Deferasirox treatment of iron-overloaded chelation-naïve and prechelated patients with myelodysplastic syndromes in medical practice: results from the observational studies eXtend and eXjange

EXtend and eXjange were prospective, 1‐yr, non‐interventional, observational, multicentre studies that investigated deferasirox, a once‐daily oral iron chelator, in iron‐overloaded chelation‐naïve and prechelated patients with myelodysplastic syndromes (MDS), respectively, treated in the daily‐routine setting of office‐based physicians. No inclusion or exclusion criteria or additional monitoring procedures were applied. Deferasirox was administered as recommended in the European Summary of Product Characteristics. Haematological parameters and adverse events (AEs) were collected at two‐monthly intervals. Data from 123 chelation‐naïve patients with MDS (mean age 70.4 yrs) with median baseline serum ferritin level of 2679 (range 184–16 500) ng/mL, and 44 prechelated patients with MDS (mean age 69.6 yrs) with median baseline serum ferritin level of 2442 (range 521–8565) ng/mL, were assessed. The mean prescribed daily dose of deferasirox at the first visit was 15.7 and 18.7 mg/kg/d, respectively. Treatment with deferasirox produced a significant reduction in median serum ferritin levels in chelation‐naïve patients with MDS from 2679 to 2000 ng/mL (P = 0.0002) and a pronounced decrease in prechelated patients with MDS from 2442 to 2077 ng/mL (P = 0.06). The most common drug‐related AEs were gastrointestinal, increased serum creatinine levels and rash. These studies demonstrate that deferasirox used in physicians’ medical practices is effective in managing iron burden in transfusion‐dependent patients with MDS.     

铁过载对骨髓增生异常综合征患者的危害及地拉罗司祛铁疗效探讨

长期规律输血是骨髓增生异常综合征(MDS)最为重要的支持疗法,然而长期输血带来的铁过载会导致器官损害,严重影响患者的生存预后。祛铁治疗对于改善MDS患者造血机能、减少心脏事件、延长生存起着重要作用。地拉罗司是一种新型的口服铁螯合剂,能有效改善MDS患者的造血机能、促进血液学缓解并改善脏器功能,是MDS患者祛铁治疗的一线药物。本文就铁过载对MDS患者的危害、MDS祛铁治疗指南及地拉罗司在MDS铁过载治疗中的应用做一综述。     

Second-generation and newly approved antipsychotics,serum prolactin levels and sexual dysfunctions: a critical literature review

A record 4113 fatalities were reported in 2012 in a postmarketing surveillance of patients treated with deferasirox, despite warnings of life-threatening toxic side effects, and the need for regular monitoring and prophylactic measures. In an EMA report, the mortality rate was estimated at 11.7% and a warning was issued for increasing the dose from 30 to 40 mg/kg/day. In an earlier FDA report of 2474 individual fatality cases, it was revealed that deferasirox was used in many categories of patients. Among the fatal cases reported were many young individuals and about 500 patients with normal iron stores such as cancer, leukaemia, cardiovascular and neurological diseases. The iron-loaded patient categories included myelodysplasia, sickle cell disease, haemochromatosis and thalassaemia. The rate of fatalities and the number of patient categories involved suggest that there has been an indiscriminate and uncontrollable use of deferasirox. These findings raise major concerns on patient safety and question the role, practices and procedures adopted by pharmaceutical companies, regulatory authorities, physicians, etc. in the development of new drugs and their safety. The generic drugs deferiprone, deferoxamine and their combination offer a safer, less expensive and complete treatment of iron overload in thalassaemia and other iron loading conditions.     

Introduction of higher doses of deferasirox: better efficacy but not effective iron removal from the heart and increased risks of serious toxicities

Importance of the field: Thousands of iron loaded patients are using deferasirox, who are not aware of the new, fatal and irreversible serious toxic side effects, the need for prophylaxis and the availability of more effective and less toxic chelation therapies.

Areas covered in this review: Updating on efficacy issues in relation to the introduction of higher deferasirox doses and comparison to existing chelation therapies. A new maximum dose of 40 mg/kg/day has been introduced for deferasirox in an attempt to achieve negative iron balance in thalassemia and other transfused iron loaded patients. A marginal increase in cardiac iron removal using doses of 30 – 40 mg/kg/day suggests that the rate of iron removal by deferasirox is insufficient by comparison to the deferiprone/deferoxamine combination, where total and rapid clearance of excess cardiac iron and normalization of the body iron stores could be achieved.

What the reader will gain: Identification of drug interactions and new fatal and permanent toxic side effects of deferasirox and implications on efficacy, toxicity and cost of using higher doses. Deferasirox has been identified to cause fatal gastrointestinal hemorrhages, renal tubulopathy, hepatic and renal failure, alopecia and anaphylactic reactions in addition to previously reported fatal or serious toxic side effects such as agranulocytosis, renal and hepatic toxicity, skin rash and gastric intolerance. Interactions with UDP-glucuronosyl transferase inducers, CYP2C8 and CYP3A4 substrates and drugs affecting enterohepatic recycling are likely to affect deferasirox's efficacy and toxicity. Increased toxicity is expected from the use of higher doses of deferasirox and regular prophylactic monitoring is required to avoid fatal and permanent toxicity incidences. The increased costs from higher doses of deferasirox will mostly affect patients living in the developing countries.

Take home message: Only few patients may benefit from the introduction of higher doses of deferasirox. There is a need for introducing more effective prophylactic measures. Safer, more effective and less costly chelation treatments are available using deferiprone, deferoxamine and their combination.     

Synthesis of deuterium‐labelled isotopomer of deferasirox

A d₄‐labeled isotopomer of deferasirox was synthesized as internal standard for use in a LC/mass spectroscopy (MS)/MS method developed for the simultaneous quantitative determination of deferasirox in human serum. d₄‐deferasirox was synthesized from d₈‐toluene.     

铁螯合剂去铁斯若的药理与临床评价

去铁斯若是首个1日1次的口服铁螯合剂，用于治疗成人和2岁及以上儿童由于输血引起的慢性铁超负荷。现对其药理作用、药动学、临床评价以及安全耐受性做一综述。     

铁过载概述及口服祛铁新药地拉罗司

规则输血是维持重度慢性贫血患者生命的重要治疗手段,患者长期依赖输血治疗不可避免地引起体内铁沉积增加。输血相关性铁过载可导致多脏器的损害,特别是沉积在肝脏或心脏,甚至可危及生命。作为传统的铁螯合剂,去铁酮和去铁胺因其不良反应或治疗依从性差等问题无法满足临床治疗需要。地拉罗司是一种新型的口服铁螯合剂,多个II期或III期试验证实其在输血依赖性患者中可获得与去铁胺相似的疗效。近期前瞻性、多中心EPIC研究也证实了其祛铁疗效,且有助于改善地中海贫血患者的心脏铁沉积。本文就铁过载的临床特征、危害性以及祛铁新药地拉罗司对比传统药物的优势做一综述。     

Improved efficacy and tolerability of oral deferasirox by twice-daily dosing for patients with transfusion-dependent β-thalassemia

Background

Deferasirox is an oral iron‐chelating agent taken once‐daily by patients with transfusion‐dependent iron overload. However, some patients are unresponsive or unable to tolerate once‐daily deferasirox. The current study evaluated whether twice‐daily deferasirox treatment showed increased efficacy or tolerability in unresponsive or intolerant patients.

Procedure

Patients from two Taiwanese hospitals with transfusion‐dependent β‐thalassemia, including those who showed increasing serum ferritin levels for six consecutive months, with at least one level >2,500 ng/dl, while treated with >30 mg/kg/day of once‐daily deferasirox (unresponsive) or developed deferasirox‐related adverse events (AEs) at the dosage required to maintain the iron burden balance (intolerant) and were treated twice‐daily with the same total daily dose of deferasirox since 2008, were enrolled in the study and evaluated retrospectively by medical record review.

Results

Eighteen patients were included for analysis. A statistically significant median decrease in serum ferritin levels was detected in the 11 unresponsive patients after 6 months of continuous twice‐daily deferasirox treatment. Five out of the seven intolerant patients experienced either no deferasirox‐related AEs or less severe AEs. The 12 patients from both groups (11 unresponsive, 1 intolerant) who received continuous twice‐daily deferasirox for 6 months showed a mild but significant median increase in serum creatinine levels.

Conclusions

Twice‐daily deferasirox dosing is effective in iron chelation and improves tolerability in transfusion‐dependent β‐thalassemia patients who are unresponsive to or intolerant of once‐daily deferasirox. Future studies with greater patient numbers will be required to confirm the results reported herein. Pediatr Blood Cancer 2011;56:420–424. © 2010 Wiley‐Liss, Inc.