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依鲁替尼联用维奈托克治疗套细胞淋巴瘤
Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma


Constantine S. Tam ... 肿瘤 • 2018.03.29
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• 套细胞淋巴瘤的联合靶向治疗 • ASCO 2017报告——血液系统恶性肿瘤 • 套细胞淋巴瘤患者自体干细胞移植后的利妥昔单抗治疗 • 套细胞淋巴瘤的维持性免疫治疗

摘要


背景

Bruton酪氨酸激酶(BTK)抑制剂依鲁替尼(ibrutinib)和B细胞淋巴瘤-2蛋白(BCL2)抑制剂维奈托克(venetoclax)单独使用治疗套细胞淋巴瘤都有效。作为长期持续治疗用药,这两种药物获得的完全缓解率都达到21%。临床前模型预测两药联用能产生协同效应。

 

方法

我们进行了一次单组2期试验,让患者每日口服依鲁替尼和维奈托克,将治疗结果与历史记录对照比较。患者开始时接受每日560 mg依鲁替尼单药治疗。4周之后,开始联用维奈托克,剂量每周逐步增加,直至达到每日400 mg。患者持续服用这两种药物,直到癌症进展或发生不可接受的不良事件。主要终点为16周时的完全缓解率。使用骨髓流式细胞计数和血液等位基因特异性寡核苷酸-聚合酶链反应(ASO-PCR)来评估微小残留病(MRD)。

 

结果

本研究纳入了24例患者,其中23例患复发或难治性套细胞淋巴瘤,1例患既往未经治疗的套细胞淋巴瘤。患者年龄为47~81岁,先前接受过的治疗种数为0~6种。半数患者带有TP53畸变,75%患者的预后评分为高危。根据计算机断层扫描结果,16周时的完全缓解率为42%,高于依鲁替尼单药治疗在这一时间点达到的9%的历史结果(P<0.001)。根据正电子发射断层扫描评估的16周时的完全缓解率为62%,总体缓解率为71%。流式细胞计数确认67%患者体内的微小残留病已清除,而用ASO-PCR确认的这一比例为38%。按照至事件发生时间分析的估计,获得缓解的患者中有78%至15个月时仍将缓解。两例患者发生肿瘤溶解综合征。常见副作用大多属于低级别,包括腹泻(见于83%的患者)、疲劳(75%的患者)和恶心或呕吐(71%的患者)。

 

结论

在这项以历史记录为对照的研究中,联用依鲁替尼和维奈托克同时针对BTK和BCL2进行双靶向治疗改善了套细胞淋巴瘤患者的结局。这些患者用目前疗法的预期结局不佳(由杨森等资助;AIM在ClinicalTrials.gov注册号为NCT02471391)。





作者信息

Constantine S. Tam, M.B., B.S., M.D., Mary Ann Anderson, M.B., B.S., Ph.D., Christiane Pott, M.D., Ph.D., Rishu Agarwal, M.B., B.S., Sasanka Handunnetti, M.B., B.S., Rodney J. Hicks, M.B., B.S., Kate Burbury, M.B., B.S., Gillian Turner, B.N., M.I.P.H., Juliana Di Iulio, Ph.D., Mathias Bressel, M.Sc., David Westerman, M.B., B.S., Stephen Lade, M.B., B.S., Martin Dreyling, M.D., Sarah-Jane Dawson, M.B., B.S., Ph.D., Mark A. Dawson, M.B., B.S., Ph.D., John F. Seymour, M.B., B.S., Ph.D., and Andrew W. Roberts, M.B., B.S., Ph.D.
From the Peter MacCallum Cancer Centre, Melbourne, VIC (C.S.T., M.A.A., R.A., S.H., R.J.H., K.B., G.T., J.D.I., M.B., D.W., S.L., S.-J.D., M.A.D., J.F.S., A.W.R.), and the Victorian Comprehensive Cancer Centre (C.S.T., M.A.A., R.A., S.H., R.J.H., K.B., D.W., S.-J.D., M.A.D., J.F.S., A.W.R.), the Faculty of Medicine (C.S.T., R.J.H., S.-J.D., M.A.D., J.F.S., A.W.R.) and Centre for Cancer Research (S.-J.D., M.A.D.), University of Melbourne, the Department of Clinical Haematology and Bone Marrow Transplantation, the Royal Melbourne Hospital (C.S.T., M.A.A., K.B., J.F.S., A.W.R.), and the Division of Cancer and Haematology, Walter and Eliza Hall Institute of Medical Research (M.A.A., A.W.R.), Parkville, VIC — all in Australia; and the University Hospital of Schleswig–Holstein, Kiel (C.P.), and Klinikum der Universität, Ludwig–Maximilian University of Munich, Munich (M.D.) — both in Germany. Address reprint requests to Dr. Tam at the Department of Haematology, Peter MacCallum Cancer Centre, 305 Grattan St., Melbourne, VIC 3000, Australia, or at constantine.tam@petermac.org.

 

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