12月3日，第58届美国血液学年会（ASH，12月3日~6日）于美国圣地亚哥召开。其间，在“慢性髓系白血病：治疗”专场上，一项口头报告表明达到深分子学响应的慢性髓系白血病患者停用酪氨酸激酶（TKI），安全可行。研究详情如下：

背景

酪氨酸激酶抑制剂（TKI）已经明显改善了慢性髓系白血病（CML）患者的预后，很大一部分患者达到了深分子学响应（DMR）。中断TKI是CML治疗过程中非常关键的一个问题。很多研究已经证实，相当一部分DMR患者能够安全顺利地停用TKI，但其具体的先决条件还不确定。为了明确这一问题，研究人员开展了这项EURO-SKI试验。

方法

考虑停用TKI的患者需满足：先前TKI治疗未失败、经伊马替尼、尼洛替尼或达沙替尼后达DMR（BCR-ABL <0.01%， MR4）且持续至少1年的慢性期CML患者。分子学复发被定义为缺失主要分子学缓解（MMR， BCR-ABL <0.1% IS），应用 Kaplan-Meier 法评估无分子学复发生存率（MRFS），通过单变量和多变量分析评价MR潜在的预后价值，最小p值法明确截断值（ cut-off ）。

结果

从2012年6月到2014年12月，该研究共纳入821名慢性期CML患者，其中750名患者 MRFS可评估。期中数据显示，在这750名患者中，348名患者缺失MMR，5名患者死亡；6个月时的MRFS为62%，12个月时56%，24个月时52%。在评估大部分重新达到DMR的患者时，未发现有患者进展为晚期疾病。基于伊马替尼治疗的448例患者，建立了一个预后模型。单变量分析表明，在停用TKI后的6个月时，患者的年龄、性别、分子学响应深度（（MR^4.5 vs. 非MR^4.5）或Sokal、EURO、EUTOS或ELTS评分与MMR无明显的相关性，伊马替尼治疗持续时间和停用前的MR4持续时间与6个月时的 MMR显著相关。治疗持续时间的比值比为1.16，这就表明额外增加1年的治疗增大了6个月时保持MMR16%的可能性。对于伊马替尼治疗超过5.8年的患者而言，6个月时无分子学复发生存率为65.5%，而治疗时间不超过5.8年的患者为42.6%。

结论

该研究表明，对于一大部分慢性期CML患者而言，停用TKI是安全可行的，并且也可达到较高的MRFS率。另外，停用伊马替尼前，治疗时间更长（最好超过5.8年），达到MRFS的可能性也更大。

摘要详情

787 Cessationof Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patientswith Deep Molecular Response: Results of the Euro-Ski Trial

Background: Tyrosine kinase inhibitors (TKI)have dramatically improved survival in chronic myeloid leukemia (CML) with ahigh proportion of patients reaching deep molecular responses (DMR). Theeffectiveness of stopping TKI treatment is a key question regarding themanagement of CML. Actually, in several studies, it has been proven that asubstantial part of patients in DMR can safely and successfully stop TKItherapy. However, the exact preconditions for stopping CML treatments are notyet defined. This is the aim of the European stop TKI (EURO-SKI) trial(ClinicalTrials.gov numbers: NCT01596114).

Methods: Chronic phase CML patients withoutprior TKI failure, treated with either imatinib, nilotinib or dasatinib, in DMR(BCR-ABL <0.01% on the international scale, MR4) for the duration of atleast one year were proposed to stop TKI treatment. Molecular recurrence (MR)was defined by the loss of the major molecular response (MMR, BCR-ABL <0.1%IS) at any one point. We estimated molecular recurrence-free survival (MRFS)with the Kaplan-Meier method. The potential prognostic values for MR weretested by univariate and multivariable analyses and the cut-off was identifiedwith the minimal p-value approach.

Results: From June 2012 to December 2014, 821CP CML patients were included in 11 European countries belonging to theEuropean Leukemia Net (ELN). 750 patients had assessable molecular data(European standardization according to Cross et al, Leukemia 2012) for theestimation of MRFS. Of these patients, 348 lost MMR and 5 died in remission ;MRFS was 62% (95% confidence interval (CI): 59% - 67%) at 6 months (m), 56%(CI: 52% - 59%) at 12 m and 52% (CI: 48% - 56%) at 24 m on an “Intention toTreat Basis ”. At the time of evaluation most patients regained DMR, andimportantly, no progression to advanced disease phase was noted. A prognosticmodelling was performed based on 448 patients treated with imatinib. Univariateanalysis showed no significant association between age, gender, depth ofmolecular response (MR4.5 vs. no MR4.5) or any variable part of the Sokal,EURO, EUTOS, or ELTS scores and MMR status at 6 months after treatment stop.Treatment duration with imatinib and MR4duration prior to the stop weresignificantly (p<0.001) correlated with MMR status at 6 months. The oddsratio for treatment duration was 1.16 (95%-CI: 1.08-1.25), meaning that oneadditional year of treatment increases the odds to stay in MMR at 6 months by16%. Molecular relapse-free survival at 6 months was 65.5% for imatinibtreatment > 5.8 years and 42.6% for treatment ≤ 5.8 years. This cut-off was identified withthe minimal p-value approach.

A true pharmaco-economic study will benecessary but taking into account the number of months without treatment in 603patients, Imatinib front line (with a median observation time of 24 m forpatients still off treatment) and the cost of imatinib in each of the 11European countries (range: 1.734-3.370 Euro per month) the total estimatedsavings amounted to 27.85 million Euro.

Conclusion: Using standardized molecularmonitoring, stopping TKI therapy in a very large cohort of CML-patients appearsfeasible and safe and high MRFS rates are achievable. Longer duration ofimatinib-therapy (optimal ≥ 5.8 years) prior to TKI-stop is associatedwith a higher probability of MRFS. Taking into account the long follow-upwithout molecular relapse in the historical studies such as STIM1 (Etienne etal; JCO 2016) the “operational” cure of CML with oral TKI is an up-to-dateissue.