Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study

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 trea tment with cytarabine and daunorubicin (DNR) in patients with poor-risk acu te myeloid leukemia (AML). A total of 226 patients were randomly assigned t o sequential treatment with cytarabine and infusional DNR with or without i ntravenous CsA. Remitting patients received one course of consolidation che motherapy that included DNR with or without CsA as assigned during inductio n. Addition of CsA significantly reduced the frequency of resistance to ind uction chemotherapy (31% versus 47%, P = .0077). Whereas the rate of comple te remission was not significantly improved (39% versus 33%, P = .14), rela pse-free survival (34% versus 9% at 2 years, P = .031) and overall survival (22% versus 12%, P = .046) were significantly increased with CsA. The effe ct of CsA on survival was greatest in patients with moderate or bright Pgp expression (median 12 months with CsA versus 4 months for controls) compare d to patients with absent or low Pgp expression (median 6 months in both ar ms). 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 con centration in CsA-treated patients but not in controls, suggesting a target ed interaction by CsA to enhance anthracycline cytotoxicity. These results indicate that addition of CsA to an induction and consolidation regimen con taining infusional DNR significantly reduces resistance to DNR, prolongs th e duration of remission, and improves overall survival in patients with poo r-risk AML. (Blood. 2001;98:3212-3220) (C) 2001 by The American Society of Hematology.