Dasatinib - In chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia
Dasatinib - In chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia
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DOI：
10.2165/00063030-200822010-00007
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发表时间：
2008-01-01
期刊：
影响因子：
6.8
通讯作者：
Keam, Susan J.
中科院分区：
文献类型：
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作者：
Keam, Susan J.
达沙替尼是多种酪氨酸激酶的小分子抑制剂，包括纳摩尔浓度的BCR-ABL、SRC、c-KIT、肝配蛋白A受体和血小板衍生生长因子-P受体激酶。在体外，达沙替尼对表达野生型BCR-ABL的细胞的作用是伊马替尼的325倍。口服达沙替尼的疗效和耐受性已在慢性粒细胞白血病（CML）或费城染色体阳性急性淋巴细胞白血病成人患者的START II期试验中得到证实（Ph阳性ALL）对伊马替尼不耐受或耐药，在III期随机试验中确定了最佳达沙替尼剂量方案。在慢性期CML患者中，START-C试验中的主要细胞遗传学缓解率达沙替尼组（中位随访15.2个月）为59%，而在随机START-R试验（中位随访15个月）中，达沙替尼组高于高剂量伊马替尼组（52% vs 33%）。在加速期CML患者中，达沙替尼的主要血液学缓解率为63（随访9个月; START-A试验），髓系原始细胞期CML患者为34%，淋巴样原始细胞期CML患者为35%（随访>= 12个月; START-B和START-L试验），41%的Ph阳性ALL患者（随访>= 12个月; START-L试验）。基于III期结果，认为每日一次达沙替尼方案是慢性期CML的最佳方案（起始剂量100 mg，每日一次），而在加速期继续推荐每日两次方案，髓系原始细胞期或淋巴样原始细胞期CML和Ph阳性ALL（起始剂量70 mg，每日两次）。在接受达沙替尼治疗的患者中，不良事件频繁发生，但大多数严重程度为轻度至中度。3/4级不良事件不常见，临床上可管理。
Dasatinib is a small-molecule inhibitor of multiple tyrosine kinases, including BCR-ABL, SRC, c-KIT, ephrin A receptor and platelet-derived growth factor-P receptor kinases, at nanomolar concentrations. In vitro, dasatinib is 325-fold more potent than imatinib against cells expressing wild-type BCR-ABL.The efficacy and tolerability of oral dasatinib has been established in the START phase II trials in adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) who were intolerant or resistant to imatinib, and optimal dasatinib dosage regimens were identified in phase III randomized trials.In patients with chronic phase CML, the major cytogenetic response rate in the START-C trial (median follow-up 15.2 months) was 59% with dasatinib, and in the randomized START-R trial (median follow-up 15 months), was greater with dasatinib than with high-dose imatinib (52% vs 33%). Major hematologic response rates with dasatinib were 63% in patients with accelerated phase CML (follow-up 9 months; START-A trial), 34% in patients with myeloid blast phase CML and 35% in those with lymphoid blast phase CML (follow-up >= 12 months; START-B and START-L trials), and 41% in patients with Ph-positive ALL (follow-up >= 12 months; START-L trial).Based on phase III results, a once-daily dasatinib regimen is considered optimal in chronic phase CML (starting dosage 100 mg once daily), while a twice-daily regimen continues to be recommended in accelerated phase, myeloid blast phase or lymphoid blast phase CML and Ph-positive ALL (starting dosage 70 mg twice daily).Adverse events were frequent in patients treated with dasatinib, but most were mild to moderate in severity. Grade 3/4 adverse events were uncommon and were clinically manageable.