@article{947ac4970f1e4a9a99379afe932b87ca,
title = "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. Copyright (C) 2000 Elsevier Science Ltd.",
keywords = "Acute myelogenous leukemia, Drug resistance, Etoposide, Mitoxantrone, P-glycoprotein, mdr1",
author = "Chauncey, {Thomas R.} and Cathryn Rankin and Anderson, {Jeanne E.} and Chen, {I. Ming} and Kopecky, {Kenneth J.} and Godwin, {John E.} and Kalaycio, {Matt E.} and Moore, {Dennis F.} and Shurafa, {Muhammad S.} and Petersdorf, {Stephen H.} and Kraut, {Eric H.} and Leith, {Catherine P.} and Head, {David R.} and Luthardt, {Frederick W.} and Willman, {Cheryl L.} and Appelbaum, {Frederick R.}",
note = "Funding Information: T.R. Chauncy and J.E. Anderson contributed to the study design, analysis of the data, drafting of the paper, and gave final approval of the manuscript. C.R. Rankin and K.J. Kopecky contributed to the study design, provided statistical expertise with data interpretation and analysis, and gave final approval of the manuscript. I.M. Chen and C.L. Leith performed drug resistance assays. C.L. Williams performed drug resistance assays and gave final approval of the manuscript. J.A. Godwin, M.E. Kalaycio, D.F. Moore, M.S. Shurafa, S.H. Petersdorf, and E.H. Kraut provided patients to the study and gave final approval of the manuscript. D.R. Head performed the pathology review and gave final approval of the manusript. F.W. Luthardt performed cytogenetic analysis. F.R. Appelbaum contributed to the study design, analysis of the data, drafting of the paper, provided administrative support and gave final approval of the manuscript. We are indebted to the efforts of the institutions who participated in the trial and their data management teams, and to the personnel in the Statistical Center and Operations Office of the SWOG who made this study possible. The investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA38926, CA32102, CA04919, CA58416, CA46282, CA04920, CA20319, CA35431, CA22433, CA12213.",
year = "2000",
month = jul,
doi = "10.1016/S0145-2126(00)00024-2",
language = "English (US)",
volume = "24",
pages = "567--574",
journal = "Leukemia Research",
issn = "0145-2126",
publisher = "Elsevier Limited",
number = "7",
}