Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: A randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999 Academic Article uri icon

Overview

MeSH Major

  • Antineoplastic Agents
  • Dibenzocycloheptenes
  • Leukemia, Myeloid, Acute
  • P-Glycoprotein
  • Quinolines

abstract

  • Zosuquidar, which modulates P-glycoprotein (P-gp) with minimal delay of anthracycline clearance, may reverse P-gp-mediated resistance in acute myeloid leukemia without increased toxicity. A total of 449 adults older than 60 years with acute myeloid leukemia or high-risk myelodysplastic syndrome enrolled in a randomized placebo-controlled double-blind trial (Eastern Cooperative Oncology Group 3999). Overall survival was compared between patients receiving conventional-dose cytarabine and daunorubicin and either zosuquidar (550 mg; 212 patients) or placebo (221 patients). Median and 2-year overall survival values were 7.2 months and 20% on zosuquidar and 9.4 months and 23% on placebo, respectively (P = .281). Remission rate was 51.9% on zosuquidar and 48.9% on placebo. All cause mortality to day 42 was not different (zosuquidar 22.2% vs placebo 16.3%; P = .158). In vitro modulation of P-gp activity by zosuquidar and expression of P-gp, multidrug resistance-related protein 1, lung resistance protein, and breast cancer resistance protein, were comparable in the 2 arms. Poor-risk cytogenetics were more common in P-gp(+) patients. P-gp expression and cytogenetics were correlated, though independent prognostic factors. We conclude that zosuquidar did not improve outcome in older acute myeloid leukemia, in part, because of the presence P-gp independent mechanisms of resistance. This trial is registered at www.clinicaltrials.gov as #NCT00046930.

publication date

  • November 18, 2010

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2993615

Digital Object Identifier (DOI)

  • 10.1182/blood-2010-04-277269

PubMed ID

  • 20716770

Additional Document Info

start page

  • 4077

end page

  • 85

volume

  • 116

number

  • 20