Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia
Mené sur 19 patients atteints d'une leucémie myéloïde aiguë (âge médian : 70 ans), cet essai de phase I évalue la toxicité et l'activité clinique d'un traitement combinant decitabine et bortezomib
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 upregulation, resulting in loss of transcriptional activation for several genes relevant to myeloid leukemogenesis including DNA methyltransferases (DNMTs) and receptor tyrosine kinases (RTKs). Thus, a phase I trial of bortezomib and decitabine was developed. Nineteen poor-risk AML patients (median age 70 years; range, 32-84) enrolled. Induction with decitabine (20mg/m2 IV 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), 5/10 had CR (complete remission, N=4) or incomplete CR (CRi, N=1); 7/19 overall had CR/CRi. Pharmacodynamic analysis showed FLT3 downregulation on day 26 of cycle 1 (P=0.02). Additional mechanistic studies showed that FLT3 downregulation was due to bortezomib-induced miR-29b upregulation; this led to SP1 downregulation and destruction of the SP1/NFκB complex that transactivated FLT3. In conclusion, this study demonstrated feasibility and preliminary clinical activity of decitabine plus bortezomib in AML and identified FLT3 as a novel pharmacodynamic endpoint for future trials. This study is registered at the NCI Clinical Trials Network as NCT00703300.