A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy.
Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately one third of patients with acute myeloid leukemia (AML) and are associated with adverse prognosis. The important role played by FLT3 in the survival and proliferation of blasts, and its overexpression in most patients with AML, make FLT3 an attractive therapeutic target. We undertook a phase 2 trial of the FLT3-selective tyrosine kinase inhibitor lestaurtinib (CEP701) used as monotherapy in untreated older patients with AML not considered fit for intensive chemotherapy, irrespective of FLT3 mutation status. Lestaurtinib was administered orally for 8 weeks, initially at a dose of 60 mg twice daily, escalating to 80 mg twice daily, and was generally well tolerated. Clinical activity, manifest as transient reductions in bone marrow and peripheral-blood blasts or longer periods of transfusion independence, was seen in 3 (60%) of 5 patients with mutated FLT3 and 5 (23%) of 22 evaluable wild-type FLT3 patients. Laboratory data demonstrated that clinical responses occurred where the presence of sustained FLT3-inhibitory drug levels were combined with in vitro cytotoxic sensitivity of blasts to lestaurtinib. Further evaluation of this compound, in combination with cytotoxic chemotherapy or other targeted agents, is warranted in both FLT3 mutant and wild-type patients.
Knapper
Steven
S
Department of Haematology, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XW, United Kingdom.
Burnett
Alan K
AK
Littlewood
Tim
T
Kell
W Jonathan
WJ
Agrawal
Sam
S
Chopra
Raj
R
Clark
Richard
R
Levis
Mark J
MJ
Small
Donald
D
D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000633:toxicity; D001772:Blood Cell Count; D002227:Carbazoles / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D005663:Furans; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000633:toxicity; D007951:Leukemia, Myeloid / Q000150:complications / Q000188:drug therapy*; D008297:Male; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics
D000970:Antineoplastic Agents; D002227:Carbazoles; D005663:Furans; D007211:Indoles; C119379:lestaurtinib; D051941:fms-Like Tyrosine Kinase 3