Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors
Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors
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DOI：
10.1182/blood-2013-07-513937
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发表时间：
2014-02-27
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：
Kantarjian, Hagop M.;Cortes, Jorge E.;Gambacorti-Passerini, Carlo
博舒替尼是一种口服、双重SRC/ABL酪氨酸激酶抑制剂（TKI），对费城染色体阳性（Ph+）白血病具有临床活性。我们在一项I/II期研究中评估了博舒替尼500 mg/天在慢性期（CP）慢性粒细胞白血病（CML）或晚期Ph+白血病患者中的安全性和耐受性，这些患者对伊马替尼和可能的其他TKI耐药/不耐受。患者队列包括二线CP CML（n = 286）、三线/四线CP CML（n 5 118）和晚期白血病（n 5 166）。博舒替尼的中位持续时间为11.1（范围：0.03-83.4）个月。每个队列中的治疗后出现的不良事件（TEAE）主要为胃肠道（腹泻[86%/83%/74%]、恶心[46%/48%/48%]和呕吐[37%/38%/43%]）。腹泻出现较早，少数（8%）患者发生3/4级事件; 6%的受影响患者因腹泻降低剂量。41%的患者报告了3/4级骨髓抑制TEAE;在受累患者中，46%的患者通过中断博舒替尼治疗进行管理，32%的患者通过降低剂量进行管理。17%的患者发生丙氨酸氨基转移酶升高TEAE（3/4级，7%）;在中断给药的患者中，74%的患者成功进行了博舒替尼再激发。博舒替尼在Ph+白血病中表现出可接受的安全性和可管理的毒性。本试验（NCT 00261846）在www.ClinicalTrials.gov上注册（本手稿基于与ClinicalTrials.gov不同的数据快照）。
Bosutinib is an oral, dual SRC/ABL tyrosine kinase inhibitor (TKI) with clinical activity in Philadelphia chromosome-positive (Ph+) leukemia. We assessed the safety and tolerability of bosutinib 500 mg per day in a phase 1/2 study in chronic-phase (CP) chronic myeloid leukemia (CML) or advanced Ph+ leukemia following resistance/intolerance to imatinib and possibly other TKIs. Patient cohorts included second-line CP CML (n = 286), third-/fourth-line CP CML (n 5 118), and advanced leukemia (n 5 166). Median bosutinib duration was 11.1 (range, 0.03-83.4) months. Treatment-emergent adverse events (TEAEs) in each cohort were primarily gastrointestinal (diarrhea [86%/83%/74%], nausea [46%/48%/48%], and vomiting [37%/38%/43%]). Diarrhea presented early, with few (8%) patients experiencing grade 3/4 events; dose reduction due to diarrhea occurred in 6% of affected patients. Grade 3/4 myelosuppression TEAEs were reported in 41% of patients; among affected patients, 46% were managed with bosutinib interruption and 32% with dose reduction. Alanine aminotransferase elevation TEAEs occurred in 17% of patients (grade 3/4, 7%); among patients managed with dose interruption, bosutinib rechallenge was successful in 74%. Bosutinib demonstrated acceptable safety with manageable toxicities in Ph+ leukemia. This trial (NCT00261846) was registered at www.ClinicalTrials.gov (this manuscript is based on a different data snapshot from that in ClinicalTrials.gov).