학술논문
Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia.
Document Type
Article
Author
Blum, William; Schwind, Sebastian; Tarighat, Somayeh S.; Geyer, Susan; Eisfeld, Ann-Kathrin; Whitman, Susan; Walker, Alison; Klisovic, Rebecca; Byrd, John C.; Santhanam, Ramasamy; Wang, Hongyan; Curfman, John P.; Devine, Steven M.; Jacob, Samson; Garr, Celia; Kefauver, Cheryl; Perrotti, Danilo; Chan, Kenneth K.; Bloomfield, Clara D.; Caligiuri, Michael A.
Source
Subject
*ACUTE myeloid leukemia
*PHARMACODYNAMICS
*DNA methyltransferases
*PROTEIN-tyrosine kinases
*MICRORNA genetics
*OLDER patients
*PROTEASOME inhibitors
*NEUROPATHY
*
*
*
*
*
*
*
Language
ISSN
0006-4971
Abstract
We recently reported promising clinical activity for a 10-day regimen of decitabine in older AML patients; high miR-29b expression associated with clinical response. Subsequent preclinical studies with bortezomib in AML cells have shown drug-induced miR-29b up-regulation, resulting in loss of transcriptional activation for several genes relevant to myeloid leukemogenesis, including DNA methyltransferases and receptor tyrosine kinases. Thus, a phase 1 trial of bortezomib and decitabine was developed. Nineteen poor-risk AML patients (median age 70 years; range, 32-84 years) enrolled. Induction with decitabine (20 mg/m2 intravenously on days 1-10) plus bortezomib (escalated up to the target 1.3 mg/m2 on days 5, 8, 12, and 15) was tolerable, but bortezomib-related neuropathy developed after repetitive cycles. Of previously untreated patients (age a 65 years), 5 of 10 had CR (complete remission, n = 4) or incomplete CR (CRi, n = 1); 7 of 19 overall had CR/CRi. Pharmacodynamic analysis showed FLT3 down-regulation on day 26 of cycle 1 (P = .02). Additional mechanistic studies showed that FLT3 down-regulation was due to bortezomib-induced miR-29b up-regulation; this led to SP1 downregulation and destruction of the SP1/ NF-KB complex that transactivated FLT3. This study demonstrates the feasibility and preliminary clinical activity of decitabine plus bortezomib in AML and identifies FLT3 as a novel pharmacodynamic end point for future trials. This study is registered at http://www.clinicaltrials.gov as NCT00703300. [ABSTRACT FROM AUTHOR]