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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.

Authors
  • van der Holt, Bronno
  • Löwenberg, Bob
  • Burnett, Alan K
  • Knauf, Wolfgang U
  • Shepherd, John
  • Piccaluga, Pier Paolo
  • Ossenkoppele, Gert J
  • Verhoef, Gregor E G
  • Ferrant, Augustin
  • Crump, Michael
  • Selleslag, Dominik
  • Theobald, Matthias
  • Fey, Martin F
  • Vellenga, Edo
  • Dugan, Margaret
  • Sonneveld, Pieter
Type
Published Article
Journal
Blood
Publication Date
Oct 15, 2005
Volume
106
Issue
8
Pages
2646–2654
Identifiers
PMID: 15994288
Source
Medline
License
Unknown

Abstract

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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