Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia
Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia
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DOI：
10.1182/blood-2012-03-413898
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发表时间：
2012-06-21
期刊：
影响因子：
20.3
通讯作者：
Marcucci, Guido
中科院分区：
文献类型：
--
作者：
Blum, William;Schwind, Sebastian;Marcucci, Guido
我们最近报道了地西他滨10天方案在老年AML患者中的有希望的临床活性;高miR-29 b表达与临床应答相关。随后在AML细胞中进行的硼替佐米临床前研究显示，药物诱导的miR-29 b上调，导致与髓性白血病发生相关的几个基因（包括DNA甲基转移酶和受体酪氨酸激酶）的转录激活丧失。因此，开发了硼替佐米和地西他滨的I期试验。入组了19例低风险AML患者（中位年龄70岁;范围32-84岁）。地西他滨（20 mg/m2，第1-10天静脉注射）加硼替佐米（在第5、8、12和15天递增至目标1.3 mg/m2）诱导是可耐受的，但硼替佐米相关神经病变在重复周期后发生。在既往未经治疗的患者（年龄≥ 65岁）中，10例患者中有5例达到CR（完全缓解，n = 4）或不完全CR（CRi，n = 1）; 19例患者中有7例达到CR/CRi。药效学分析显示FLT 3在第1周期第26天下调（P = .02）。其他机制研究表明，FLT 3下调是由于硼替佐米诱导的miR-29 B上调;这导致SP1下调和反式激活FLT 3的SP1/NF-κ B复合物的破坏。本研究证明了地西他滨联合硼替佐米治疗AML的可行性和初步临床活性，并将FLT 3确定为未来试验的新药效学终点。本研究在http://www.clinicaltrials.gov注册为NCT 00703300。（血。2012; 119（25）：6025-6031）
We recently reported promising clinical activity for a 10-day regimen of decitabine in older AML patients; high miR-29b expression associated with clinical response. Subsequent preclinical studies with bortezomib in AML cells have shown drug-induced miR-29b up-regulation, resulting in loss of transcriptional activation for several genes relevant to myeloid leukemogenesis, including DNA methyltransferases and receptor tyrosine kinases. Thus, a phase 1 trial of bortezomib and decitabine was developed. Nineteen poor-risk AML patients (median age 70 years; range, 32-84 years) enrolled. Induction with decitabine (20 mg/m(2) intravenously on days 1-10) plus bortezomib (escalated up to the target 1.3 mg/m(2) on days 5, 8, 12, and 15) was tolerable, but bortezomib-related neuropathy developed after repetitive cycles. Of previously untreated patients (age >= 65 years), 5 of 10 had CR (complete remission, n = 4) or incomplete CR (CRi, n = 1); 7 of 19 overall had CR/CRi. Pharmacodynamic analysis showed FLT3 down-regulation on day 26 of cycle 1 (P = .02). Additional mechanistic studies showed that FLT3 down-regulation was due to bortezomib-induced miR-29b up-regulation; this led to SP1 down-regulation and destruction of the SP1/NF-kappa B complex that transactivated FLT3. This study demonstrates the feasibility and preliminary clinical activity of decitabine plus bortezomib in AML and identifies FLT3 as a novel pharmacodynamic end point for future trials. This study is registered at http://www.clinicaltrials.gov as NCT00703300. (Blood. 2012; 119(25): 6025-6031)