新数据证明白血病患者可安全停药

David Ross博士

阿姆斯特丹(EGMN)—— 根据澳大利亚白血病与淋巴瘤CML-8试验的最新结果，对于已稳定缓解至少2年的慢性髓细胞性白血病(CML)患者停用伊马替尼，似乎是一种安全的治疗策略。

澳大利亚SA 病理学与Flinders 医疗中心的David Ross博士在欧洲血液病学会(EHA)年会上报告，截至2012年4月，在获得稳定完全分子学应答(CMR)且停止治疗的患者中，大约40%(18/40)在中位随访3年期间仍能保持CMR。尽管仍有22例患者在停用伊马替尼(格列卫)之后出现分子学复发，但这些患者均对伊马替尼再诱导治疗有应答，多数患者迅速获得CMR。

上述结果再结合STIM(停用伊马替尼)试验(Lancet Oncol. 2010;11:1029-35)和STOP 2G-TKI研究已发表的结果，共同表明对于部分CML患者，伊马替尼、达沙替尼(Sprycel)与尼洛替尼(Tasigna)停药是一种可行的治疗策略。

CML-8试验招募了40例伊马替尼治疗≥3年、获得CMR≥2年的成人CML患者。受试者的中位年龄为60岁，停药前接受伊马替尼治疗的中位时间为5.8年(范围：3~9年)。CMR定义为实时定量聚合酶链反应(RT-PCR)检测不到BCR-ABL mRNA。停用伊马替尼后第1年内每个月做1次RT-PCR检测，第2年内每2个月检测1次，之后每3个月检测1次，最长随访至第5年。该试验于2011年招募了最后1例患者，因此未来还将发表进一步研究数据。

Ross 博士表示：“在停药2年后没有出现任何复发。由于所有的活动都发生在停药后6个月内，因此假如我能重新设计研究，我只会在这6个月内每个月行RT-PCR检测。”他强调，虽然该试验规模非常小，但得出了与法国STIM研究相似的结果，二者的持续分子学应答率几乎完全一致。

“我们也发现，复发的最强预测因素是Sokal评分，这提示经过多年的治疗之后，从很早期就存在的不良疾病生物学仍是复发风险的最重要预测因素。”单因素分析显示，与Sokal 评分高的患者相比，Sokal评分低或中等者有更高比例保持无复发状态(在35例患者中，14.3%  vs. 49.3%，P=0.002)。

研究者还发现，既往曾接受1年干扰素治疗也可预测无复发生存率：曾接受干扰素治疗1年的患者的无复发生存率显著优于干扰素治疗不足1年者(在21例患者中，60% vs. 20%，P=0.0042)。“如果患者接受干扰素治疗达1年以上，就意味着患者对干扰素有良好应答，所以这一结果从另个角度引出了同样的结论(不良疾病生物学是复发的强预测因素)。”

“下一步应当评估第二代酪氨酸激酶抑制剂(TKI)的情况。随着尼罗替尼和达沙替尼的使用日益增多，使用伊马替尼的患者很可能会减少。另外，努力获得CMR(定义为测不到BCR-ABL)是否比获得主要分子学应答(MMR，定义为BCR-ABL降至0.1%以下)更有价值，也是可能的研究方向。”

EURO-SKI(欧洲停用激酶抑制剂)研究将进一步评估对CML患者停用TKI的可能性。这项由欧洲白血病网络发起的多中心、开放性、非对照的试验已经启动，刚刚开始招募患者。

EURO-SKI 的主要研究者、同时供职于海德堡大学和曼海姆大学医学中心的Susanne Saussele 博士表示：“我们希望能招募500例患者，但这项试验并未获得制药公司的支持，因而在部分国家存在资金困难。到目前为止，该试验仅在德国和瑞典启动。”EURO-SKI的主要目标是评估CML患者停止TKI治疗后的持续分子学缓解情况，指标为MMR 4(BCR-ABL≤0.01%)和MMR(BCR-ABL≤0.1%)。患者必须获得MMR 4至少1年才能停止TKI治疗，如果丧失MMR(BCR-ABL转录水平升至0.1%以上)则判定为达到终点。预计该试验将于2017年结束，将在3年内发表第一批数据。

CML-8研究由澳大利亚白血病与淋巴瘤组实施，获得了由诺华提供的资金。Ross博士曾从诺华获得研究资金和酬金。Saussele博士无利益冲突披露。

爱思唯尔  版权所有

BY SARA FREEMAN
Elsevier Global Medical News
Breaking News

AMSTERDAM (EGMN) – Stopping imatinib in patients who have achieved stable remission of chronic myeloid leukemia for at least 2 years appears to be a safe therapeutic strategy, according to updated results of the Australasian Leukemia and Lymphoma CML-8 trial.

“Approximately 40% of patients who had been in a stable complete molecular response and stopped their treatment are in a complete molecular response with a median follow-up of 3 years,” said consultant hematologist Dr. David Ross in an interview at the annual congress of the European Hematology Association.

As of April 2012, 18 of 40 patients remained in stable complete molecular remission (CMR) while off treatment. Although 22 patients had a molecular recurrence at some point after imatinib (Gleevec) withdrawal, they all responded to the reintroduction of imatinib, with most patients rapidly regaining CMR.

These data build on those already released from the STIM (Stop Imatinib) trial (Lancet Oncol. 2010;11:1029-35) and the STOP 2G-TKI study, which have also shown that imatinib, dasatinib (Sprycel), and nilotinib (Tasigna) withdrawal is a feasible therapeutic strategy for some patients with chronic myeloid leukemia (CML).

The CML-8 trial involved 40 adult patients who had been treated with imatinib for at least 3 years and were in CMR for at least 2 years. CMR was defined as no detectable BCR-ABL mRNA as determined by real-time quantitative polymerase chain reaction (RT-PCR) analysis. The latter was checked every month during the first year after imatinib withdrawal, every 2 months in the second year, and then every 3 months for up to 5 years of total follow-up. The last patient entered the trial in 2011, so further data from the trial are likely in the future.

“We’ve not seen any relapses later than 2 years,” said Dr. Ross, of SA Pathology and Flinders Medical Centre in Adelaide, Australia.

“If I were designing the study again now, I would only do the monthly testing for 6 months because all of the action is in the first 6 months,” Dr. Ross said.

The median age of patients participating in the study was 60 years. The median duration of imatinib therapy prior to withdrawal was 5.8 years (range, 3-9 years).

Although it is much smaller, the CML-8 trial provides findings similar to those of the French STIM study, Dr. Ross said. “We have seen an almost identical rate of sustained molecular response,” he observed.

“We’ve also seen that the strongest predictor [for relapse] is the Sokal score, which suggests that unfavorable disease biology at the very beginning is still, after all these years of treatment, the single most important predictor of relapse risk.”

Univariate analysis showed a higher percentage of patients with a low to intermediate Sokal score remaining relapse free compared with those with a high Sokal score (49.3% vs. 14.3% of 35 patients, P = .002).

One year of prior interferon therapy was also found to be predictive of relapse-free survival, with patients who had taken interferon for 1 year faring significantly better than those who had taken it for less than 1 year (60% vs. 20% of 21 patients, P = .0042).

“Again, if you stayed on interferon for more than 12 months it means that you had a good response to interferon, so it’s probably telling you the same thing in a different way,” Dr. Ross suggested.

“I think the next step from this [CML-8 study] is to look at what is going to happen with the second-generation drugs,” he added. “With the increasing use of nilotinib and dasatinib, the number of patients on imatinib is potentially going to diminish.”

Another possible research question, Dr. Ross said, was to determine whether there is any value in pushing patients to achieve a CMR (that is, no detectable BCR-ABL) over achieving a major molecular response (MMR), in which BCR-ABL falls to less than 0.1%.

One trial that will look further at the issue of stopping tyrosine kinase inhibitors (TKIs) in CML is the EURO-SKI (European Stop Kinase Inhibitor) study. This multicenter, open-label, uncontrolled trial is being run by the European LeukemiaNet, and has just started to accrue patients.

“We hope to accrue 500 patients,” said the trial’s principal investigator Dr. Susanne Saussele in an interview. Dr. Saussele of the University Medical Centre Mannheim and the University of Heidelberg, both in Germany, noted, however, that the trial does not have the backing of pharmaceutical companies, so getting funding is proving to be a challenge for some countries. To date, the trial has only started in Germany and in Sweden.

The primary aim is to estimate the persistence of molecular remission in CML after stopping treatment with available TKIs. EURO-SKI will measure MMR 4 (BCR-ABL of 0.01% or less) and MMR (BCR-ABL of 0.1% or less). Patients will need to achieve MMR 4 for at least 1 year before they can stop TKI therapy, and will have reached the end point if they lose MMR and the BCR-ABL transcript level rises over the 0.1% threshold.

“We are using MMR, which is one log higher than MMR 4 used in the STIM study,” Dr. Saussele said. “This is because the STIM study showed that a lot of patients are between MMR4 and MMR.”

The estimated date for completion of the trial is June 2017, with the first data available from the trial expected in roughly 3 years’ time.

The CML-8 study was conducted by the Australasian Leukemia and Lymphoma Group with funding from Novartis. Dr. Ross has received research funding and honoraria from Novartis. Dr. Saussele had no disclosures.