title: Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia.
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/m(2) intravenously on days 1-10) plus bortezomib (escalated up to the target 1.3 mg/m(2) 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 down-regulation 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.
authors.affiliation: Division of Hematology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, B310 Starling-Loving Hall, Columbus, OH 43210, USA. william.blum@osumc.edu
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schwind
authors.forename: Somayeh S
authors.initials: SS
authors.lastname: Tarighat
authors.forename: Susan
authors.initials: S
authors.lastname: Geyer
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Eisfeld
authors.forename: Susan
authors.initials: S
authors.lastname: Whitman
authors.forename: Alison
authors.initials: A
authors.lastname: Walker
authors.forename: Rebecca
authors.initials: R
authors.lastname: Klisovic
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Santhanam
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
authors.forename: John P
authors.initials: JP
authors.lastname: Curfman
authors.forename: Steven M
authors.initials: SM
authors.lastname: Devine
authors.forename: Samson
authors.initials: S
authors.lastname: Jacob
authors.forename: Celia
authors.initials: C
authors.lastname: Garr
authors.forename: Cheryl
authors.initials: C
authors.lastname: Kefauver
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Chan
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D001897:Boronic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D000077209:Decitabine; D004353:Drug Evaluation, Preclinical; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D016896:Treatment Outcome; D054928:Validation Studies as Topic
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D000077209:Decitabine; D001374:Azacitidine