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Blood, 15 October 2005, Vol. 106, No. 8, pp. 2646-2654.
Prepublished online as a Blood First Edition Paper on June 30, 2005; DOI 10.1182/blood-2005-04-1395.
 Previous Article | Table of Contents | Next Article 
CLINICAL TRIALS AND OBSERVATIONS
The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis
Bronno van der Holt,
Bob Löwenberg,
Alan K. Burnett,
Wolfgang U. Knauf,
John Shepherd,
Pier Paolo Piccaluga,
Gert J. Ossenkoppele,
Gregor E. G. Verhoef,
Augustin Ferrant,
Michael Crump,
Dominik Selleslag,
Matthias Theobald,
Martin F. Fey,
Edo Vellenga,
Margaret Dugan,
Pieter Sonneveld, on behalf of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) and the United Kingdom Medical Research Council (MRC)
From the Department of Trials & Statistics–HOVON Data Center, Erasmus MC–Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; Department of Hematology, Erasmus MC, Rotterdam, The Netherlands; Department of Hematology, Wales School of Medicine, Cardiff University, United Kingdom; Department of Hematology, University Hospital Benjamin Franklin, Berlin, Germany; Department of Medicine, Division of Hematology, Vancouver Hospital, Canada; Department of Hematology and Medical Oncology "L. and A. Seràgnoli," S. Orsola-Malpighi Hospital, University of Bologna, Italy; Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands; Department of Hematology, University Hospital Gasthuisberg, Leuven, Belgium; Department of Hematology, Cliniques Universitaires St Luc, Brussels, Belgium; Division of Hematology and Medical Oncology, Princess Margaret Hospital, Toronto, Canada; Department of Hematology, St Jan's Hospital, Brugge, Belgium; Department of Hematology and Oncology, Johannes Gutenberg University, Mainz, Germany; Department of Medical Oncology, Inselspital Bern, Switzerland; Department of Internal Medicine, University Medical Center Groningen, The Netherlands; and Early Clinical Development Oncology, Novartis Pharmaceuticals, East Hanover, NJ.
To determine whether MDR1 reversal by the addition of the P-glycoprotein (P-gp) inhibitor PSC-833 to standard induction chemotherapy would improve event-free survival (EFS), 419 untreated patients with acute myeloid leukemia (AML) aged 60 years and older were randomized to receive 2 induction cycles of daunorubicin and cytarabine with or without PSC-833. Patients in complete remission were then given 1 consolidation cycle without PSC-833. Neither complete response (CR) rate (54% versus 48%; P = .22), 5-year EFS (7% versus 8%; P = .53), disease-free survival (DFS; 13% versus 17%; P = .06) nor overall survival (OS; 10% in both arms; P = .52) were significantly improved in the PSC-833 arm. An integrated P-gp score (IPS) was determined based on P-gp function and P-gp expression in AML cells obtained prior to treatment. A higher IPS was associated with a significantly lower CR rate and worse EFS and OS. There was no significant interaction between IPS and treatment arm with respect to CR rate and survival, indicating also a lack of benefit of PSC-833 in P-gp–positive patients. The role of strategies aimed at inhibitory P-gp and other drug-resistance mechanisms continues to be defined in the treatment of patients with AML.
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