文章：

一项关于西罗莫司联合“7&3”诱导化疗治疗新诊断急性髓系白血病患者的I期临床试验

A Phase I Trial of Sirolimus with “7&3” Induction Chemotherapy in Patients with Newly Diagnosed Acute Myeloid Leukemia

原文发布日期：25 October 2023

DOI: 10.3390/cancers15215129

类型: Article

开放获取: 是

英文摘要：

Chemotherapy remains a primary treatment for younger AML patients, though many relapse. Data from our group have shown that highly phosphorylated S6 in blasts may predict response to sirolimus given with chemotherapy. We report the results of a phase I study of this combination in newly diagnosed AML and the pharmacodynamic analysis of pS6 before and after treatment. Subjects received sirolimus (12 mg on day 1, 4 mg daily, days 2–10), then idarubicin and cytarabine (days 4–10). Response was assessed at hematologic recovery or by day 42 using a modified IWG criteria. Fifty-five patients received sirolimus. Toxicity was similar to published 7 + 3 data, and 53% had high-, 27% intermediate-, and 20% favorable-risk disease. Forty-four percent of the high-risk patients entered into CR/CRp. Seventy-nine percent of the intermediate-risk subjects had a CR/CRp. All favorable-risk patients had a CR by day 42; 9/11 remained alive and in remission with a median follow-up of 660 days. Additionally, 41/55 patients had adequate samples for pharmacodynamic analysis. All patients demonstrated activation of S6 prior to therapy, in contrast to 67% seen in previous studies of relapsed AML. mTORC1 inhibition was observed in 66% of patients without enrichment among patients who achieved remission. We conclude that sirolimus and 7 + 3 is a well-tolerated and safe regimen. mTORC1 appears to be activated in almost all patients at diagnosis of AML. Inhibition of mTORC1 did not differ based on response, suggesting that AML cells may have redundant signaling pathways that regulate chemosensitivity in the presence of mTORC1 inhibition.

摘要翻译： 

化疗仍是年轻急性髓系白血病患者的主要治疗手段，但多数患者会出现复发。本课题组前期数据显示，原始细胞中高度磷酸化的S6蛋白可能预测患者对西罗莫司联合化疗的治疗反应。本研究报道该联合方案在新诊断急性髓系白血病患者中的I期临床试验结果，以及治疗前后pS6的药效学分析。受试者接受西罗莫司治疗（第1天12mg，第2-10天每日4mg），随后接受伊达比星联合阿糖胞苷治疗（第4-10天）。采用改良版国际工作组标准在血液学恢复时或第42天评估治疗反应。共55例患者接受西罗莫司治疗，其毒性与已发表的"7+3"方案数据相似，其中53%为高危、27%为中危、20%为低危患者。高危患者中44%达到完全缓解/血小板未完全恢复的完全缓解，中危患者中79%达到完全缓解/血小板未完全恢复的完全缓解。所有低危患者在第42天均达到完全缓解；中位随访660天后，11例中有9例仍存活且处于缓解状态。此外，55例患者中有41例获得符合药效学分析要求的样本。所有患者在治疗前均显示S6激活，而既往复发急性髓系白血病研究中该比例仅为67%。66%的患者观察到mTORC1抑制现象，且该现象在获得缓解的患者中未见富集。本研究结论：西罗莫司联合"7+3"方案耐受性良好且安全性可靠。mTORC1通路在几乎所有初诊急性髓系白血病患者中均呈激活状态。mTORC1抑制程度与治疗反应无相关性，提示在mTORC1抑制状态下，急性髓系白血病细胞可能通过冗余信号通路调控化疗敏感性。

原文链接：

A Phase I Trial of Sirolimus with “7&3” Induction Chemotherapy in Patients with Newly Diagnosed Acute Myeloid Leukemia