Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia
Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia
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DOI：
10.1200/jco.2007.14.9260
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发表时间：
2008-07-01
影响因子：
45.3
通讯作者：
Hochhaus, Andreas
中科院分区：
文献类型：
--
作者：
Shah, Neil P.;Kantarjian, Hagop M.;Hochhaus, Andreas
目的达沙替尼是一种bcr-abl抑制剂，体外抗突变bcr-abl的效力是伊马替尼的325倍。II期研究已经证明，在伊马替尼治疗失败后，达沙替尼每天两次70 mg对慢性期(CP)慢性粒细胞白血病(CML)的疗效和安全性。在I期，尽管只有间歇性的bcr-abl抑制，但每天给药一次仍有反应。每天治疗一次的毒性较小，这表明毒性是由于对非预期靶点的持续抑制造成的。在这项开放的III期试验中，670例对伊马替尼耐药或耐药的慢性粒细胞白血病患者按1：1：1：1随机分为四组：每日100毫克、每日两次50毫克、每日140毫克或每日两次70毫克。完全，41%至45%)，在四组中观察到应答率。细胞遗传学反应的时间和持续时间与无进展生存期相似(8%至11%的患者经历了疾病进展或死亡)。与批准的每日2次70 mg方案相比，每日1次达沙替尼100 mg可显著降低胸腔积液(所有级别，7%对16%；P=.024)和3~4级血小板减少的发生率(22%对37%；P=0.004)，且需要停药(51%对68%)、减量(30%对55%)或停药(16%对23%)的患者较少。用酪氨酸激酶抑制剂间歇性靶向抑制可以保持疗效并减少不良事件。
PurposeDasatinib is a BCR-ABL inhibitor, 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Phase II studies have demonstrated efficacy and safety with dasatinib 70 mg twice daily in chronic-phase (CP) chronic myelogenous leukemia (CML) after imatinib treatment failure. In phase I, responses occurred with once-daily administration despite only intermittent BCR-ABL inhibition. Once-daily treatment resulted in less toxicity, suggesting that toxicity results from continuous inhibition of unintended targets. Here, a dose-and schedule-optimization study is reported.Patients and MethodsIn this open-label phase III trial, 670 patients with imatinib-resistant or -intolerant CP-CML were randomly assigned 1: 1: 1: 1 between four dasatinib treatment groups: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily.ResultsWith minimum follow-up of 6 months (median treatment duration, 8 months; range, = 1 to 15 months), marked and comparable hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41% to 45%) response rates were observed across the four groups. Time to and duration of cytogenetic response were similar, as was progression-free survival (8% to 11% of patients experienced disease progression or died). Compared with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily resulted in significantly lower rates of pleural effusion (all grades, 7% v 16%; P = .024) and grade 3 to 4 thrombocytopenia (22% v 37%; P = .004), and fewer patients required dose interruption (51% v 68%), reduction (30% v 55%), or discontinuation (16% v 23%).ConclusionDasatinib 100 mg once daily retains the efficacy of 70 mg twice daily with less toxicity. Intermittent target inhibition with tyrosine kinase inhibitors may preserve efficacy and reduce adverse events.