A phase I study of induction chemotherapy for older patients with newly diagnosed acute myeloid leukemia (AML) using mitoxantrone, etoposide, and the MDR modulator PSC 833: a southwest oncology group study 9617.
Older patients with acute myelogenous leukemia (AML) have overexpression of P-glycoprotein (Pgp+), and this has been shown to correlate quantitatively with therapeutic outcome. Since Pgp-mediated efflux of cytotoxic drugs can be inhibited by the cyclosporine analogue, PSC 833, we investigated the use of this agent with a 5-day mitoxantrone/etoposide regimen in patients over age 55 with newly diagnosed AML. Previous studies suggested a 33% incidence of grade IV/V non-hematologic toxicity with the use of mitoxantrone 10 mg/M(2) and etoposide 100 mg/M(2), each for 5 days, in this patient population. Since PSC 833 alters the pharmacokinetic excretion of MDR-related cytotoxins, this phase I dose-finding study was performed to identify doses of mitoxantrone/etoposide associated with a similar 33% incidence of grade IV/V non-hematologic toxicity, when given with PSC 833. Mitoxantrone/etoposide (M/E) doses were escalated in fixed ratio from a starting dose of M: 4 mg/M(2) and E: 40 mg/M(2), to M: 7 mg/M(2) and E: 70 mg/M(2), in successive cohorts of eight patients each. PSC 833 was well tolerated and the MTD of this M/E regimen with PSC 833 in this population was M: 6 mg/M(2) and E: 60 mg/M(2). The complete response (CR) rate for all patients was 50% (15/30) and was considerably higher for de novo than for secondary AML. These data suggest that the addition of PSC 833 to an M/E regimen for older patients with untreated AML is well tolerated but requires a reduction in M/E dosing to avoid increased toxicity.
Chauncey
T R
TR
University of Washington School of Medicine, Seattle, WA, USA.
Rankin
C
C
Anderson
J E
JE
Chen
I
I
Kopecky
K J
KJ
Godwin
J E
JE
Kalaycio
M E
ME
Moore
D F
DF
Shurafa
M S
MS
Petersdorf
S H
SH
Kraut
E H
EH
Leith
C P
CP
Head
D R
DR
Luthardt
F W
FW
Willman
C L
CL
Appelbaum
F R
FR
D000208:Acute Disease; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003524:Cyclosporins / Q000008:administration & dosage / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D005047:Etoposide / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000493:pharmacokinetics; D016019:Survival Analysis; D016896:Treatment Outcome
D003524:Cyclosporins; D005047:Etoposide; D008942:Mitoxantrone; C070272:valspodar