A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia.
Outcomes for older adults with acute myelogenous leukemia (AML) are poor due to both disease and host-related factors. In this phase 2 study, we tested the oral farnesyltransferase inhibitor tipifarnib in 158 older adults with previously untreated, poor-risk AML. The median age was 74 years, and a majority of patients had antecedent myelodysplastic syndrome. Complete remission (CR) was achieved in 22 patients (14%); partial remission or hematologic improvement occurred in 15 patients, for an overall response rate of 23%. The median duration of CR was 7.3 months and the median survival of complete responders was 18 months. Adverse karyotype, age 75 years or older, and poor performance status correlated negatively with survival. Early death in the absence of progressive disease was rare, and drug-related nonhematologic serious adverse events were observed in 74 patients (47%). Inhibition of farnesylation of the surrogate protein HDJ-2 occurred in the large majority of marrow samples tested. Baseline levels of phosphorylated mitogen-activated protein kinase and AKT did not correlate with clinical response. Tipifarnib is active and well tolerated in older adults with poor-risk AML and may impart a survival advantage in those patients who experience a clinical response.
Lancet
Jeffrey E
JE
H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612, USA. lancetje@moffitt.org
Gojo
Ivana
I
Gotlib
Jason
J
Feldman
Eric J
EJ
Greer
Jacqueline
J
Liesveld
Jane L
JL
Bruzek
Laura M
LM
Morris
Lawrence
L
Park
Youn
Y
Adjei
Alex A
AA
Kaufmann
Scott H
SH
Garrett-Mayer
Elizabeth
E
Greenberg
Peter L
PL
Wright
John J
JJ
Karp
Judith E
JE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D050956:HSP40 Heat-Shock Proteins; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D015363:Quinolones / Q000008:administration & dosage*; D012074:Remission Induction; D012306:Risk; D015996:Survival Rate; D016896:Treatment Outcome
C107481:DNAJA1 protein, human; D050956:HSP40 Heat-Shock Proteins; D015363:Quinolones; D051231:Farnesyltranstransferase; C402769:tipifarnib