Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study
Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study
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DOI：
10.1182/blood-2007-02-073528
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发表时间：
2007-10-01
期刊：
影响因子：
20.3
通讯作者：
Coutre, Steven
中科院分区：
文献类型：
--
作者：
Ottmann, Oliver;Dombret, Herve;Coutre, Steven
费城（Ph）染色体阳性急性淋巴细胞白血病（ALL）患者病程快，预后差。达沙替尼是一种新型、口服、多靶点的BCR-ABL和SRC家族激酶抑制剂，此前已在茚达替尼耐药或不耐受的Ph阳性ALL患者中诱导应答。我们介绍了一项旨在进一步评估达沙替尼140 mg在该患者人群（n = 36）中的疗效、安全性和耐受性的2期研究的中期结果。在至少8个月的随访中，达沙替尼治疗产生了显著的血液学和细胞遗传学缓解率。42%（15/36）的患者实现了主要血液学缓解，其中67%的患者保持无进展。58%（21/36）的患者获得完全细胞遗传学缓解。存在BCR-ABL突变导致伊马替尼耐药并不排除对达沙替尼的应答。达沙替尼也是可耐受的，6%（2/36）的患者由于研究药物毒性而停止治疗。大多数不良事件（AE）为1级或2级;发热性中性粒细胞减少症是最常见的重度AE，但该事件和其他血细胞减少症可通过降低剂量进行管理。达沙替尼是一种安全有效的治疗选择，是Ph阳性ALL患者治疗的重要进展。
Patients with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL) have a rapid disease course and a poor prognosis. Dasatinib, a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, has previously induced responses in patients with indatinib-resistant or -intolerant Ph-positive ALL. We present the interim results of a phase 2 study designed to further assess the efficacy, safety, and tolerability of dasatinib 140 mg in this patient population (n = 36). With a minimum follow-up of 8 months, treatment with dasatinib resulted in substantial hematologic and cytogenetic response rates. Major hematologic responses were achieved in 42% (15/36) of patients, 67% of whom remained progression-free. Complete cytogenetic responses were attained by 58% (21/36) of patients. The presence of BCR-ABL mutations conferring imatinib resistance did not preclude a response to dasatinib. Dasatinib was also tolerable, with 6% (2/36) of patients discontinuing therapy as a result of study- drug toxicity. Most adverse events (AEs) were grade 1 or 2; febrile neutropenia was the most frequent severe AE, but this and other cytopenias were manageable with dose reduction. Dasatinib represents a safe and effective treatment option and an important therapeutic advance for patients with Ph-positive ALL.