title: Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study.
abstract: 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 daunorubicinol (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.
authors.affiliation: Southwest Oncology Group, Operations Office, 14980 Omicron Dr, San Antonio, TX, USA. alist@azcc.arizona.edu
authors.forename: A F
authors.initials: AF
authors.lastname: List
authors.forename: K J
authors.initials: KJ
authors.lastname: Kopecky
authors.forename: C L
authors.initials: CL
authors.lastname: Willman
authors.forename: D R
authors.initials: DR
authors.lastname: Head
authors.forename: D L
authors.initials: DL
authors.lastname: Persons
authors.forename: M L
authors.initials: ML
authors.lastname: Slovak
authors.forename: R
authors.initials: R
authors.lastname: Dorr
authors.forename: C
authors.initials: C
authors.lastname: Karanes
authors.forename: H E
authors.initials: HE
authors.lastname: Hynes
authors.forename: J H
authors.initials: JH
authors.lastname: Doroshow
authors.forename: M
authors.initials: M
authors.lastname: Shurafa
authors.forename: F R
authors.initials: FR
authors.lastname: Appelbaum
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D020732:Cytogenetic Analysis; D003630:Daunorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D018572:Disease-Free Survival; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D012307:Risk Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003561:Cytarabine; D016572:Cyclosporine; D003630:Daunorubicin