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Phase I and Pharmacokinetic Study of Bortezomib in Combination with Idarubicin and Cytarabine in Patients with Acute Myelogenous Leukemia

Authors' Affiliations: ¹ Hematology/Oncology Unit, Massachusetts General Hospital; ² Division of Hematologic Malignancies and ³ Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute; ⁴ Division of Hematology and Oncology, Beth Israel-Deaconess Medical Center, Boston, Massachusetts; and ⁵ Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts

Requests for reprints: Eyal C. Attar, Center for Leukemia, Massachusetts General Hospital Cancer Center, 32 Fruit Street, Yawkey 7, Boston, MA 02114. Phone: 617-724-4000; Fax: 617-643-1915; E-mail: eattar{at}partners.org.

Purpose: Proteasome inhibition results in cytotoxicity to the leukemia stem cell in vitro. We conducted this phase I study to determine if the proteasome inhibitor bortezomib could be safely added to induction chemotherapy in patients with acute myelogenous leukemia (AML).

Experimental Design: Bortezomib was given on days 1, 4, 8, and 11 at doses of 0.7, 1.0, 1.3, or 1.5 mg/m² with idarubicin 12 mg/m² on days 1 to 3 and cytarabine 100 mg/m²/day on days 1 to 7.

Results: A total of 31 patients were enrolled. The median age was 62 years, and 16 patients were male. Nine patients had relapsed AML (ages, 18-59 years, n = 4 and 60 years, n = 5). There were 22 patients of 60 years with previously untreated AML (eight with prior myelodysplasia/myeloproliferative disorder or cytotoxic therapy). All doses of bortezomib, up to and including 1.5 mg/m², were tolerable. Nonhematologic grade 3 or greater toxicities included 12 hypoxia (38%; 11 were grade 3), 4 hyperbilirubinemia (13%), and 6 elevated aspartate aminotransferase (19%). Overall, 19 patients (61%) achieved complete remission (CR) and three had CR with incomplete platelet recovery. Pharmacokinetic studies revealed that the total body clearance of bortezomib decreased significantly (P < 0.01, N = 26) between the first (mean ± SD, 41.9 ± 17.1 L/h/m²) and third (18.4 ± 7.0 L/h/m²) doses. Increased bone marrow expression of CD74 was associated with CR.

Conclusions: The combination of bortezomib, idarubicin, and cytarabine showed a good safety profile. The recommended dose of bortezomib for phase II studies with idarubicin and cytarabine is 1.5 mg/m².