Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase
Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase
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DOI：
10.1182/blood-2006-09-046839
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发表时间：
2007-05-15
期刊：
影响因子：
20.3
通讯作者：
Talpaz, Moshe
中科院分区：
文献类型：
--
作者：
Guilhot, Francois;Apperley, Jane;Talpaz, Moshe
对于对伊马替尼耐药或不耐受的加速期慢性髓细胞白血病(CML-AP)患者，治疗选择有限。达沙替尼是一种新型的、有效的、口服的、多靶点的BCR-ABL和SRC家族激酶抑制剂，在对伊马替尼耐药的CML患者的1期试验中显示出显著的疗效。107名对伊马替尼耐药或不耐药的CML-AP患者进行了2期开放研究，进一步评估了达沙替尼的有效性和安全性。在最少8个月的随访中，81%、和39%的患者分别获得了总体、主要(MARR)和完全的血液学应答，而33%和24%的患者获得了主要和完全的细胞遗传学缓解。69例达到MARR，7例进展。据估计，76%的患者在10个月时还活着，病情没有进展。60%的基线bcr-abl突变患者的应答率与总人口没有差别。达沙替尼耐受性良好：大多数非血液学不良事件(AEs)为轻至中度；没有伊马替尼耐受患者因AEs而停用Dasatinib。尽管细胞减少症很常见(76%的严重中性粒细胞减少症患者)，但通过调整剂量是可以控制的。总之，达沙替尼在伊马替尼耐药或不耐受患者中诱导了显著的血液学和细胞遗传学反应，耐受性良好，可能成为CML-AP的一种有效的新治疗选择。有必要进行进一步的跟进。这项试验已在WWW上注册。ClinicalTrials.gov AS#CA180005。
Treatment options are limited for patients with imatinib-resistant or -intolerant accelerated phase chronic myeloid leukemia (CML-AP). Dasatinib is a novel, potent, oral, multitargeted kinase inhibitor of BCR-ABL and SRC-family kinases that showed marked efficacy in a phase 1 trial of patients with imatinib-resistant CML. Results are presented for 107 patients with CML-AP with imatinib-resistance or -intolerance from a phase 2, open-label study further evaluating dasatinib efficacy and safety. At 8 months' minimum follow-up, 81%, 64%, and 39% of patients achieved overall, major (MaHR), and complete hematologic responses, respectively, whereas 33% and 24% attained major and complete cytogenetic remission. Of 69 patients who achieved MaHR, 7 progressed. Seventy-six percent of patients are estimated to be alive and progression-free at 10 months. Response rates for the 60% of patients with baseline BCR-ABL mutations did not differ from the total population. Dasatinib was well tolerated: most nonhematologic adverse events (AEs) were mild to moderate; no imatinib-intolerant patients discontinued dasatinib because of AEs. Although common (76% of patients with severe neutropenia), cytopenias were manageable through dose modification. In summary, dasatinib induced significant hematologic and cytogenetic responses in patients with imatinib resistance or intolerance, was well tolerated, and may represent a potent new therapeutic option for CML-AP. Further follow-up is warranted. This trial was registered at www. clinicaltrials.gov as #CA180005.