Title: Dose-finding study of valspodar (PSC 833) with daunorubicin and cytarabine to reverse multidrug resistance in elderly patients with previously untreated acute myeloid leukemia
Authors: Sonneveld, P ×
Burnett, A
Vossebeld, P
Ben-Am, M
Rosenkranz, G
Pfister, C
Verhoef, Gregor
Dekker, A
Ossenkoppele, G
Ferrant, C
Yin, L
Gratwohl, A
Kovacsovics, T
Vellenga, E
Capdeville, R
Löwenberg, B #
Issue Date: Jan-2000
Series Title: The hematology journal : the official journal of the European Haematology Association / EHA vol:1 issue:6 pages:411-21
Abstract: INTRODUCTION: This trial was designed to determine the maximum tolerated dose of intravenous daunorubicin (DNR) in combination with valspodar and to test the feasibility of P-glycoprotein modulation using valspodar in elderly patients with previously untreated acute myelogenous leukemia receiving standard induction chemotherapy. METHODS: Patients > or =60 years of age with previously untreated AML received valspodar (10 mg/kg/24 h by continuous intravenous infusion [CIV] on days 1-4 with a 2-mg/kg loading dose on day 1) in conjunction with two cycles of induction chemotherapy consisting of cytarabine (200 mg/m(2) CIV on days 1-7), and DNR (35 mg/m(2) [cohort 1] or 45 mg/m(2) [cohort 2] on days 1-3, intravenous bolus). Patients were assessed for dose-limiting toxicities (DLT), response rate, event-free and overall survival, and pharmacokinetics of valspodar and DNR. RESULTS: Valspodar was well tolerated at the lower DNR dose level (ie, 35 mg/m(2)) resulting in a 21% rate of DLT and only three toxic deaths. Treatment-related mortality was unacceptably high at the 45 mg/m(2) DNR dose level. The complete response rate was 49% overall and similar in both cohorts. The median overall survival of patients was 333 days in cohort 1 compared to 98 days in cohort 2. At baseline, 70% of assessable patients were P-glycoprotein positive. CONCLUSION: Substantial inhibition of P-glycoprotein activity can be achieved in this patient population at clinically tolerable doses of valspodar and DNR. The maximum tolerated dose of DNR was established as 35 mg/m(2). This regimen is being further evaluated in phase III trials.
ISSN: 1466-4860
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Hematology Section (-)
× corresponding author
# (joint) last author

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