Deferasirox for the treatment of iron overload in thalassemia ：a rapid health technology assessment / 中国药房

OBJECTIVE To eval uate the effectiveness ，safety and economy of deferasir ox for the treatment of iron overload in thalassemia with rapid health technology assessment ，and to provide evidence-based basis for rational clinical use. METHODS Retrieved from Chinese and English database/website as PubMed ，Embase，Cochrane Library ，NHS EED ，CADTH，CNKI and Wanfang database ，health technology assessment （HTA），systematic evaluation/meta-analysis and pharmacological studies about deferasirox versus deferoxamine/deferiprone for the treatment of iron overload in thalassemia were collected from the inception to June 2021. Based on literature screening and data extraction ，the quality of literature about HTA reports ，systematic evaluation/ Meta-analysis and pharmacoeconomic research were evaluated with HTA checklist ，A Measurement Tool to As sess Systematic Reviews，standard scale of economic evaluation report. The effectiveness and safety results were described quantitatively ，and the economic evaluation results were described qualitatively. RESULTS One HTA report ，five systematic evaluation/meta-analysis and five pharmacoeconomic studies were selected from 1 569 literature. Included HTA reports ， systematic evaluation/meta-analysis，pharmacoeconomic studies were high in quality. Most studies reported that 30 mg/（kg·d） deferasirox was E-mail：aydgs@126.com better than deferoxamine in reducing the levels of s erum ferritin and liver iron overload ；ADR induced by deferasirox were mainly gastrointestinal irritation symptoms ，skin itching ，joint pain，transaminase elevation ，etc.，which generally did not affect subsequent treatment. There was no statistical significance in severe ADR between deferoxamine group and deferasirox group [RR ＝0.96，95％CI（0.85，1.08），P＝0.52]. Compared with deferoxamine，deferasirox had higher cost-effectiveness ；but deferasirox was less likely to be cost-effective than deferiprone. CONCLUSIONS Deferasirox has good effectiveness and safety for iron overload in thalassemia ，and has good economic advantages in Britain and Iran ，compared with deferoxamine.

Effect of deferasirox on serum ferritin level in children with thalassemia major: impact of transfusional iron load

Background: Ongoing transfusional iron load (TIL) is an important determinant while deciding starting and subsequent dose adjustment of deferasirox during course of chelation therapy. So present study aims to find out effect of different dosing of deferasirox over the serum ferritin level in children with thalassemia major with impact of rate of transfusional iron load.Methods: This one year observational study was carried out in 35 transfusion dependent ?-thalassemic patients aged 2-18 years. Patients with baseline serum ferritin 1000-1500ng/ml and/or receiving TIL 0.2-0.3mg/kg/day were started 20mg/kg/day deferasirox and patients with ferritin>1500ng/ml and/or having TIL > 0.3mg/kg/day were started 30mg/kg/day deferasirox. Serum ferritin was repeated in every three months. Dose adjustments were performed on serum ferritin trends in steps of 5-10mg/kg /day to maximum 40mg/kg/day. Evaluation of relationship between dose adjustment, percentage of reduction in serum ferritin and TIL was done.Results: Group-1 patients(42.8%) had TIL 0.2 to 0.3mg/kg/day whereas Group-2(37.1%) and Group-3(20%) children had TIL >0.3-0.4mg/kg/day and >0.4 mg/kg/day respectively. Starting dose of deferasirox in 25.7% patients was 20mg/kg/day and in rest were 30mg/kg/day. Average dose of deferasirox in group-1 was significantly lower as compared to group-2 and group-3 patients ( p< 0.05). Significant decline in mean serum ferritin was observed in all three groups (p < 0.05). There was a significant positive correlation between TIL and average drug dose prescribed (r=0.5411and p=0.0007) but negative insignificant correlation was observed with percentage of reduction in serum ferritin(r=0.0027and p=0.98).Conclusions: Deferasirox 30mg/kg/day significantly reduces serum ferritin and is well tolerated in majority of patients having TIL 0.3-0.4mg/kg/day where as 20mg/kg/day is required in patients having low transfusional iron intake.

Protective effects of deferasirox and N-acetyl-L-cysteine on iron overload-injured bone marrow

Using an iron overload mouse model, we explored the protective effect of deferasirox (DFX) and N-acetyl-L-cysteine (NAC) on injured bone marrow hematopoietic stem/progenitor cells (HSPC) induced by iron overload. Mice were intraperitoneally injected with 25 mg iron dextran every 3 days for 4 weeks to establish an iron overload (Fe) model. DFX or NAC were co-administered with iron dextran in two groups of mice (Fe+DFX and Fe+NAC), and the function of HSPCs was then examined. Iron overload markedly decreased the number of murine HSPCs in bone marrow. Subsequent colony-forming cell assays showed that iron overload also decreased the colony forming capacity of HSPCs, the effect of which could be reversed by DFX and NAC. The bone marrow hematopoiesis damage caused by iron overload could be alleviated by DFX and NAC.

Comparative Efficacy and Safety of Oral Iron Chelators and their Novel Combination in Children with Thalassemia.

Objective: To compare the efficacy and safety of oral iron chelators (Deferiprone and Deferasirox) when used singly and in combination in multi-transfused children with thalassemia. Design: Prospective comparative study. Setting: Thalassemia Center of a medical college affiliated hospital Participants and Intervention: 49 multi-transfused children with thalassemia with a mean (SD) age 11.6 (6.21) y received daily chelation therapy with either deferiprone alone (75 mg/kg/day in 3 divided doses), deferasirox alone (30 mg/kg/day single dose) or their daily combination (same dose as monotherapy) for 12 months. Outcome measures: Serum ferritin levels at the start of study, after 6 months and after 12 months. MRI T2* of liver and heart initially and after 6 months of follow up. 24-hour urinary iron excretion values at the outset and after 12 months of chelation therapy. At every visit for blood transfusion, all patients were clinically assessed for any adverse effects; liver and renal functions were monitored 6-monthly. Results: After 12 months of respective chelation therapy, serum ferritin values decreased from a mean of 3140.5 ng/mL to 2910.0 ng/mL in deferiprone alone group, 3859.2 ng/mL to 3417.4 ng/mL in deferasirox alone group and from 3696.5 ng/mL to 2572.1 ng/mL in the combination group. The combination therapy was more efficacious in causing fall in serum ferritin levels compared to deferiprone and deferasirox monotherapy (P=0.035 and 0.040, respectively). Results of MRI T2* were equivocal. Combined drug usage produced maximum negative iron balance in the body by maximally increasing the iron excretion in urine from 61.1 µmol/day to 343.3 µmol/day (P=0.002). No significant adverse reactions were noticed in either the monotherapy or the combination group. Conclusion: Oral combination therapy of deferiprone and deferasirox appears to be an efficacious and safe modality to reduce serum ferritin in multi-transfused children with thalassemia.

Synthesis of the related substances of deferasirox / 中国药科大学学报

@#To perform the quality control of deferasirox and establish its quality criterion, three related substances which were determined by analyzing the synthetic route were synthesized, and their structures were confirmed by 1H NMR and MS. These substances were 2-(2-hydroxyphenyl)-4H-benzo［1, 3-e］oxazin-4-one(A), 2-hydroxy-N-(2-hydroxyben-zoyl)-benzamide(B), and methyl-4-［3, 5-bis(2-hydroxyphenyl)- 1H- ［1, 2, 4］triazol-1-yl］-benzoate(C).

Use of deferasirox, an iron chelator, to overcome imatinib resistance of chronic myeloid leukemia cells

BACKGROUND/AIMS: The treatment of chronic myeloid leukemia (CML) has achieved impressive success since the development of the Bcr-Abl tyrosine kinase inhibitor, imatinib mesylate. Nevertheless, resistance to imatinib has been observed, and a substantial number of patients need alternative treatment strategies. METHODS: We have evaluated the effects of deferasirox, an orally active iron chelator, and imatinib on K562 and KU812 human CML cell lines. Imatinib-resistant CML cell lines were created by exposing cells to gradually increasing concentrations of imatinib. RESULTS: Co-treatment of cells with deferasirox and imatinib induced a synergistic dose-dependent inhibition of proliferation of both CML cell lines. Cell cycle analysis showed an accumulation of cells in the subG1 phase. Western blot analysis of apoptotic proteins showed that co-treatment with deferasirox and imatinib induced an increased expression of apoptotic proteins. These tendencies were clearly identified in imatinib-resistant CML cell lines. The results also showed that co-treatment with deferasirox and imatinib reduced the expression of BcrAbl, phosphorylated Bcr-Abl, nuclear factor-kappaB (NF-kappaB) and beta-catenin. CONCLUSIONS: We observed synergistic effects of deferasirox and imatinib on both imatinib-resistant and imatinib-sensitive cell lines. These effects were due to induction of apoptosis and cell cycle arrest by down-regulated expression of NF-kappaB and beta-catenin levels. Based on these results, we suggest that a combination treatment of deferasirox and imatinib could be considered as an alternative treatment option for imatinib-resistant CML.

The effect of combination treatment using iron chelator deferasirox and cisplatin on proliferation and apoptosis in non-small cell lung cancer / 天津医药

Objective To investigate the combination effect using iron chelators deferasirox and cisplatin on A549 cell proliferation and apoptosis and to provide evidences to explore an effective way to treat lung cancer. Methods Lung adeno?carcinoma cells were cultured by conventional way, with administration of different concentrations of deferasirox and cisplat?in. Cell growth inhibition was observed under an inverted microscope. Proliferation inhibition was evaluated by MTT assay. Morphological changes of cell apoptosis was detected using DAPI,AO/EB straning and flow cytometry. Results After a cer?tain time of incubation with different concentrations of the combined drugs,the cell number reduce significantly, which was counted under invert microscope. Cells were dispersed with each other and adherent cells appear shrunken and poor in re?fractivity. MTT assay showed that inhibition of cell proliferation was in a concentration-time-dependent manner. Chromatin condensation, nuclear condensation and other typical apoptotic morphology were detected after DAPI and AO/EB straning. Flow cytometry showed that apoptosis increased with rising drug concentration. So combination therapy was significantly pro-apoptotic. Conclusion Deferasirox has the ability to inhibit proliferation of A549 cells and can promote tumor cell apoptosis and enhances cancer cell tolerance when combined with cisplatin. It can also reduce the amount and toxicity of cis?platin. It provides a basis for finding an effective way to treat lung cancer.

Anti-leukemic properties of deferasirox via apoptosis in murine leukemia cell lines

BACKGROUND: Although deferasirox (DFX) is reported to have anti-tumor effects, its anti-leukemic activity remains unclear. We evaluated the effect of DFX treatment on two murine lymphoid leukemia cell lines, and clarified the mechanisms underlying its potential anti-leukemic activity. METHODS: L1210 and A20 murine lymphoid leukemia cell lines were treated with DFX. Cell viability and apoptosis were evaluated by the 3-(4,5-dimethylthaizol-2-yl)-5-(3-carboxymethylphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and fluorescence-activated cell sorting (FACS) analysis, respectively. Immunoblotting was performed to detect the expression of key apoptotic proteins. RESULTS: In dose- and time-dependent manner, DFX decreased viability and increased apoptosis of murine leukemic cells. Fas expression was significantly higher in A20 cells than in L1210 cells at all DFX concentrations tested. Although both cell lines exhibited high caspase 3 and caspase 9 expression, a critical component of the intrinsic mitochondrial apoptotic pathway, expression was greater in L1210 cells. In contrast, caspase 8, a key factor in the extrinsic apoptotic pathway, showed greater expression in A20 cells. Cytochrome c expression was significantly higher in L1210 cells. In both cell lines, co-treatment with ferric chloride and DFX diminished the expression of these intracellular proteins, as compared to DFX treatment alone. CONCLUSION: Treatment with DFX increased caspase-dependent apoptosis in two murine lymphoid leukemia cell lines, with differing apoptotic mechanisms in each cell line.

Brazilian Thalassemia Association protocol for iron chelation therapy in patients under regular transfusion

In the absence of an iron chelating agent, patients with beta-thalassemia on regular transfusions present complications of transfusion-related iron overload. Without iron chelation therapy, heart disease is the major cause of death; however, hepatic and endocrine complications also occur. Currently there are three iron chelating agents available for continuous use in patients with thalassemia on regular transfusions (desferrioxamine, deferiprone, and deferasirox) providing good results in reducing cardiac, hepatic and endocrine toxicity. These practice guidelines, prepared by the Scientific Committee of Associação Brasileira de Thalassemia (ABRASTA), presents a review of the literature regarding iron overload assessment (by imaging and laboratory exams) and the role of T2* magnetic resonance imaging (MRI) to control iron overload and iron chelation therapy, with evidence-based recommendations for each clinical situation. Based on this review, the authors propose an iron chelation protocol for patients with thalassemia under regular transfusions.

Korean Guideline for Iron Chelation Therapy in Transfusion-Induced Iron Overload

Many Korean patients with transfusion-induced iron overload experience serious clinical sequelae, including organ damage, and require lifelong chelation therapy. However, due to a lack of compliance and/or unavailability of an appropriate chelator, most patients have not been treated effectively. Deferasirox (DFX), a once-daily oral iron chelator for both adult and pediatric patients with transfusion-induced iron overload, is now available in Korea. The effectiveness of deferasirox in reducing or maintaining body iron has been demonstrated in many studies of patients with a variety of transfusion-induced anemias such as myelodysplastic syndromes, aplastic anemia, and other chronic anemias. The recommended initial daily dose of DFX is 20 mg/kg body weight, taken on an empty stomach at least 30 min before food and serum ferritin levels should be maintained below 1000 ng/mL. To optimize the management of transfusion-induced iron overload, the Korean Society of Hematology Aplastic Anemia Working Party (KSHAAWP) reviewed the general consensus on iron overload and the Korean data on the clinical benefits of iron chelation therapy, and developed a Korean guideline for the treatment of iron overload.

Efficacy and Safety of Deferasirox for Reducing Total Body and Cardiac Iron in Thalassemia.

Objective: To assess the efficacy of deferasirox as an iron chelator, with specific reference to reducing cardiac iron overload. Design: Prospective, open label, single arm study between 2008- 2010. Setup: Thalassemia center at a teaching hospital. Participants: 30 multitransfused Thalassemia Major (TM) patients receiving deferasirox (DFX) therapy. Methods: All patients had MRI T2*evaluation for cardiac iron load before starting DFX therapy. MRI T2* was performed on a 1.5 tesla Siemens sonata machine using thalassemia tools software and the ejection fraction measured using standard cardiac magnetic resonance sequence. Quantification of cardiac iron deposit was categorized into T2* <10 ms as high cardiac risk, 10- 20 ms as intermediate risk, and >20 ms as low risk. We also estimated left ventricular ejection fraction (LVEF), end systolic volume (ESV) and end diastolic volume (EDV) using standard sequence. EF <56 % was considered to be significant cardiac dysfunction. DFX was administered in an initial dose of 20mg/kg/ day and increased to a maximum of 35mg/kg/day. Serum ferritin level was estimated in pretransfusion samples at 1-3 monthly intervals. The primary end point of the study was change in serum ferritin level and cardiac MRI T2* value after 12-18 months therapy. Results: Of the 30 patients, cardiac iron value of >20 ms was seen in 15 (50%), whereas 9 (30% ) had 20-10 ms, and 6 (20% ) had ≤10 ms. The mean serum ferritin pre DFX therapy of all cases was 3859.8 ± 1690.70 ng/mL (1066 – 6725 ng/mL) and mean cardiac T2* was 23.8±15.2 ms (6.24-69.2 ms). After 12 to 18 months of DFX therapy on a mean dose of 33 mg/kg/day, the mean serum ferritin was 2693.4 ±1831.5 ng/mL (drop by 30.2%, P<0.001) and mean cardiac T2* was 24.2±12.9 ms (increase of 1.6 %, P=0.87). Percentage change in cardiac iron was greater in high risk (24.8%) and intermediate risk (33.4%) patients than low risk patients (8.4%), though these values were not statistically significant. LVEF was 62.0 (±7.0%) before treatment and changed to 58.9 (± 4.8%) after 18 months of therapy but the values remained within normal range and this change was not significant (P=0.061). Adverse effect of DFX included diarrhea, maculopapular skin rash and transient proteinuria that necessitated temporary stoppage of medication. Conclusion: Deferasirox monotherapy has a good safety profile and effectively chelates total body iron. It is also a good myocardial iron chelator, more efficacious in moderate to severe cardiac iron overloaded patients.

Effects of oral iron chelator deferasirox on human malignant lymphoma cells / 대한혈액학회지

BACKGROUND: Iron is essential for cell proliferation and viability. It has been reported that iron depletion by a chelator inhibits proliferation of some cancer cells. Deferasirox is a new oral iron chelator, and a few reports have described its effects on lymphoma cells. The goal of this study was to determine the anticancer effects of deferasirox in malignant lymphoma cell lines. METHODS: Three human malignant lymphoma cell lines (NCI H28:N78, Ramos, and Jiyoye) were treated with deferasirox at final concentrations of 20, 50, or 100 microM. Cell proliferation was evaluated by an MTT assay, and cell cycle and apoptosis were analyzed by flow cytometry. Western blot analysis was performed to determine the relative activity of various apoptotic pathways. The role of caspase in deferasirox-induced apoptosis was investigated using a luminescent assay. RESULTS: The MTT assay showed that deferasirox had dose-dependent cytotoxic effects on all 3 cell lines. Cell cycle analysis showed that the sub-G1 portion increased in all 3 cell lines as the concentration of deferasirox increased. Early apoptosis was also confirmed in the treated cells by Annexin V and PI staining. Western blotting showed an increase in the cleavage of PARP, caspase 3/7, and caspase 9 in deferasirox-treated groups. CONCLUSION: We demonstrated that deferasirox, a new oral iron-chelating agent, induced early apoptosis in human malignant lymphoma cells, and this apoptotic effect is dependent on the caspase-3/caspase-9 pathway.

Effect of deferasirox on DLL4 expression and angiogenesis in a slender narrow pedicle and random flap in rats / 中华医学美学美容杂志

Objective To investigate the effect of deferasirox on DLL4 expression and angiogenesis in a narrow pedicle and random flap in rats.Methods Twenty SD rats were randomly divided into the deferagirox group and control group.Rats were subjected to deferagirox of 100 mg · kg-1 · d-1 inthe experimental groups,respectively and the same dose saline in the control group for 1 week. In each group,flap were created in the bilateral back of each rats.Ratio of length to width of tissue in the pedicle portion and the flap portion was 1 cm × 1 cm and 3 cm × 3 cm,respectively.The tissue samples were taken from the pedicle and the middle portions of the flap.The DLL4 and CD105 expression was also detected with immunohistochemistry (SABC).Results Compared with control group,whatever in the pedicle portion or the middle portion,there was a significant increase of microvessels marked by CD105 and a significant decrease of flap microvessels stained by DLL4 in the deferagirox group.In both groups,compared with the pedicle portion,there was a significant increase of microvessels marked by CD105 and DLL4 in the the middle portion.Conclusions Deferasirox can in crease the CD105 expression and angiogenesis of the slender narrow pedicle random flap.This process might be related to the inhibition of DLL4 protein expression,which is significant in the notch signaling pathway.

Mimic hypoxia of deferasirox in improving growth of micrangium in a narrow pedicle flap / 中华医学美学美容杂志

Objective To study the function of hypoxia mimics of different exposure time of deferasirox in improving the growth of micrangium in a narrow pedicle flap.Methods Fourty male SD rats were divided into 2 groups:experimental group was fed with deferasirox 100 mg/kg per day from 1d,3d,5d and 7d,respectively,before the surgery of transferring the narrow pedicle flap,while control group just fed with saline.After 7 days,the immunohistochemistry,Western blot and quantitative reverse transcription-PCR (qPCR) were performed to examine the expression of CD34.qPCR was used to examine the expression of HIF-1α,VEGF in order to investigate the regulatory effect of deferasirox in improving the growth of micrangium and the distinction among the different exposed time of deferasirox in the narrow pedicle flap.Results The deferasirox group exhibited a marked improvement in flap healing time,and with the increasing administration time of deferasirox,the expression of MVD,HIF-1α and VEGF was improved in each treated group (P＜0.05).Conclusions Deferasirox can induce HIF-1α secretion and increase CD34 expression,and so deferasirox can protect endothelial cells from hypoxic and ischaemic injury.

Iron Overload during Follow-up after Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with High-Risk Neuroblastoma

Multiple RBC transfusions inevitably lead to a state of iron overload before and after high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT). Nonetheless, iron status during post-SCT follow-up remains unknown. Therefore, we investigated post-SCT ferritin levels, factors contributing to its sustained levels, and organ functions affected by iron overload in 49 children with high-risk neuroblastoma who underwent tandem HDCT/autoSCT. Although serum ferritin levels gradually decreased during post-SCT follow-up, 47.7% of the patients maintained ferritin levels above 1,000 ng/mL at 1 yr after the second HDCT/autoSCT. These patients had higher serum creatinine (0.62 vs 0.47 mg/mL, P = 0.007) than their counterparts (< 1,000 ng/mL). Post-SCT transfusion amount corresponded to increased ferritin levels at 1 yr after the second HDCT/autoSCT (P < 0.001). A lower CD34+ cell count was associated with a greater need of RBC transfusion, which in turn led to a higher serum ferritin level at 1 yr after HDCT/autoSCT. The number of CD34+ cells transplanted was an independent factor for ferritin levels at 1 yr after the second HDCT/autoSCT (P = 0.019). Consequently, CD34+ cells should be transplanted as many as possible to prevent the sustained iron overload after tandem HDCT/autoSCT and consequent adverse effects.

Iron Overload during Follow-up after Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with High-Risk Neuroblastoma

Multiple RBC transfusions inevitably lead to a state of iron overload before and after high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT). Nonetheless, iron status during post-SCT follow-up remains unknown. Therefore, we investigated post-SCT ferritin levels, factors contributing to its sustained levels, and organ functions affected by iron overload in 49 children with high-risk neuroblastoma who underwent tandem HDCT/autoSCT. Although serum ferritin levels gradually decreased during post-SCT follow-up, 47.7% of the patients maintained ferritin levels above 1,000 ng/mL at 1 yr after the second HDCT/autoSCT. These patients had higher serum creatinine (0.62 vs 0.47 mg/mL, P = 0.007) than their counterparts (< 1,000 ng/mL). Post-SCT transfusion amount corresponded to increased ferritin levels at 1 yr after the second HDCT/autoSCT (P < 0.001). A lower CD34+ cell count was associated with a greater need of RBC transfusion, which in turn led to a higher serum ferritin level at 1 yr after HDCT/autoSCT. The number of CD34+ cells transplanted was an independent factor for ferritin levels at 1 yr after the second HDCT/autoSCT (P = 0.019). Consequently, CD34+ cells should be transplanted as many as possible to prevent the sustained iron overload after tandem HDCT/autoSCT and consequent adverse effects.

Deferasirox: Oral, once daily iron chelator - An expert opinion.

Iron overload is a serious and potentially fatal condition that results from multiple blood transfusions required over a long period of time to treat certain types of anemias such as, that caused by β-thalassemia, sickle cell disease and myelodysplastic syndrome. Deferoxamine, which has been used since four decades as an iron chelator has limited efficacy due to its demanding therapeutic regimen, leading to poor compliance. Deferasirox, once daily oral iron chelator provides an effective alternative to Deferoxamine in the treatment of transfusional hemosiderosis. In this review, the role of Deferasirox as an ideal iron chelator has been discussed. Pubmed searches on Deferasirox were carried out for the same. Several studies demonstrated the safety and efficacy of Deferasirox in reducing iron burden in iron-overloaded patients with β-thalassemia, sickle cell anemia and myelodysplastic anemia. Thus, convenient, effective and tolerable chelation therapy with oral Deferasirox is likely to be a significant development in the treatment of transfusional iron overload, due to its ability to provide constant chelation coverage and the potential to improve compliance.

Economic Evaluation of Iron Chelation Agents: Oral Deferasirox versus Infusional Deferoxamine / 대한혈액학회지

BACKGROUND: Patients with transfusional iron overload have relied on treatment with deferoxamine, a standard chelating agent. Deferoxamine is administered by intravenous or subcutaneous infusion over an 8~12 hour period 5~7 times per week; however, administration of deferoxamine may lead to poor compliance and reduced quality of life in patients. The use of deferasirox, a once daily oral chelation agent, was recently approved. We conducted an economic evaluation of these two iron-chelating medications in transfusion-dependent patients. METHODS: The efficacy of oral deferasirox and infusion deferoxamine was assumed equal based on clinical trials of non-inferiority with the administration of 20mg/kg/day deferasirox versus 40mg/kg/day deferoxamine. Depending on the methods utilized for measuring administration time, travel time and convenience between the use of infusion and oral therapy, either cost analysis or cost-utility analysis was undertaken, respectively. Cost analysis included determination of direct medical costs (drug costs and administration costs), non-medical costs (travel costs), and indirect costs (productivity loss associated medical utilization). For cost utility analysis, the cost per QALYs (quality-adjusted life years) was calculated based on costs subtracting indirect costs (productivity loss) and gains of QALYs between the two agents. RESULTS: Deferasirox therapy resulted in a cost savings per patient of 23,471,777 Korean won based on cost analysis. Based on cost utility analysis, the cost per QALYs gained was -398,576 Korean won (4,527,819 Korean won savings with a gain of 11.5 QALYs per patient). CONCLUSION: The results of cost analysis and cost utility analysis of the use of oral deferasirox versus infusion deferoxamine showed that deferasirox is a more economical and potentially socially beneficial iron-chelating agent in Korea.

Comparison of Immune Responses Induced by Deferoxamine and Deferasirox / 대한혈액학회지

BACKGROUND: The iron chelating agents (ICA) have various biological effects besides iron chelation. We investigated the immunomodulatory effects of Deferasirox (DFS) compared to Deferoxamine (DFO). METHODS: Spleen cells (SP) were obtained from 5 week-old C57/BL6 (H-2(b)). The cytotoxicity of ICAs was examined using the CCK8 method. For the cell proliferation assay, SP were cultured with irradiated in addition to 10, 50, 100micrometer of DFS or DFO and 200ng/mL of cyclosporin A (CSA). Cytokines and nitrite levels were evaluated from supernatants by ELISA. RESULTS: The viability of ICA was reported to be over 100%. Both DFS and DFO inhibited cell proliferation in a manner comparable to CSA. Cell proliferation without iron was reduced at the concentration of 100micrometer of DFO. With iron treatment, the reduction of the stimulation index was dependent on DFO concentrations. DFS decreased the proliferation without reference to the concentrations. After stimulation of phytohemagglutinin, the nitrite concentrations increased with iron. With lipopolysaccharides, the nitrite levels were higher in DFO with iron than control, but similar in DFS regardless of iron treatment. The levels of interleukin-2 were not different. Interleukin-10 was more abundantly produced in 50micrometer of DFO compared to DFS. Transforming growth factor-beta was higher in DFS than DFO at the low concentration, but opposite at the high concentration. CONCLUSION: These data suggested that both iron chelating agents possessed immune suppressive effects comparable to CSA. The immunosuppressive effect of DFS may be distinct from DFO. More experiments are required to determine the exact mechanism of the immunosuppressive effect of DFS.

Acute Tubulointerstitial Nephritis Induced by Deferasirox following Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia / 대한혈액학회지

Deferasirox is a once-daily, oral iron-chelating agent that is now widely available for the treatment of transfusional hemosiderosis. Deferasirox represents a significant advance in the treatment of iron overload, as the availability of an effective oral therapy has the potential to relieve many patients from the burden of frequent parenteral therapy with the previous reference standard iron chelator, deferoxamine. The well-known drug-related adverse events associated with deferasirox include gastrointestinal disturbances, rash, elevations in liver enzyme levels, and mild increases in serum creatinine levels, but acute renal failure is not common. The authors report a case of acute tubulointerstitial nephritis induced by deferasirox following hematopoietic stem cell transplantation for severe aplastic anemia