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 Journal Article
| Authors: | Cripe, L. D.; Uno, H.; Paietta, E. M.; Litzow, M. R.; Ketterling, R. P.; Bennett, J. M.; Rowe, J. M.; Lazarus, H. M.; Luger, S.; Tallman, M. S. |
| Article Title: | 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. 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. © 2010 by The American Society of Hematology. |
| Keywords: | controlled study; protein expression; treatment outcome; aged; aged, 80 and over; survival analysis; acute granulocytic leukemia; major clinical study; overall survival; leukemia, myeloid, acute; clinical trial; fatigue; mortality; placebo; diarrhea; antineoplastic agents; cytarabine; anorexia; progression free survival; controlled clinical trial; infection; nausea; randomized controlled trial; stomatitis; cytogenetics; continuous infusion; dyspnea; febrile neutropenia; pneumonia; hypoxia; confusion; hypotension; myelodysplastic syndrome; breast cancer resistance protein; daunorubicin; remission induction; multivariate analysis; double blind procedure; hallucination; epistaxis; ataxia; hematologic disease; p-glycoprotein; placebos; leukemia remission; glycoprotein p; multidrug resistance protein 1; heart supraventricular arrhythmia; lung resistance protein; zosuquidar; petechia; typhus; dibenzocycloheptenes; quinolines |
| Journal Title: | Blood |
| Volume: | 116 |
| Issue: | 20 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2010-11-18 |
| Start Page: | 4077 |
| End Page: | 4085 |
| Language: | English |
| DOI: | 10.1182/blood-2010-04-277269 |
| PUBMED: | 20716770 |
| PROVIDER: | scopus |
| PMCID: | PMC2993615 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 20 April 2011" - "CODEN: BLOOA" - "Source: Scopus" |
