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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 (ECOG 3999).

Author(s): Cripe LD, Uno H, Paietta EM, Litzow MR, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Luger S, Tallman MS

Affiliation(s): Indiana University Simon Cancer Center, Indianapolis, IN, United States;

Publication date & source: 2010-08-17, Blood., [Epub ahead of print]

Zosuquidar (Z), which modulates P-glycoprotein (P-gp) with minimal delay of anthracycline clearance, may reverse P-gp mediated resistance in acute myeloid leukemia (AML) without increased toxicity. 449 adults >60 years old with AML or high risk myelodysplastic syndrome enrolled in a randomized placebo-controlled double-blind trial (E3999). Overall survival (OS) was compared between patients receiving conventional-dose cytarabine and daunorubicin and either Z (550 mg; 212 pts) or placebo (P; 221 pts). Consolidation consisted of intermediate dose cytarabine followed by a second induction. Median and 2-year OS were 7.2 months and 20% on Z and 9.4 months and 23% on P, respectively (p=.281). Remission rate was 51.9% on Z and 48.9% on P. All cause mortality to day 42 was not statistically different (Z: 22.2% v. placebo: 16.3%; p=0.158). In vitro modulation of P-gp activity by Z and expression of P-gp, MRP1, LRP, and BCRP, were comparable in the two arms. P-gp positivity predicted worse OS for all patients (p<0.0001). Poor risk cytogenetics were more common in P-gp positive patients. P-gp expression and cytogenetics were correlated, though independent prognostic factors. We conclude Z did not improve outcome in older AML, in part, due to the presence P-gp independent mechanisms of resistance. This trial is registered at http://www.clinicaltrials.gov as NCT00046930.

Page last updated: 2010-10-05

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