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

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

Research output: Contribution to journalArticle

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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. Atotal 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.

Original languageEnglish (US)
Pages (from-to)4077-4085
Number of pages9
JournalBlood
Volume116
Issue number20
DOIs
StatePublished - Nov 18 2010

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Oncology
P-Glycoprotein
Acute Myeloid Leukemia
Modulators
Randomized Controlled Trials
Placebos
Cytogenetics
Daunorubicin
Anthracyclines
Cytarabine
Survival
Myelodysplastic Syndromes
Toxicity
Proteins
Modulation
Breast Neoplasms
Mortality

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

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. / Cripe, Larry D.; Uno, Hajime; Paietta, Elisabeth M.; Litzow, Mark R.; Ketterling, Rhett P.; Bennett, John M.; Rowe, Jacob M.; Lazarus, Hillard M.; Luger, Selina; Tallman, Martin S.

In: Blood, Vol. 116, No. 20, 18.11.2010, p. 4077-4085.

Research output: Contribution to journalArticle

Cripe, Larry D. ; Uno, Hajime ; Paietta, Elisabeth M. ; Litzow, Mark R. ; Ketterling, Rhett P. ; Bennett, John M. ; Rowe, Jacob M. ; Lazarus, Hillard M. ; Luger, Selina ; Tallman, Martin S. / 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. In: Blood. 2010 ; Vol. 116, No. 20. pp. 4077-4085.
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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. Atotal 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.",
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AU - Uno, Hajime

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AU - Litzow, Mark R.

AU - Ketterling, Rhett P.

AU - Bennett, John M.

AU - Rowe, Jacob M.

AU - Lazarus, Hillard M.

AU - Luger, Selina

AU - Tallman, Martin S.

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