Prospective, Multicenter Clinical Trial of Everolimus as Primary Therapy in Waldenstrom Macroglobulinemia (WMCTG 09-214)
Prospective, Multicenter Clinical Trial of Everolimus as Primary Therapy in Waldenstrom Macroglobulinemia (WMCTG 09-214)
复制标题
依维莫司作为华氏巨球蛋白血症主要治疗的前瞻性、多中心临床试验 (WMCTG 09-214)
DOI：
--
复制
发表时间：
2016
影响因子：
11.5
通讯作者：
I. Ghobrial
中科院分区：
文献类型：
--
作者：
S. Treon;K. Meid;C. Tripsas;L. Heffner;H. Eradat;A. Badros;Lian Xu;Z. Hunter;Guang Yang;C. Patterson;J. Gustine;J. Castillo;J. Matous;I. Ghobrial
目的：依维莫司抑制 mTOR，mTOR 是华氏巨球蛋白血症中由 MYD88 和 CXCR4 激活突变触发的 PI3K/AKT 促生存信号传导的一个组成部分。实验设计：我们在一项前瞻性、多中心研究中评估了依维莫司，该研究对 33 名有症状、既往未经治疗的华氏巨球蛋白血症患者进行了评估。预期治疗包括依维莫司（10 mg/天）直至病情进展或出现不可接受的毒性。允许剂量降级。该研究已在 www.clinicaltrials.gov 上注册 (NCT00976248)。结果：在最佳缓解情况下，连续活检患者的中位血清 IgM 水平从 4,440 下降至 1,360 mg/dL (P < 0.0001)，中位血红蛋白从 10.8 升至 12 g/dL (P = 0.001)，中位骨髓疾病负担从 75% 下降至 52.5%。 ORR 和主要缓解率分别为 72.7% 和 60.6%。在基因分型患者中，无反应者与野生型 MYD88 和突变 CXCR4 状态相关。中位响应时间为 4 周。血清 IgM 水平与骨髓疾病负担之间存在显着差异。中位随访时间为 13.1 次（范围为 1.6-64.6 个月），所有患者的中位进展时间为 21 个月，主要缓解者为 33 个月。停用依维莫司导致 7 名患者血清 IgM 快速反弹，2 名患者出现症状性高粘滞血症。毒性导致 27% 的患者停止治疗，其中 18% 的患者因肺炎而停止治疗。结论：依维莫司对先前未经治疗的华氏巨球蛋白血症有活性。 IgM 不一致很常见，停止治疗通常会导致血清 IgM 快速反弹。与既往接受过治疗的华氏巨球蛋白血症患者相比，未经治疗的肺炎也显得更为明显。应仔细权衡依维莫司与其他华氏巨球蛋白血症主要治疗方案的风险和益处。临床癌症研究； 23（10）； 2400–4。 ©2016 AACR。
Purpose: Everolimus inhibits mTOR, a component of PI3K/AKT prosurvival signaling triggered by MYD88 and CXCR4-activating mutations in Waldenstrom macroglobulinemia. Experimental design: We evaluated everolimus in a prospective, multicenter study of 33 symptomatic, previously untreated Waldenstrom macroglobulinemia patients. Intended therapy consisted of everolimus (10 mg/day) until progression or unacceptable toxicity. Dose deescalation was permitted. The study was registered at www.clinicaltrials.gov (NCT00976248). Results: At best response, median serum IgM levels declined from 4,440 to 1,360 mg/dL (P < 0.0001), median hemoglobin rose from 10.8 to 12 g/dL (P = 0.001), and median bone marrow disease burden declined from 75% to 52.5% in serially biopsied patients. The ORR and major response rates were 72.7% and 60.6%, respectively. Among genotyped patients, nonresponders associated with wild-type MYD88 and mutated CXCR4 status. Median time to response was 4 weeks. Discordance between serum IgM levels and bone marrow disease burden was remarkable. With a median follow-up of 13.1 (range, 1.6–64.6 months), the median time to progression was 21 months for all patients and 33 months for major responders. Discontinuation of everolimus led to rapid serum IgM rebound in 7 patients and symptomatic hyperviscosity in 2 patients. Toxicity led to treatment discontinuation in 27% of patients, including 18% for pneumonitis. Conclusions: Everolimus is active in previously untreated Waldenstrom macroglobulinemia. IgM discordance is common, and treatment cessation can often lead to rapid serum IgM rebound. Pneumonitis also appears more pronounced in untreated versus previously treated Waldenstrom macroglobulinemia patients. The risks and benefits of everolimus should be carefully weighed against other primary Waldenstrom macroglobulinemia therapy options. Clin Cancer Res; 23(10); 2400–4. ©2016 AACR.
影响因子：
20.3
作者：
Xu, Lian;Hunter, Zachary R.;Treon, Steven P.
通讯作者：
Treon, Steven P.