Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias
Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias
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DOI：
10.1056/nejmoa055229
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发表时间：
2006-06-15
影响因子：
158.5
通讯作者：
Sawyers, Charles L.
中科院分区：
文献类型：
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作者：
Talpaz, Moshe;Shah, Neil P.;Sawyers, Charles L.
背景：BCR-ABL酪氨酸激酶抑制剂伊马替尼对费城染色体阳性（Ph阳性）白血病有效，但复发发生，主要是由于具有伊马替尼耐药BCR-ABL突变的白血病亚克隆的生长。我们评估了达沙替尼，一种BCR-ABL抑制剂，针对大多数伊马替尼耐药的BCR-ABL突变，在慢性粒细胞白血病（CML）或Ph阳性急性淋巴细胞白血病（ALL）患者。方法：患者与各阶段的CML或Ph阳性ALL谁不能耐受或耐伊马替尼参加了1期剂量递增研究。达沙替尼（15至240毫克，每天）口服给药，在为期四周的治疗周期，每日一次或两次。结果：一个完全的血液学反应是在37的40例慢性期CML患者，主要血液学反应，在31的44例加速期CML，CML急变，或Ph阳性ALL。在这两个阶段，主要细胞遗传学缓解率分别为45%和25%。在95%的慢性期疾病患者和82%的加速期疾病患者中维持了反应，中位随访时间分别超过12个月和5个月。几乎所有淋巴母细胞危象和Ph阳性ALL患者均在6个月内复发。所有BCR-ABL基因型都有反应，T315 I突变除外，该突变在体外对达沙替尼和伊马替尼均产生耐药性。骨髓抑制很常见，但不具有剂量限制性。结论：达沙替尼可诱导对伊马替尼不能耐受或耐药的CML或Ph阳性ALL患者的血液学和细胞遗传学反应。
BACKGROUND:The BCR-ABL tyrosine kinase inhibitor imatinib is effective in Philadelphia chromosome-positive (Ph-positive) leukemias, but relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. We evaluated dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL).METHODS:Patients with various phases of CML or with Ph-positive ALL who could not tolerate or were resistant to imatinib were enrolled in a phase 1 dose-escalation study. Dasatinib (15 to 240 mg per day) was administered orally in four-week treatment cycles, once or twice daily.RESULTS:A complete hematologic response was achieved in 37 of 40 patients with chronic-phase CML, and major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or Ph-positive ALL. In these two phases, the rates of major cytogenetic response were 45 percent and 25 percent, respectively. Responses were maintained in 95 percent of patients with chronic-phase disease and in 82 percent of patients with accelerated-phase disease, with a median follow-up more than 12 months and 5 months, respectively. Nearly all patients with lymphoid blast crisis and Ph-positive ALL had a relapse within six months. Responses occurred among all BCR-ABL genotypes, with the exception of the T315I mutation, which confers resistance to both dasatinib and imatinib in vitro. Myelosuppression was common but not dose-limiting.CONCLUSIONS:Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib.