铁过载,由于慢性贫血患者的输血,历史上一直用常规去铁胺控制,但它的肠胃外需求鼓励口服活性剂的研究,包括地拉罗司和去铁酮。Deferasirox,根据随机对照试验的结果,2005年获得美国食品和药物管理局的许可,现在是全球一线治疗。相比之下,研究者提出安全性问题后,早期研究者发起的去铁酮试验被提前终止.FDA拒绝了去铁酮的市场批准;几年后,它许可这种药物作为“最后手段”疗法,只有在一线药物失败的情况下才能开处方。我们承诺在一家输血诊所中评估去铁酮和地拉罗司的长期有效性和毒性。
根据IRB批准的研究,我们回顾性检查了2009年至2015年在大学健康网络(UHN)管理的同意的铁负荷患者的电子病历,多伦多。我们比较了肝脏和心脏铁的变化,不利影响和其他结果,在使用去铁酮或地拉罗司治疗的患者中。
尽管去铁剂在加拿大是未经许可的,三分之一(n=41)的局部输血患者已从一线转换,未经许可的去铁酮疗法(去铁胺或地拉罗司)。铁过载监测的主要终点,肝铁浓度(HIC),去铁酮单药治疗期间增加(恶化)(平均10±2-18±2mg/g;p<0.0003),50%的患者超过危及生命的并发症阈值(15mg铁/g肝脏)。在地拉罗司单药治疗期间,平均HIC降低(改善)(11±1-6±1mg/g;p<0.0001)。去铁酮和地拉罗司单一疗法后,后续HIC显着不同(p<0.0000002)。在去铁酮中添加低剂量去铁胺(<40mg/kg/天)不会导致HIC降低至<15mg/g(基线20±4mg/g;随访,18±4mg/g;p<0.2)或HIC超过15mg/g的患者比例降低(p<0.2)。在去铁酮暴露期间,新的糖尿病,铁控制不足的公认后果,在17%的患者中被诊断出,其中大多数人的HIC持续超过15mg/g多年;一名妇女在接受去铁酮和低剂量地拉罗司方案13个月后死亡。在去铁酮暴露期间,血清ALT升高超过基线65%的患者。平均血清ALT增加6.6倍(p<0.001),通常持续数年。在地拉罗司暴露期间,平均ALT不变(p<0.84)。在估计具有升高的心脏铁的患者比例中,在治疗组之间没有观察到显著差异。
去铁酮在大多数患者中显示无效和显著毒性。与低剂量的一线治疗相结合并不能改善去铁酮的有效性。暴露于去铁酮,在六年多的时间里,这种药物是无牌的,面对无效和严重的毒性,要求审查当地医疗实践标准。去铁酮的监管批准范围有限,全世界,应该限制其暴露于少数真正无法耐受这两种有效的患者,一线治疗。
Iron overload, resulting from blood transfusions in patients with chronic anemias, has historically been controlled with regular deferoxamine, but its parenteral requirement encouraged studies of orally-active agents, including deferasirox and deferiprone. Deferasirox, licensed by the US Food and Drug Administration in 2005 based upon the results of randomized controlled trials, is now first-line therapy worldwide. In contrast, early investigator-initiated trials of deferiprone were prematurely terminated after investigators raised safety concerns. The FDA declined market approval of deferiprone; years later, it licensed the drug as \"last resort\" therapy, to be prescribed only if first-line drugs had failed. We undertook to evaluate the long-term effectiveness and toxicities of deferiprone and deferasirox in one transfusion clinic.
Under an IRB-approved
study, we retrospectively inspected the electronic medical records of consented iron-loaded patients managed between 2009 and 2015 at The University Health Network (UHN), Toronto. We compared changes in liver and heart iron, adverse effects and other outcomes, in patients treated with deferiprone or deferasirox.
Although deferiprone was unlicensed in Canada, one-third (n = 41) of locally-transfused patients had been switched from first-line, licensed therapies (deferoxamine or deferasirox) to regimens of unlicensed deferiprone. The primary endpoint of monitoring in iron overload, hepatic iron concentration (HIC), increased (worsened) during deferiprone monotherapy (mean 10±2-18±2 mg/g; p < 0.0003), exceeding the threshold for life-threatening complications (15 mg iron/g liver) in 50% patients. During deferasirox monotherapy, mean HIC decreased (improved) (11±1-6±1 mg/g; p < 0.0001). Follow-up HICs were significantly different following deferiprone and deferasirox monotherapies (p < 0.0000002). Addition of low-dose deferoxamine (<40 mg/kg/day) to deferiprone did not result in reductions of HIC to <15 mg/g (baseline 20±4 mg/g; follow-up, 18±4 mg/g; p < 0.2) or in reduction in the proportion of patients with HIC exceeding 15 mg/g (p < 0.2). During deferiprone exposure, new diabetes mellitus, a recognized consequence of inadequate iron control, was diagnosed in 17% patients, most of whom had sustained HICs exceeding 15 mg/g for years; one woman died after 13 months of a regimen of deferiprone and low-dose deferasirox. During deferiprone exposure, serum ALT increased over baseline in 65% patients. Mean serum ALT increased 6.6-fold (p < 0.001) often persisting for years. During deferasirox exposure, mean ALT was unchanged (p < 0.84). No significant differences between treatment groups were observed in the proportions of patients estimated to have elevated cardiac iron.
Deferiprone showed ineffectiveness and significant toxicity in most patients. Combination with low doses of first-line therapies did not improve the effectiveness of deferiprone. Exposure to deferiprone, over six years while the drug was unlicensed, in the face of ineffectiveness and serious toxicities, demands review of the standards of local medical practice. The limited scope of regulatory approval of deferiprone, worldwide, should restrict its exposure to the few patients genuinely unable to tolerate the two effective, first-line therapies.