Journal of Clinical Oncology, Vol 11, 1652-1660, Copyright © 1993 by American Society of Clinical Oncology
Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia
AF List, C Spier, J Greer, S Wolff, J Hutter, R Dorr, S Salmon, B Futscher, M Baier and W Dalton
Arizona Cancer Center, University of Arizona, Tucson 85724.
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 [i.v.]) 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
nephrotoxic antibiotics. Steady-state blood concentrations of CsA > or =
1,500 ng/mL were achieved in all patients receiving CI doses > or = 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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