Midostaurin, bortezomib and MEC in relapsed/refractory acute myeloid leukemia

• Published in: Leukemia & lymphoma Vol. 57; no. 9; pp. 2100 - 2108
• Main Authors: Walker, Alison R., Wang, Hongyan, Walsh, Katherine, Bhatnagar, Bhavana, Vasu, Sumithira, Garzon, Ramiro, Canning, Renee, Geyer, Susan, Wu, Yue-Zhong, Devine, Steven M., Klisovic, Rebecca, Blum, William, Marcucci, Guido
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.09.2016
• Subjects: Adult; Aged; AML; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; bortezomib; Bortezomib - administration & dosage; chemotherapy; Chromosome Aberrations; Cytarabine - administration & dosage; Cytarabine - therapeutic use; Drug Monitoring; Drug Resistance, Neoplasm; Etoposide - administration & dosage; Etoposide - therapeutic use; Female; Humans; Leukemia, Myeloid, Acute - diagnosis; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - pathology; Male; Maximum Tolerated Dose; Middle Aged; midostaurin; Mitoxantrone - administration & dosage; Mitoxantrone - therapeutic use; Recurrence; Remission Induction; Retreatment; Staurosporine - administration & dosage; Staurosporine - analogs & derivatives; Treatment Outcome; tyrosine kinase; Young Adult; AML; midostaurin; bortezomib; chemotherapy; tyrosine kinase
• ISSN: 1042-8194; 1029-2403
• DOI: 10.3109/10428194.2015.1135435

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).