Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib
Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib
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DOI：
10.1182/blood-2011-05-355594
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发表时间：
2011-10-27
期刊：
影响因子：
20.3
通讯作者：
Gambacorti-Passerini, Carlo
中科院分区：
文献类型：
--
作者：
Cortes, Jorge E.;Kantarjian, Hagop M.;Gambacorti-Passerini, Carlo
博舒替尼是一种Src/Abl双重激酶抑制剂，已显示出对慢性粒细胞白血病（CML）的有效活性。在这项I/II期研究中，我们评估了博舒替尼在慢性期伊马替尼耐药或伊马替尼不耐受CML患者中的疗效。第1部分是一项剂量递增研究，旨在确定第2部分的推荐起始剂量;第2部分评价了博舒替尼500 mg每日一次给药的疗效和安全性。该研究入组了288例伊马替尼耐药（n = 200）或伊马替尼不耐受（n = 88）CML患者，既往无其他激酶抑制剂暴露。在24周时，31%的患者达到主要细胞遗传学缓解（主要终点）。在中位随访24.2个月后，86%的患者达到血液学完全缓解，53%的患者达到主要细胞遗传学缓解（41%达到完全细胞遗传学缓解），64%达到完全细胞遗传学缓解的患者达到主要分子学缓解。2年时，无进展生存率为79%; 2年总生存率为92%。除了T315 I之外，在Bcr-Abl突变体中观察到反应。博舒替尼显示出可接受的安全性特征;最常见的治疗后出现的不良事件为轻度/中度，通常为自限性腹泻。3/4级非血液学不良事件（> 2%的患者）包括腹泻（9%）、皮疹（9%）和呕吐（3%）。这些数据表明，博舒替尼对慢性期伊马替尼耐药或伊马替尼不耐受的CML患者有效且可耐受。本试验在http://www.clinicaltrials.gov上注册为NCT 00261846。（血。2011; 118（17）：4567-4576）
Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinib-intolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846. (Blood. 2011; 118(17): 4567-4576)