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Venetoclax靶向BCL2治疗复发性慢性淋巴细胞白血病
Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia


Andrew W. Roberts ... 肿瘤 • 2016.01.28

摘要


背景

新疗法改善了复发性慢性淋巴细胞白血病(CLL)患者的结局,但完全缓解的情况仍不多见。Venetoclax具有独特的作用机制;该药物靶向作用于与CLL细胞生存至关重要的蛋白质BCL2。

 

方法

我们开展了一项一期剂量递增的研究;在研究中,复发或难治性CLL或小淋巴细胞淋巴瘤(SLL)患者每天口服venetoclax,以评估药物的安全性、药物代谢动力学特征和疗效。在剂量递增阶段,56例患者接受活性药物治疗,每天从150到1,200 mg的8个剂量组。在扩展队列中,另外60例患者的治疗剂量每周逐步增加,最高达到每天400 mg。

 

结果

大多数研究患者曾经接受过多种药物治疗,并且89%的患者具有预后不良的临床或遗传学特征。所有剂量水平的venetoclax均有治疗活性。在剂量递增队列的56例患者中,有3例发生临床肿瘤溶解综合征,其中1例死亡。我们调整剂量递增方案之后,扩展队列的60例患者均未发生临床肿瘤溶解综合征。其他毒性作用包括轻度腹泻(52%的患者)、上呼吸道感染(48%)、恶心(47%)及3级或4级中性粒细胞减少(41%)。未能确定最大耐受剂量。接受venetoclax治疗的116例患者中,92例(79%)有某种程度的缓解。在下列具有预后不良因素的亚组患者中,包括对氟达拉滨耐药的患者、染色体17p缺失(17p缺失的CLL)的患者和携带未突变IGHV基因的患者,缓解率范围为71%~79%。有20%的患者达到完全缓解,其中包括5%的经流式细胞术未检出微小残留病患者。400 mg剂量组的15个月无进展生存率估计值为69%。

 

结论

venetoclax选择性靶向作用于BCL2的安全性可控,并且,在复发性CLL和SLL患者(包括具有预后不良特征的患者)中,可以带来显著的疗效(由艾伯维[AbbVie]和基因泰克[Genentech]公司资助;ClinicalTrials.gov注册号为NCT01328626)。





作者信息

Andrew W. Roberts, M.B., B.S., Ph.D., Matthew S. Davids, M.D., John M. Pagel, M.D., Ph.D., Brad S. Kahl, M.D., Soham D. Puvvada, M.D., John F. Gerecitano, M.D., Ph.D., Thomas J. Kipps, M.D., Ph.D., Mary Ann Anderson, M.B., B.S., Jennifer R. Brown, M.D., Ph.D., Lori Gressick, B.S., Shekman Wong, Ph.D., Martin Dunbar, Dr.P.H., Ming Zhu, Ph.D., Monali B. Desai, M.D., M.P.H., Elisa Cerri, M.D., Sari Heitner Enschede, M.D., Rod A. Humerickhouse, M.D., Ph.D., William G. Wierda, M.D., Ph.D., and John F. Seymour, M.B., B.S., Ph.D.
From the Department of Clinical Haematology and the Bone Marrow Transplantation Unit, Royal Melbourne Hospital (A.W.R., M.A.A.), the Division of Cancer and Haematology, Walter and Eliza Hall Institute of Medical Research (A.W.R., M.A.A.), and the Victorian Comprehensive Cancer Centre (A.W.R., J.F.S.), Parkville, VIC, and the University of Melbourne (A.W.R., J.F.S.) and Peter MacCallum Cancer Centre (J.F.S.), Melbourne, VIC — all in Australia; Dana–Farber Cancer Institute, Boston (M.S.D., J.R.B.); the Swedish Medical Center, Seattle (J.M.P.); Washington University, St. Louis (B.S.K.); University of Arizona, Tucson (S.D.P.); Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (J.F.G.); University of California, San Diego, San Diego (T.J.K.); AbbVie, North Chicago, IL (L.G., S.W., M.D., M.Z., M.B.D., E.C., S.H.E., R.A.H.); and University of Texas M.D. Anderson Cancer Center, Houston (W.G.W.). Address reprint requests to Dr. Roberts at Royal Melbourne Hospital, Melbourne, VIC 3050, Australia, or atandrew.roberts@mh.org.au.

 

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