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

121 Citations (Scopus)

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

Fingerprint

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 - 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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