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July 17, 2008 — 研究证实，Imatinib对于新诊断的慢性期BCR-ABL阳性慢性骨髓性白血病(CML)病患是高度有效的第一线治疗，不过，近三分之一的病患，使用标准剂量的imatinib没有效果。
在7月10日的临床肿瘤学期刊(Journal of Clinical Oncology)中，研究者发现，在5年时，对于标准剂量之imatinib累积的完全细胞学反应(CCyR)发生率是 82.7%，主要分子反应比率为50.1%，估计的整体存活率为83.2%，无恶化存活率为 82.7%，在5年时，25%的病患因为缺乏反应和/或毒性而中断治疗；在5年时，有主要细胞学反应仍继续服用imatinib的病患比率为62.7%。
根据一篇编辑评论，尽管imatinib用于CML病患的资料迄今看来相当不错，但仍有改善的需要与空间；然而，如何改善这些结果，是个难以回答的问题。
【改善结果】
德州大学安德森癌症中心的Jorge E. Cortes医师在编辑评论中写道，imatinib治疗失败的病患，目前有不错的第二线治疗方法；第二代的酪胺酸激酶抑制剂dasatinib与 nilotinib已经获得当局核准，其他制剂也正在研发中。对于imatinib反应不佳或者无法耐受的病患，或许可藉由这些新的治疗获得较佳的长期结果。
改善CML病患之长期结果的另一种方法是，使用较高剂量的imatinib；初步报告建议，此策略可以获得较多与较快的缓解。Cortes医师指出，干扰素、cytarabine与其他临床已知对CML有活性的制剂，或者干扰其他CML相关路径，都可以和imatinib有协同作用，但并用治疗的初步尝试尚未达成功的标准。
Cortes医师认为，应放弃将imatinib作为新诊断CML病患的标准照护；他指出，虽然我们最终可能可以改善存活，但期望在短期内改善是不切实际的，imatinib治疗病患5年才会有不错的存活。
他写道，改善没有转化的存活也是困难的，不过，改善无意外的存活是有价值的，而且是比较可达到的目标，特别是无意外的定义是广义的时候，例如目前有些研究作者认为，包括毒性反应以及无法达到主要的细胞学缓解(MCyR)或者CCyR。
有关imatinib用于新诊断CML的现有资料，是来自International Randomized Study of Interferon (IRIS)，在制造商的监控之下进行；大部分的病患达到持久的CCyR，估计5年时的整体存活率为89%，20%的病患因各种原因进行审查，仅对继续使用imatinib的病患进行无意外存活与恶化成加速期或者急性转化期(blastic phase)之评估。
【与IRIS比较】
英国伦敦Hammersmith医院与Imperial学院的Hugues de Lavallade医师等人，进行单一中心试验，评估imatinib用于204个新诊断慢性期BCR-ABL阳性CML成年病患的效果，从2000年6月治疗到2006年8月，研究的初级目标是比较整体结果和治疗意向分析的结果是否有差异。
所有的病患接受imatinib作为第一线治疗，在诊断后6个月内开始；研究者评估血液学、细胞学、与分子反应，以及无恶化和整体存活。
他们的平均追踪期38个月，虽然比IRIS研究短，但结果相似；在IRIS试验中，60个月的CCyR累积发生率为87%，无意外存活为83%，整体存活为89%；目前的研究中，上述三个指标分别为82.7%、81.3%与 83.2%。
平均15.5个月之后，54名病患(26%)永久停用imatinib，原因包括副作用、失去完整血液学反应、恶化成加速期或者急性转化期、失去MCyR；研究期间有75名病患(37%)增加imatinib 的剂量。
激酶区域(KD)突变与后天对于酪胺酸激酶抑制剂之阻抗有关，追踪期间，在11名病患发现有12个不同的KD突变，发生KD突变可明显预测失去CCyR，但无法预测失去完整的血液学反应、无恶化存活或者整体存活；研究者也指出，如同之前报告提及的，整体存活和无恶化存活的主要预测因子是一年的细胞学反应。
作者写道，难以定义imatinib失败，一部分是因为有些病患迅速达到血液学反应，但达到CCyR时间较长；不过，不能无限期的等待CCyR。
他们指出，在IRIS研究中，病患未达到MCyR，但在失去完整血液学反应前停止imatinib，并不被视为imatinib治疗失败；此外，有病患是因为副用作而停止治疗。
他们写道，从而得知，无意外存活，一如IRIS研究中定义的，可能被高估了；若适当考量这些失败，一如治疗意向分析，imatinib在5年的实际反应率为62.7%。
此研究由健康研究生物医学研究中心资金计划(Health Research Biomedical Research Centre Funding Scheme)支持，以及"Fondation de France"提供资金。作者们宣称没有相关资金上的往来。
J Clin Oncol. 26:3308-3309, 3358-3363. 摘要，摘要。
One Third of CML Patients Need Alternative to Imatinib
By Roxanne Nelson
Medscape Medical News
July 17, 2008 — Imatinib has proven to be a highly effective first-line therapy for newly diagnosed patients with BCR-ABL-positive chronic myeloid leukemia (CML) in the chronic phase. However, for approximately one third of patients, standard-dose imatinib is not effective.
In the July 10 issue of the Journal of Clinical Oncology, researchers found that at 5 years, the cumulative incidence of complete cytogenetic response (CCyR) to standard-dose imatinib was 82.7% and of major molecular response was 50.1%. Estimated overall survival was 83.2% and progression-free survival was 82.7%. At 5 years, 25% of patients had discontinued treatment because of a lack of response and/or toxicity. The probability, at 5 years, of patients remaining in major cytogenetic response while still taking imatinib was 62.7%.
Despite the outstanding results obtained to date with imatinib in CML patients, there is still a need and room for improvement, according to an accompanying editorial. But the more difficult question to answer is how to improve these results.
Improving Results
There are currently excellent second-line therapies for patients who have experienced failure with imatinib; the second-generation tyrosine kinase inhibitors dasatinib and nilotinib have received regulatory approval, and other agents are likely on their way, writes Jorge E. Cortes, MD, from the University of Texas MD Anderson Cancer Center, in Houston, in his editorial. "Patients that do not respond well or are intolerant to imatinib may still have a favorable long-term outcome with these new therapies."
Another approach for improving the long-term outcome of CML patients is the use of higher doses of imatinib; initial reports have suggested that this strategy might result in more and faster remissions. Dr. Cortes notes that interferon, cytarabine, and other agents with known clinical activity in CML or that interfere with other pathways involved in CML have been found to be synergistic with imatinib, although initial attempts at combination therapies have not been met with much success.
Dr. Cortes wonders what would be needed to dethrone imatinib as the standard of care for patients with newly diagnosed CML. He points out that although we would ultimately like to improve survival, it is unrealistic to expect an improvement in the short term, given the excellent survival at 5 years for patients treated with imatinib.
"Improving survival free from transformation is similarly difficult," he writes. However, an improvement in event-free survival would be valuable and is a more reachable goal, particularly if a broader definition of "event free" is used, such as the one suggested by the authors of the current study, which includes toxicity and failure to achieve (or loss of) major cytogenetic remission (MCyR) or CCyR.
Most of the available data on imatinib efficacy in newly diagnosed CML patients is drawn from the International Randomized Study of Interferon (IRIS), which was conducted under the supervision of the manufacturer. Most patients achieved a durable CCyR, with an estimated overall survival of 89% at 5 years, but 20% of patients were censored for various reasons, and event-free survival and progression to accelerated or blastic phase were only evaluated for patients who continued to use imatinib.
Comparison with IRIS
Hugues de Lavallade, MD, and colleagues from Hammersmith Hospital and Imperial College, in London, United Kingdom, performed a single-center trial that evaluated the efficacy of imatinib in 204 consecutive adult patients with newly diagnosed BCR-ABL-positive CML in the chronic phase who were treated from June 2000 until August 2006. The primary goal of their study was to see whether overall results differed from those obtained from an analysis performed on an intention-to-treat basis where all events were recorded.
All patients received imatinib as first-line therapy; it was started within 6 months of their diagnosis. The researchers evaluated hematologic, cytogenetic, and molecular response, and progression-free and overall survival.
Even though the median follow-up of 38 months in their study was shorter than that in the IRIS study, the results were similar. In the IRIS trial, the cumulative incidence of CCyR at 60 months was 87%, event-free survival was 83%, and overall survival was 89%. In the current study, the rates were 82.7%, 81.3%, and 83.2%, respectively.
After a median of 15.5 months, 54 patients (26%) had permanently discontinued imatinib, for reasons that included adverse events, loss of complete hematologic response, progression to accelerated or blastic phase, and loss of MCyR. The dose of imatinib was increased in 75 patients (37%) during the study period.
Kinase domain (KD) mutations have been associated with an acquired resistance to tyrosine kinase inhibitors and, during follow-up, 12 different KD mutations were detected in 11 patients. The development of KD mutations was significant for predicting loss of CCyR, but not for predicting loss of a complete hematologic response, progression-free survival, or overall survival. The researchers also noted that the major predictor for both overall and progression-free survival was a cytogenetic response at 1 year, which has been reported previously.
"It is difficult to define imatinib failure, in part because some patients achieve hematologic response rapidly but take substantial time to achieve a CCyR," write the authors. "However, it may be inappropriate to wait indefinitely for a CCyR."
They point out that in the IRIS study, patients who did not achieve a MCyR but who discontinued imatinib before loss of a complete hematologic response were not considered to have failed imatinib therapy. In addition, patients who stopped treatment because of adverse effects were censored.
"Consequently, event-free survival, as defined in the IRIS study, is likely to be an overestimate," they write. "When these failures are considered appropriately, as in an intention-to-treat analysis, the real response rate to imatinib at 5 years is 62.7%."
The study was supported by the Health Research Biomedical Research Centre Funding Scheme and a grant from the "Fondation de France" The authors have disclosed no relevant financial relationships.
J Clin Oncol. 26:3308-3309, 3358-3363. Abstract, Abstract