Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC833 (Valspodar)
Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC833 (Valspodar)
复制标题
DOI：
10.1182/blood.v93.3.787.403k30_787_795
复制
发表时间：
1999-02-01
期刊：
影响因子：
20.3
通讯作者：
Greenberg, PL
中科院分区：
文献类型：
--
作者：
Advani, R;Saba, HI;Greenberg, PL
多药耐药（MDR-1）基因产物P-糖蛋白（P-gp）是急性髓系白血病（AML）化疗耐药的一个潜在机制，它在难治性或复发性AML的成髓细胞中经常过表达。在一项多中心II期临床试验中，37例具有这些低风险AML形式的患者接受PSC 833（Valspodar; Novartis Pharmaceutical Corporation，东汉诺威，NJ）治疗，PSC 833是MDR-1外排泵的强效抑制剂，pins米托蒽醌、依托泊苷和阿糖胞苷（PSC-MEC）。依托泊苷和米托蒽醌与PSC的药代动力学（PK）相互作用是预期的，与无PSC的历史对照相比进行测量，显示依托泊苷清除率降低57%（P = .001），血浆中米托蒽醌的β半衰期延长1.8倍（P < .05）。为了补偿这些相互作用和临床毒性，米托蒽醌和依托泊苷的剂量显著降低，在队列II中，米托蒽醌4 mg/m2、依托泊苷40 mg/m2和C 1 g/m2的剂量水平每日给药5天耐受性良好。总的来说，33例患者出现化疗后骨髓发育不全。12例患者（32%）达到完全缓解，4例部分缓解，21例治疗失败。PK观察结果与毒性增强相关。任一药物PK参数较高的患者感染性早期死亡的概率为36%（4/11），而PK参数较低的患者感染性早期死亡的概率为5%（1/20）（P = .04）。P-gp功能进行了评估，在19例患者使用罗丹明-123流出和PSC抑制。与缺乏PSC可识别的罗丹明外排的17%相比，PSC可识别的罗丹明外排的白血病细胞表达P-gp的原始细胞百分比中位数增加（49%）（P = 0.004）。PSC-MEC在这些低风险AML患者中耐受性相对良好，并具有令人鼓舞的抗白血病作用。东部肿瘤协作组目前正在一项III期试验E2995中在类似的患者人群中测试该方案与标准MEC化疗的比较。(C)1999年，美国血液学会。
A potential mechanism of chemotherapy resistance in acute myeloid leukemia (AML) is the multidrug resistance (MDR-1) gene product P-glycoprotein (P-gp), which is often overexpressed in myeloblasts from refractory or relapsed AML. In a multicenter phase II clinical trial, 37 patients with these poor risk forms of AML were treated with PSC 833 (Valspodar; Novartis Pharmaceutical Corporation, East Hanover, NJ), a potent inhibitor of the MDR-1 efflux pump, pins mitoxantrone, etoposide, and cytarabine; (PSC-MEC). Pharmacokinetic (PK) interactions of etoposide and mitoxantrone with PSC were anticipated, measured in comparison with historical controls without PSC, and showed a 57% decrease in etoposide clearance (P = .001) and a 1.8-fold longer beta half-life for mitoxantrone in plasma (P < .05). The doses of mitoxantrone and etoposide were substantially reduced tb compensate for these interactions and clinical toxicity and in Cohort II were well tolerated at dose levels of 4 mg/m(2) mitoxantrone, 40 mg/m(2) etoposide, and 1 g/m(2) C daily for 5 days. overall, postchemotherapy marrow hypoplasia was achieved in 33 patients. Twelve patients (32%) achieved complete remission, four achieved-partial remission, and 21 failed therapy. The PK observations correlated with enhanced toxicity. The probability of an infectious early death was 36% (4 of 11) in patients with high PK parameters for either drug versus 5% (1 of 20) in those with lower PK parameters (P = .04). P-gp function was assessed in 19 patients using rhodamine-123 efflux and its inhibition by PSC. The median percentage of blasts expressing P-gp was increased (49%) for leukemic cells with PSC-inhibitable rhodamine efflux compared with 17% in cases lacking PSC-inhibitable efflux (P = .004). PSC-MEC was relatively well tolerated in these patients with poor-risk AML, and had encouraging antileukemic effects. The Eastern Cooperative Oncology Group is currently testing this regimen versus standard MEC chemotherapy in a phase III trial, E2995, in a similar patient population. (C) 1999 by The American Society of Hematology.