Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib.
Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib.
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DOI：
10.1002/ajh.24360
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发表时间：
2016-06
影响因子：
12.8
通讯作者：
Gambacorti-Passerini C
中科院分区：
文献类型：
--
作者：
Cortes JE;Jean Khoury H;Kantarjian H;Brümmendorf TH;Mauro MJ;Matczak E;Pavlov D;Aguiar JM;Fly KD;Dimitrov S;Leip E;Shapiro M;Lipton JH;Durand JB;Gambacorti-Passerini C
酪氨酸激酶抑制剂（TKI）治疗期间的血管和心脏安全性是一个新出现的问题。我们在两项研究中，基于治疗后出现的不良事件（TEAE）以及QTc间期和射血分数的变化，评估了与长期博舒替尼治疗费城染色体阳性（Ph+）白血病相关的血管/心脏毒性：一项二线/三线/四线博舒替尼治疗对既往TKI耐药/不耐受的Ph+白血病的I/II期研究（N = 570）和一项一线-线博舒替尼（n = 248）与伊马替尼（n = 251）在慢性期慢性粒细胞白血病。随访时间≥48个月（两项研究）。博舒替尼治疗患者中血管/心脏TEAE的发生率总体为7%/10%，一线博舒替尼（5%/8%）和伊马替尼（4%/6%）的发生率相似。少数患者发生≥3级血管/心脏事件（4%/4%），在>2%的博舒替尼患者中未发生个体TEAE。二线或更高剂量博舒替尼的暴露调整血管/心脏TEAE发生率（发生事件的患者/患者年）较低（0.037/0.050），一线博舒替尼（0.015/0.024）和伊马替尼（0.011/0.017; P ≥ 0.267）之间无显著差异。血管/心脏事件主要通过合并用药（39%/44%）、博舒替尼治疗中断（18%/21%）或剂量降低（4%/8%）进行管理;因这些事件而停药的情况罕见（0.7%/1.0%）。基于逻辑回归模型，体力状态>0和血管或心脏疾病史是复发性/难治性患者血管/心脏事件的预后因素;高脂血症/高胆固醇血症和年龄较大是心脏事件的预后因素。在新诊断的患者中，年龄较大是血管/心脏事件的预后;糖尿病史是血管事件的预后。在Ph+白血病患者长期治疗后的一线和复发/难治性环境中，博舒替尼的血管和心脏事件发生率较低。
Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long-term bosutinib treatment for Philadelphia chromosome-positive (Ph+) leukemia based on treatment-emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second-/third-/fourth-line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N = 570) and a phase 3 study of first-line bosutinib (n = 248) versus imatinib (n = 251) in chronic phase chronic myeloid leukemia. Follow-up time was ≥48 months (both studies). Incidences of vascular/cardiac TEAEs in bosutinib-treated patients were 7%/10% overall with similar incidences observed with first-line bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade ≥3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in >2% of bosutinib patients. Exposure-adjusted vascular/cardiac TEAE rates (patients with events/patient-year) were low for second-line or later bosutinib (0.037/0.050) and not significantly different between first-line bosutinib (0.015/0.024) and imatinib (0.011/0.017; P ≥ 0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status >0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with bosutinib in the first-line and relapsed/refractory settings following long-term treatment in patients with Ph+ leukemia.
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影响因子：
3.8
作者：
Doherty, Kimberly R.;Wappel, Robert L.;Bacus, Sarah
通讯作者：
Bacus, Sarah
影响因子：
10.3
作者：
Gambacorti-Passerini, Carlo;Antolini, Laura;Kim, Dong-Wook
通讯作者：
Kim, Dong-Wook
影响因子：
4.7
作者：
Hayman, Suzanne R.;Leung, Nelson;Grande, Joseph P.;Garovic, Vesna D.
通讯作者：
Garovic, Vesna D.
影响因子：
12.8
作者：
Cortes, Jorge;Mauro, Michael;Wallis, Nicola T.
通讯作者：
Wallis, Nicola T.
DOI：
10.1056/nejmoa1306494
发表时间：
2013-11-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Cortes JE;Kim DW;Pinilla-Ibarz J;le Coutre P;Paquette R;Chuah C;Nicolini FE;Apperley JF;Khoury HJ;Talpaz M;DiPersio J;DeAngelo DJ;Abruzzese E;Rea D;Baccarani M;Müller MC;Gambacorti-Passerini C;Wong S;Lustgarten S;Rivera VM;Clackson T;Turner CD;Haluska FG;Guilhot F;Deininger MW;Hochhaus A;Hughes T;Goldman JM;Shah NP;Kantarjian H;PACE Investigators
通讯作者：
PACE Investigators