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

William Blum, Sebastian Schwind, Somayeh S. Tarighat, Susan Geyer, Ann Kathrin Eisfeld, Susan Whitman, Alison Walker, Rebecca Klisovic, John C. Byrd, Ramasamy Santhanam, Hongyan Wang, John P. Curfman, Steven M. Devine, Samson Jacob, Celia Garr, Cheryl Kefauver, Danilo Perrotti, Kenneth K. Chan, Clara D. Bloomfield, Michael A. CaligiuriMichael R. Grever, Ramiro Garzon, Guido Marcucci

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

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 ≥ 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.

Original languageEnglish (US)
Pages (from-to)6025-6031
Number of pages7
JournalBlood
Volume119
Issue number25
DOIs
StatePublished - Jun 21 2012

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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