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.
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.
van der Holt
Bronno
B
Department of Hematology, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands. p.sonneveld@erasmusmc.nl.
Löwenberg
Bob
B
Burnett
Alan K
AK
Knauf
Wolfgang U
WU
Shepherd
John
J
Piccaluga
Pier Paolo
PP
Ossenkoppele
Gert J
GJ
Verhoef
Gregor E G
GE
Ferrant
Augustin
A
Crump
Michael
M
Selleslag
Dominik
D
Theobald
Matthias
M
Fey
Martin F
MF
Vellenga
Edo
E
Dugan
Margaret
M
Sonneveld
Pieter
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D003524:Cyclosporins / Q000009:adverse effects / Q000627:therapeutic use*; D003561:Cytarabine / Q000009:adverse effects / Q000627:therapeutic use*; D003630:Daunorubicin / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015996:Survival Rate; D016896:Treatment Outcome
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D003561:Cytarabine; C070272:valspodar; D003630:Daunorubicin