Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom's macroglobulinemia.
Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom's macroglobulinemia.
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DOI：
10.1158/1078-0432.ccr-09-1837
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发表时间：
2010-02-01
期刊：
影响因子：
--
通讯作者：
Richardson PG
中科院分区：
文献类型：
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作者：
Ghobrial IM;Roccaro A;Hong F;Weller E;Rubin N;Leduc R;Rourke M;Chuma S;Sacco A;Jia X;Azab F;Azab AK;Rodig S;Warren D;Harris B;Varticovski L;Sportelli P;Leleu X;Anderson KC;Richardson PG
华氏巨球蛋白血症 (WM) 是一种罕见的低度淋巴细胞增殖性疾病。基于临床前研究，我们进行了一项 II 期临床试验，测试 Akt 抑制剂哌立福辛对复发/难治性 WM 患者的疗效和安全性。 37 名患者每天口服哌立福辛 150 mg，治疗 6 个周期。稳定或有反应的患者被允许继续治疗直至病情进展。中位年龄为 65 岁（范围：44-82 岁）。先前治疗线的中位数为 2（范围，1-5）。在 37 名患者中，4 名获得部分缓解（11%），9 名获得最低缓解（24%），20 名患者病情稳定（54%）。中位无进展生存期为 12.6 个月。此外，>3.5mg/dL 的 β-2 微球蛋白与不良无事件生存率相关（p=0.002）。哌立福辛一般耐受性良好；与治疗相关的不良事件包括血细胞减少（3-4 级，13%）、胃肠道症状（1-2 级，81%）和关节炎发作（所有级别，11%）。使用基因表达谱和免疫组织化学的转化研究表明，哌立福辛抑制 Akt 下游的 pGSK 活性，并抑制 NF-kB 活性。哌立福辛至少对 35% 的患者产生最小缓解，对复发或复发/难治性 WM 患者的中位无进展生存期为 12.6 个月，并且体内抑制 pGSK 活性。这项研究的结果值得进一步评估哌立福辛联合利妥昔单抗或其他活性药物治疗 WM 患者的效果。
Waldenstrom's Macroglobulinemia (WM) is a rare low-grade lymphoproliferative disorder. Based on preclinical studies, we conducted a phase II clinical trial testing the efficacy and safety of the Akt inhibitor perifosine in patients with relapsed/refractory WM. Thirty-seven patients were treated with oral perifosine 150 mg daily for 6 cycles. Stable or responding patients were allowed to continue therapy until progression. The median age was 65 years (range, 44-82). The median number of prior therapy lines was 2 (range, 1-5). Of the 37 patients, 4 achieved partial response (11%), 9 minimal response (24%), and 20 showed stable disease (54%). The median progression-free survival was 12.6 months. Additionally, beta-2 microglobulin of >3.5mg/dL was associated with poor event-free survival, (p=0.002). Perifosine was generally well tolerated; adverse events related to therapy were cytopenias (grade 3-4, 13%), gastrointestinal symptoms (grade 1-2, 81%), and arthritis flare (all grades, 11%). Translational studies using gene expression profiling and immunohistochemistry showed perifosine inhibited pGSK activity downstream of Akt, and inhibited NF-kB activity. Perifosine results in at least a minimal response in 35% of patients and a median progression-free survival of 12.6 months in patients with relapsed or relapsed/refractory WM, as well as in vivo inhibition of pGSK activity. The results of this study warrant further evaluation of perifosine in combination with rituximab or other active agents in patients with WM.