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.
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.
Cripe
Larry D
LD
Indiana University Simon Cancer Center, Indianapolis, IN, USA. lcripe@iupui.edu
Uno
Hajime
H
Paietta
Elisabeth M
EM
Litzow
Mark R
MR
Ketterling
Rhett P
RP
Bennett
John M
JM
Rowe
Jacob M
JM
Lazarus
Hillard M
HM
Luger
Selina
S
Tallman
Martin S
MS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000378:metabolism; D003986:Dibenzocycloheptenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D015999:Multivariate Analysis; D010919:Placebos; D011379:Prognosis; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012074:Remission Induction; D016019:Survival Analysis; D016896:Treatment Outcome
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D003986:Dibenzocycloheptenes; D010919:Placebos; D011804:Quinolines; C095179:zosuquidar trihydrochloride; C000847:daunorubicinol; D003630:Daunorubicin