Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML
Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML
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DOI：
10.1182/blood-2010-11-320093
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发表时间：
2011-08-11
期刊：
影响因子：
20.3
通讯作者：
Feldman, Eric J.
中科院分区：
文献类型：
--
作者：
Scandura, Joseph M.;Roboz, Gail J.;Feldman, Eric J.
我们进行了一项开放标签的1期研究，探讨在急性髓性白血病（AML）风险低于有利风险的患者中，在标准诱导化疗前使用地西他滨进行表观遗传引发的可行性、安全性和生物活性。我们直接比较了地西他滨20 mg/m2 1小时输注（A组）或连续输注（B组）3、5或7天的临床和DNA低甲基化活性，然后单次标准诱导，输注阿糖胞苷（100 mg/m2，7天）和柔红霉素（60 mg/m2，3次剂量）。毒性与单独的标准诱导化疗相似。虽然我们没有确定最大耐受剂量，但地西他滨预充7天后胃肠道毒性更大。地西他滨在所有剂量水平下均诱导DNA低甲基化，并且当通过短脉冲递送地西他滨时（A组），CD 34（+）骨髓细胞中存在更大的低甲基化趋势。27例受试者（90%）对治疗有反应：17例完全缓解（57%），10例部分缓解（33%）。在方案治疗部分缓解的患者中，8例在下一次治疗中获得缓解，使总体完全缓解率达到83%。我们的结论是，表观遗传引发的强化化疗可以安全地交付，试图提高反应率。该试验在www. clinicaltrials上注册。gov as NCT 00538876.（血。2011;118（6）：1472-1480）
We conducted an open-label phase 1 study exploring the feasibility, safety, and biologic activity of epigenetic priming with decitabine before standard induction chemotherapy in patients with less-than-favorable risk of acute myelogenous leukemia (AML). We directly compared the clinical and DNA-hypomethylating activity of decitabine delivered at 20 mg/m(2) by either a 1-hour infusion (Arm A) or a continuous infusion (Arm B) for 3, 5, or 7 days before a single, standard induction with infusional cytarabine (100 mg/m(2) for 7 days) and daunorubicin (60 mg/m(2) x 3 doses). Toxicity was similar to that of standard induction chemotherapy alone. Although we did not identify a maximum tolerated dose, there was more gastrointestinal toxicity with 7 days of decitabine priming. Decitabine induced DNA hypomethylation at all dose levels and there was a trend toward greater hypomethylation in CD34(+) bone marrow cells when decitabine was delivered by a short pulse (Arm A). Twenty-seven subjects (90%) responded to therapy: 17 with complete remission (57%) and 10 with partial remission (33%). Of the patients with partial remission to protocol treatment, 8 achieved remission to their next therapy, bringing the overall complete remission rate to 83%. We conclude that epigenetic priming of intensive chemotherapy can be safely delivered in an attempt to improve response rates. This trial was registered at www.clinicaltrials. gov as NCT00538876. (Blood. 2011;118(6):1472-1480)