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

Alan F. List, Kenneth J. Kopecky, Cheryl L. Willman, David R. Head, Diane L. Persons, Marilyn L. Slovak, Robert T Dorr, Chatchada Karanes, Harry E. Hynes, James H. Doroshow, Muhammad Shurafa, Frederick R. Appelbaum

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3212-3220
Number of pages9
JournalBlood
Volume98
Issue number12
DOIs
StatePublished - Dec 1 2001
Externally publishedYes

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Oncology
Drug Resistance
Acute Myeloid Leukemia
Cyclosporine
Modulation
Daunorubicin
Pharmaceutical Preparations
P-Glycoprotein
Survival
Chemotherapy
Anthracyclines
Cytarabine
Consolidation
Consolidation Chemotherapy
Induction Chemotherapy
Cytotoxicity
Randomized Controlled Trials

ASJC Scopus subject areas

  • Hematology

Cite this

List, A. F., Kopecky, K. J., Willman, C. L., Head, D. R., Persons, D. L., Slovak, M. L., ... Appelbaum, F. R. (2001). Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: A Southwest Oncology Group study. Blood, 98(12), 3212-3220. https://doi.org/10.1182/blood.V98.12.3212

Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia : A Southwest Oncology Group study. / List, Alan F.; Kopecky, Kenneth J.; Willman, Cheryl L.; Head, David R.; Persons, Diane L.; Slovak, Marilyn L.; Dorr, Robert T; Karanes, Chatchada; Hynes, Harry E.; Doroshow, James H.; Shurafa, Muhammad; Appelbaum, Frederick R.

In: Blood, Vol. 98, No. 12, 01.12.2001, p. 3212-3220.

Research output: Contribution to journalArticle

List, AF, Kopecky, KJ, Willman, CL, Head, DR, Persons, DL, Slovak, ML, Dorr, RT, Karanes, C, Hynes, HE, Doroshow, JH, Shurafa, M & Appelbaum, FR 2001, 'Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: A Southwest Oncology Group study', Blood, vol. 98, no. 12, pp. 3212-3220. https://doi.org/10.1182/blood.V98.12.3212
List, Alan F. ; Kopecky, Kenneth J. ; Willman, Cheryl L. ; Head, David R. ; Persons, Diane L. ; Slovak, Marilyn L. ; Dorr, Robert T ; Karanes, Chatchada ; Hynes, Harry E. ; Doroshow, James H. ; Shurafa, Muhammad ; Appelbaum, Frederick R. / Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia : A Southwest Oncology Group study. In: Blood. 2001 ; Vol. 98, No. 12. pp. 3212-3220.
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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.",
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