Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation.
Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation.
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DOI：
10.1111/j.1365-2141.2010.08213.x
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发表时间：
2010-07
影响因子：
6.5
通讯作者：
Byrd JC
中科院分区：
文献类型：
--
作者：
Blum KA;Liu Z;Lucas DM;Chen P;Xie Z;Baiocchi R;Benson DM;Devine SM;Jones J;Andritsos L;Flynn J;Plass C;Marcucci G;Chan KK;Grever MR;Byrd JC
地西他滨靶向慢性淋巴细胞白血病（CLL）和非霍奇金淋巴瘤（NHL）异常DNA高甲基化可能逆转b细胞恶性肿瘤的表观遗传沉默。20名患者参加了两项I期试验，以确定复发/难治性CLL （n=16）和NHL （n=4）患者地西他滨的最小有效药理学剂量（MEPD）。患者接受1-3个周期地西他滨治疗。在接受地西他滨15mg /m2/d治疗的4例CLL患者和2例NHL患者中观察到剂量限制性毒性（DLT），包括3-4级血小板减少症和高胆红素血症。6例CLL患者接受地西他滨治疗，剂量为10mg /m2/d，第1-10天无DLT；然而，没有观察到甲基化基因的重新表达或整体DNA甲基化的变化。因此，我们研究了一个5天的地西他滨计划。使用15 mg/m2/d地西他滨第1-5天，6例CLL患者中2例和2例NHL患者中2例发生DLT，包括3-4级中性粒细胞减少症、血小板减少症和发热性中性粒细胞减少症。8例病情稳定。在17例患者中，全基因组甲基化或靶基因再表达没有显著变化。剂量限制的骨髓抑制和感染并发症可防止地西他滨剂量上升到与CLL和NHL中总甲基化或基因再表达变化相关的水平。
Targeting aberrant DNA hypermethylation in chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL) with decitabine may reverse epigenetic silencing in B-cell malignancies. Twenty patients were enrolled in two phase I trials to determine the minimum effective pharmacologic dose (MEPD) of decitabine in patients with relapsed/refractory CLL (n=16) and NHL (n=4). Patients received 1–3 cycles of decitabine. Dose limiting toxicity (DLT) was observed in 2 of 4 CLL and 2 of 2 NHL patients receiving decitabine at 15 mg/m2/d days 1–10, consisting of grade 3–4 thrombocytopenia and hyperbilirubinemia. Six patients with CLL received decitabine at 10 mg/m2/d days 1–10 without DLT; however, re-expression of methylated genes or changes in global DNA methylation were not observed. Therefore, a 5-day decitabine schedule was examined. With 15 mg/m2/d decitabine days 1–5, DLT occurred in 2 of 6 CLL and 2 of 2 NHL patients, consisting of grade 3–4 neutropenia, thrombocytopenia, and febrile neutropenia. Eight patients had stable disease. In 17 patients, there were no significant changes in genome-wide methylation or in target gene re-expression. Dose-limiting myelosuppression and infectious complications prevents dose escalation of decitabine to levels associated with changes in global methylation or gene re-expression in CLL and NHL.
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影响因子：
11.2
作者：
Rush, LJ;Raval, A;Plass, C
通讯作者：
Plass, C
影响因子：
20.3
作者：
Katzenellenbogen, RA;Baylin, SB;Herman, JG
通讯作者：
Herman, JG
影响因子：
45.3
作者：
Harris, NL;Jaffe, ES;Bloomfield, CD
通讯作者：
Bloomfield, CD
影响因子：
30.8
作者：
Yu, L;Liu, CH;Plass, C
通讯作者：
Plass, C
影响因子：
8.8
作者：
Hubeek, I;Stam, RW;Kaspers, GJL
通讯作者：
Kaspers, GJL