Henry B. Koon and Zhenghe Wang, Case Comprehensive Cancer Center, Case Western Reserve University; Kord Honda, University Hospitals; Cleveland, OH; Susan E. Krown, Ariela Noy, Memorial Sloan-Kettering Cancer Center, New York, NY; Jeannette Y. Lee, University of Arkansas for Medical Sciences, Little Rock, AR; Suthee Rapisuwon, Georgetown University Medical Center, Washington, DC; David Aboulafia, Virginia Mason Medical Center, Seattle, WA; Erin G. Reid, University of California San Diego Moores Cancer Center, San Diego, CA; Michelle A. Rudek, Johns Hopkins University, Baltimore, MD; Bruce J Dezube, Beth Israel Deaconess Medical Center, Boston, MA.
J Clin Oncol. 2014 Feb 10;32(5):402-8. doi: 10.1200/JCO.2012.48.6365. Epub 2013 Dec 30.
Kaposi's sarcoma (KS) is a disease of multifocal vascular proliferation that requires infection with KS herpes virus (KSHV/HHV-8). Activation of the c-kit and platelet-derived growth factor (PDGF) receptors by autocrine/paracrine mechanisms follows endothelial cell KSHV infection. In a pilot study, imatinib, a c-kit/PDGF-receptor inhibitor, induced partial regression of AIDS-associated KS (AIDS-KS) in five of 10 patients.
This multicenter phase II study was designed to estimate the response rate to imatinib in AIDS-KS. Secondary objectives included investigation of predictors of response and imatinib pharmacokinetics in patients on antiretrovirals. Patients received imatinib 400 mg/day by mouth for up to 12 months with dose escalation up to 600 mg/day at 3 months if their disease was stable.
Thirty patients were treated at 12 AIDS Malignancy Consortium sites. Ten patients (33.3%) achieved partial response, six (20%) had stable disease, and seven (23.3%) exhibited KS progression. Nine patients completed 52 weeks of imatinib therapy. The median treatment duration was 22.5 weeks. Only five patients (16.7%) discontinued therapy owing to adverse events. Antiretroviral regimens did not significantly alter imatinib metabolism. Activating mutations in PDGF-R and c-kit were not found at baseline or at disease progression. We found no correlation with response with changes in any of the candidate cytokines.
Imatinib has activity in AIDS-KS. Pharmacokinetic interactions with antiretroviral drugs did not correlate with toxicity. Thirty percent of patients showed long-term clinical benefit and remained on imatinib for the entire year. These results suggest imatinib is well tolerated and may be an alternative therapy for some patients with AIDS-KS.
卡波济肉瘤（KS）是一种多灶性血管增生性疾病，需要感染卡波济肉瘤疱疹病毒（KSHV/HHV-8）。内皮细胞 KSHV 感染后，通过自分泌/旁分泌机制激活 c-kit 和血小板衍生生长因子（PDGF）受体。在一项初步研究中，c-kit/PDGF 受体抑制剂伊马替尼可使 10 名 AIDS-KS 患者中的 5 名部分缓解。
本多中心二期研究旨在评估伊马替尼治疗 AIDS-KS 的反应率。次要目标包括调查反应的预测因子和接受抗逆转录病毒治疗的患者的伊马替尼药代动力学。患者口服伊马替尼 400mg/天，持续 12 个月，如果疾病稳定，则在 3 个月时增加剂量至 600mg/天。
在 12 个艾滋病恶性肿瘤联盟中心治疗了 30 名患者。10 名患者（33.3%）获得部分缓解，6 名患者（20%）病情稳定，7 名患者（23.3%）出现 KS 进展。9 名患者完成了 52 周的伊马替尼治疗。中位治疗持续时间为 22.5 周。只有 5 名患者（16.7%）因不良反应而停止治疗。抗逆转录病毒方案并未显著改变伊马替尼的代谢。在基线或疾病进展时均未发现 PDGF-R 和 c-kit 的激活突变。我们没有发现任何候选细胞因子的变化与反应有任何相关性。
伊马替尼对 AIDS-KS 有效。与抗逆转录病毒药物的药代动力学相互作用与毒性无关。30%的患者表现出长期临床获益，并在整个治疗期间继续使用伊马替尼。这些结果表明伊马替尼具有良好的耐受性，可能是某些 AIDS-KS 患者的替代治疗方法。
