新型铁螯合剂地拉罗司治疗骨髓增生异常综合征铁过载的临床研究

目的分析新型铁螯合剂地拉罗司治疗骨髓增生异常综合征(MDS)继发性铁过载的临床疗效及不良反应。方法回顾性分析了解放军总医院2012年1月至2014年4月期间应用新型铁螯合剂地拉罗司治疗MDS继发性铁过载患者的临床资料,观察治疗前后血清铁蛋白(SF)、红细胞输注量、血红蛋白及药物不良反应。结果共有8例MDS继发性铁过载患者服用地拉罗司,其中男性7例,女性1例,中位年龄52(38~71)岁。治疗3个月后,疗效评价为完全反应(CR)3例,微小反应(MiR)3例,稳定铁过载(SIL)2例,总反应率为75.0%(6/8),中位红细胞输注量为2(1~3)u/月。治疗1年后,疗效评价为CR 5例,MiR 2例,SIL1例,总反应率为87.5%(7/8)。与治疗前相比,患者治疗1年后SF显著降低[(871.0±584.2)vs(2164.9±1233.6)ng/m1]、血红蛋白显著升高[(101.5±34.59)vs(65.37±21.35)g/L],差异均具有统计学意义(P0.05)。1年后5例患者脱离输血,其余3例中位红细胞输注量分别为0.5 u/月、1.5 u/月及2.0 u/月。治疗1年后,仅1例患者死亡。服药后出现恶心、呕吐者3例,腹泻1例。结论地拉罗司治疗MDS继发性铁过载安全有效。     

Iron‐chelating therapy with deferasirox in transfusion‐dependent,higher risk myelodysplastic syndromes: a retrospective,multicentre study

Iron chelation is controversial in higher risk myelodysplastic syndromes (HR‐MDS), outside the allogeneic transplant setting. We conducted a retrospective, multicentre study in 51 patients with transfusion‐dependent, intermediate‐to‐very high risk MDS, according to the revised international prognostic scoring system, treated with the oral iron chelating agent deferasirox (DFX). Thirty‐six patients (71%) received azacitidine concomitantly. DFX was given at a median dose of 1000 mg/day (range 375–2500 mg) for a median of 11 months (range 0·4–75). Eight patients (16%) showed grade 2–3 toxicities (renal or gastrointestinal), 4 of whom (8%) required drug interruption. Median ferritin levels decreased from 1709 μg/l at baseline to 1100 μg/l after 12 months of treatment (P = 0·02). Seventeen patients showed abnormal transaminase levels at baseline, which improved or normalized under DFX treatment in eight cases. One patient showed a remarkable haematological improvement. At a median follow up of 35·3 months, median overall survival was 37·5 months. The results of this first survey of DFX in HR‐MDS are comparable, in terms of safety and efficacy, with those observed in lower‐risk MDS. Though larger, prospective studies are required to demonstrate real clinical benefits, our data suggest that DFX is feasible and might be considered in a selected cohort of HR‐MDS patients.     

Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with β-thalassemia major

Background

Prospective data on cardiac iron removal are limited beyond one year and longer-term studies are, therefore, important.

Design and Methods

Seventy-one patients in the EPIC cardiac substudy elected to continue into the 3^rd year, allowing cardiac iron removal to be analyzed over three years.

Results

Mean deferasirox dose during year 3 was 33.6±9.8 mg/kg per day. Myocardial T2*, assessed by cardiovascular magnetic resonance, significantly increased from 12.0 ms ±39.1% at baseline to 17.1 ms ±62.0% at end of study (P<0.001), corresponding to a decrease in cardiac iron concentration (based on ad hoc analysis of T2*) from 2.43±1.2 mg Fe/g dry weight (dw) at baseline to 1.80 ±1.4 mg Fe/g dw at end of study (P<0.001). After three years, 68.1% of patients with baseline T2* 10 to <20 ms normalized (≥20 ms) and 50.0% of patients with baseline T2* >5 to <10 ms improved to 10 to <20 ms. There was no significant variation in left ventricular ejection fraction over the three years. No deaths occurred and the most common investigator-assessed drug-related adverse event in year 3 was increased serum creatinine (n=9, 12.7%).

Conclusions

Three years of deferasirox treatment along with a clinically manageable safety profile significantly reduced cardiac iron overload versus baseline and normalized T2* in 68.1% (32 of 47) of patients with T2* 10 to <20 ms.     

Iron chelation: a potential therapeutic strategy in oesophageal cancer

Raised intracellular iron has been identified as a potential aetiological factor in the development of several epithelial malignancies, including those of the gastrointestinal tract. The mechanism behind this increase is thought to include disorders of iron uptake and storage. Several iron chelators have been identified as potential anti-tumour agents, with much work undertaken to ascertain the exact mode of action. Despite this, there is little known about the role that these drugs play in the cellular iron metabolism of oesophageal cancer. Consequently, the present study looks to review the relationship of two clinically important iron-chelating agents, deferoxamine and deferasirox, on cellular iron uptake and storage in oesophageal squamous and adenocarcinoma. This provides important evidence for the debate about the role these agents have in the clinical management of such tumours.

Linked Article

This article is a commentary on Ford et al., pp. 1316–1328 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12045     

Long-term experience with deferasirox (ICL670), a once-daily oral iron chelator,in the treatment of transfusional iron overload

Background: Chronic iron overload from frequent blood transfusions to treat patients with severe anaemias leads to significant morbidity and mortality. While deferoxamine, the current standard of care, is an effective iron chelator, it requires subcutaneous infusion for 8 – 12 h/day, 5 – 7 days/week. This regimen is problematic and impacts significantly on patients' daily life. Objective: To evaluate the efficacy and tolerability of deferasirox, a once-daily oral iron chelator. Method: To review the available data reported in peer-reviewed journals (using PubMed) and at medical conferences. Results/conclusions: Deferasirox is effective in reducing or maintaining iron burden in patients with transfusion-dependent anaemias. As deferasirox is orally administered, the inconvenience of parenteral administration with deferasirox is avoided. Deferasirox improves patient satisfaction and is expected to improve compliance with iron chelation therapy.     

Deferasirox chelation therapy in patients with transfusion‐dependent MDS: a ‘real‐world’ report from two regional Italian registries: Gruppo Romano Mielodisplasie and Registro Basilicata

Deferasirox (DFX) is an orally administered iron chelator approved for use in patients with transfusion‐dependent iron overload due to myelodysplastic syndromes (MDS). The safety and efficacy of DFX has been explored in clinical trial settings, but there is little data on unselected patients with MDS. The aim of this study was to retrospectively evaluate the safety, compliance, efficacy and effect on haematopoiesis of DFX in a large ‘real‐world’ MDS population. One hundred and eighteen patients with transfusion‐dependent MDS were treated with DFX across 11 centres in Italy. Serum ferritin levels, haematological response, dosing, adverse events and transfusion dependence were recorded at baseline, 3, 6, 12 and 24 months following initiation of treatment. DFX reduced mean serum ferritin levels from 1790 to 1140 ng/mL (P < 0.001), with 7.1% of patients achieving transfusion independence. Significant haematological improvement was seen in erythroid (17.6%), platelet (5.9%) and neutrophil counts (7.1%). Adverse events were reported in 47.5% of patients, including gastrointestinal and renal toxicity. Regression analysis showed that higher starting doses of DFX are associated with transfusion independence at 24 months. DFX is a safe, effective treatment for transfusion‐dependent MDS that can lead to transfusion independence and haematological improvement in a subset of patients.