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

Thomas R. Chauncey, Cathryn Rankin, Jeanne E. Anderson, I. Ming Chen, Kenneth J. Kopecky, John E. Godwin, Matt E. Kalaycio, Dennis F. Moore, Muhammad S. Shurafa, Stephen H. Petersdorf, Eric H. Kraut, Catherine P. Leith, David R. Head, Frederick W. Luthardt, Cheryl L. Willman, Frederick R. Appelbaum

Research output: Contribution to journalArticlepeer-review

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. Copyright (C) 2000 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)567-574
Number of pages8
JournalLeukemia Research
Volume24
Issue number7
DOIs
StatePublished - Jul 2000

Keywords

  • Acute myelogenous leukemia
  • Drug resistance
  • Etoposide
  • mdr1
  • Mitoxantrone
  • P-glycoprotein

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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