Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations
Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations
复制标题
DOI：
10.1182/blood-2009-04-214221
复制
发表时间：
2009-12-03
期刊：
影响因子：
20.3
通讯作者：
Hochhaus, Andreas
中科院分区：
文献类型：
--
作者：
Mueller, Martin C.;Cortes, Jorge E.;Hochhaus, Andreas
达沙替尼是一种BCR-ABL抑制剂，在体外对未突变的BCR-ABL的效力比伊马替尼高325倍。伊马替尼失败通常是由BCR-ABL突变引起的。在此，在既往伊马替尼治疗后招募的伴有或不伴有BCR-ABL突变的慢性期慢性髓性白血病2/3期试验患者中分析了达沙替尼的疗效。在1043例患者中，39%的患者存在BCR-ABL突变，包括805例伊马替尼耐药或疗效欠佳的患者中的48%。在基线时检测到63种不同的BCR-ABL突变，影响49种氨基酸，其中G250、M351、M244和F359最常见。随访2年后，达沙替尼治疗伊马替尼耐药患者（有或无突变）的缓解率显著（完全细胞遗传学缓解：43% vs 47%）和持久的无进展生存期（70% vs 80%）。除T315 I外，其他不同突变（包括P环区的伊马替尼高度耐药突变）均获得了高缓解率。在达沙替尼中位抑制浓度（IC 50）大于3 nM的一些突变中观察到应答受损;在IC 50较低或未知的突变患者中，疗效与无突变患者相当。总体而言，达沙替尼在有或无BCR-ABL突变的患者中具有持久疗效。所有试验均在http://www.clinicaltrials.gov上注册为NCT 00123474、NCT 00101660和NCT 00103844。（血。2009; 114：4944-4953）
Dasatinib is a BCR-ABL inhibitor with 325-fold higher potency than imatinib against unmutated BCR-ABL in vitro. Imatinib failure is commonly caused by BCR-ABL mutations. Here, dasatinib efficacy was analyzed in patients recruited to phase 2/3 trials with chronic-phase chronic myeloid leukemia with or without BCR-ABL mutations after prior imatinib. Among 1043 patients, 39% hada preexisting BCR-ABL mutation, including 48% of 805 patients with imatinib resistance or suboptimal response. Sixty-three different BCR-ABL mutations affecting 49 amino acids were detected at baseline, with G250, M351, M244, and F359 most frequently affected. After 2 years of follow-up, dasatinib treatment of imatinib-resistant patients with or without a mutation resulted in notable response rates (complete cytogenetic response: 43% vs 47%) and durable progression-free survival (70% vs 80%). High response rates were achieved with different mutations except T315I, including highly imatinib-resistant mutations in the P-loop region. Impaired responses were observed with some mutations with a dasatinib median inhibitory concentration (IC50) greater than 3nM; among patients with mutations with lower or unknown IC50, efficacy was comparable with those with no mutation. Overall, dasatinib has durable efficacy in patients with or without BCR-ABL mutations. All trials were registered at http://www.clinicaltrials.gov as NCT00123474, NCT00101660, and NCT00103844. (Blood. 2009; 114: 4944-4953)