A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma.
A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma.
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DOI：
10.1002/ajh.21664
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发表时间：
2010-05
影响因子：
12.8
通讯作者：
Witzig, Thomas E.
中科院分区：
文献类型：
--
作者：
Johnston, Patrick B.;Inwards, David J.;Colgan, Joseph P.;Laplant, Betsy R.;Kabat, Brian F.;Habermann, Thomas M.;Micallef, Ivana N.;Porrata, Luis F.;Ansell, Stephen M.;Reeder, Craig B.;Roy, Vivek;Witzig, Thomas E.
依维莫司是一种口服抗肿瘤药物，靶向雷帕霉素（mTORC1）的猛禽哺乳动物靶点。磷脂酰肌醇3-激酶/mTOR信号转导通路已被证明在霍奇金淋巴瘤（HL）患者的肿瘤样本中被激活。该试验的目的是了解依维莫司对复发/难治性HL患者的抗肿瘤活性和毒性。如果患者有可测量的疾病，血小板计数≥75,000，绝对中性粒细胞计数≥1,000，则符合条件。患者每日服用依维莫司10mg PO。剂量减少是允许的。在2和6个周期后评估疗效，然后每3个周期评估一次，直到病情进展。患者可继续用药直至病情恶化或出现毒性。19名患者入组。中位年龄37岁（范围27-68岁）。患者既往接受治疗的中位数为6次（范围3-14），84%患者既往接受过自体干细胞移植。ORR为47% (95% CI: 24-71%)， 8例患者达到PR， 1例患者达到CR。中位TTP为7.2个月。4名应答者在12个月时仍无进展。患者平均接受7个疗程的治疗。在19例患者中，1例在36个月时仍在接受治疗；其余因疾病进展（16例）、毒性（1例）和感染死亡（1例）而退出研究。4例患者出现3级或更高级别肺毒性。依维莫司在复发/难治性HL中具有单药活性，并提供了靶向HL中mTOR通路具有临床相关性的概念证明。
Everolimus is an oral antineoplastic agent that targets the raptor mammalian target of rapamycin (mTORC1). The phosphatidylinositol 3-kinase/mTOR signal transduction pathway has been demonstrated to be activated in tumor samples from patients with Hodgkin Lymphoma (HL). The goal of this trial was to learn the anti-tumor activity and toxicity of everolimus in patients with relapsed/refractory HL. Patients were eligible if they had measurable disease, a platelet count ≥75,000 and an absolute neutrophil count ≥1,000. Patients received everolimus 10 mg PO daily. Dose reductions were allowed. Response was assessed after 2 and 6 cycles and then every 3 cycles until progression. Patients could remain on drug until progression or toxicity. Nineteen patients were enrolled. Median age was 37 years (range, 27-68). Patients had received a median of 6 prior therapies (range, 3-14) and 84% had undergone prior autologous stem cell transplant. The ORR was 47% (95% CI: 24-71%) with 8 patients achieving a PR and 1 patient achieving a CR. The median TTP was 7.2 months. Four responders remained progression free at 12 months. Patients received a median of 7 cycles of therapy. Of the 19 patients, 1 remains on therapy at 36 months; the others went off-study due to progressive disease (16), toxicity (1), and death from infection (1). Four patients experienced a grade three or higher pulmonary toxicity. Everolimus has single-agent activity in relapsed/refractory HL and provides proof-of-concept that targeting the mTOR pathway in HL is clinically relevant.
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