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

Leuk Lymphoma. 2016 Sep;57(9):2100-8. doi: 10.3109/10428194.2015.1135435. Epub 2016 Jan 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bortezomib / administration & dosage
  • 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
  • Mitoxantrone / administration & dosage
  • Mitoxantrone / therapeutic use
  • Recurrence
  • Remission Induction
  • Retreatment
  • Staurosporine / administration & dosage
  • Staurosporine / analogs & derivatives
  • Treatment Outcome
  • Young Adult

Substances

  • Cytarabine
  • Bortezomib
  • Etoposide
  • Mitoxantrone
  • Staurosporine
  • midostaurin

Supplementary concepts

  • MAV protocol

Associated data

  • ClinicalTrials.gov/NCT01174888