Detailed Investigation On Characteristics of Japanese Patients with Chronic Phase CML Who Achieved a Durable CMR After Discontinuation of Imatinib – an Updated Result of the Keio STIM Study.
Detailed Investigation On Characteristics of Japanese Patients with Chronic Phase CML Who Achieved a Durable CMR After Discontinuation of Imatinib – an Updated Result of the Keio STIM Study.
复制标题
对停用伊马替尼后获得持久 CMR 的日本慢性期 CML 患者特征的详细调查——庆应义塾 STIM 研究的最新结果。
DOI：
10.1182/blood.v120.21.2788.2788
复制
发表时间：
2012
期刊：
影响因子：
20.3
通讯作者：
S. Okamoto
中科院分区：
文献类型：
--
作者：
E. Matsuki;Y. Ono;Koharu Tonegawa;M. Sakurai;H. Kunimoto;J. Ishizawa;Norisato Hashimoto;Takayuki Shimizu;A. Yamane;M. Matsushita;K. Yokoyama;S. Okamoto
摘要2788背景和目的：酪氨酸激酶抑制剂（TKI）治疗已成为慢性粒细胞白血病（CML）患者的标准治疗方法。它可以诱导持久的血液学、细胞遗传学和分子学应答，从而显著改善无进展生存期（PFS）。另一方面，许多研究小组最近对长期停用TKI进行了研究。我们的研究旨在确认在维持完全分子学缓解（CMR）至少2年的日本患者中是否可以安全地停用TKI，并确定与无药生存期（DFS）延长相关的可能因素，包括免疫学特征。还评估了伊马替尼停药对生活质量（QOL）的影响。方法：持续CMR（定义为骨髓中bcr-abl定量和定性PCR阴性）超过2年的CML成人患者入组本研究。如果外周血定量PCR（TMA方法）值超过100个拷贝，则开始伊马替尼或其他TKI治疗。在停药前和停药后6个月或复发情况下重新诱导药物后进行淋巴细胞亚群分析。在6例患者中，WT-1特异性细胞毒性T淋巴细胞（CTL）频率也进行了评估前，3个月和6个月后停药。使用SF-36问卷在伊马替尼停药前、停药后2个月和1年进行QOL分析。患者：入组41例患者，分析40例患者。患者的中位年龄为54岁（范围28 - 83岁）。索卡尔风险评分为低24例（60%），中等10例（25%）和高3例（7.5%）。伊马替尼治疗的中位时间为98个月（范围24-126），CMR的中位持续时间为49.5个月（范围24-106）。结果：分析时患者的中位随访时间为15.5个月（范围2-18）。18例患者（45%）重新开始治疗，12个月时的估计DFS率为55.4%（图1）。5例患者再次开始伊马替尼治疗，13例患者再次接受达沙替尼治疗。除1例患者外，所有患者在开始TKI后均恢复了CMR。在包括年龄、既往干扰素治疗、伊马替尼治疗持续时间、CMR持续时间、至CMR的时间、性别、巨细胞病毒血清学和索卡尔风险评分在内的各种因素中，CMR持续时间在单变量分析中被确定为与DFS延长相关的显著因素（p=0.027），在多变量分析中差异也显著（p=0.014）。关于外周血淋巴细胞亚群，在CD 4、19、56、ab TCR、gd TCR、CD 4/CD 25阳性细胞群中未观察到显著变化，但在复发和未复发患者中，CD 8阳性T细胞的比例显著增加（2.4% vs − 2.4%，p=0.04）。在重新开始TKI治疗的患者中，WT-1特异性CTL的比例有增加的趋势。尽管诸如面部浮肿或肌肉痉挛等症状随着伊马替尼的停药而显著降低，但身体和精神领域的QOL评分在伊马替尼停药或重新开始治疗时没有显著差异。根据用于再治疗的药物的选择，患者9的QOL也没有差异。共有6例患者在随访期间出现PCR拷贝数波动，其中2例重新开始治疗。其他人保持低拷贝数或在随访期间恢复为阴性。由于患者数量较少，未发现与持续低计数PCR相关的特定临床因素或免疫表型。结论：在CMR超过2年的患者中，有相当比例的患者实现了持续CMR。所有重新开始TKI治疗的患者仍对治疗敏感。在我们的患者人群中，较长的CMR时间被确定为与持续CMR相关的重要因素。CTL的增加也可能与重新开始治疗的必要性相关。需要更长的观察期和更多的患者数量来得出具体的结论，并确定免疫学特征相对于CMR持续性的作用。披露：没有相关的利益冲突。
Abstract 2788 Background and Purpose: Tyrosine kinase inhibitor (TKI) therapy has become the standard treatment for patients with chronic myelogenous leukemia (CML). It can induce durable hematologic, cytogenetic and molecular response, leading to a marked improvement of progression-free survival (PFS). On the other hand, long-term discontinuation of TKIs has recently been investigated by many groups. Our study was designed to confirm whether TKI could be safely discontinued in Japanese patients who have maintained complete molecular response (CMR) for at least 2 years, and to identify possible factors associated with prolonged drug-free survival (DFS), including immunologic profile. The effect of imatinib discontinuation in terms of quality of life (QOL) was also assessed. Method: Adult patients with CML who have sustained CMR (defined as negative quantitative and qualitative PCR of bcr-abl in the bone marrow) for more than 2 years were enrolled in the study. Treatment with imatinib or one of the other TKIs was initiated if the peripheral blood quantitative PCR (TMA method) value exceeded 100 copies. Lymphocyte subset analysis was performed before discontinuation of the drug, and at 6 months after discontinuation or re-induction of the drug in case of relapse. In 6 patients, WT-1 specific cytotoxic T lymphocyte (CTL) frequency was also assessed before, 3 and 6 months after drug discontinuation. QOL analysis was performed using SF-36 questionnaire before, 2 months and 1 year after discontinuation of imatinib. Patients: 41 patients were enrolled in the study, among which 40 patients were analyzed. The median age of the patients was 54 (range 28 – 83) years old. The Sokal risk score was low in 24 (60%), intermediate in 10 (25%) and high in 3 (7.5%) patients. The median time on imatinib treatment was 98 (range 24–126) months and the median duration of CMR was 49.5 months (range 24–106). Results: The median follow-up of the patients at the time of this analysis was 15.5 months (range 2–18). Treatment was restarted in 18 patients (45%), and the estimated DFS rate at 12 months was 55.4% (Fig 1). In 5 patients, imatinib was commenced again, whereas 13 patients were re-treated with dasatinib. All but one patient restored CMR after commencing TKIs. Among various factors including age, previous interferon treatment, duration of imatinib treatment, duration of CMR, time until CMR, sex, cytomegalovirus serology and Sokal risk score, duration of CMR was identified as a significant factor associated with prolonged DFS on univariate analysis (p=0.027), the difference which was also significant upon multivariate analysis (p=0.014). Regarding lymphocyte subsets in the peripheral blood, no significant changes were observed in CD4, 19, 56, ab TCR, gd TCR, CD4/CD25 positive cell population, but, there was a significant increase in the proportion of CD8 positive T cells among those who relapsed and those who did not (2.4% vs −2.4%, p=0.04). There was a trend for increased proportion of WT-1 specific CTL in patients who were restarted on TKI therapy. QOL scores of both physical and mental domains did not differ significantly with the discontinuation of imatinib or re-initiation of treatment, although symptoms such as facial puffiness or muscle cramping were markedly decreased with discontinuation. There was also no difference in the patients9 QOL according to the choice of drug used for re-treatment. Altogether 6 patients had fluctuating PCR copy number during follow-up, of which 2 were restarted on treatment. Others have maintained low copy number or have returned to negative during follow-up. Due to the small number of patients, no specific clinical factors or immunophenotypes associated with sustained low count PCR were identified. Conclusion: Sustained CMR was achieved in a substantial proportion of patients who had been in CMR for over 2 years. All patients restarted on TKI treatment remained sensitive to treatment. Longer time in CMR was identified as a significant factor related to sustained CMR in our patient population. Increase in CTL may also correlate with the necessity to restart treatment. Longer observation period and increased number of patients is necessary to draw a concrete conclusion, and to identify the role of immunologic profiles relative to persistence of CMR. Disclosures: No relevant conflicts of interest to declare.