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.

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.

• Authors: Larry D Cripe, Hajime Uno, Elisabeth M Paietta, Mark R Litzow, Rhett P Ketterling, John M Bennett, Jacob M Rowe, Hillard M Lazarus, Selina Luger, Martin S Tallman
• Journal: Blood (Blood) Vol. 116 Issue 20 Pg. 4077-85 (Nov 18 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20716770 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Dibenzocycloheptenes
• Placebos
• Quinolines
• zosuquidar trihydrochloride
• daunorubicinol
• Daunorubicin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Daunorubicin (analogs & derivatives, metabolism)
• Dibenzocycloheptenes (adverse effects, pharmacokinetics, therapeutic use)
• Female
• Humans
• Leukemia, Myeloid, Acute (diagnosis, drug therapy, mortality)
• Male
• Multivariate Analysis
• Placebos
• Prognosis
• Quinolines (adverse effects, pharmacokinetics, therapeutic use)
• Remission Induction
• Survival Analysis
• Treatment Outcome