TY - JOUR
T1 - Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia
AU - Blum, William
AU - Schwind, Sebastian
AU - Tarighat, Somayeh S.
AU - Geyer, Susan
AU - Eisfeld, Ann Kathrin
AU - Whitman, Susan
AU - Walker, Alison
AU - Klisovic, Rebecca
AU - Byrd, John C.
AU - Santhanam, Ramasamy
AU - Wang, Hongyan
AU - Curfman, John P.
AU - Devine, Steven M.
AU - Jacob, Samson
AU - Garr, Celia
AU - Kefauver, Cheryl
AU - Perrotti, Danilo
AU - Chan, Kenneth K.
AU - Bloomfield, Clara D.
AU - Caligiuri, Michael A.
AU - Grever, Michael R.
AU - Garzon, Ramiro
AU - Marcucci, Guido
PY - 2012/6/21
Y1 - 2012/6/21
N2 - 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 ≥ 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-κB 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.
AB - 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 ≥ 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-κB 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.
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U2 - 10.1182/blood-2012-03-413898
DO - 10.1182/blood-2012-03-413898
M3 - Article
C2 - 22566605
AN - SCOPUS:84862726260
SN - 0006-4971
VL - 119
SP - 6025
EP - 6031
JO - Blood
JF - Blood
IS - 25
ER -