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

Abstract

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 11at doses of 0.7, 1.0, 1.3, or 1.5 mg/m 2 with idarubicin 12 mg/m 2 on days 1to 3 and cytarabine 100 mg/m 2 /day on days 1to 7. Results: A total of 31patients 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 z60 years, n = 5). There were 22 patients of z60 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/m 2 , 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

High Basal Nuclear Levels of Nrf2 in Acute Myeloid Leukemia Reduces Sensitivity to Proteasome Inhibitors

“…These unique features of bortezomib make it easier to administer in an in vivo setting and result in its decreased toxicity. However, as we and others have discovered, using better targeted proteasome inhibitors like bortezomib leads to no preferential apoptosis in AML cells over control cells (14,15,22). We show here that bortezomib preferentially induced apoptosis in control cells over AML cells, making it less likely to be used to treat AML.…”

“…Bortezomib is already used for effective treatment of multiple myeloma and mantle cell lymphoma and is well tolerated clinically. With regards to AML, a small number of clinical trials have been conducted with proteasome inhibitors revealing relatively disappointing results (14)(15)(16). The present studies were undertaken to investigate the mechanism by which treating AML with proteasome inhibitors alone is ineffective.…”

Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia

“…Six additional patients were treated at the highest planned dose of bortezomib (1.3 mg/m 2 on days 5, 8, 12, and 15); 1 respiratory death before cycle 2 occurred at this dose. Patients received a median of 2 cycles of treatment (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Only 2 patients received treatment with both drugs beyond 3 cycles.…”

“…3 Despite lack of single-agent activity, bortezomib has shown promise when used in combination regimens for AML. 4 We recently demonstrated a unique mechanism of activity of bortezomib: the drug is an indirect transcriptional inhibitor for several target genes that are relevant to AML. 5,6 We showed an important role for bortezomib in disrupting a network that operates on the basis of interactions of miR-29b, the transcription factor SP1, and NF-B(p65).…”

Prospects of targeted therapy of acute leukemias in children

“…Бортезомиб ингибирует активность ядерного фактора NF-kB, транскрипционного активатора с антиапоптотическими свойствами, в качестве моно-препарата и безопасен в сочетании с химиотерапией OMЛ, хотя возможны редкие случаи развития острого респираторного дистресс-синдрома (ОРДС) в соче-тании с высокими дозами цитарабина [27]. По пред-варительным результатам исследования AAML07P1 COG (фаза II) при использовании бортезомиба со-вместно со стандартной химиотерапией при лечении OMЛ ни у одного из детей ОРДС не развился.…”