Dose escalation studies of cytarabine, daunorubicin, and etoposide with and without multidrug resistance modulation with PSC-833 in untreated adults with acute myeloid leukemia younger than 60 years: Final induction results of cancer and leukemia group B study 9621
Dose escalation studies of cytarabine, daunorubicin, and etoposide with and without multidrug resistance modulation with PSC-833 in untreated adults with acute myeloid leukemia younger than 60 years: Final induction results of cancer and leukemia group B study 9621
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DOI：
10.1200/jco.2004.11.106
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发表时间：
2004-11-01
影响因子：
45.3
通讯作者：
Larson, RA
中科院分区：
文献类型：
--
作者：
Kolitz, JE;George, SL;Larson, RA
目的 PSC-833 强烈抑制 P-糖蛋白 (Pgp)。在 60 岁以下未经治疗的急性髓系白血病患者中进行了一项 PSC-833 化疗剂量递增研究。使用临床终点而不是药代动力学终点来开发两种诱导疗法，其中含有对 Pgp 介导的外流敏感的药物，并且在最大耐受剂量下与相似的毒性相关。 患者和方法 总共招募了 410 名患者。包含可变剂量柔红霉素 (DNR) 和依托泊苷 (ETOP) 以及固定剂量阿糖胞苷的 15 种诱导方案在使用 (ADEP) 或不使用 (ADE) 固定剂量 PSC-833 的情况下进行了评估。结果 为 ADE 中选择的 I II I 期测试剂量为 DNR 90 mg/m(2) 和 ETOP 100 mg/m(2)，DNR 和 ETOP 各 40 ADEP 中的 mg/m(2)。较高剂量的 ADEP 会发生无法耐受的粘膜毒性。尽管本研究的设计排除了直接比较，但在 45 岁患者的无病生存和总生存方面，接受 ADEP 具有明显的优势，尽管与 ADE 相比，ADEP 中给予的 DNR 和 ETOP 剂量显着较低。结论 使用大型临床数据集来开发包含两种对 Pgp 介导的外流敏感的药物的诱导方案，有或没有 Pgp 功能抑制剂。所选剂量具有相当的抗白血病活性和毒性，使其适合用于 60 岁以下急性髓性白血病患者诱导化疗的 III 期比较研究。该试验还将阐明 5 至 45 岁的患者是否特别有可能在诱导治疗期间从 Pgp 抑制中受益。 0 2004 年美国临床肿瘤学会
Purpose P-glycoprotein (Pgp) is strongly inhibited by PSC-833. A chemotherapy dose-escalation study was performed with PSC-833 in patients younger than 60 years with untreated acute myeloid leukemia. Clinical rather than pharmacokinetic end points were used to develop two induction therapies containing drugs susceptible to Pgp-mediated efflux and associated with comparable toxicities at the maximum-tolerated doses.Patients and Methods A total of 410 patients were enrolled. Fifteen induction regimens containing variable doses of daunorubicin (DNR) and etoposide (ETOP) and fixed doses of cytarabine were evaluated with (ADEP) or without (ADE) a fixed dose of PSC-833.Results Doses selected for phase I I I testing were DNR 90 mg/m(2) and ETOP 100 mg/m(2) in ADE, and DNR and ETOP each 40 mg/m(2) in ADEP. Intolerable mucosal toxicity occurred at higher doses of ADEP. Although the design of this study precludes direct comparisons, there was an apparent advantage for receiving ADEP with respect to disease-free and overall survival in patients : 45 years old, despite the significantly lower doses of DNR and ETOP given in ADEP compared with ADE.Conclusion A large clinical data set was used to develop induction regimens containing two drugs susceptible to Pgp-mediated efflux, with and without an inhibitor of Pgp function. The chosen doses have comparable antileukemia activity and toxicity, making them suitable for use in a phase III comparative study of induction chemotherapy for patients with acute myeloid leukemia younger than 60 years. That trial will also clarify whether patients :5 45 years old are especially likely to benefit from Pgp inhibition during induction therapy. 0 2004 by American Society of Clinical Oncology