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

• Published in: Leukemia Vol. 25; no. 6; pp. 945 - 952
• Main Authors: Brandwein, J M, Hedley, D W, Chow, S, Schimmer, A D, Yee, K W L, Schuh, A C, Gupta, V, Xu, W, Kamel-Reid, S, Minden, M D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2011; Nature Publishing Group
• Subjects: 631/92/436/2388; 692/699/67/1990/283/1897; 692/700/565/1436/1437; Acute myeloid leukemia; Adult; AKT protein; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Benzamides; Biological and medical sciences; c-Kit protein; Cancer; Cancer Research; Critical Care Medicine; Cytarabine; Dosage; Etoposide; Female; Flow cytometry; Hematologic and hematopoietic diseases; Hematology; Humans; Imatinib; Imatinib Mesylate; Intensive; Internal Medicine; Karyotypes; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Mitoxantrone; Oncology; original-article; Peripheral blood; Phosphorylation; Physiological aspects; Piperazines - administration & dosage; Prognosis; Protein kinases; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-kit; Pyrimidines - administration & dosage; Relapse; Remission Induction - methods; Salvage Therapy - methods; Therapy; Treatment Outcome; Canada; acute myeloid leukemia; c-kit; chemotherapy; Antineoplastic agent; Imatinib; Acute myelogenous leukemia; Relapse; Treatment resistance; Hematology; Enzyme; Tyrosine kinase inhibitor; Transferases; Enzyme inhibitor; Akt protein kinase; Malignant hemopathy; Chemotherapy; Treatment; C-Onc gene; Phase II trial; Phase I trial; Protein-tyrosine kinase; kit Gene; Protooncogene; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2011.34

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.