Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia

Alan F. List, Catherine S Perry, John Greer, Steven Wolff, John Hutter, Robert T Dorr, Sydney Salmon, Bernard W Futscher, Monika Baier, William Dalton

Research output: Contribution to journalArticle

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Abstract

Purpose: To determine the toxicities and maximum-tolerated dose of cyclosporine (CsA) administered with daunorubicin as a modulator of multidrug resistance (MDR) in acute leukemia, and to evaluate response to treatment and its relationship to mdr1 gene expression. Patients and Methods: Patients with poor-risk acute myeloid leukemia (AML) received sequential treatment with cytarabine (3 g/m2/d intravenously [IV]) days 1 to 5, and daunorubicin (45 mg/m2/d) plus CsA as a 72-hour continuous infusion (CI) days 6 through 8 in a phase I/II trial. A loading dose of CsA administered over 1 to 2 hours preceded the CI. CsA dose escalations ranged from 1.4 to 6 mg/kg (load) and 1.5 to 20 mg/kg/d (CI). Whole-blood concentrations of CsA were monitored by immunoassay; plasma concentration of daunorubicin and daunorubicinol were determined by high-pressure liquid chromatography (HPLC). Specimens were analyzed for P-glycoprotein expression, and results confirmed by a quantitative RNA polymerase chain reaction (PCR) assay for the mdr1 gene transcript. Results: Forty-two patients are assessable for toxicity and response. P-glycoprotein was detected in 70% of cases. Dose-dependent CsA toxicities included nausea and vomiting (22%), hypomagnesemia (61%), burning dysesthesias (21%), and prolongation of myelosuppression. Transient hyperbilirubinemia developed in 62% of treatment courses and was CsA-dose-dependent. Reversible azotemia occurred in three patients receiving concurrent treatment with potentially nephro-toxic antibiotics. Steady-state blood concentrations of CsA ≥ 1,500 ng/mL were achieved in all patients receiving CI doses ≥ 16 mg/kg/d. Mean plasma daunorubicin, but not daunorubicinol, levels were significantly elevated in patients who developed hyperbilirubinemia (P = .017). Twenty-six (62%) patients achieved a complete remission (CR) or restored chronic phase and three patients achieved a partial remission (PR) for an overall response rate of 69% (95% confidence interval, 54% to 84%). The response rate was higher in patients who developed hyperbilirubinemia (P = .001), whereas MDR phenotype did not influence response to treatment. Among five patients with MDR-positive leukemia, cellular mdr1 mRNA decreased (n = 1) or was absent from relapsed specimens (n = 4), while mdr1 RNA remained undetectable at relapse in two patients who were MDR-negative before treatment. Conclusion; High doses of CsA, which achieve blood concentrations capable of reversing P-glycoprotein-mediated anthracycline resistance in vitro, can be incorporated into induction regimens with acceptable nonhematologic toxicity. Transient hyperbilirubinemia occurs commonly with CsA administration and may alter daunorubicin pharmacokinetics. Recommended doses of CsA for phase II and III trials are a load of 6 mg/kg and CI of 16 mg/kg/d.

Original languageEnglish (US)
Pages (from-to)1652-1660
Number of pages9
JournalJournal of Clinical Oncology
Volume11
Issue number9
StatePublished - 1993

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Cyclosporine
Leukemia
Drug Therapy
Daunorubicin
Hyperbilirubinemia
Multiple Drug Resistance
P-Glycoprotein
Therapeutics
Azotemia
Maximum Tolerated Dose
Paresthesia
Poisons
Anthracyclines
Cytarabine
DNA-Directed RNA Polymerases
Immunoassay
Acute Myeloid Leukemia
Nausea
Vomiting
Pharmacokinetics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia. / List, Alan F.; Perry, Catherine S; Greer, John; Wolff, Steven; Hutter, John; Dorr, Robert T; Salmon, Sydney; Futscher, Bernard W; Baier, Monika; Dalton, William.

In: Journal of Clinical Oncology, Vol. 11, No. 9, 1993, p. 1652-1660.

Research output: Contribution to journalArticle

List, AF, Perry, CS, Greer, J, Wolff, S, Hutter, J, Dorr, RT, Salmon, S, Futscher, BW, Baier, M & Dalton, W 1993, 'Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia', Journal of Clinical Oncology, vol. 11, no. 9, pp. 1652-1660.
List, Alan F. ; Perry, Catherine S ; Greer, John ; Wolff, Steven ; Hutter, John ; Dorr, Robert T ; Salmon, Sydney ; Futscher, Bernard W ; Baier, Monika ; Dalton, William. / Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia. In: Journal of Clinical Oncology. 1993 ; Vol. 11, No. 9. pp. 1652-1660.
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title = "Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia",
abstract = "Purpose: To determine the toxicities and maximum-tolerated dose of cyclosporine (CsA) administered with daunorubicin as a modulator of multidrug resistance (MDR) in acute leukemia, and to evaluate response to treatment and its relationship to mdr1 gene expression. Patients and Methods: Patients with poor-risk acute myeloid leukemia (AML) received sequential treatment with cytarabine (3 g/m2/d intravenously [IV]) days 1 to 5, and daunorubicin (45 mg/m2/d) plus CsA as a 72-hour continuous infusion (CI) days 6 through 8 in a phase I/II trial. A loading dose of CsA administered over 1 to 2 hours preceded the CI. CsA dose escalations ranged from 1.4 to 6 mg/kg (load) and 1.5 to 20 mg/kg/d (CI). Whole-blood concentrations of CsA were monitored by immunoassay; plasma concentration of daunorubicin and daunorubicinol were determined by high-pressure liquid chromatography (HPLC). Specimens were analyzed for P-glycoprotein expression, and results confirmed by a quantitative RNA polymerase chain reaction (PCR) assay for the mdr1 gene transcript. Results: Forty-two patients are assessable for toxicity and response. P-glycoprotein was detected in 70{\%} of cases. Dose-dependent CsA toxicities included nausea and vomiting (22{\%}), hypomagnesemia (61{\%}), burning dysesthesias (21{\%}), and prolongation of myelosuppression. Transient hyperbilirubinemia developed in 62{\%} of treatment courses and was CsA-dose-dependent. Reversible azotemia occurred in three patients receiving concurrent treatment with potentially nephro-toxic antibiotics. Steady-state blood concentrations of CsA ≥ 1,500 ng/mL were achieved in all patients receiving CI doses ≥ 16 mg/kg/d. Mean plasma daunorubicin, but not daunorubicinol, levels were significantly elevated in patients who developed hyperbilirubinemia (P = .017). Twenty-six (62{\%}) patients achieved a complete remission (CR) or restored chronic phase and three patients achieved a partial remission (PR) for an overall response rate of 69{\%} (95{\%} confidence interval, 54{\%} to 84{\%}). The response rate was higher in patients who developed hyperbilirubinemia (P = .001), whereas MDR phenotype did not influence response to treatment. Among five patients with MDR-positive leukemia, cellular mdr1 mRNA decreased (n = 1) or was absent from relapsed specimens (n = 4), while mdr1 RNA remained undetectable at relapse in two patients who were MDR-negative before treatment. Conclusion; High doses of CsA, which achieve blood concentrations capable of reversing P-glycoprotein-mediated anthracycline resistance in vitro, can be incorporated into induction regimens with acceptable nonhematologic toxicity. Transient hyperbilirubinemia occurs commonly with CsA administration and may alter daunorubicin pharmacokinetics. Recommended doses of CsA for phase II and III trials are a load of 6 mg/kg and CI of 16 mg/kg/d.",
author = "List, {Alan F.} and Perry, {Catherine S} and John Greer and Steven Wolff and John Hutter and Dorr, {Robert T} and Sydney Salmon and Futscher, {Bernard W} and Monika Baier and William Dalton",
year = "1993",
language = "English (US)",
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pages = "1652--1660",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
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TY - JOUR

T1 - Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia

AU - List, Alan F.

AU - Perry, Catherine S

AU - Greer, John

AU - Wolff, Steven

AU - Hutter, John

AU - Dorr, Robert T

AU - Salmon, Sydney

AU - Futscher, Bernard W

AU - Baier, Monika

AU - Dalton, William

PY - 1993

Y1 - 1993

N2 - Purpose: To determine the toxicities and maximum-tolerated dose of cyclosporine (CsA) administered with daunorubicin as a modulator of multidrug resistance (MDR) in acute leukemia, and to evaluate response to treatment and its relationship to mdr1 gene expression. Patients and Methods: Patients with poor-risk acute myeloid leukemia (AML) received sequential treatment with cytarabine (3 g/m2/d intravenously [IV]) days 1 to 5, and daunorubicin (45 mg/m2/d) plus CsA as a 72-hour continuous infusion (CI) days 6 through 8 in a phase I/II trial. A loading dose of CsA administered over 1 to 2 hours preceded the CI. CsA dose escalations ranged from 1.4 to 6 mg/kg (load) and 1.5 to 20 mg/kg/d (CI). Whole-blood concentrations of CsA were monitored by immunoassay; plasma concentration of daunorubicin and daunorubicinol were determined by high-pressure liquid chromatography (HPLC). Specimens were analyzed for P-glycoprotein expression, and results confirmed by a quantitative RNA polymerase chain reaction (PCR) assay for the mdr1 gene transcript. Results: Forty-two patients are assessable for toxicity and response. P-glycoprotein was detected in 70% of cases. Dose-dependent CsA toxicities included nausea and vomiting (22%), hypomagnesemia (61%), burning dysesthesias (21%), and prolongation of myelosuppression. Transient hyperbilirubinemia developed in 62% of treatment courses and was CsA-dose-dependent. Reversible azotemia occurred in three patients receiving concurrent treatment with potentially nephro-toxic antibiotics. Steady-state blood concentrations of CsA ≥ 1,500 ng/mL were achieved in all patients receiving CI doses ≥ 16 mg/kg/d. Mean plasma daunorubicin, but not daunorubicinol, levels were significantly elevated in patients who developed hyperbilirubinemia (P = .017). Twenty-six (62%) patients achieved a complete remission (CR) or restored chronic phase and three patients achieved a partial remission (PR) for an overall response rate of 69% (95% confidence interval, 54% to 84%). The response rate was higher in patients who developed hyperbilirubinemia (P = .001), whereas MDR phenotype did not influence response to treatment. Among five patients with MDR-positive leukemia, cellular mdr1 mRNA decreased (n = 1) or was absent from relapsed specimens (n = 4), while mdr1 RNA remained undetectable at relapse in two patients who were MDR-negative before treatment. Conclusion; High doses of CsA, which achieve blood concentrations capable of reversing P-glycoprotein-mediated anthracycline resistance in vitro, can be incorporated into induction regimens with acceptable nonhematologic toxicity. Transient hyperbilirubinemia occurs commonly with CsA administration and may alter daunorubicin pharmacokinetics. Recommended doses of CsA for phase II and III trials are a load of 6 mg/kg and CI of 16 mg/kg/d.

AB - Purpose: To determine the toxicities and maximum-tolerated dose of cyclosporine (CsA) administered with daunorubicin as a modulator of multidrug resistance (MDR) in acute leukemia, and to evaluate response to treatment and its relationship to mdr1 gene expression. Patients and Methods: Patients with poor-risk acute myeloid leukemia (AML) received sequential treatment with cytarabine (3 g/m2/d intravenously [IV]) days 1 to 5, and daunorubicin (45 mg/m2/d) plus CsA as a 72-hour continuous infusion (CI) days 6 through 8 in a phase I/II trial. A loading dose of CsA administered over 1 to 2 hours preceded the CI. CsA dose escalations ranged from 1.4 to 6 mg/kg (load) and 1.5 to 20 mg/kg/d (CI). Whole-blood concentrations of CsA were monitored by immunoassay; plasma concentration of daunorubicin and daunorubicinol were determined by high-pressure liquid chromatography (HPLC). Specimens were analyzed for P-glycoprotein expression, and results confirmed by a quantitative RNA polymerase chain reaction (PCR) assay for the mdr1 gene transcript. Results: Forty-two patients are assessable for toxicity and response. P-glycoprotein was detected in 70% of cases. Dose-dependent CsA toxicities included nausea and vomiting (22%), hypomagnesemia (61%), burning dysesthesias (21%), and prolongation of myelosuppression. Transient hyperbilirubinemia developed in 62% of treatment courses and was CsA-dose-dependent. Reversible azotemia occurred in three patients receiving concurrent treatment with potentially nephro-toxic antibiotics. Steady-state blood concentrations of CsA ≥ 1,500 ng/mL were achieved in all patients receiving CI doses ≥ 16 mg/kg/d. Mean plasma daunorubicin, but not daunorubicinol, levels were significantly elevated in patients who developed hyperbilirubinemia (P = .017). Twenty-six (62%) patients achieved a complete remission (CR) or restored chronic phase and three patients achieved a partial remission (PR) for an overall response rate of 69% (95% confidence interval, 54% to 84%). The response rate was higher in patients who developed hyperbilirubinemia (P = .001), whereas MDR phenotype did not influence response to treatment. Among five patients with MDR-positive leukemia, cellular mdr1 mRNA decreased (n = 1) or was absent from relapsed specimens (n = 4), while mdr1 RNA remained undetectable at relapse in two patients who were MDR-negative before treatment. Conclusion; High doses of CsA, which achieve blood concentrations capable of reversing P-glycoprotein-mediated anthracycline resistance in vitro, can be incorporated into induction regimens with acceptable nonhematologic toxicity. Transient hyperbilirubinemia occurs commonly with CsA administration and may alter daunorubicin pharmacokinetics. Recommended doses of CsA for phase II and III trials are a load of 6 mg/kg and CI of 16 mg/kg/d.

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