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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 | Next Article 
Submitted April 5, 2005
Accepted June 12, 2005
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 Lowenberg, Alan K Burnett, Wolfgang U Knauf, John Shepherd, Pier P Piccaluga, Gert J Ossenkoppele, Gregor E Verhoef, Augustin Ferrant, Michael Crump, Dominik Selleslag, Matthias Theobald, Martin F Fey, Edo Vellenga, Margaret Dugan, and Pieter Sonneveld
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, Cardiff, United Kingdom
Department of Hematology, University Hospital Benjamin Franklin, Berlin, Germany
Department of Medicine, Division of Hematology, Vancouver Hospital, Vancouver, Canada
Department of Hematology and Medical Oncology 'L. and A. Seragnoli', S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands
Department of Hematology, University Hospital Gasthuisberg, Leuven, Belgium
Department of Hematology, UCL 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, Bern, Switzerland
Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands
Early Clinical Development Oncology, Novartis Pharmaceutical Corp., East Hanover, NJ, USA
* Corresponding author; email: b.vanderholt{at}erasmusmc.nl.
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 (CR) were then given one consolidation cycle without PSC-833. Neither CR rate (54% versus 48%, P = .22), 5-year EFS (7% versus 8%, P = .53) nor disease-free survival (DFS, 13% versus 17%, P = .06) and 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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