Safety of Deferasirox (Exjade®) in Patients with Transfusion-Dependent Anemias and Iron Overload Who Achieve Serum Ferritin Levels <1000 Ng/Ml during Long-Term Treatment

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5423-5423 ◽  
Author(s):  
John B Porter ◽  
Antonio Piga ◽  
Alan Cohen ◽  
John M Ford ◽  
Janet Bodner ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Abdominal Pain ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Safety Profile ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Liver Iron ◽  
Long Term Treatment ◽  
Baseline Characteristics

Abstract Background: Maintaining serum ferritin (SF) levels below 1000 ng/mL has been reported to predict longer survival and a reduced risk of complications (eg heart failure) in patients with thalassemia major. Experience with deferoxamine (Desferal®, DFO) has indicated that the toxicity of DFO may increase as SF levels decrease. A target SF value in the deferasirox clinical trials was not specified per protocol, but was determined by the individual investigators. This analysis evaluates the safety of deferasirox (Exjade®) in a cohort of adult and pediatric patients with transfusion-dependent anemias and iron overload from two large clinical trials (107 and 108) who were chelated to SF levels &lt;1000 ng/mL. Methods: In core studies 107 and 108, frequently-transfused patients with chronic anemias ≥2 years old received deferasirox 5–30 mg/kg/day for 1 year. Eligible patients were then enrolled in 4-year extension trials, where initial dosing was based on the end of core study liver iron concentration; dose adjustments were based on SF levels. Patients eligible for this analysis had an initial SF ≥1000 ng/mL. Patients who achieved a SF level &lt;1000 ng/mL on ≥2 consecutive visits, any time after starting deferasirox, were identified. The number of days when SF was &lt;1000 ng/mL was calculated for each patient. AEs in these patients were calculated for the entire period on deferasirox, and for the period following the first SF measurement of &lt;1000 ng/mL, irrespective of future SF levels. Results: 474 patients were included in this analysis: underlying anemias were β-thalassemia (n=379), myelodysplastic syndromes (n=43), Diamond-Blackfan anemia (n=30) and other anemias (n=22). Overall, 13.5% patients achieved SF&lt;1000 ng/mL in year 1, 18.6% in year 2, 25.7% in year 3, 32.5% in year 4 and 36.7% by the time of this analysis. Therefore, overall 174 patients (36.7%) reached a SF level &lt;1000 ng/mL on ≥2 consecutive visits, while in 300 patients SF levels remained ≥1000 ng/mL. The median period for a SF value &lt;1000 ng/mL was 149 days [range 18–1726]. Patient demographics, baseline characteristics and safety profiles of the two groups throughout deferasirox treatment are shown in Table 1. At month 54, median SF levels in the &lt;1000 and &gt;1000 ng/mL groups were 872 and 2118 ng/mL, respectively. The incidence of drug-related AEs (gastrointestinal, renal and liver) did not appear to increase during the periods after SF levels first decreased below 1000 ng/mL (data not shown). Table 1. Demographics, baseline characteristics and safety profile of patients who achieved SF levels &lt;1000 ng/mL and patients who did not Patients who achieved SF &lt;1000 ng/mL Patients who did not achieve SF &lt;1000 ng/mL *Investigator-assessed; SCr, serum creatinine; ULN, upper limit of normal; ALT, alanine aminotransferase n 174 300 Male:female 85:89 145:155 Mean age ± SD, years 23.8 ± 16.7 23.5 ± 18.2 &lt;16, n (%) 65 (37.4) 123 (41.0) ≥16, n (%) 109 (62.6) 177 (59.0) Enrolled from study 107:108 120:54 175:125 Median exposure to deferasirox, months 56.3 45.2 Mean actual deferasirox dose, mg/kg/day 20.3 22.9 Median baseline SF, ng/mL 1791 2883 Drug-related AEs* (≥5% in either group), n (%) Nausea 26 (14.9) 38 (12.7) Diarrhea 17 (9.8) 42 (14.0) Vomiting 14 (8.0) 25 (8.3) Abdominal pain 12 (6.9) 32 (10.7) Upper abdominal pain 6 (3.4) 20 (6.7) Rash 9 (5.2) 16 (5.3) Audiological abnormalities 7 (4.0) 4 (1.3) Ophthalmological abnormalities 4 (2.3) 5 (1.7) Two consecutive SCr increases &gt;33% above baseline and above ULN 26 (14.9) 36 (12.0) Increase in ALT &gt;10×ULN on at least 1 visit 12 (6.9) 20 (6.7) Baseline levels elevated 6 (3.4) 16 (5.3) Conclusions: Over the core and extension phases of these clinical studies, the safety profile of patients achieving SF levels &lt;1000 ng/mL was similar to that observed in patients who did not achieve SF levels &lt;1000 ng/mL. There was also no apparent increase in AEs associated with a decrease in SF levels &lt;1000 ng/mL. In particular, no increase in the proportion of patients with creatinine increases &gt;33% above baseline and ULN or with ALTs &gt;10×ULN were observed in these patients. These findings suggest that ironoverloaded patients can be safely chelated with deferasirox to low SF levels.

scholarly journals MRI Evaluation of Liver and Cardiac Iron Overload Impact on Hematopoietic Stem Cell Transplantation with β-Thalassemia Major

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5738-5738
Author(s):  
Libai Chen ◽  
Yuelin He ◽  
Jianyun Wen ◽  
Wenjing Yang ◽  
Xuan Liu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Iron Overload ◽  
Hematopoietic Stem Cell ◽  
Serum Ferritin ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Liver Iron ◽  
Hematopoietic Stem ◽  
Cardiac Iron

OBJECTIVE: To assess the effects of liver and cardiac iron overload detected by magnetic resonance imaging (MRI) T2* on hematopoietic stem cell transplantation in children with β-thalassemia major. METHODS:Summary of 380 cases of β-thalassemia major patients more than 5 years old in Nanfang hospital, southern medical university from 2012 to 2019.Iron concentrations in the liver and heart were calculated based on MRI T2* test results of liver and heart. Age, serum ferritin, left ventricular ejection fraction (LVEF), and liver function were compared to evaluate the effect of iron overload on organ function in patients with β-thalassemia major before transplantation.168 patients underwent allogeneic hematopoietic stem cell transplantation, 48 were HLA-mismatched transplantation, and 120 were HLA-identical allogeneic hematopoietic stem cell transplantation.To analysis the influence between implantation rate, hematopoietic reconstruction time, mortality, and common complications after transplantation such as graft-versus-host disease, hepatic venous obstruction, infection, immune hemolysis, and pancytopenia and liver and cardiac iron overload detected by magnetic resonance imaging (MRI) T2*. RESULTS:Myocardial iron overload occurred in 73 cases (19.2%), including 29 cases of cardiac T2*15~20 ms (mild), 23 cases of 10~14 ms (moderate), and 21 cases of <10 ms (severe).There were 305 cases (80.2%) with liver iron overload, including 98 cases with 2.7~6.3 ms (mild), 166 cases with 1.4~2.7 ms (moderate), and 41 cases with <1.4 ms (severe).LVEF decreased in 5 cases (1.6%).Liver iron was positively correlated with serum ferritin (r=0.523, P=0.001), cardiac iron concentration was positively correlated with serum ferritin (r=0.33, P=0.1), age was positively correlated with cardiac iron concentration (r=0.4, P=0.14), and age was negatively correlated with left ventricular ejection fraction (r=-0.36, P=0.001).After transplantation, liver iron concentration was positively correlated with hemoglobin implantation time (r=0.49, P=0.043), heart iron concentration was positively correlated with mortality (r=0.39, P=0.012), serum ferritin was negatively correlated with implantation rate (r=-0.26, P=0.012), and serum ferritin was positively correlated with infection incidence correlation (r=0.441, P=0.034).There were no statistically significant differences in liver, heart MRI T2*, liver iron concentration and heart iron concentration between the two groups before and after transplantation. CONCLUSION:Magnetic resonance imaging (T2*) is an effective and non-invasive method to detect the iron overload in the heart and liver caused by blood transfusion in β-thalassemia patients. Iron overload can have adverse effects on hematopoietic stem cell transplantation,and effective iron removal before transplantation can improve the success rate of transplantation.Quantitative assessment of iron overload in the liver and heart by MRI can be used as a necessary examination before transplantation. Disclosures No relevant conflicts of interest to declare.

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

Transfusion History, Iron Chelation Practices and Status of Iron Overload across Various Transfusion-Dependent Anemias: Data from the Large- Scale, Prospective, 1-Year EPIC Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3880-3880
Author(s):  
Maria Domenica Cappellini ◽  
Norbert Gattermann ◽  
Vip Viprakasit ◽  
Jong Wook Lee ◽  
John B Porter ◽  
...  
Keyword(s):  
Iron Overload ◽  
Large Scale ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Dry Weight ◽  
Thalassemia Major ◽  
Liver Iron ◽  
Baseline Characteristics ◽  
Transfusion History

Abstract Background: The prospective, 1-yr multicenter EPIC trial evaluated the efficacy and safety of once-daily oral deferasirox (Exjade®) in more than 1700 patients (pts) with transfusion-dependent anemias. Data were collected from each patient at enrollment, providing an insight into transfusion history, body iron burden, and the nature and success of previous chelation therapy in a large group of pts with iron overload previously treated with chelation therapy. Methods: Enrolled pts were aged ≥2 yrs, had transfusion-dependent anemia and serum ferritin (SF) levels of ≥1000 ng/mL, or <1000 ng/mL with a history of multiple transfusions (>20 transfusions or >100 mL/kg of RBCs) and MRI-assessed liver iron concentration (LIC) >2 mg Fe/g dry weight (dw). Baseline assessments included transfusion history, previous chelation therapy, SF levels and LIC (if carried out) in the previous yr. Results: 1744 pts (901 M, 843 F) were enrolled. Underlying anemias were: thalassemia major (TM; n=937), thalassemia intermedia (TI; n=84), myelodysplastic syndromes (MDS; n=341), aplastic anemia (AA; n=116), sickle cell disease (SCD; n=80), rare anemias (red cell aplasia and anemias mostly hemolytic in nature; n=43), Diamond-Blackfan anemia (DBA; n=14), and various other conditions associated with anemias requiring transfusion (n=129). Baseline characteristics for key underlying anemias are presented in Table 1. Median SF levels were >2500 ng/mL and mean LIC in the previous yr was >7 mg Fe/g dw in all groups (except DBA for SF levels). MDS pts had received the most transfusions in the previous yr, although they had also spent a smaller proportion of their lifetime, and less total time, receiving transfusions than any other cohort. Together with AA pts, the MDS cohort also contained the highest proportion of pts who were chelation-naïve (68% and 48%). SCD pts were the least-transfused group in terms of amount of blood given, but had been receiving transfusions for more than 13 yrs. As expected, TM pts had spent the greatest proportion of their lifetime on transfusions and received the greatest volume of blood per kg in the previous yr. The group labeled by investigators as TI were relatively heavily transfused for this patient population. Table 1. Baseline characteristics for key underlying anemias All (n=1744) TM (n=937) TI (n=84) MDS (n=341) AA (n=116) SCD (n=80) Rare (n=43) DBA (n=14) *Mean ± SD; **Median Age, yrs* 30.6±23.3 18.4±10.8 19.2±14.4 67.9±11.4 33.3±17.1 23.9±13.2 39.5±22.7 17.3±13.2 Transfusions in last yr* 17.8±12.5 17.5±8.8 13.5±7.1 24.3±17.7 12.5±13.0 10.7±8.2 21.0±18.7 19.0±18.7 Total transfused in last yr, mL/kg* 159±136 190±139 155±87 116±123 116±179 84±57 153±142 185±148 Total yrs on transfusions* 12.3±10.4 16.8±10.4 10.2±7.8 3.6±4.6 6.1±5.7 13.0±9.6 10.9±11.8 13.3±10.0 % of lifetime on transfusions* 62.9±39.4 89.8±15.2 61.2±28.8 5.7±8.4 27.1±29.3 59.5±30.1 44.3±41.5 87.5±23.2 LIC in last yr, mg Fe/g dw* 10.7±9.0 9.5±7.8 9.7±5.5 14.4±8.5 12.0±4.3 11.8±8.4 – 8.8±4.2 SF, ng/mL** 3135 3157 3493 2730 3254 3163 3161 2289 Prior chelation, % DFO 58.6 66.7 78.6 40.2 26.7 62.5 55.8 71.4 Deferiprone 1.6 1.3 – 4.1 – 1.3 2.3 – DFO/deferiprone 16.7 25.0 4.8 7.0 5.2 12.5 11.6 14.3 Other 0.3 0.4 – 0.3 – – – – None 23.0 7.0 16.7 48.4 68.1 23.8 30.2 14.3 Conclusions: Data from this study population show that, although most pts with thalassemia, SCD, DBA and rare anemias had received previous chelation therapy, LIC and SF levels were above levels associated with significant negative outcomes (>7 mg Fe/g dw and >2500 ng/mL, respectively), which suggests that previous chelation practices were sub-optimal. Many pts with MDS and AA were chelation-naïve despite being heavily iron overloaded, highlighting that the risks of iron overload are still underestimated. These data highlight the need to carefully monitor iron levels in pts at risk of iron overload and initiate chelation therapy to avoid serious clinical sequelae.

Quantitative T2*MRI for Bone Marrow Iron Overload Assessment in Thalassemia Major and Intemedia Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4042-4042
Author(s):  
Antonella Meloni ◽  
Roberta Renni ◽  
Nicola Romano ◽  
Carla Cirotto ◽  
Francesco Gagliardotto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Conflicts Of Interest ◽  
Iron Concentration ◽  
Lumbar Vertebra ◽  
Thalassemia Major ◽  
Liver Iron ◽  
Transfusion Requirements ◽  
T2 Mri

Abstract Introduction. Multiecho T2* MRI is a well-established technique for cardiac and hepatic iron overload assessment, but there are limited data on its potential to quantify iron in other organs. The aims of this study were to describe for the first time the T2* values of the bone marrow in patients with thalassemia major (TM) and intermedia (TI) and to investigate the correlation between bone marrow T2* and iron deposition in myocardium and liver. Methods. 283 TM patients (32.25±8.28 years, 144 females) and 46 TI patients (38.30±8.73 years, 17 females) enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network underwent MRI. For the measurement of iron overload, multiecho T2* sequences were used. Bone marrow T2* values were obtained on a circular regions of interest (ROI) located in the visible body of the first or second lumbar vertebra. The left ventricle was segmented into a 16-segments standardized model and the T2* value on each segment was calculated as well as the global value. In the liver the T2* value was assessed in a single ROI defined in a homogeneous area of the parenchyma]and it was converted into liver iron concentration (LIC). Results. Bone marrow T2* values were significantly lower in TM than in TI patients (7.65±6.29 vs 13.22±6.01 ms; P<0.0001). Bone marrow T2* values were significantly lower in females than in males in both the diseases (Figure 1), but they increased with age in a significant manner only in TM (R=0.343, P<0.0001). In TM bone marrow T2* values were weakly associated with global heart T2* values (R=0.143; P=0.016) and negatively correlated with LIC values (R=-0.439; P<0.0001) and mean serum ferritin levels (R=-0.582; P<0.0001). In TI no association was present between bone marrow and global heart T2* value, but bone marrow T2* values were negatively correlated with LIC values (R=-0.273; P=0.046) and mean serum ferritin levels (R=-0.569; P<0.0001). One hundred and sixty-six TM patients (58.7%) were splenectomised and splenectomised TM patients showed significant higher bone marrow T2* values than non-splenectomised patients (9.78±6.78 ms vs 4.61±3.85 ms, P<0.0001). The difference remained significant also correcting for the age, significantly higher in splenectomised patients. Fourty TI patients (87.0%) were splenectomised and bone marrow T2* were comparable between splenectomised and non-splenectomised TI patients (13.46±6.26 ms vs 11.61±4.05 ms, P=0.493). Conclusions. In both TM and TI groups, males showed significantly higher T2* values. This difference may be due to the fact that the male sex is associated with severely low bone mass , which can influence the T2* values. Bone marrow T2* values were associated with heart T2* values only in TM, maybe because in TI cardiac iron overload was not common. In both TM and TI a positive correlation was found between hepatic and bone marrow siderosis. Splenectomised TM patients showed higher bone marrow T2* values, probably due to the fact that splenectomy is generally performed in patients with hypersplenism to reduce transfusion requirements. Conversely, bone marrow T2* values were comparable in splenectomised and non-splenectomised TI patients. In fact, the current indications for splenectomy in TI include growth retardation, leukopenia, thrombocytopenia, increased transfusion demand, symptomatic splenomegaly. Moreover the transfusion iron intake is significantly lower in TI. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Consequences and management of iron overload in sickle cell disease

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 447-456 ◽  
Author(s):  
John Porter ◽  
Maciej Garbowski
Keyword(s):  
Sickle Cell Disease ◽  
Blood Transfusion ◽  
Iron Overload ◽  
Sickle Cell ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Iron Loading ◽  
Cell Disease ◽  
Liver Iron Concentration ◽  
Liver Iron

Abstract The aims of this review are to highlight the mechanisms and consequences of iron distribution that are most relevant to transfused sickle cell disease (SCD) patients and to address the particular challenges in the monitoring and treatment of iron overload. In contrast to many inherited anemias, in SCD, iron overload does not occur without blood transfusion. The rate of iron loading in SCD depends on the blood transfusion regime: with simple hypertransfusion regimes, rates approximate to thalassemia major, but iron loading can be minimal with automated erythrocyte apheresis. The consequences of transfusional iron overload largely reflect the distribution of storage iron. In SCD, a lower proportion of transfused iron distributes extrahepatically and occurs later than in thalassemia major, so complications of iron overload to the heart and endocrine system are less common. We discuss the mechanisms by which these differences may be mediated. Treatment with iron chelation and monitoring of transfusional iron overload in SCD aim principally at controlling liver iron, thereby reducing the risk of cirrhosis and hepatocellular carcinoma. Monitoring of liver iron concentration pretreatment and in response to chelation can be estimated using serum ferritin, but noninvasive measurement of liver iron concentration using validated and widely available MRI techniques reduces the risk of under- or overtreatment. The optimal use of chelation regimes to achieve these goals is described.

Safety and Efficacy of Alternate Desferrioxamine and Deferiprone Compared to Desferrioxamine Alone in the Treatment of Iron Overload in Transfusion-Dependent Thalassemia Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3611-3611 ◽  
Author(s):  
Renzo Galanello ◽  
Antonios Kattamis ◽  
Antonio Piga ◽  
Fernando Tricta
Keyword(s):  
Adverse Events ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Iron Concentration ◽  
Comparable Efficacy ◽  
Liver Iron ◽  
Safety And Efficacy ◽  
Alternate Therapy ◽  
Significant Difference ◽  
Wet Weight

The safety and efficacy of alternating desferrioxamine and deferiprone for the treatment of iron overload in patients with transfusion-dependent anemias was studied in 60 thalassemia patients regularly treated with desferrioxamine. Patients were randomized to continue desferrioxamine alone (20–60 mg/kg/day, 5–7 days/week) or to alternate desferrioxamine (20–60 mg/kg/day, 2 days/week) with oral deferiprone (25 mg/kg tid, 5 days/week). Both treatment groups were similar for age (19.8 ± 6.1 years for desferrioxamine alone and 18.7 ± 4.8 years for alternate therapy) as was gender distribution and mean standard dose of desferrioxamine at the time of study initiation. Over the following 12 months, all patients were monitored weekly for adverse events and for their white blood cell count. Efficacy of the chelation was evaluated by measurement of the serum ferritin, liver iron concentration (magnetic susceptometry by SQUID), and by Non-Transferrin Bound Iron (NTBI). Compliance was comparable for both arms (96.1 ± 5.0% for alternate therapy vs 95.7 ± 5.7 % for desferrioxamine alone; p=0.7883). There was no significant difference in the proportion of patients with adverse events in the two therapy groups but the chelation regimens were associated with distinct adverse events. The alternate therapy was associated with transient gastrointestinal symptoms, such as vomiting in 5 patients (17%), abdominal pain in 3 patients (10%), or diarrhea in one patient (3%), or transient increase of serum ALT levels in one patient (3%), occurring mainly in the first weeks of therapy and were mild/moderate in severity. Daily infusions of desferrioxamine were associated with abscess at the site of infusion in one patient (3%), and allergic reactions in another patient (3%). Mean serum ALT levels were not significantly different between the two therapies. There were no episodes of agranulocytosis and only one patient, treated with desferrioxamine alone, experienced milder neutropenia. Both therapies resulted in similar decreases of serum ferritin (−349 ± 573 mg/L for the desferrioxamine arm; −248 ± 791 for the alternate arm; p=0.5802), and of liver iron concentrations (−239 ± 474 μg/g wet weight for the desferrioxamine arm; −65 ± 615 μg/g wet weight for the alternate therapy arm; p=0.2263) by the end of the treatment period. No significant changes in NTBI were observed between the two treatment arms (1.10 ± 7.19 μmol/L for the desferrioxamine arm; −0.03 ± 8.13 μmol/L for the alternate arm; p=0.5775). In conclusion, this 12 month study in transfusion-dependent thalassemia demonstrated that the alternating therapy with deferiprone and desferrioxamine is not associated with a significant increase in the incidence of adverse events and that it has comparable efficacy to desferrioxamine alone in controlling iron overload.

Safety and Efficacy of High Dose Intravenous Desferoxamine for Reduction of Iron Overload Due to Chronic Transfusion in Sickle Cell Patients.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1430-1430
Author(s):  
Ram Kalpatthi ◽  
Brittany Peters ◽  
David Holloman ◽  
Elizabeth Rackoffe ◽  
Deborah Disco ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Iron Overload ◽  
Sickle Cell ◽  
Serum Ferritin ◽  
Liver Tissue ◽  
Iron Concentration ◽  
P Value ◽  
High Dose ◽  
Liver Iron ◽  
Iron Storage

Abstract Background: Patients with sickle cell disease (SCD) receiving chronic blood transfusions are at risk of developing iron overload and organ toxicity. Chelation therapy with either subcutaneous (SQ) desferoxamine (DFO) or oral deferasirox is effective in preventing and reducing iron overload but poses significant challenges with patient compliance. Intravenous (IV) infusions of high dose DFO (HDD) have been utilized in non compliant patients with heavy iron overload in small case series. We review our experience of high dose IV DFO in a large cohort of SCD patients with significant iron overload who are non compliant with SQ DFO. Methods: The medical records of SCD patients who received HDD in our center between 1993 and 2004 were reviewed. All of them were on chronic transfusion, had significant iron overload defined by serum ferritin &gt; 1500 and/or liver iron concentration (LIC) more than 10 μg/g of liver tissue and were non-compliant with SQ DFO. All patients underwent annual ophthalmologic, hearing, pulmonary and cardiac evaluation. Demographic data, treatment details, serum ferritin levels, liver iron concentration (LIC), liver enzymes, renal function tests, audiogram and other relevant clinical data were collected. Results: There were 27 patients (19 males, 8 females), 19 patients were on transfusion for history of cerebrovascular accident, 5 for abnormal transcranial Doppler flow velocity, 2 for transient ischemic attack and one for recurrent pain crises. All continued to receive packed red blood cell transfusions aimed to keep HbS levels below 30 or 50% during this time. They were treated in-hospital with DFO 15 mg/kg/hr IV for 48 hrs every 2 weeks (20 patients), 3 weeks (4 patients) and 4 weeks (3 patients). The mean age at start of high dose regimen was 14.6 years (range 9–27 years). The mean duration of HDD treatment was 8.9 months (range 3–49 months). Fourteen patients had LIC determined by liver biopsy. Significant reductions in LIC were observed after HD (table I). This was more pronounced in patients who had higher LIC and received at least 6 months of HDD. Histological examination of liver biopsies revealed a decrease in the grade of liver iron storage. Four patients had portal triaditis initially which resolved after starting HDD therapy. Also there was significant improvement in liver enzymes (ALT, AST) after HDD. There was a trend in decreasing ferritin levels after HDD but this did not achieve statistical significance. All patients tolerated HDD without any major reactions. No audiologic or ophthalmologic toxicity or acute or chronic pulmonary complications were observed. Blood urea nitrogen remained normal in all patients after HDD but there was mild increase in serum creatinine. One patient had high serum creatinine (1.2 mg/dL) after two doses HDD. This patient had focal segmental glomeurosclerosis which was most probably the cause for the rise in creatinine. There was no significant increase in serum creatinine in our series when this patient was excluded. Conclusions: In our cohort of SCD patients we observed a significant decrease in liver iron burden with high dose IV DFO. Our patients tolerated the therapy well without any major toxicity. This regimen is safe and may be an option for poorly compliant patients with significant iron overload. In addition, combination of this regimen with oral iron chelators may be of benefit to patients with significant iron overload and organ dysfunction. Table 1: Laboratory characteristics of sickle cell patients before and after high dose IV DFO Parameter No. of Patients Mean (SD) prior to HDD Mean (SD)after HDD p Value* * Changes in mean levels analyzed using two-tailed Paired T Test with significant p value ≤ 0.05. SD – Standard deviation + See text Liver iron (μg/g of liver tissue ) 14 16864 (10903) 12681 (8298) 0.04 Liver iron min of 6 months of HDD (μg/g of liver tissue ) 8 18677 (8319) 9362 (4521) 0.01 Liver iron &gt;10 mg & minimum 6 months of HDD (μg/g of liver tissue) 7 21181 (7054) 10092 (4443) 0.01 Grade of liver iron storage 14 3.57 (0.9) 3.07 (1) 0.05 Serum Ferritin (ng/mL) 27 3842 (2619) 3238 (1780) 0.06 Serum AST (IU/L) 27 54.1 (27.2) 44.6 (17.6) 0.04 Serum ALT (IU/L) 27 39.2 (36) 27.5 (14.2) 0.01 Blood urea nitrogen (mg/dL) 27 8.9 (2.9) 9.5 (4.3) 0.20 Serum Creatinine (mg/dL)+ 26 0.50 (0.1) 0.55 (0.2) 0.07

Liver Transient Elastography (FibroScan) Correlates with Liver Iron Concentration and Reflects Liver Fibrosis In Patients with Sickle Cell Disease

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1646-1646 ◽  
Author(s):  
Ersi Voskaridou ◽  
Maria Schina ◽  
Eleni Plata ◽  
Dimitrios Christoulas ◽  
Maria Tsalkani ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Iron Overload ◽  
Hepatic Fibrosis ◽  
Sickle Cell ◽  
Serum Ferritin ◽  
Transient Elastography ◽  
Iron Concentration ◽  
Liver Stiffness ◽  
Cell Disease ◽  
Liver Iron

Abstract Abstract 1646 Liver transient elastography (FibroScan) is an interesting new technology that allows estimation of hepatic fibrosis through measurement of liver stiffness. The technique is based on changes in tissue elasticity induced by hepatic fibrosis and is considered as a noninvasive, reproducible and reliable method to assess hepatic fibrosis as well as to diagnose liver cirrhosis. Hepatic iron overload is a severe complication of chronic transfusion therapy in patients with hemoglobinopathies and plays an important role in the development of hepatic fibrosis and cirrhosis. Iron overload is present in several cases of sickle cell disease (SCD) including sickle cell anemia (HbS/HbS) and double heterozygous sickle-cell/beta-thalassemia (HbS/beta-thal). The aim of the study was to evaluate liver fibrosis by measuring the liver rigidity (Liver Stiffness Measurement, LSM, kPascals) using transient elastography (FibroScan, Echosens, Paris, France) in patients with SCD and explore possible correlations with clinical and laboratory characteristics of the patients, including iron overload. We studied 110 consecutive patients with SCD who are followed-up in the Thalassemia Center of Laikon General Hospital in Athens, Greece. Forty-four patients were males and 66 females; their median age was 44 years (range: 21–73 years). Twenty-two patients had HbS/HbS and 88 patients had HbS/beta-thal. On the day of Fibroscan, all patients had a thorough hematology and biochemical evaluation, including hemoglobin, reticulocyte counts, serum ferritin, liver biochemistry, bilirubin, lactate dehydrogenase (LDH) and serology for viral hepatitis. Liver iron concentration was evaluated by magnetic resonance imaging (MRI) T2* in all patients. The median LSM of all patients was 6.1 kPascals (range: 3.4–48.8 kPascals) with no differences between HbS/HbS (6.1 kPascals, 3.5–17.3 kPascals) and HbS/beta-thal (6.1 kPascals, 3.4–48.8 kPascals) patients (p=0.835). LSM values strongly correlated with liver MRI T2* values (r=0.337, p<0.001), serum ferritin (r=0.328, p=0.001), number of transfusions (r=0.332, p=0.001), bilirubin (r=0.299, p=0.003), LDH (r=0.287, p=0.004), Hb (r=-0.275, p=0.006) and reticulocyte counts (r=0.244, p=0.015). LSM values showed also strong positive correlations with biochemical indicators of liver function: gamma-glutamyl transpeptidase (r=0.522, p<0.0001), glutamic oxaloacetic transaminase (r=0.484, p<0.0001), glutamic pyruvic transaminase (r=0.422, p<0.0001), alkaline phosphatase (r=0.334, p=0.001), gamma-globulin (r=0.296, p=0.005) and weak correlation with PT-International Normalized Ratio (r=0.184, p=0.094). The above correlations were similar in patients with HbS/HbS and in patients with HbS/beta-thal. However, in HbS/HbS patients the correlation between LSM and liver T2* values was very strong (r=0.770, p=0.001). Patients who were regularly transfused had higher values of LSM (median: 6.7 kPascals, range: 2.3–48.8 kPascals) compared with patients who were sporadically transfused or were not transfused (4.4 kPascals, 3.6–17.5 kPascals, p=0.003). Patients who were under iron chelation therapy had lower values of LSM (6.3 kPascals, 3.4–15 kPascals) compared with those who did not receive iron chelators (13.9 kPascals, 8.5–17.3 kPascals, p=0.013). We found no correlations between the presence of HBV or HCV positivity and the levels of LSM. In conclusion, FibroScan may constitute a reliable and easy to apply noninvasive method to assess liver fibrosis in patients with SCD; the strong correlations between LSM values with MRI T2* values and serum ferritin supports this observation. Furthermore, FibroScan seems also to reflect the presence of chronic hepatic injury in these patients. If our results are confirmed by other studies, FibroScan may be regularly used in the management of SCD patients in whom liver is the main target organ of the disease. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document