scholarly journals Renal function in β-thalassemia major patients treated with two different iron-chelation regimes

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Osama Tanous ◽  
Yossi Azulay ◽  
Raphael Halevy ◽  
Tal Dujovny ◽  
Neta Swartz ◽  
...  
Keyword(s):  
Renal Function ◽  
Serum Ferritin ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Tubular Damage ◽  
Chronic Anemia ◽  
High Prevalence ◽  
Moderate Negative Correlation ◽  
Renal Tubular

Abstract Background Renal injury in transfusion dependent β thalassemia patients (TDT) has been attributed to iron overload, chronic anemia and iron-chelation therapy (ICT) toxicity. We studied renal function in TDT patients treated with two different ICT regimes. Patients and methods We studied 36 TDT patients: 26 received deferasirox (DFX) and 10 were treated with deferoxamine (DFO) +/− deferiprone (DFP). Results Increased uNAG was found in 30% of the DFX group vs. 10% of the DFO+/−DFP group, the mean uNAG level in the DFX group was significantly higher than in the DFO+/−DFP group, (P < 0.05). A moderate negative correlation was found between uNAG levels and mean serum ferritin for the prior 10 years (P = 0.03), more pronounced for the DFO+/−DFP group. Twenty nine patients had had their renal function evaluated 10 years earlier; eGFR significantly declined in patients switched to DFX (P = 0.0093) but not in patients who continued DFO+/−DFP. Conclusions A high prevalence of renal tubular damage was observed in our TDT patients, particularly those treated with DFX; uNAG was negatively associated with mean 10-year serum ferritin, suggesting ICT’s involvement in tubular injury. A significant decline in eGFR compared to a decade earlier was observed only in patients currently treated with DFX. Strict follow-up of renal function in TDT patients is warranted.

scholarly journals Renal Function in β-Thalassemia Major Patients Treated with Two Different Iron-Chelation Regimes.

2021 ◽  
Author(s):  
Osama Tanous ◽  
Yossi Azulay ◽  
Raphael Halevy ◽  
Tal Dujovny ◽  
Neta Swartz ◽  
...  
Keyword(s):  
Renal Function ◽  
Serum Ferritin ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Tubular Damage ◽  
Chronic Anemia ◽  
High Prevalence ◽  
Moderate Negative Correlation ◽  
Renal Tubular

Abstract Background: Renal injury in Transfusion dependent β thalassemia patients (TDT) has been attributed to iron overload, chronic anemia and iron-chelation therapy (ICT) toxicity. We studied renal function in TDT patients treated with two different ICT regimes. Patients and methods: We studied 36 TDT patients: 26 received deferasirox (DFX) and 10 were treated with deferoxamine (DFO) +/- deferiprone (DFP).Results: Increased uNAG was found in 30% of the DFX group vs. 10% of the DFO+/-DFP group, the mean uNAG level in the DFX group was significantly higher than in the DFO+/-DFP group, (P < 0.05). A moderate negative correlation was found between uNAG levels and mean serum ferritin for the prior 10 years (P = 0.03), more pronounced for the DFO+/-DFP group. 29 patients had had their renal function evaluated 10 years earlier; eGFR significantly declined in patients switched to DFX (P = 0.0093) but not in patients who continued DFO+/-DFP. Conclusions: A high prevalence of renal tubular damage was observed in our TDT patients, particularly those treated with DFX; uNAG was negatively associated with mean 10-year serum ferritin, suggesting ICT's involvement in tubular injury. A significant decline in eGFR compared to a decade earlier was observed only in patients currently treated with DFX. Strict follow-up of renal function in TDT patients is warranted.

scholarly journals Renal Function in Children with β-Thalassemia Major Treated with Iron Chelating Agent

2020 ◽  
Vol 12 (3) ◽  
pp. 214-9
Author(s):  
Olga Rasiyanti Siregar ◽  
Rosmayanti Syafriani Siregar ◽  
Bidasari Lubis
Keyword(s):  
Renal Function ◽  
Serum Ferritin ◽  
Iron Chelation ◽  
Chelating Agent ◽  
Thalassemia Major ◽  
Term Therapy ◽  
Excess Iron ◽  
Function Impairment ◽  
Abnormal Hemoglobin ◽  
Long Term Therapy

BACKGROUND: Thalassemia is a disorder of inherited blood and inticated by the abnormal hemoglobin. Transfusion and iron chelation are part of thalassemia management. Iron chelating agent reduces complications due to the excess iron as a result of repeated transfusions, hence, increasing the survival rate. However, prolonged intake of iron chelating agent may increase the risk of renal function impairment. To date, evaluation of renal function in children with β-thalassemia in Medan has never been reported. The objective of this study was to evaluate renal function and other factors in children with β-thalassemia.METHODS: Fourty-five children with β-thalassemia was recruited in this study. Renal function, represented by estimated glomerular filtration rate (eGFR)and serum ferritin levels were examined. The measurement of eGFR was using Schwartz method.RESULTS: Decreased eGFR observed in some the children (2 patients) with β-thalassemia major treated with iron chelating agent. None of the factors examined had association with serum creatinine level. Children's age and duration of iron chelating agent intake had positive correlation with their eGFR (r=0.506, p<0.001 and r=0.518, p<0.001, respectively). However, serum ferritin levels was not a predictor for renal function impairment.CONCLUSION: Most of children with β-thalassemia major treated with iron chelating agent have normal renal function, nevertheless, decreased renal function is observed in few children. Highlighted, renal function examinations should be performed routinely as iron chelating agent administration is a long-term therapy in children with β-thalassemia major.KEYWORDS: β-thalassemia major, renal function, serum ferritin levels, iron chelating agent

scholarly journals Renal Function in Transfusion-Dependent β-Thalassemia Patients: A Decade of Follow-up and Comparison between Chelation Regimes

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 949-949
Author(s):  
Osama Tanous ◽  
Yossi Azulay ◽  
Tal Dujovny ◽  
Netta Schwarz ◽  
Raul Colodner ◽  
...  
Keyword(s):  
Renal Function ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Fractional Excretion ◽  
Tubular Injury ◽  
Normal Range ◽  
Glomerular Function ◽  
Group A ◽  
Moderate Negative Correlation

Abstract Introduction: Glomerular and tubular dysfunctions in β-thalassemia major (β-TM) patients (pts) have been attributed to iron overload, chronic anemia and iron-chelation therapy (ICT) toxicity. We studied glomerular and tubular function in β-TM pts treated with 2 different ICT regimes. Patients and methods: We studied 36 β-TM pts (18 females and 18 males). Mean age was 20.92 ± 9.7 (range 5-45) years. Pts were treated at Emek Medical Center under standard protocols for regular blood transfusions and ICT: 26 pts received deferasirox (DFX) for a mean period of 59 months; this was the first ICT for 6 of them; 10 pts were treated with deferoxamine (DFO) or DFO + deferiprone (DFP) (4 and 6 pts, respectively; hereafter DFO+/-DFP group). Clinical data were collected from pts' files. We evaluated serum urea, creatinine (sCr) and electrolytes, and estimated glomerular filtration rate (eGFR) according to the Schwartz formula for pediatric pts and the Chronic Kidney Disease Epidemiology Collaboration formula for adults; fractional excretion of sodium (feNa), fractional excretion of potassium (feK), calcium-to-creatinine ratio (Ca/Cr), uric acid excretion (UAE), and tubular phosphorus reabsorption were calculated. Urinary N-acetyl-β-D-glucosaminidase (uNAG) was also measured as a marker of tubular injury. Results: No significant differences were found in age, gender or mean hemoglobin (Hb) level between the groups. Levels of sCr, K, Na and feNa were in the normal range for all pts, as was eGFR (mean 104.6 ± 19 mL/min per 1.73 m2); in the DFX group, eGFR was slightly lower than in the DFO+/-DFP group (100.9 ± 17.09 vs. 114.0 ± 22.31 mL/min per 1.73 m2; p= 0.0676). Hypercalciuria (Ca/Cr &gt; 0.25) was found in 28% of pts, increased feK (&gt;15%) in 33%, high UAE (&gt;0.56 mg/dL) in 64%, and high levels of TmP /GFR (&gt;5mg/dL) in 25%. There were no differences in these parameters between the DFX and DFO+/-DFP groups. Increased uNAG was found in 9 pts (25%)-30% in the DFX group vs. 10% in the DFO+/-DFP group, and was significantly higher in the DFX group (mean 10.4 ± 6.1 vs. 5.3 ± 2.7 IU/L, p= 0.012). A moderate negative correlation was found between uNAG levels and mean serum ferritin for the prior 10 years (r= -0.35, p= 0.03). In the DFO+/-DFP group, a strong positive correlation was found between uNAG levels and the amount of iron transfused over the prior 10 years (r= 0.7647, p= 0.021); this correlation was not found in DFX pts. A moderate negative correlation was found for urinary Ca/Cr ratio with 10-year mean serum ferritin level and with 10-year amount of transfused iron (r= -0.35, p= 0.34; r= -0.4, p= 0.014, respectively). These correlations were stronger in the DFO+/-DFP group. A positive correlation was found between urinary Ca/Cr ratio and Hb levels, strongest in the DFO+/-DFP group than the DFX group (r= 0.41, p= 0.001, r= 0.7, p= 0.018), respectively. Renal function had been previously evaluated in 20 pts treated with DFO (Smolkin et al, 2008) and those results were compared with the current values. The eGFR significantly declined in pts switched to DFX (mean eGFR in first study 113.5 ± 26 vs. 100.1 ± 17 mL/min per 1.73 m2, p= 0.0093) but not in pts who continued DFO+/-DFP. A significant increase in sCr compared to the previous study was found in pts who switched to DFX (mean 0.51 ± 0.9 vs. 0.67 ± 0.1 mg/dl, p= 0.0008), but not in pts who continued treatment with DFO+/-DFP. The same observation was made regarding urine Ca/Cr (mean 0.08 ± 0.11 vs. 0.176 ± 0.12, p= 0.001). Conclusion: Ahigh prevalence of renal tubular abnormalities was observed in our pediatric and adult β-TM pts, particularly in the DFX group. The marker of tubular injury-uNAG-was negatively associated with mean 10-year serum ferritin, suggesting ICT's involvement in tubular injury. Moreover, uNAG was associated with transfusional iron burden in the DFO+/-DFP group, but not in the DFX group, proposing a mechanism other than iron overload for the pathogenesis of tubular injury in DFX-treated pts. Finally, glomerular function remained within the normal range in all pts; however a significant decline in glomerular function compared to a decade earlier was observed only in the pts currently treated with DFX. Strict follow-up of renal function in β-TM pts, especially children, is warranted. Disclosures No relevant conflicts of interest to declare.

scholarly journals Long-Term Outcome of Deferasirox Chelation in Patients with Thalassemia Major

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3620-3620
Author(s):  
Sule Unal ◽  
Neslihan Kalkan ◽  
Mualla Cetin ◽  
Fatma Gumruk
Keyword(s):  
Serum Creatinine ◽  
Sample Size ◽  
Serum Ferritin ◽  
Thalassemia Major ◽  
Iron Chelator ◽  
The Other ◽  
Single Center ◽  
Other Hand

Abstract Introduction: Iron overload is one of themajor complicationsof transfusion treatment in patient with thalassemia major. Deferasirox is a once-daily orally active iron chelator and long-term efficacy and safety data are being published. Herein we report the long-term follow-up data of thalassemia major patients in a single center. Methods: Of the 67 patients with thalassemia major who were under follow-up in a single center, 42 who were on deferasirox chelation for at least three years were included in the study. Patients' initial serum ferritin, ALT, creatinine, cardiac T2* and hepatic T2* values were recorded at the time of deferasirox initiation and at last visit. Deferasirox was not initiated as an iron chelator to none of the patients with a cardiac T2* value below 8 ms. All of the patients had creatinine clearance above 40 ml/minute and had serum creatinine levels within age appropriate normals at deferasirox initiation. None of the patients received any other chelations during the follow-up period. Results: Mean age of the patients were 16±9.4 years (2-33.4 years) at initiation of deferasirox and 22 (52%) were females. Eighteen (43%) of the patients were splenectomized. Median follow-up time of deferasirox chelation was 7.9 years (3-10). The median deferasirox doses at initiation of chelation and at last visit were 20.5 mg/kg/day and 30.7 mg/kg/day (7-40), respectively. Serum ferritin levels decreased significantly with deferasirox chelation (median 1969 ng/ml (516-5404) vs 1113 ng/ml (339-4003), p<0,001). We did not find statistically significant difference between the inital cardiac T2* values and the values at the last visit (median 25 .3 ms((8.7-42) vs 32 ms (6.6-42), p=0.607), despite a dramatic increase. On the other hand, hepatic T2* values did not significantly change compared to initial values, as well (median 3.7 ms (1-13.6) vs 3.3 (1-16), p=0.865). However of the patients who had cardiac T2* value between 10-20 ms, 67% was found to have T2* value above 20 ms by the end of the follow-up duration. On the other hand 53% of the patients with hepatic T2* value below 3.5 ms, had T2* values above 3.5 ms by the end of the follow-up, indicating improvement in iron stores. None of the patients exibited an adverse event that requires cessation of the drug totally, but patients exibited transient hypertransaminasemia that required transient cessation and/or dose decrement. The changes in serum ALT and serum creatinine levels at the initiation and at last visit were not significant. Conclusions: This is a a study that includes patients with a relatively long duration of follow-up. Although the cardiac T2* values improved by the end of the follow-up, this change was not found statistically significant. This can be attributed to the sample size and in a larger sample size, the change might be found significant. Additionally, the patients included in the study were composed of not only naive patients to chelation but also of the patients who were imcomplant to previous chelation and who were highly iron loaded before initiation of deferasirox. Disclosures No relevant conflicts of interest to declare.

scholarly journals Intrarenal activation of adaptive immune effectors is associated with tubular damage and impaired renal function in lupus nephritis

2018 ◽  
Vol 77 (12) ◽  
pp. 1782-1789 ◽  
Author(s):  
Cristina Pamfil ◽  
Zuzanna Makowska ◽  
Aurélie De Groof ◽  
Gaëlle Tilman ◽  
Sepideh Babaei ◽  
...  
Keyword(s):  
Renal Function ◽  
Lupus Nephritis ◽  
Cell Activation ◽  
Immune Cell ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Tubular Cell ◽  
Chronic Renal Impairment ◽  
Adaptive Immune ◽  
Renal Tubular

ObjectivesChronic renal impairment remains a feared complication of lupus nephritis (LN). The present work aimed at identifying mechanisms and markers of disease severity in renal tissue samples from patients with LN.MethodsWe performed high-throughput transcriptomic studies (Illumina HumanHT-12 v4 Expression BeadChip) on archived kidney biopsies from 32 patients with LN and eight controls (pretransplant donors). Histological staging (glomerular and tubular scores) and immunohistochemistry experiments were performed on the same and on a replication set of 37 LN kidney biopsy samples.ResultsA group of LN samples was identified by unsupervised clustering studies based on their gene expression features, that is, the overexpression of transcripts involved in antigen presentation, T and B cell activation. These samples were characterised by a significantly lower estimated glomerular filtration rate (eGFR) at the time of biopsy (T0) compared with the other systemic lupus erythematosus samples. Yet, apparent disease duration at T0, double-stranded DNA antibody titres at T0 and other relevant characteristics (serum C3, proteinuria, histological scores, numbers of previous flares) were not different between groups.Immunohistochemistry studies confirmed the association between interstitial infiltration by adaptive immune effectors and decreased renal function in the same and in a replication group of LN kidney biopsies. This was associated with transcriptomic, histological and immunohistochemical evidence of renal tubular cell involvement.ConclusionInterstitial infiltration of LN kidney biopsies by adaptive immune effectors is associated with impaired renal tubular cell function and decreased eGFR. These results open new perspectives in evaluating and treating patients with LN, focusing on intrarenal mechanisms of immune cell activation.

Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 884-893 ◽  
Author(s):  
M. Domenica Cappellini ◽  
Mohamed Bejaoui ◽  
Leyla Agaoglu ◽  
Duran Canatan ◽  
Marcello Capra ◽  
...  
Keyword(s):  
Adverse Events ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Dry Weight ◽  
Thalassemia Major ◽  
Efficacy And Safety ◽  
Liver Iron ◽  
Median Serum

Abstract Patients with β-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with β-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.

scholarly journals LONGITUDINAL STUDY ON LIVER FUNCTIONS IN PATIENTS WITH THALASSEMIA MAJOR BEFORE AND AFTER DEFERASIROX (DFX) THERAPY

2014 ◽  
Vol 6 (1) ◽  
pp. e2014025 ◽  
Author(s):  
Ashraf Tawfik Soliman ◽  
Mohamed Yassin ◽  
Fawzia AlYafei ◽  
Lolwa Al-Naimi ◽  
Noora Almarri ◽  
...  
Keyword(s):  
Liver Function ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Negative Correlation ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Growth Potential ◽  
Igf I ◽  
Liver Functions

With regular blood transfusion and iron chelation therapy, most patients with thalassemia major (BTM) now survive beyond the third decade of life . Liver disease is becoming an important cause of morbidity and mortality in these patients. Chronic hepatitis and/or severe iron overload are important causes of liver pathology. Iron chelation with desferrioxamine (Desferal)  reduces excessive body iron, but its efficacy is limited by poor compliance and dose related toxicity. The recent use of Deferasirox (Exjade- DFX ), an  oral single dose therapy has improved the compliance to chelation therapy.Aims: To study the long-term liver functions in BMT patients, seronegative for liver infections before versus after DFX therapy in relation to ferritin level and IGF-I level.Methods: Liver function tests including: serum bilirubin, alanine transferase (ALT), aspartate transferase (AST) , albumin, insulin-like growth factor – I (IGF-I) and serum ferritin concentrations were followed every 6 months in 40 patients with BTM, with hepatitis negative screening (checked every year), for at  least   five years of DFO therapy and 4-5 years of DFX therapy .Results: DFX  therapy (20 mg/kg/day)  significantly decreased serum ferritin level in patients with BTM, this was associated with significant decrease in serum ALT, AST, ALP and increase in IGF-I concentrations. Albumin concentrations did not change after DFX treatment. ALT and AST levels were correlated significantly with serum  ferritin concentrations ( r = 0.45 and 0.33 respectively , p < 0.05) . IGF-I concentrations were correlated significantly with serum ALT (r= 0.26, p = 0.05) but not with AST, ALP, bilirubin or albumin levels.The negative correlation between serum ferritin concentrations and ALT suggests that impairment of hepatic function negatively affects IGF-I synthesis in these patients due to iron toxicity, even in the absence of hepatitis.Conclusions: Some impairment of liver function can occur in hepatitis negative BMT patients with iron overload. The use of DFX was associated with mild but significant reduction of ALT, AST and ALP and increase in IGF-I levels. The negative correlation between IGF-I and ALT concentrations suggest that preventing hepatic dysfunction may improve the growth potential in these patients.

Neither Serum Ferritin Nor Number of Red Blood Cell Transfusions Affect Overall Survival in Refractory Anemia with Ringed Sideroblasts.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2454-2454 ◽  
Author(s):  
Cheng E. Chee ◽  
David P. Steensma ◽  
Curtis A. Hanson ◽  
Ayalew Tefferi
Keyword(s):  
Overall Survival ◽  
Blood Cell ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Red Blood Cell ◽  
Iron Chelation ◽  
Refractory Anemia ◽  
International Prognostic Scoring System ◽  
Ringed Sideroblasts

Abstract Background: Most experts agree that iron chelation therapy is unlikely to benefit myelodysplastic syndrome (MDS) patients with a bone marrow (BM) blast percentage of ≥ 5% because of the associated short life expectancy. In contrast, using a serum ferritin of 1,000 ng/mL as a surrogate for iron overload, a recent study suggested a negative impact of iron overload on overall survival in MDS patients with &lt; 5% BM blasts including those with refractory anemia with ringed sideroblasts (RARS) (Malcovati et al. JCO2005:23:7594). In the current retrospective study, we examined the validity of this observation in a large group of RARS patients seen at a single institution. Methods: The diagnosis of RARS was based on the French-American-British cooperative group criteria. Serum ferritin levels obtained both at diagnosis and during follow-up as well as total number of packed red blood cells transfused were recorded. Standard statistical methods were used for survival and other analyses. Results: A total of 126 RARS patients (median age 73 years, range 44-90; 67% males) were seen at our institution over the last several years. At diagnosis, median (range) values were 9.4 g/dL (5.7-13.4) for hemoglobin (Hgb), 2.8 × 109/L (0.3-13.7) for absolute neutrophil count (ANC) and 214× 109/L (22-819) for platelet count; 38% of the patients had received red blood cell (RBC) transfusions at the time of initial diagnosis. International Prognostic Scoring System (IPSS) risk distributions in evaluable patients were 66% for low, 28% for intermediate-1 and 6% for intermediate-2 risk. Median follow-up was 36 months and during this time 83 patients (66%) had died and leukemic transformation was documented antemortem in 8 patients (6%). As expected, IPSS was highly predictive of survival outcome (p&lt;0.0001). In addition, history of RBC transfusions at diagnosis (p=0.001) but not the total number of RBC transfusions received during the entire disease course (p=0.17) carried an independent prognostic value for inferior survival. There were no significant correlations between overall survival and serum ferritin level at either diagnosis (median 567 ng/mL, range 16-3,475; p=0.24) or the maximum value during follow-up (median 1,108 ng/mL; range 238-43,500; p=0.72). Similarly, Kaplan-Meier plots of 77 evaluable patients stratified by serum ferritin levels of &lt; or ≥1000 ng/mL at diagnosis or 107 evaluable patients stratified by maximal serum ferritin levels of &lt; 1000, 1000-5000, or &gt; 5000 ng/mL during follow-up revealed similar curves (Figure). Conclusions: The current study suggests no significant association between transfusional hemosiderosis and survival even in good risk patients with MDS. The study also undermines the utility of serum ferritin as a surrogate for assessing the value of therapeutic iron chelation. Figure Figure Figure Figure

The Palatability and Tolerability of Deferasirox (Exjade®) Taken with Meals, Different Liquids, or Crushed and Added to Food

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5155-5155
Author(s):  
Stuart L Goldberg ◽  
Patricia Giardina ◽  
Joan Parkhurst Cain ◽  
Deborah Chirnomas ◽  
Jason Esposito ◽  
...  
Keyword(s):  
Adverse Events ◽  
Serum Ferritin ◽  
Research Funding ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Iron Chelation Therapy ◽  
Age Group ◽  
Baseline Serum ◽  
Off Label

Abstract Abstract 5155 Introduction: Deferasirox (Exjade®, Novartis Pharmaceuticals) is an oral iron chelator indicated for the treatment of transfusional iron overload. The recommended mode of administration is to be taken on an empty stomach in water, apple juice or orange juice ≥30 minutes before food. However, there have been post-marketing reports of discontinuation or reduced compliance of deferasirox secondary to palatability and gastrointestinal adverse events. Registration trials with deferasirox did not evaluate different food combinations in an attempt to maintain predictable plasma levels. Early single dose studies suggested that the bioavailability of deferasirox is increased when administered with or before meals, and is positively influenced by fat content, but is not affected by degree of dispersion nor type of liquid. Long-term pharmacokinetic and tolerability studies involving a food effect have not been conducted to date, and the ability of alternate methods of administration to improve patient compliance with iron chelation therapy is unknown. Method: This is an ongoing single-arm, open-label, multi-center study designed to evaluate the palatability, safety, tolerability and pharmacokinetics of deferasirox when administered with food, dispersed in any liquid of choice, or crushed and added to food. The patient population includes patients with transfusional hemosiderosis (minimum entry serum ferritin ≥500 μ g/L) aged >2 years with thalassemia major, sickle cell disease (SCD), low or intermediate (INT-1) risk MDS or other anemias, who are on, starting, or resuming treatment with deferasirox. The study began with a 1-month run-in phase with deferasirox dosed according to prescribing information, then a 3-month assessment phase where subjects could choose each week from 5 general administration options including with or without meals, in the morning or evening, crushed and added to a soft food, or mixed in a liquid of choice. Subject diaries are used to record the meal and method of administration at the end of each week. Palatability is assessed with a modified facial hedonic scale, with additional directed questions capturing gastrointestinal side effects. This is a data analysis of the run-in phase. Result: Target enrollment has been met with 65 patients. Baseline data on the first 58 subjects include 8 in the 2 to <10 years of age group (median 7.5 years; range 3–9); 42 in the 10 to <60 years of age group (median 18.5 years; range 10–48); and 8 in the ≥60 years of age group (median 74 years; range71-83). Underlying hematologic diagnoses included SCD (41%), thalassemia major (29%), MDS (12%) and other anemias (17%). Sixty-nine percent of subjects were receiving deferasirox prior to entering the study. The median baseline serum ferritin level was 2405 μ g/L (range 560–8660) and was distributed as shown in Table 1. The most frequent adverse events were diarrhea (19%) and nausea (9%) (Table 2), which were more common in MDS (P=0.23 and P<0.01, respectively). Conclusion: This ongoing trial (NCT00845871) is evaluating whether alternative modes of administration improve palatability and tolerability while maintaining safety. Preliminary data from the assessment phase (deferasirox taken with meals, different liquids, or crushed and added to food) will be presented at the meeting. Disclosures: Goldberg: Novartis Oncology: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Exjade, iron chelation therapy, off-label method of administration. Giardina:Novartis: Research Funding. Parkhurst Cain:Novartis: Research Funding. Chirnomas:Novartis: Research Funding. Esposito:Novartis: Employment. Paley:Novartis: Employment. Vichinsky:Novartis: Consultancy, Research Funding, Speakers Bureau; Hemaquest: Consultancy, Membership on an entity's Board of Directors or advisory committees; Apotex: Consultancy, Research Funding.

Clinical Effectiveness of Iron Chelation Therapies in Syrian Patients with β Thalassemia Major: Suboptimal Clinical Outcomes and High Prevalence of Iron Overload

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1719-1719
Author(s):  
Youssef A Lama ◽  
Hanan Touma ◽  
Khawla AlKeba ◽  
Osama Maksoud
Keyword(s):  
Combination Therapy ◽  
Iron Overload ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Clinical Effectiveness ◽  
Thalassemia Major ◽  
Iron Chelation Therapy ◽  
Ferritin Concentration ◽  
Therapeutic Outcomes ◽  
High Prevalence

Abstract Background Thalassemia is the most prevalent autosomal abnormality in the population of Syria. In 2013, the total number of registered thalassemia patients is 8300. Disease prevalence is reinforced by the high rate of consanguineous marriages especially in the rural regions of this Middle Eastern and Mediterraneancountry. Regular blood transfusions and iron chelation therapy (ICT) have significantly improved survival and reduced morbidity of patients withβ thalassemia major (BTM). Although ICTs are provided free of charge by the government to all (BTM) patients, adequate monitoring of therapeutic outcomes is lacking, and cardiac complications still represent significant morbidity and remain the leading cause of mortality. Objective This study aimed at evaluating the prevalence of poor chelation in Syrian patients with BTM, and assessing the effectiveness of different iron chelation regimens provided by the National Thalassemia Program. Methods We conducted a single-centered study encompassing two phases; i) a retrospective chart review of serum ferritin levels of all female and male patients (≥ 3y) with (BTM) receiving iron chelation regimens (mono- or combination therapy) in 2009 and 2010; and ii) a 15 month prospective observational study to evaluate the effectiveness of desferrioxamine (DFO) monotherapy (at a dose of 40-50 mg/kg given over 8–10 h on 5-7 d/week), versus DFO (at the same dose used for DFO monotherapy) in combination with deferiprone (DFP) (at a dose of 75 mg/kg/day) [DFO+DFP] in patients received prior monotherapy with DFO but had poor response. Endpoints were defined as reducing iron stores in iron overloaded patients and improving cardiac function assessed by left ventricular ejection measurements using Doppler Echocardiogram. Statistical analysis of data sets was performed using Prism Graphpad, version 5. Results A total of 493 records of all patients registered at the National Thalassemia Centre in Homs were evaluated. 280 (56.8%) of these patients were diagnosed with BTM, and 245/280 (87.5%) were receiving iron chelation therapy. The average age was 11.35 ± 5.69 year-old (mean ± SD), age range [3-32 year], and male-to-female sex ratiowas 102:103. 39% of the patients were administered DFO, 30% and 10% received oral deferasirox (DFX) and deferiprone (DFP) respectively, whereas 21% received a combination of [DFO + DFP]. The average ferritin concentration of the study population was 3954.89 ± 1431.37 [range from 1362 to 8656] ug/l in 2009, and 4038.22 ± 1572.49 [range from 1173 to 8210] ug/l in 2010. Strikingly, 98% of patients had iron overload; [15% mild, 35% moderate and 48% severe] in 2009, and [12.3% mild, 42.5% moderate and 45.2% severe] in 2010. Patients on DFX had the lowest ferritin concentrations when compared with these of their peers on the DFO and [DFO + DFP] regimens (P=0.0001 and P=0.02 respectively). Patients of DFX also had the lowest percentage of sever iron overload (31%) in comparison with 58%, 51%, and 40% in patients on DOF, [DFO+DFP], and DFP respectively. In the prospective observational phase of our study, several comparative assessments were conducted. The combination of [DFO+DFP] reduced ferritin concentration by 14% from a mean baseline concentration of 4662.4 ±1266.17 to 3697.1 ±1547.9 (μg/l) after the study 15 month follow up period (P=0.0006), whereas DFO alone was ineffective. Cardiac function decreased by a percentage of (-4.74 ± 12.89) from 68.64%±6.97% to 60.98%±7.22% in patients on DFO (p= 0.0001) and from 67.39%±6.49% to 63.91%±8.51% in patients receiving combination therapy (p= 0.031). Mean decrease was greater in DFO regimen (-10.53 ± 11.89) than that seen in patients on combination therapy (-4.74 ± 12.89) (p= 0.035). Conclusions This study reveals aspects of the current status of ICT outcomes in Syria. Our results prove high prevalence of iron overload in patients with BTM despite their receiving ICTs free of charge. Patients are not achieving target serum ferritin thresholds despite chronic treatment with DFO for iron overload. This may suggest its poor clinical effectiveness within the real-world, and necessitates active measures to improve patients’ compliance. The underlying causes of these suboptimal therapeutic outcomes of all ICT regimens should be further investigated, and the cost-effectiveness of ICTs should be reconsidered by decision makers. Disclosures: No relevant conflicts of interest to declare.

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