Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study
Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study
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DOI：
10.1182/blood.v98.12.3212
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发表时间：
2001-12-01
期刊：
影响因子：
20.3
通讯作者：
Appelbaum, FR
中科院分区：
文献类型：
--
作者：
List, AF;Kopecky, KJ;Appelbaum, FR
环孢素A（CsA）在临床可达到的浓度下抑制P-糖蛋白（Pgp）介导的蒽环类药物的细胞输出。这项随机对照试验旨在检测CsA加阿糖胞苷和柔红霉素（DNR）治疗低风险急性髓细胞白血病（AML）患者的获益。共有226例患者被随机分配到序贯治疗阿糖胞苷和DNR输注或不静脉注射CsA。缓解患者接受一个疗程的巩固化疗，包括诱导期间分配的DNR加或不加CsA。加入CsA显著降低了诱导化疗耐药的频率（31%对47%，P = 0.0077）。CsA组完全缓解率无显著改善（39%对33%，P = 0.14），但2年无复发生存率（34%对9%，P = 0.031）和总生存率（22%对12%，P = 0.046）显著增加。与Pgp表达缺失或低表达的患者（两组中位时间均为6个月）相比，CsA对中度或轻度Pgp表达患者（CsA组中位时间为12个月，对照组中位时间为4个月）的生存期影响最大。CsA组诱导死亡率为15%，对照组为18%。CsA治疗患者的DNR（P = 0.0089）和柔红霉素（P <0.0001）稳态血清浓度显著较高。生存率（P = 0.0003）和诱导反应（P = 0.028）在CsA治疗的患者中随着DNR浓度的增加而改善，但在对照组中没有，这表明CsA的靶向相互作用增强了蒽环类药物的细胞毒性。这些结果表明，在含有DNR的诱导和巩固治疗方案中加入CsA可显著降低DNR的耐药性，延长缓解持续时间，并改善低风险AML患者的总生存率。（血。2001;98：3212-3220）（C）2001由美国血液学学会。
Cyclosporine A (CsA) inhibits P-glycoprotein (Pgp)-mediated cellular export of anthracyclines at clinically achievable concentrations. This randomized controlled trial was performed to test the benefit of CsA addition to treatment with cytarabine and daunorubicin (DNR) in patients with poor-risk acute myeloid leukemia (AML). A total of 226 patients were randomly assigned to sequential treatment with cytarabine and infusional DNR with or without intravenous CsA. Remitting patients received one course of consolidation chemotherapy that included DNR with or without CsA as assigned during induction. Addition of CsA significantly reduced the frequency of resistance to induction chemotherapy (31% versus 47%, P = .0077). Whereas the rate of complete remission was not significantly improved (39% versus 33%, P = .14), relapse-free survival (34% versus 9% at 2 years, P = .031) and overall survival (22% versus 12%, P = .046) were significantly increased with CsA. The effect of CsA on survival was greatest in patients with moderate or bright Pgp expression (median 12 months with CsA versus 4 months for controls) compared to patients with absent or low Pgp expression (median 6 months in both arms). The frequency of induction deaths was 15% with CsA and 18% in controls. Steady-state serum concentrations of DNR (P = .0089) and dauno-rubicinol (P < .0001) were significantly higher in CsA-treated patients. Survival (P = .0003) and Induction response (P = .028) Improved with increasing DNR concentration in CsA-treated patients but not in controls, suggesting a targeted interaction by CsA to enhance anthracycline cytotoxicity. These results indicate that addition of CsA to an induction and consolidation regimen containing infusional DNR significantly reduces resistance to DNR, prolongs the duration of remission, and improves overall survival in patients with poor-risk AML. (Blood. 2001;98:3212-3220) (C) 2001 by The American Society of Hematology.