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).

Keywords: AML; bortezomib; chemotherapy; midostaurin; tyrosine kinase.

Conflict of interest statement

Conflict of Interest: None of the authors report a conflict of interest.

Figures

Figure 1

Disease response (upper panels) and survival (lower panels) A. Patients who received midostaurin and bortezomib (DLs 1 and 2); B. Patients who received midostaurin and bortezomib and MEC (DLs 3, 3*, 3A and 4). CR, complete remission; CRi, CR with incomplete count recovery (neutrophil or platelet); NR, non- responders

Figure 2

Midostaurin, bortezomib combined with MEC upregulates pri-miR-29b, and downregulates FLT3 and miR-155 expression in AML patients. BM samples were collected prior treatment (Day 0) or posttreatment on Days 3 or 8 from patients receiving only midostaurin and bortezomib (Mid & Bortz) and those treated with midostaurin, bortezomib and MEC (Mid, Bortz & MEC). Samples were analyzed by quantitative RT-PCR for expression levels of (A) pri-miR-29b; (B) FLT3 mRNA; (C) miR-155. Data are normalized by the internal controls and presented as mean ± SE for each group of patients. *p<0.05; **p<0.01, when compared with the pretreatment basal level of each group.