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Cureus Nov 2023Despite the established efficacy of iron chelation therapy in transfusion-induced iron-overloaded patients, there is no universal agreement regarding the choice of an... (Review)
Review
Despite the established efficacy of iron chelation therapy in transfusion-induced iron-overloaded patients, there is no universal agreement regarding the choice of an optimal chelating regimen. Deferasirox (DFX) and deferiprone (DFP) are two oral iron chelators, and combination usage demonstrated effectiveness as an alternative to monotherapies in patients with a limited response to monotherapy. The present systematic review aimed to assess the evidence regarding the outcomes of combined DFP and DFX in iron-overloaded patients. An online search was conducted in PubMed, Scopus, Web of Science, and CENTRAL databases. Interventional and observational studies that assessed the outcomes of combined DFP and DFX in iron-overloaded patients were included. Eleven studies (12 reports) were considered in this meta-analysis. The studies included dual iron chelation strategies for a number of diagnoses. Single-arm studies (n =7) showed a reduction of serum ferritin, which reached the level of statistical significance in three studies. Likewise, most studies reported a numerical reduction in liver iron concentration (LIC) and increased cardiac MRI-T2* values after chelating therapy. Alternatively, comparative studies showed no significant difference in post-treatment serum ferritin between DFX plus DFP and DFX/DFP plus deferoxamine (DFO). The adherence to combination therapy was good to average in nearly 66.7-100% of the patients across four studies. One study reported a poor adherence rate. The combined regimen was generally tolerable, with no reported incidence of serious adverse events among the included studies. In conclusion, the DFP and DFX combination is a safe and feasible option for iron overload patients with a limited response to monotherapy.
PubMed: 38058350
DOI: 10.7759/cureus.48276 -
BMJ Open Feb 2024Despite the improvement in medical management, many patients with transfusion-dependent β-thalassaemia die prematurely due to transfusion-related iron overload. As per...
Efficacy and safety of deferoxamine, deferasirox and deferiprone triple iron chelator combination therapy for transfusion-dependent β-thalassaemia with very high iron overload: a protocol for randomised controlled clinical trial.
INTRODUCTION
Despite the improvement in medical management, many patients with transfusion-dependent β-thalassaemia die prematurely due to transfusion-related iron overload. As per the current guidelines, the optimal chelation of iron cannot be achieved in many patients, even with two iron chelators at their maximum therapeutic doses. Here, we evaluate the efficacy and safety of triple combination treatment with deferoxamine, deferasirox and deferiprone over dual combination of deferoxamine and deferasirox on iron chelation in patients with transfusion-dependent β-thalassaemia with very high iron overload.
METHODS AND ANALYSIS
This is a single-centre, open-label, randomised, controlled clinical trial conducted at the Adult and Adolescent Thalassaemia Centre of Colombo North Teaching Hospital, Ragama, Sri Lanka. Patients with haematologically and genetically confirmed transfusion-dependent β-thalassaemia are enrolled and randomised into intervention or control groups. The intervention arm will receive a combination of oral deferasirox, oral deferiprone and subcutaneous deferoxamine for 6 months. The control arm will receive the combination of oral deferasirox and subcutaneous deferoxamine for 6 months. Reduction in iron overload, as measured by a reduction in the serum ferritin after completion of the treatment, will be the primary outcome measure. Reduction in liver and cardiac iron content as measured by T2* MRI and the side effect profile of trial medications are the secondary outcome measures.
ETHICS AND DISSEMINATION
Ethical approval for the study has been obtained from the Ethics Committee of the Faculty of Medicine, University of Kelaniya (Ref. P/06/02/2023). The trial results will be disseminated in scientific publications in reputed journals.
TRIAL REGISTRATION NUMBER
The trial is registered in the Sri Lanka Clinical Trials Registry (Ref: SLCTR/2023/010).
Topics: Adult; Adolescent; Humans; Deferasirox; Deferiprone; Deferoxamine; beta-Thalassemia; Benzoates; Triazoles; Pyridones; Iron Overload; Iron Chelating Agents; Iron; Randomized Controlled Trials as Topic
PubMed: 38331857
DOI: 10.1136/bmjopen-2023-077342 -
Journal of the American Heart... Jan 2024Ferroptosis, an iron-dependent form of regulated cell death, is a major cell death mode in myocardial ischemia reperfusion (I/R) injury, along with mitochondrial...
BACKGROUND
Ferroptosis, an iron-dependent form of regulated cell death, is a major cell death mode in myocardial ischemia reperfusion (I/R) injury, along with mitochondrial permeability transition-driven necrosis, which is inhibited by cyclosporine A (CsA). However, therapeutics targeting ferroptosis during myocardial I/R injury have not yet been developed. Hence, we aimed to investigate the therapeutic efficacy of deferasirox, an iron chelator, against hypoxia/reoxygenation-induced ferroptosis in cultured cardiomyocytes and myocardial I/R injury.
METHODS AND RESULTS
The effects of deferasirox on hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis were examined in cultured cardiomyocytes. In a mouse model of I/R injury, the infarct size and adverse cardiac remodeling were examined after treatment with deferasirox, CsA, or both in combination. Deferasirox suppressed hypoxia- or hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis in cultured cardiomyocytes. Deferasirox treatment reduced iron levels in the endoplasmic reticulum and prevented increases in lipid peroxidation and ferroptosis in the I/R-injured myocardium 24 hours after I/R. Deferasirox and CsA independently reduced the infarct size after I/R injury to a similar degree, and combination therapy with deferasirox and CsA synergistically reduced the infarct size (infarct area/area at risk; control treatment: 64±2%; deferasirox treatment: 48±3%; CsA treatment: 48±4%; deferasirox+CsA treatment: 37±3%), thereby ameliorating adverse cardiac remodeling on day 14 after I/R.
CONCLUSIONS
Combination therapy with deferasirox and CsA may be a clinically feasible and effective therapeutic approach for limiting I/R injury and ameliorating adverse cardiac remodeling after myocardial infarction.
Topics: Mice; Animals; Cyclosporine; Myocardial Reperfusion Injury; Deferasirox; Ferroptosis; Ventricular Remodeling; Myocytes, Cardiac; Myocardial Infarction; Reperfusion Injury; Iron; Hypoxia; Iron Overload; Myocardial Ischemia
PubMed: 38158218
DOI: 10.1161/JAHA.123.031219 -
Cureus Feb 2024This network meta-analysis was conducted with the aim of comparing the efficacy and safety of deferiprone (DFP), deferasirox (DFX), and deferoxamine (DFO) in individuals... (Review)
Review
Compare the Efficacy and Safety of Deferoxamine, Deferasirox, and Deferiprone in Patients With Sickle Cell Disease or Transfusion-Dependent Anemia: A Network Meta-Analysis of Randomized Control Trials.
This network meta-analysis was conducted with the aim of comparing the efficacy and safety of deferiprone (DFP), deferasirox (DFX), and deferoxamine (DFO) in individuals with sickle cell disease (SCD) or transfusion-dependent anemia. This systematic review and meta-analysis adhered to the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)" guidelines. The search was conducted on electronic databases, including PubMed, CINAHIL, and EMBASE, from the inception of databases to January 10, 2024. Outcomes assessed in this study included a change in liver iron concentration (LIC) and a change in ferritin from baseline. For safety analysis, adverse events were compared among three treatment groups. A total of five studies were included in this meta-analysis. The pooled analysis showed that the change in LIC and serum ferritin from baseline was not significantly different in patients with SCD or other anemias. In terms of adverse events, deferiprone was the safest among all. In conclusion, deferiprone demonstrated noninferiority to deferoxamine and deferasirox in measures of iron load, presenting a viable treatment option. Safety outcomes revealed deferasirox carried a higher risk of adverse events compared to deferiprone, supporting its favorable safety profile.
PubMed: 38455804
DOI: 10.7759/cureus.53644 -
Bulletin Du Cancer Nov 2023Iron overload (IO) is probably as toxic in elderly patients with low-risk myelodysplastic syndromes (MDS) as in young thalassemic patients. This impact is more difficult... (Review)
Review
Iron overload (IO) is probably as toxic in elderly patients with low-risk myelodysplastic syndromes (MDS) as in young thalassemic patients. This impact is more difficult to demonstrate because of associated comorbidities. Cardiovascular disease increases vulnerability to the toxic effects of IO. In recent years, registry studies have shown a survival benefit of Iron Chelation Therapy (ICT) in these patients. These findings are now corroborated by an improvement in event-free survival in a single randomized study: the Telesto study. The EFS curves separate after two years of follow-up. This indicates inertia in the occurrence of complications. The benefits of ICT are also very slowly being revealed. It is possible to offer ICT to patients with transfusion-dependent MDS with a life expectancy of at least two years. In Telesto, patients had a serum ferritin (F) level of at least 1000ng/mL, recommendations using this F threshold as a trigger for chelation seem to be reinforced. It remains an open question whether chelation should be started earlier for effective suppression of IO-related oxidative stress. ICTs could be used in transfusion-dependent MDS patients with life expectancy greater than two years. including possibly higher risk patients responding to hypomethylating agents.
Topics: Humans; Aged; Iron Chelating Agents; Myelodysplastic Syndromes; Blood Transfusion; Iron Overload; Progression-Free Survival
PubMed: 37543453
DOI: 10.1016/j.bulcan.2023.06.004 -
Haematologica May 2024CALYPSO (clinicaltrials gov. Identifier: NCT02435212), a randomized, open-label, multicenter, phase II study evaluated the compliance, clinical benefits, and safety of... (Randomized Controlled Trial)
Randomized Controlled Trial
Compliance and clinical benefit of deferasirox granule and dispersible tablet formulation in pediatric patients with transfusional iron overload: in a randomized, open-label, multicenter, phase II study.
CALYPSO (clinicaltrials gov. Identifier: NCT02435212), a randomized, open-label, multicenter, phase II study evaluated the compliance, clinical benefits, and safety of deferasirox granules and dispersible tablets (DT) in pediatric patients with iron overload. Iron chelation therapy-naive and iron chelation therapy-pretreated patients aged 2 to <18 years with transfusion- dependent anemias were enrolled. Patients were randomized 1:1 to deferasirox granules or DT for 48 weeks, stratified by age group and prior iron chelation therapy. In this study, the co-primary objectives are to evaluate compliance and change from baseline in serum ferritin after 24 weeks for both formulations in iron chelation therapy-naive patients. In total, 224 patients, mostly with β-thalassemia major (63.4%), were randomized to granules (N=112) or DT (N=112). Primary analysis was conducted when 96 iron chelation therapy-naive patients had completed 24 weeks of treatment/discontinued early; least squares mean (LSM) compliance in the deferasirox granules and DT groups, was 86.8% and 84.3% (difference 2.6%; P=0.360) respectively, while least squares mean change from baseline in serum ferritin was +4.8 and -171.5 ng/mL (difference: 176.4 ng/mL; P=0.255). Slight differences were observed in the observer/patient-reported outcome scores between the granule and dispersible-tablet groups and the overall scores indicate good adherence, satisfaction/preference, fewer concerns and good palatability with both deferasirox formulations. Safety analyses (N=221) found that the most frequently observed adverse events (granules and DT) were increased urine protein/creatinine ratio (>0.5 mg/mg; 24.5% and 34.2%), upper respiratory tract infection (28.2% and 29.7%), and pyrexia (26.4% and 23.4%). In iron chelation therapy-naive patients, mean compliance and change from baseline in serum ferritin with both deferasirox formulations were not significantly different. The safety profile was comparable between granule and DT formulations, and was consistent with the general safety profile of deferasirox.
Topics: Humans; Deferasirox; Child; Iron Overload; Male; Female; Child, Preschool; Adolescent; Tablets; Iron Chelating Agents; Treatment Outcome; Medication Adherence; Ferritins; Drug Compounding
PubMed: 37855069
DOI: 10.3324/haematol.2023.283133 -
The Korean Journal of Internal Medicine Nov 2023Although rituximab, an antiCD20 monoclonal antibody, has dramatically improved the clinical outcomes of diffuse large B-cell lymphoma, rituximab resistance remains a...
BACKGROUND/AIMS
Although rituximab, an antiCD20 monoclonal antibody, has dramatically improved the clinical outcomes of diffuse large B-cell lymphoma, rituximab resistance remains a challenge.
METHODS
We developed a rituximab-resistant cell line (RRCL) by sequential exposure to gradually increasing concentrations of rituximab in a rituximab-sensitive cell line (RSCL). When the same dose of rituximab was administered, RRCL showed a smaller decrease in cell viability and apoptosis than RSCL. To determine the differences in gene expression between RSCL and RRCL, we performed next-generation sequencing.
RESULTS
In total, 1,879 differentially expressed genes were identified, and in the over-representation analysis of Consensus-PathDB, mitogen-activated protein kinase (MAPK) signaling pathway showed statistical significance. MAPK13, which encodes the p38δ protein, was expressed more than four-fold in RRCL. Western blot analysis revealed that phosphop38 expression mainwas increased in RRCL, and when p38 inhibitor was administered, phosphop38 expression was significantly decreased. Therefore, we hypothesized that p38 MAPK activation was associated with rituximab resistance. Previous studies have suggested that p38 is associated with NF-κB activation. Deferasirox has been reported to inhibit NF-κB activity and suppress phosphorylation of the MAPK pathway. Furthermore, it also has cytotoxic effects on various cancers and synergistic effects in overcoming drug resistance. In this study, we confirmed that deferasirox induced dose-dependent cytotoxicity in both RSCL and RRCL, and the combination of deferasirox and rituximab showed a synergistic effect in RRCL at all combination concentrations.
CONCLUSION
We suggest that p38 MAPK, especially p38δ, activation is associated with rituximab resistance, and deferasirox may be a candidate to overcome rituximab resistance.
Topics: Humans; Rituximab; Deferasirox; Mitogen-Activated Protein Kinase 13; NF-kappa B; Antibodies, Monoclonal, Murine-Derived; Drug Resistance, Neoplasm; Lymphoma, Large B-Cell, Diffuse; Apoptosis; High-Throughput Nucleotide Sequencing; Cell Line, Tumor; p38 Mitogen-Activated Protein Kinases
PubMed: 37599392
DOI: 10.3904/kjim.2023.134