A phase I study using bortezomib with weekly idarubicin for treatment of elderly patients with acute myeloid leukemia

Abstract

We report the results of a phase I study with four dose levels of bortezomib in combination with idarubicin. Eligible patients were newly diagnosed with acute myeloid leukemia (AML) age ≥60 years, or any adult with relapsed AML. Bortezomib was given twice weekly at 0.8, 1.0, or 1.2 mg/m(2) with once weekly idarubicin 10 mg/m(2) for four weeks. Twenty patients were treated: 13 newly diagnosed (median age 68, range 61-83) and 7 relapsed (median age 58, range 40-77). Prior myelodysplastic syndrome (MDS) was documented in 10/13 (77%) newly diagnosed and 1/7 (14%) relapsed patients; the three newly diagnosed patients without prior MDS had dyspoietic morphology. Two dose-limiting toxicities occurred at the initial dose level (bortezomib 0.8 mg/m(2) and idarubicin 10 mg/m(2)); idarubicin was reduced to 8 mg/m(2) without observing subsequent dose-limiting toxicities. The maximum tolerated dose in this study was bortezomib 1.2 mg/m(2) and idarubicin 8 mg/m(2). Common adverse events included: neutropenic fever, infections, constitutional symptoms, and gastrointestinal symptoms. No subjects experienced neurotoxicity. Most patients demonstrated hematologic response as evidenced by decreased circulating blasts. Four patients (20%) achieved complete remission. There was one treatment-related death. The combination of bortezomib and idarubicin in this mostly poor-risk, older AML group was well tolerated and did not result in high mortality. This trial was registered at www.clinicaltrials.gov as #NCT00382954.

Keywords: AML; Acute myeloid leukemia; Bortezomib; DLT; DSMC; Data Safety Monitoring Committee; EMSA; Elderly; FACS; Idarubicin; LSC; MDS; MTD; NF-kB; acute myeloid leukemia; dose-limiting toxicity; electrophoretic mobility shift assay; fluorescence-activated cell sorting; iKBa; inhibitor of NF-kB; leukemic stem cell; maximum tolerated dose; myelodysplastic syndrome; nuclear factor kappa B.

Copyright © 2013 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Patients with circulating blasts demonstrated a biologic effect by decreased absolute blast counts.

Figure 2

Subgroup survival – patients who did not achieve remission, survived beyond 50 days; potential benefit from treatment not reflected as complete remission.

Figure 3

Overall group survival.

Figure 4

Patients with a biologic effect demonstrated decreased NF-kB activity and activation of p53 post-treatment. (A) Electrophoretic mobility shift (EMSA) assays for NF-kB in mononuclear cells. (B) immunoblots for phospho-p53 and β-actin.