant conflicts of interest to declare.

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