Disparities in Criteria for Initiating Chelation Therapy for Iron Overload in Patients with Myelodysplastic Syndromes (MDS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2535-2535 ◽  
Author(s):  
John M. Bennett ◽  
Alan F. List ◽  
Keyword(s):  
Serum Ferritin ◽  
Chelation Therapy ◽  
Transferrin Saturation ◽  
Clinical Signs ◽  
Iron Chelation ◽  
International Prognostic Scoring System ◽  
Quantitative Ct ◽  
Liver Iron ◽  
Number Of Patients ◽  
Sole Criterion

Abstract In the majority of MDS cases, isolated anemia is the only clinical evidence of impaired hematopoiesis at the time of MDS diagnosis. It is estimated that >40% of MDS patients require regular red blood cell transfusions during some stage of their disease. Findings from The MDS Foundation’s 2004–2005 Practices & Treatment Survey indicate that a substantial proportion of MDS patients in all International Prognostic Scoring System (IPSS) risk groups are transfusion-dependent: Low, 30%; Intermediate-1, 50%; Intermediate-2, 70%; High, 90% (median values). Seventy (38 US and 22 international) of the MDS Foundation’s102 Centers of Excellence responded to the survey as of July 1, 2005. Survey responses revealed that an average of 30% of transfusion-dependent patients receive parenteral iron chelation therapy (median, 20%; range: 3–100%) and that the criteria for initiating chelation therapy are not uniform. The number of transfusions was reported as a determining criterion by 46% of respondents, with a mean number of 35 transfusions (median, 30; range: 4–100). 15% of respondents indicated at the number of transfusions was the sole criterion used. Serum ferritin levels were reported as a determining criterion by 57% of respondents, with the following cutoff values: Ferritin concentrations for initiating chelation therapy *% respondents using this cutoff as criterion >1000 ng/mL 41%* >1500 ng/mL 11% >2000 ng/mL 37% Other (>3000, unspecified) 9% 32% of respondents indicated that serum ferritin was the sole criterion used. (Irrespective of chelation therapy, 92% indicated that they monitored ferritin levels in transfusion-dependent patients.) Other criteria used to determine start of chelation therapy included age/life expectancy, MDS subtype, clinical signs of hemochromatosis, quantitative CT liver iron estimation, liver function, transferrin saturation >50%, BMT, anticipated chronic transfusion need, and logistical issues and insurance coverage. A combination of criteria was reported to be used by 38% of respondents. The majority of respondents (90%) reported that they would increase the number of patients on chelation therapy if an oral agent were available. Although the decision for initiating chelation therapy in transfusion-dependent anemic MDS patients is individualized because of the heterogeneous patient population, this data analysis suggests a need for the standardization of select criteria (e.g., number of transfusions, serum ferritin).

scholarly journals Imaging of Body Iron Stores in Transfusion-Dependent Patients By Liver Dual- Energy CT

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2677-2677
Author(s):  
Hironori Kobayashi ◽  
Norihiko Yoshimura ◽  
Takashi Ushiki ◽  
Yasuhiko Shibasaki ◽  
Masato Moriyama ◽  
...  
Keyword(s):  
Blood Cell ◽  
Serum Ferritin ◽  
Red Blood Cell ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Iron Deposition ◽  
Liver Iron ◽  
Body Iron ◽  
Iron Stores ◽  
Red Blood Cell Transfusions

Abstract [Background] Chronic red blood cell transfusions, leading to iron overload, cause hepatic, cardiac, and endocrine dysfunction. It is very important to monitor body iron stores and to start optimal iron chelation therapy. Serum ferritin, which is widely used as a surrogate marker of body iron stores, elevate under inflammation or liver injury. Therefore, reliable techniques to evaluate body iron stores are needed. The liver iron concentration (LIC) is thought to be an indicator of total body iron stores and measurement of the T2* value by MRI has been a standard noninvasive technique to evaluate LIC. It should be worthwhile using CT, which is lower cost and widely applied in clinical setting. Dual-energy CT (DECT) is a technique to obtain additional information regarding tissue composition compared with what single-energy CT can provide. This technique is based on the fact that substances show different densities by two different energies. However, the role of DECT in monitoring LIC remains to be clarified. We examined whether a DECT could be a new technique for the measurement of LIC. [Patients and Methods] Eight transfusion-dependent patients underwent DECT. Patient 1 was a 54-year-old male with MDS (RCMD-RS). He received 66 U red blood cell transfusions in our hospital, and depended on transfusion in another hospital, but the total doses were not available. Patient 2 was a 37-year-old male with AML in 2nd relapse. His total red blood cell transfusions were 54 U. Patient 3 was a 66-year-old female with AML with MRC in 1st CR. She received 37 U red blood cell transfusions in our hospital, and depended on transfusion in another hospital, but total doses were not available. Patient 4 was a 47-year-old female who had received renal transplantation for chronic renal failure. She received 12 U red blood cell transfusions in our hospital, and had a long history of transfusion dependence in another hospital, but total doses were not available. Patient 5 was a 57-year-old male with MDS (RCMD). His total red blood cell transfusions were 148 U, and he received iron chelation therapy. Patient 6 was a 65-year-old male with AML with MRC. His total red blood cell transfusions were 82 U, and he received iron chelation therapy. Patient 7 was a 47-year-old male with AML in 3rd CR. He received 28 U red blood cell transfusions in our hospital, and depended on transfusion in another hospital, but total doses were not available. Patient 8 was a 52-year-old female with AA. Her total blood cell transfusions were 92 U. [Results] All patients were examined for serum ferritin and patients 1, 3, 4, 6, 7, and 8 also underwent liver MRI. Serum ferritin levels of patients 1, 3, 4, 6, 7, and 8 were 961, 2168, 7875, 795, 1921, and 5104 ng/ml, respectively. These patients showed hypointensity on MRI T2*-weighted images, and also showed liver iron deposition by DECT. Serum ferritin of patient 5 was 4042 ng/ml, and he showed liver iron deposition by DECT. Serum ferritin of patient 2 was 6113 ng/ml, and he did not show liver iron deposition by DECT. [Conclusion] Our results suggest that liver DECT could visualize liver iron deposition of transfusion-dependent patients and could be a new technique for the measurement of LIC instead of MRI. Disclosures No relevant conflicts of interest to declare.

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.

Deferasirox Safety Profile in Patients with Transfusion-Dependent Anaemias:Results From the Interim Analysis of a Hellenic Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3183-3183
Author(s):  
Vassilis Ladis ◽  
Marouso Drossou ◽  
Dimitria Vini ◽  
Ersi Voskaridou ◽  
Miranda Athanasiou-Metaxa ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Safety Profile ◽  
Interim Analysis ◽  
Pediatric Patients ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Iron Chelation Therapy ◽  
Liver Iron ◽  
Liver Iron Overload

Abstract Abstract 3183 Background: The introduction of iron chelation treatment has led to a significant improvement in morbidity and overall survival in patients with transfusion-dependent anemias. Deferasirox is a once-daily, oral iron chelator approved for the treatment of transfusional iron overload in both adult and pediatric patients. The efficacy and safety of deferasirox in a variety of transfusion-dependent anemias has been established in numerous Phase II/III clinical trials. Since most patients with transfusion-dependent anemias require lifelong iron chelation therapy, there is a need to assess the long-term safety of deferasirox in both adult and pediatric patients. Aim: To assess the safety profile of deferasirox in patients with transfusional iron overload in a real-world clinical setting. To further investigate the safety profile of deferasirox in patients with congenital erythrocyte disorders and transfusional iron overload, with ferritin levels <4000 ng/ml and without severe cardiac siderosis. Methods: Between July 2009 and September 2010, 85 patients with transfusion-induced iron overload treated with deferasirox as per the approved product labeling were enrolled in the study. These data represent the 24-week planned interim analysis of a 12-month observational study on deferasirox safety profile in the treatment of pediatric and adult patients with transfusion-dependent anemias who were newly-treated with deferasirox. Safety was evaluated through the monitoring and recording of all adverse events and serious adverse events, as well as routine laboratory testing, including hematology, blood chemistry and hepatic function assessments. Results: The population had a median age of 37.6 years (range: 5.3–61.4) and a female to male ratio of 1.3. Beta-thalassemia (67.1%) was the most common transfusion-dependent anemia, followed by thalassemia intermedia requiring periodic transfusions (20.0%) and sickle cell anemia (12.9%). Mean baseline ferritin levels were 1502.1±870.5 (pediatric group: 1480.2±522.8 and adult group: 1503.6±891.4), while 53 out of the 85 patients (62.4%) had serum ferritin level above 1000 ng/ml. Mean baseline liver T2* value was 10.4±9.7 ms; 44.4% of patients demonstrated minimal liver iron deposition (MRI T2* > 6.3 ms), 51.4% had mild to moderate liver iron overload (T2* ≤ 6.3 ms), and 4.2% had severe liver iron overload (T2*<1.4 ms). 54 (63.5%) of patients analysed had been pre-treated with iron chelators and 31 (36.5%) were chelation-naïve. The initial average daily dose of deferasirox was 25.9±4.8 mg/kg, and 70.6% of patients had no dose modification during the 24-week follow-up period. A statistical significant decrease in median serum ferritin levels was observed by Week 24 (mean absolute change from baseline:-214.5 ng/mL; p=0.009) [Figure 1]. No statistically significant changes were observed in creatitine levels, creatinine clearance and transaminases by Week 24 [Figure 1]. 37 ADRs were reported by 17 patients (20%) over the 24-week period. Among the most frequently observed ADRs (>5%) were epigastralgia reported by 7.1% of patients (6/85) and loose stools/diarrhoea by 5.9% of patients (5/85). The majority of ADRs reported (nevents=25; 67.6%) were graded as mild in severity, while 21.6% (nevents=8) were graded as moderate and 10.8% (nevents=4) as severe. Most ADRs (nevents=31; 83.8%) resulted in full recovery by Week 24. The overall incidence of SADRs was as low as 1.2% (in particular one patient experienced severe epigastralgia and upper extremity pain which resulted in her withdrawal from the study after four months of treatment). The all-cause discontinuation rate was 9.4% (8/85), while only two patients (2.4%) discontinued the study therapy due to ADR; 1 patient due to increased transaminase levels and 1 patient due to the aforementioned SADR. Conclusions: These data highlight the safety profile of deferasirox in both adult and pediatric patients; the regular monitoring of serum ferritin levels as well as other iron-overload parameters and transfusion requirements play a major role in determining and optimizing the outcome of iron chelation therapy. Disclosures: Ladis: Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Drossou:Novartis Pharmaceuticals: Investigator participating in a trial sponsored by Novartis. Vini:Novartis Pharmaceuticals: Investigator participating in a trial sponsored by Novartis. Athanasiou-Metaxa:Novartis Hellas S.A.C.I.: Research Funding. Oikonomou:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Vlachaki:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Tigka:Novartis Hellas S.A.C.I.: Employment. Tzavelas:Novartis Hellas S.A.C.I.: Employment. Liakopoulou:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Adamopoulos:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Kattamis:Novartis Hellas S.A.C.I.: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Transfusional Iron Overload in Sickle Cell Patients:Outcomes of Chelation Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4177-4177
Author(s):  
Daniel Adamkiewicz ◽  
Abhishek A. Mangaonkar ◽  
James Son ◽  
Hongyan Xu ◽  
Leigh Wells ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Serum Ferritin ◽  
Chelation Therapy ◽  
Conflicts Of Interest ◽  
Chelating Agent ◽  
Regulatory Peptides ◽  
Beta Thalassemia ◽  
Glycoprotein Hormone ◽  
Liver Iron ◽  
Number Of Patients

Abstract Iron (Fe) overload is not rare among sickle cell disease (SCD) patients. It results from either chronic transfusions for primary or secondary stroke prevention, or more commonly sporadic, mostly unnecessary transfusions and are associated with significant morbidity, secondary to hepatic, cardiac and renal Fe deposition. Previous studies at our Center showed that 12% of the adult SCD population had Fe overload, and vast majority of these (80%) resulted from episodic transfusions (Son et al, 2013). Subsequent studies showed that the Fe regulatory peptide, hepcidin was appropriately upregulated in SCD subjects with Fe overload, and the plasma levels of the glycoprotein hormone erythroferrone (ERFE) was not as high as that found in patients with transfusion dependent beta thalassemia (TDT) due to the absence of significant ineffective erythropoiesis in SCD (Thawer et al, 2017, Mangaonkar et al, Brit. J. Haematol, 2020). We report on the utilization and outcomes in Fe overloaded SCD patients who were prescribed the oral chelating agent deferasirox. 22 patients were prescribed deferasirox; median age was 38, 12 female 10 male. 21 had Hb SS, and 1 had s-b 0 thalassemia. Deferasirox dose ranged from 720-2500 mg/day (12 to 28 mg/Kg/day). Nonadherence was ascertained by patients' own admission. Figures 1-3 show the pre and post ferritin levels in subjects who were on deferasirox, and in controls; patients who took deferasirox had a more pronounced decrease in their ferritin (p=.004 vs p=.74). Although hepatic MRI for liver iron content (LIC) was not available on all patients, in those who underwent MRI there was a correlation between LIC and serum ferritin obtained at close temporal proximity (Fig. 4). Most common side effects of deferasirox were gastrointestinal (abdominal pain, nausea, vomiting, diarrhea), which were seen less commonly with the newer oral formulation (Jadenu). Several conclusions can be drawn from our observation on relatively small number of patients: 1) Deferasirox is effective in decreasing Fe overload as shown by serum ferritin levels 2) Second generation of oral deferasirox is better tolerated, and therefore is associated with improved adherence, 3) Documentation of a decrease in LIC with chelation will be important for the reversal of Fe induced organ damage, and 4) Parallel studies of the levels of Fe regulatory peptides hepcidin and erythroferrone (ERFE) will clarify the effect of chelation therapy on biomarkers of Fe metabolism. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Iron Chelation Therapy with Deferasirox (Exjade®, ICL670) or Deferoxamine Is Effective in Reducing Iron Overload in Patients with Advanced Fibrosis and Cirrhosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2696-2696 ◽  
Author(s):  
E. Angelucci ◽  
B. Turlin ◽  
D. Canatan ◽  
A. Mangiagli ◽  
V. De Sanctis ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Iron Chelator ◽  
Advanced Fibrosis ◽  
Liver Iron ◽  
Once Daily ◽  
Tissue Iron

Abstract Introduction: Although the direct measurement of iron from a liver biopsy is the reference standard method to determine liver iron concentration (LIC), results are highly unreliable in patients with advanced fibrosis and cirrhosis. As a result, chelation therapy is difficult to monitor in this patient population where effective chelation therapy may be critical. It is therefore important to assess parameters additional to LIC in order to accurately assess body iron in these patients. Aim: To analyze the efficacy of chelation with deferoxamine (DFO) and the investigational once-daily, oral iron chelator deferasirox (DSX) in patients with advanced fibrosis participating in DSX registration studies. Methods: A subgroup of patients from DSX Studies 0107 and 0108 were selected based on a staging result according to the Ischak scale of 5 (incomplete cirrhosis) or 6 (probable or definite cirrhosis), measured either at baseline or after 1 year of chelation therapy. The subgroup of patients with β-thalassemia participating in Study 0107 received DSX (n=26) or DFO (n=30). In Study 0108, the subgroup of patients with β-thalassemia unable to be treated with DFO (n=12) or patients with anemias other than β-thalassemia (n=7) were treated with DSX only. In both studies, patients received chelation therapy according to baseline LIC. Results: In Study 0107, treatment with DSX or DFO led to a decrease in semi-quantitative tissue iron score (TIS) and LIC, which were paralleled by changes in serum ferritin. TIS, LIC and serum ferritin in a subgroup of patients with advanced fibrosis and cirrhosis treated with DSX and DFO (Study 0107) TIS LIC, mg Fe/g dw Serum ferritin, ng/mL DSX (n=26) DFO (n=30) DSX (n=26) DFO (n=30) DSX (n=26) DFO (n=30) *Median (min, max) Baseline* 35.5 (4,39) 34 (10,52) 25.5 (2.4,45.9) 19.5 (3.9,55.1) 4195 (321,12646) 4144 (653,15283) Change from baseline* −2 (−43,20) −2 (−25,16) −9.4 (−42.2,13.1) −3.1 (−24.5,12.4) −1269 (−7082,3609) −951 (−8259,1264 Similarly, in Study 0108, DSX treatment produced a decrease in all 3 parameters in patients with β-thalassemia or rare anemia. TIS, LIC and serum ferritin in a subgroup of β-thalassemia and rare anemia patients with advanced fibrosis and cirrhosis (Study 0108) TIS LIC, mg Fe/g dw Serum ferritin, ng/mL β-thalassemia (n=12) Rare anemia (n=7) β-thalassemia (n=12) Rare anemia (n=7) -thalassemia β (n=12) Rare anemia (n=7) *Median (min, max) Baseline* 35 (4,48) 41 (32,49) 29.4 (3.8,37.4) 26.3 (15,51.3) 4813 (440,11698) 2385 (1553,9099) Change from baseline* 2 (−19,27) −3 (−20,1) −1.6 (−18,9.9) −10 (−13.9,8.8) −986 (−4453,2131) −1322 (−2609,1901) Conclusions: Chelation therapy with DSX or DFO is effective in reducing iron overload in patients with advanced fibrosis and cirrhosis. The trends observed in TIS and LIC were closely mirrored by changes in serum ferritin, highlighting the validity of this method for monitoring chelation therapy in this population.

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.  

scholarly journals The Oral Ferroportin Inhibitor VIT-2763 Improves Erythropoiesis without Interfering with Iron Chelation Therapy in a Mouse Model of β-Thalassemia

2021 ◽  
Vol 22 (2) ◽  
pp. 873
Author(s):  
Naja Nyffenegger ◽  
Anna Flace ◽  
Cédric Doucerain ◽  
Franz Dürrenberger ◽  
Vania Manolova
Keyword(s):  
Mouse Model ◽  
Iron Overload ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Iron Chelation ◽  
Iron Chelator ◽  
Liver Iron Concentration ◽  
Ineffective Erythropoiesis ◽  
Liver Iron

In β-thalassemia, ineffective erythropoiesis leads to anemia and systemic iron overload. The management of iron overload by chelation therapy is a standard of care. However, iron chelation does not improve the ineffective erythropoiesis. We recently showed that the oral ferroportin inhibitor VIT-2763 ameliorates anemia and erythropoiesis in the Hbbth3/+ mouse model of β-thalassemia. In this study, we investigated whether concurrent use of the iron chelator deferasirox (DFX) and the ferroportin inhibitor VIT-2763 causes any pharmacodynamic interactions in the Hbbth3/+ mouse model of β-thalassemia. Mice were treated with VIT-2763 or DFX alone or with the combination of both drugs once daily for three weeks. VIT-2763 alone or in combination with DFX improved anemia and erythropoiesis. VIT-2763 alone decreased serum iron and transferrin saturation (TSAT) but was not able to reduce the liver iron concentration. While DFX alone had no effect on TSAT and erythropoiesis, it significantly reduced the liver iron concentration alone and in the presence of VIT-2763. Our results clearly show that VIT-2763 does not interfere with the iron chelation efficacy of DFX. Furthermore, VIT-2763 retains its beneficial effects on improving ineffective erythropoiesis when combined with DFX in the Hbbth3/+ mouse model. In conclusion, co-administration of the oral ferroportin inhibitor VIT-2763 and the iron chelator DFX is feasible and might offer an opportunity to improve both ineffective erythropoiesis and iron overload in β-thalassemia.

Adults with Severe Sickle Cell Anaemia and Iron Overload Have a High Incidence of Osteopenia and Osteoporosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1684-1684 ◽  
Author(s):  
Farrukh T. Shah ◽  
Ratna Chatterjee ◽  
Matilda Owusu-Asante ◽  
John B. Porter
Keyword(s):  
Vitamin D ◽  
Parathyroid Hormone ◽  
Iron Overload ◽  
Sickle Cell ◽  
Serum Ferritin ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Dry Weight ◽  
Iron Chelation Therapy ◽  
Liver Iron

Abstract Background: There is very little published data on osteopenia or osteoporosis in patients with sickle cell disorders (SCD) with only occasional case reports that have noted osteopenia in individual SCD patients. It is known that individuals of Afro-Caribbean decent have on average higher BMD scores then age matched Caucasian controls. The causes for bone demineralisation in SCD may be multifactoral. Putative contributory mechanisms include; marrow expansion, bone infarction, delayed puberty from anaemia, low vitamin D, iron overload from blood transfusion, iron chelation therapy, and hypogonadism. Methods and Findings: 17 consecutive SCD patients who had previously been transfused or were currently on a transfusion programme underwent DEXA scanning using a Hologic QDR 4500A. Hypogonadism was assessed for in all patients as well as Vitamin D3, parathyroid hormone (PTH), serum ferritin and haemoglobin levels. 11 of the 17 patients had undergone MRI to assess liver iron. Of 10 females, 6 had osteopenia (Z >−1.0, n= 4) or osteoporosis ( Z >−2.0, n=2) in the spine compared to age matched caucasian controls (p=0.008). In contrast, only 4 had significant hip demineralisation; 2 patients had osteoporosis and 2 were osteopenic. All patients with hip osteopenia also had spinal osteopenia. Liver iron concentration was significantly higher in the osteopenic (9.4mg/g dry wt) than the non-osteopenic group (1.95mg/g dry wt) (p=0.01). Mean serum oestradiol levels were no different between the osteopenic (235 pmol/L) and the non osteopenic patients (287 pmol/L). No differences in ferritin, units of blood transfused, parathyroid hormone or vitamin D level were seen. Only 2 females had received iron chelation with deferrioxamine one of whom was osteopenic. Among 7 males, 2 had spinal osteopenia (mean Z score −1.4) (p= 0.05) but none had osteopenia of the hip. The liver iron was higher in the osteopenic males (mean 12.9 mg/g dry weight) than in the non osteopenic group (mean 2.32 mg/g/dry weight) (p <0.05). Serum ferritin was also higher in osteopenic patients (mean 3729ug/l) than the non-osteopenic group (mean 745ug/l) (p=0.008). No significant difference between the serum testosterone and units of blood transfused, parathyroid hormone or vitamin D level was seen. Only one of the patients had received iron chelation and he was not osteopenic. Among all patients together, there was no evidence on MRI of increased cardiac iron but there was evidence of hypogonadothrophic hypogonadism is 1 female, while the remainder were not hypogonadal. There was evidence of disturbance of the Calcium- Vitamin D- PTH axis in 2 patients (1 male,1 female) both of whom were osteopenic. Conclusion: Osteopenia is a surprisingly common in adult patients with sickle disorders; 47% of patients had osteopenia. Iron loading may be a relevant contributing factor as liver iron was significantly greater in osteopenic than non-osteopenic patients. Hypogonadism and iron chelation therapy can be reasonably excluded as contributory facors in most patients but should be monitored in all patients on transfusion programmes.

Iron Chelation Therapy with Deferasirox (Exjade®, ICL670) or Deferoxamine Results in Reduced Hepatocellular Inflammation and Improved Liver Function in Patients with Transfusion-Dependent Anemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 823-823 ◽  
Author(s):  
P. Brissot ◽  
B. Turlin ◽  
G.L. Forni ◽  
G. Alimena ◽  
G. Quarta ◽  
...  
Keyword(s):  
Liver Function ◽  
Liver Biopsy ◽  
Serum Ferritin ◽  
Liver Tissue ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Iron Chelation Therapy ◽  
Hepatocellular Injury ◽  
Liver Iron

Abstract Transfusional hemosiderosis is often associated with hepatic siderosis or infection with hepatotropic viruses, resulting in hepatocellular injury and progression to chronic liver disease. Liver biopsy is the method of choice for directly assessing damage; scales have been developed to measure necroinflammatory activity (grading) and tissue fibrosis (staging). Iron chelation therapy is historically known to decrease morbidity associated with hepatosiderosis. Aim: To assess 1 year’s chelation therapy with the novel once-daily oral chelator, deferasirox (DSX), or the current standard deferoxamine (DFO), on pathology of liver tissue in chronically transfused patients. Methods: Liver biopsy was performed at baseline and after 1 year in patients participating in DSX Studies 0107 (n=454) and 0108 (n=101). All patients, except 25 in 0107 and 3 in 0108, had liver tissue evaluated by pathology. In 0107, patients with β-thalassemia were randomized to DSX (5, 10, 20 or 30 mg/kg/day; n=224) or DFO (&lt;25, 25–35, 35–50 and ≥ 50 mg/kg; n=230) according to baseline liver iron concentration (LIC). In 0108, patients with β-thalassemia unable to be treated with DFO (n=61) and patients with rare anemias (MDS, DBA and others) (n=40) were enrolled and received DSX only. Grading and staging were determined from biopsy by the Ishak method; LIC was measured in parallel by atomic absorption spectrometry. Results: DSX and DFO dose-dependently affected grading, which mirrored effects on LIC and serum ferritin. DSX 5 and 10 mg/kg increased these parameters, while stabilization and decreases were seen with the highest doses of both chelators, regardless of hepatitis C status. In 0107, a decrease in mean ±SD necroinflammatory score was noted with DSX 30 mg/kg (2.5 ±1.6 to 1.7 ±1.3, n=95) and DFO ≥ 50 mg/kg 5 days/week (2.1 ±1.6 to 1.4 ±1.3, n=95). Similar results were observed in 0108 for β-thalassemia (2.4 ±1.7 to 1.7 ±1.6, n=58) and rare anemia patients (1.8 ±1.5 to 1.5 ±1.3, n=40). This decrease was accompanied by dose-dependent modification of available liver enzyme levels in 0107 (Table); with a similar trend in 0108. No obvious modification of staging was observed after 1 year of treatment, suggesting that longer time periods are needed to observe potential reversal of fibrosis. Change in liver enzymes (ALT; U/L) by treatment (Study 0107) DSX, mg/kg DFO, mg/kg 5 10 20 30 &lt;25 25–35 35–50 ≥ 50 n=8 n=43 n=64 n=107 n=6 n=28 n=88 n=107 Mean ± SD 34.9 21.9 3.6 −2.8 −13.9 −3.7 −2.8 −12.4 ±35.1 ±25.2 ±28.7 ±79.3 ±29.7 ±17.6 ±20.7 ±38.6 Median (range) 36.8 10.0 0.5 −8.0 −10.8 −1.8 −0.8 −9.5 (−19.0, 101.5) (−7.5, 105.0) (−111.5, 91.0) (−143.0, 711.0) (−61.0, 27.0) (−55.5, 32.0) (−93.5, 70.5) (−171.0, 193.3) Conclusions: Although the data show considerable variability, results suggest that chelation therapy with DSX or DFO is associated with reduced hepatocellular inflammation and improved liver function. These modifications appear to be linked with effects on LIC and serum ferritin levels.

scholarly journals MRI evaluation of hepatic and cardiac iron burden in pediatric thalassemia major patients: spectrum of findings by T2*

2019 ◽  
Vol 50 (1) ◽  
Author(s):  
Samar M. Shehata ◽  
Mohamed I. Amin ◽  
El Sayed H. Zidan
Keyword(s):  
Chelation Therapy ◽  
Statistical Significance ◽  
Iron Chelation ◽  
Good Method ◽  
Thalassemia Major ◽  
Local Magnetic Field ◽  
Cardiac Complications ◽  
Liver Iron ◽  
Cross Sectional ◽  
Signal Decay

Abstract Background Iron deposition distorts the local magnetic field exerting T2* signal decay. Biopsy, serum ferritin, echocardiography are not reliable to adjust iron chelation therapy. Quantified MRI signal decay can replace biopsy to diagnose iron burden, guide treatment, and follow up. The objective of this study is to evaluate the role of T2* in quantification of the liver and heart iron burden in thalassemia major patients. This cross-sectional study included 44 thalassemia patients who were referred to MRI unit, underwent T2* MRI. Results Twenty-one male (47.7%) and 23 female (52.3%) were included (age range 6–15 years, mean age 10.9 ± 2.9 years). Patients with excess hepatic iron show the following: 11/40 (27.5%) mild, (13/40) 32.5% moderate, and (14/40) 35% severe liver iron overload. High statistical significance regarding association between LIC and liver T2* (p = 0.000) encountered. Cardiac T2* values showed no relationship with age (p = 0.6). Conclusion T2* is a good method to quantify, monitor hepatic and myocardial iron burden, guiding chelation therapy and prevent iron-induced cardiac complications.

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