伊马替尼长期用药似乎安全有效

芝加哥——根据美国临床肿瘤学会（ASCO）年会上报告的一项研究结果，大多数接受伊马替尼治疗10年的慢性粒细胞性白血病（CML）患者出现药物不良反应，但多属于轻度和可控制的反应。

德国CML研究组、海德堡大学的RüdigerHehlmann博士及其同事 报告称，在1,375例接受伊马替尼（格列卫）单药治疗的CML患者中，1,018例（74%）在治疗期间出现非血液性毒性反应，不过，仅有199例（14%）为3级或4级毒性反应，且未见与伊马替尼相关的死亡病例。即使伊马替尼与干扰素-α（IFN-α）联用，药物不良反应也处于可控制的范围内。

研究者指出：“10年后，伊马替尼仍是大多数CML患者的最佳选择。”

伊马替尼作为首个酪氨酸激酶抑制剂（TKI）在美国获准上市已有13年，第二代TKI以及其他靶向治疗药物也已面世，这一老药的安全性引起人们关注。研究者评估了1,501例接受伊马替尼(400mg/d或800mg/d)单药治疗以及伊马替尼（400mg/d）联合IFN-α治疗患者的长期随访数据，并对药物不良反应数据进行了分析。

在2013年11月最近1次评估时，164例患者已经死亡，1,003例仍在接受伊马替尼治疗，275例转为第二代TKI治疗，106例接受骨髓转移治疗（部分患者接受1种以上治疗，这导致总病例数有所差异）。

中位随访时间为6.5年，部分患者随访时间长达11.5年。10年生存率为84%，10年无进展生存率为81%。基于分子学应答率的生存率分析显示，达到主要分子学应答率（MMR，定义为BCR-ABL RNA水平≤0.1%）的患者总生存率为89%，达到MR4.5（BCR-ABL转录 lg值下降≥4.5）的患者总生存率为74%。

接受伊马替尼单药治疗患者8年各级不良事件发生率分别为：水肿或体液潴留过多41%、胃肠道毒性反应38%、肌痛/关节痛25%、皮疹20%、肌肉骨骼事件17%、乏力17%、神经性毒性11%以及流感样症状10%。

5例患者出现2或3级周围动脉闭塞性病变，但是否与伊马替尼相关尚不明确。

大多数患者首次药物不良反应出现在开始接受伊马替尼治疗的3年内，此后不良反应发生频率下降。

Hehlmann博士披露接受了伊马替尼生产商诺华制药的研究经费支持。

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CHICAGO – After a decade on therapy with imatinib, a majority of patients with chronic myeloid leukemia will experience an adverse drug reaction, but most reactions are mild and manageable, according to results from a study presented at the annual meeting of the American Society of Clinical Oncology.

Of 1,375 patients with CML who received imatinib (Gleevec) monotherapy at some point, 1,018 (74%) had nonhematologic toxicities sometime during therapy, but only 199 (14%) had grade 3 or 4 toxicities, and there were no deaths attributed to imatinib, reported Dr. RüdigerHehlmann of the University of Heidelberg, Germany, and his colleagues.

Adverse drug reactions were manageable even when imatinib was combined with interferon-alfa (IFN-alfa), the investigators from the German CML Study Group reported in a poster at the meeting.

"After 10 years, imatinib continues to be an excellent choice for most patients with CML," they wrote.

In the 13 years that have elapsed since imatinib was approved in the United States as the first-in-class tyrosine kinase inhibitor, second-generation TKIs and other targeted agents have emerged, drawing attention to the safety of the older regimen.

The investigators evaluated long-term follow-up data and analyzed adverse drug reaction data for 1,501 patients treated with imatinib monotherapy in doses of 400 or 800 mg/day, as well as imatinib 400 mg in combination with IFN-alfa.

At the most recent evaluation, in November 2013, 164 patients had died, 1,003 were still on imatinib, 275 had been switched to a second-generation TKI, and 106 underwent bone marrow transplant (some patients received more than one therapy, accounting for the difference in total numbers).

The median follow-up time was 6.5 years, with some patients on study for as long as 11.5 years.

The probability of 10-year survival was 84%, and of 10-year progression-free survival was 81%.

An analysis of survival by molecular response rates showed an overall survival rate of 89% for those who achieved a major molecular response (MR, defined as a BCR-ABL RNA level of 0.1% or less), and 74% for those who achieved MR 4.5 (a 4.5 log₁₀ reduction or greater in BCR-ABL transcripts).

The 8-year probabilities for all grades of adverse events among the patients who received imatinib monotherapy were 41% for edema or fluid overload, 38% for gastrointestinal toxicities, 25% for myalgia/arthralgia, 20% for rash, 17% for musculoskeletal events, 17% for fatigue, 11% for neurological toxicities, and 10% for flulike symptoms.

Five patients had grade 2 or 3 peripheral arterial occlusive disease, but it was not clear whether these events were associated with imatinib.

For most patients the first adverse drug reaction occurred within 3 years of starting on imatinib, with the frequency of reactions decreasing thereafter.

Dr. Hehlmann disclosed receiving research support from Novartis, marketer of imatinib.