PURPOSE: Imatinib is an inhibitor of the Bcr-Abl tyrosine kinase; however, 
resistance is common. Flavopiridol, a cyclin-dependent kinase (CDK) inhibitor, 
down-regulates short-lived anti-apoptotic proteins via inhibition of 
transcription. In preclinical studies, flavopiridol synergizes with imatinib to 
induce apoptosis. We investigated this novel combination regimen in patients 
with Bcr-Abl(+) malignancies.
METHODS: In a phase I dose-escalation study, imatinib was administered orally 
daily, and flavopiridol by 1 h intravenous infusion weekly for 3 weeks every 
4 weeks. Adults with chronic myelogenous leukemia or Philadelphia 
chromosome-positive acute leukemia were eligible. Patients were divided into two 
strata based on peripheral blood and bone marrow blast counts. The primary 
objective was to identify the recommended phase II doses for the combination. 
Correlative pharmacokinetic and pharmacodynamic studies were also performed.
RESULTS: A total of 21 patients received study treatment. Four dose levels were 
evaluated before the study was closed following the approval of the 
second-generation Bcr-Abl tyrosine kinase inhibitors (TKIs). Five patients 
responded, including four sustained responses. Four patients had stable disease. 
All but one responder, and all patients with stable disease had previously been 
treated with imatinib. One patient had a complete response sustained for 
30 months. Changes in expression of phospho-Bcr/Abl, -Stat5, and Mcl-1 were 
monitored. No major pharmacokinetic interaction was observed.
CONCLUSIONS: This is the first study to evaluate the combination of a CDK 
inhibitor and a TKI in humans. The combination of flavopiridol and imatinib is 
tolerable and produces encouraging responses, including in some patients with 
imatinib-resistant disease.