title: A phase I/II study of imatinib plus reinduction therapy for c-kit-positive relapsed/refractory acute myeloid leukemia: inhibition of Akt activation correlates with complete response.
abstract: This phase I/II study evaluated imatinib as a c-kit inhibitor combined with mitoxantrone, etoposide and cytarabine therapy for patients with primary refractory or relapsed c-kit+ acute myeloid leukemia (AML). Imatinib was escalated through three dose levels in successive six patient cohorts. The combination was well tolerated up to 400 mg/day imatinib. Of 21 patients treated at this dose, 13 (62%) achieved complete response (CR), 7 (33%) were non-responders and one died during induction. The CR rate was 80% in patients with standard-risk karyotype versus 33% in patients with adverse karyotype. The CR rate for primary non-responders was 6/14 (43%) versus 7/7 (100%) for relapsed patients. AML blasts from peripheral blood were assayed for phosphorylated Akt (pAkt) and phosphorylated ERK (pERK) by flow cytometry before to and after imatinib dosing. Of eight patients achieving CR with reinduction, seven demonstrated marked (≥60%) pAkt inhibition with imatinib therapy. In contrast, all the six non-responders to reinduction demonstrated <60% pAkt inhibition (P=0.005). There was no correlation between pERK inhibition and response to therapy. These results indicate that lack of pAkt inhibition in vivo is associated with resistance to reinduction therapy using this regimen. Further studies using agents that are able to inhibit Akt more effectively are warranted.
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada. joseph.brandwein@uhn.on.ca
authors.forename: J M
authors.initials: JM
authors.lastname: Brandwein
authors.forename: D W
authors.initials: DW
authors.lastname: Hedley
authors.forename: S
authors.initials: S
authors.lastname: Chow
authors.forename: A D
authors.initials: AD
authors.lastname: Schimmer
authors.forename: K W L
authors.initials: KW
authors.lastname: Yee
authors.forename: A C
authors.initials: AC
authors.lastname: Schuh
authors.forename: V
authors.initials: V
authors.lastname: Gupta
authors.forename: W
authors.initials: W
authors.lastname: Xu
authors.forename: S
authors.initials: S
authors.lastname: Kamel-Reid
authors.forename: M D
authors.initials: MD
authors.lastname: Minden
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001549:Benzamides; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D010879:Piperazines / Q000008:administration & dosage*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit; D011743:Pyrimidines / Q000008:administration & dosage*; D012074:Remission Induction / Q000379:methods; D016879:Salvage Therapy / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt