title: Midostaurin, bortezomib and MEC in relapsed/refractory acute myeloid leukemia.
abstract: Targeting aberrant tyrosine kinase activity may impact clinical outcome in acute myeloid leukemia (AML). We conducted a phase I study of the tyrosine kinase inhibitor midostaurin with bortezomib alone and in combination with chemotherapy in patients with AML. Patients on dose levels 1 and 2 (DL1 & 2) received midostaurin 50 mg bid and escalating doses of bortezomib (1 to 1.3 mg/m2). Patients on DL3 or higher received midostaurin and bortezomib following chemotherapy with mitoxantrone, etoposide, cytarabine (MEC). None of the patients enrolled to DL1 & 2 had dose-limiting toxicities (DLTs) or a clinical response. Among patients enrolled to DL3 or higher, DLTs were peripheral neuropathy, decrease in ejection fraction and diarrhea. A 56.5% CR rate and 82.5% overall response rate (CR + CR with incomplete neutrophil or platelet count recovery) were observed. The midostaurin/bortezomib/MEC combination is active in refractory/relapsed AML, but is associated with expected drug-related toxicities (NCT01174888).
authors.affiliation: a Division of Hematology, Department of Medicine , The Ohio State University and the Comprehensive Cancer Center , Columbus , OH , USA ;
authors.forename: Alison R
authors.initials: AR
authors.lastname: Walker
authors.affiliation: a Division of Hematology, Department of Medicine , The Ohio State University and the Comprehensive Cancer Center , Columbus , OH , USA ;
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
authors.affiliation: a Division of Hematology, Department of Medicine , The Ohio State University and the Comprehensive Cancer Center , Columbus , OH , USA ;
authors.forename: Katherine
authors.initials: K
authors.lastname: Walsh
authors.affiliation: a Division of Hematology, Department of Medicine , The Ohio State University and the Comprehensive Cancer Center , Columbus , OH , USA ;
authors.forename: Bhavana
authors.initials: B
authors.lastname: Bhatnagar
authors.affiliation: a Division of Hematology, Department of Medicine , The Ohio State University and the Comprehensive Cancer Center , Columbus , OH , USA ;
authors.forename: Sumithira
authors.initials: S
authors.lastname: Vasu
authors.affiliation: a Division of Hematology, Department of Medicine , The Ohio State University and the Comprehensive Cancer Center , Columbus , OH , USA ;
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.affiliation: a Division of Hematology, Department of Medicine , The Ohio State University and the Comprehensive Cancer Center , Columbus , OH , USA ;
authors.forename: Renee
authors.initials: R
authors.lastname: Canning
authors.affiliation: b Health Informatics Institute, University of South Florida , Tampa , FL , USA ;
authors.forename: Susan
authors.initials: S
authors.lastname: Geyer
authors.affiliation: a Division of Hematology, Department of Medicine , The Ohio State University and the Comprehensive Cancer Center , Columbus , OH , USA ;
authors.forename: Yue-Zhong
authors.initials: YZ
authors.lastname: Wu
authors.affiliation: a Division of Hematology, Department of Medicine , The Ohio State University and the Comprehensive Cancer Center , Columbus , OH , USA ;
authors.forename: Steven M
authors.initials: SM
authors.lastname: Devine
authors.affiliation: a Division of Hematology, Department of Medicine , The Ohio State University and the Comprehensive Cancer Center , Columbus , OH , USA ;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Klisovic
authors.affiliation: a Division of Hematology, Department of Medicine , The Ohio State University and the Comprehensive Cancer Center , Columbus , OH , USA ;
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.affiliation: c City of Hope Comprehensive Cancer Center , Gehr Family Center for Leukemia , Duarte , CA , USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib / Q000008:administration & dosage; D002869:Chromosome Aberrations; D003561:Cytarabine / Q000008:administration & dosage / Q000627:therapeutic use; D016903:Drug Monitoring; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000627:therapeutic use; D012008:Recurrence; D012074:Remission Induction; D019233:Retreatment; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D003561:Cytarabine; D000069286:Bortezomib; D005047:Etoposide; D008942:Mitoxantrone; D019311:Staurosporine; C059539:midostaurin
keywords: AML; bortezomib; chemotherapy; midostaurin; tyrosine kinase