Background: Decitabine efficacy in acute myeloid leukemia (AML) may be enhanced by the pharmacologic upregulation of microRNA miR-29b, a regulator of DNA methyltransferase (DNMT) expression. Bortezomib and sorafenib have been shown preclinically to increase miR-29b levels, providing a biologically informed strategy to sensitize leukemic blasts to DNMT inhibition. Objectives: To evaluate the safety, tolerability, biological activity, and preliminary efficacy of combining bortezomib and sorafenib followed by decitabine in patients with newly diagnosed or relapsed/refractory AML. Methods: This phase I, dose-escalation study enrolled 15 patients (11 untreated, 4 relapsed/refractory) who received fixed-dose bortezomib and sorafenib across three dose levels prior to decitabine. Dose escalation was guided by dose-limiting toxicities (DLTs) and an increase in miR-29b expression. Results: The regimen was generally well tolerated with the most frequent grade ≥3 adverse events of hypertension and febrile neutropenia. At the highest dose level, a ≥2-fold increase in miR-29b expression was observed in two of the six evaluable patients. The overall response rate was 33.3%, with clinical responses observed in both newly diagnosed and relapsed/refractory patients. However, changes in miR-29b expression did not consistently correlate with clinical response. Conclusions: Sequential treatment with bortezomib and sorafenib followed by decitabine is feasible and demonstrates acceptable safety in AML. Although the biologic modulation of miR-29b was variable, this trial provides a proof of concept for pharmacodynamic-guided dose finding in epigenetic therapy combinations.
背景：地西他滨在急性髓系白血病（AML）中的疗效可能通过药物性上调微小RNA miR-29b（一种DNA甲基转移酶表达调节因子）而增强。临床前研究表明，硼替佐米和索拉非尼可提高miR-29b水平，这为增强白血病原始细胞对DNMT抑制的敏感性提供了基于生物学的策略。目的：评估硼替佐米联合索拉非尼序贯地西他滨方案在新诊断或复发/难治性AML患者中的安全性、耐受性、生物学活性及初步疗效。方法：这项I期剂量递增研究纳入15例患者（11例初治，4例复发/难治），在给予地西他滨前接受三个剂量水平的固定剂量硼替佐米和索拉非尼治疗。剂量递增依据剂量限制性毒性和miR-29b表达水平升高情况确定。结果：该方案总体耐受性良好，最常见的≥3级不良事件为高血压和发热性中性粒细胞减少。在最高剂量水平，6例可评估患者中有2例观察到miR-29b表达量增加≥2倍。总体缓解率为33.3%，在新诊断和复发/难治患者中均观察到临床缓解。然而，miR-29b表达变化与临床反应未呈现一致性关联。结论：硼替佐米联合索拉非尼序贯地西他滨的治疗方案在AML中具有可行性且安全性可接受。尽管miR-29b的生物学调控存在个体差异，但本研究为表观遗传联合疗法中基于药效动力学的剂量探索提供了概念验证。
肿瘤(癌症)患者之家