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

Abstract 

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/M² and etoposide 100 mg/M², 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/M² and E: 40 mg/M², to M: 7 mg/M² and E: 70 mg/M², 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/M² and E: 60 mg/M². 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.

Keywords:  Acute myelogenous leukemia, P-glycoprotein, mdr1, Drug resistance, Mitoxantrone, Etoposide

Abbreviations:  AML, acute myelogenous leukemia, CR, complete remission, DLT, dose limiting toxicity, DFS, disease-free survival, FAB, French–American–British, IULN, institutional upper limit of normal, Pgp, P-glycoprotein, PR, partial remission, OS, overall survival, MDR, multidrug resistance, MTD, maximum tolerated dose, SWOG, Southwest Oncology Group, M, mitoxantrone, E, etoposide