Abstract 4713: Pharmacodynamic effects of bolus infusion flavopiridol treatment on gene expression in adult patients with relapsed and refractory acute myeloid leukemia
Authors: Nelson Dwella M. , Joseph Biju , Hillion Joelle , Resar Linda Smith , Karp Judith 
Published: June 2012

Abstract
Acute leukemia in adults is a formidable clinical challenge that demands further investigation to identify new, “personalized” therapies for high-risk patients. We are investigating an anti-leukemia therapy using a prototypical cyclin dependent kinase (cdk) inhibitor, flavopiridol, in refractory or poor-risk disease. Flavopiridol, a cytotoxic molecule, induces cell cycle arrest by blocking cyclin-dependent kinase (cdk) function, thereby interfering with Polymerase II activity and globally down-regulating gene expression. A previous study from our group showed that flavopiridol induces apoptosis in vitro in leukemic blasts from patients with refractory leukemia. A subsequent Phase I clinical trial demonstrated a decrease in leukemic blasts by over 50% in adult patients with relapsed or refractory leukemia and a 31% response rate in 16 patients with acute myeloid leukemia. Western analysis of leukemic blasts before and after flavopiridol infusions showed a decrease in one or more of the following proteins: RNA Polymerase II, STAT3, cyclin D1, Bcl-2, and Mcl-1. Serum VEGF levels were also decreased in most patients. Based on these findings, we investigated expression of the genes encoding these proteins by quantitative, RT-PCR in leukemic blasts from adult patients with refractory or poor-risk acute myeloid leukemia (AML) before and after flavopiridol therapy. Flavopiridol was administered daily for three consecutive days by a bolus-infusion schedule. Flavopiridol doses were escalated from a total flavopiridol dose of 50 mg/m2 (level 1) up to 100 mg/m2 (level 6) after treating 6-10 patients at each dose level. Leukemic blasts with adequate RNA were available from 16/26 patients. We measured mRNA expression of 8 genes (Bcl-2, HMGA1, STAT3, E2F1, POLR2A, MCL1, VEGF-A, and CCND1) before and after flavopiridol treatment using quantitative, RT-PCR. Here, we report for the first time that in vivo administration of flavopiridol up-regulates the Bcl-2 anti-apoptotic gene in leukemic blasts in 16/16 (100%) patients. Further, there was a significant decrease in the genes encoding the oncogenic transcription factors STAT3, E2F1, and HMGA1. In addition, there was a significant repression in the gene encoding the major subunit of RNA Polymerase II (POLR2A). Of the 16 patients treated, 5/16 patients achieved a complete response (CR) and 2/16 achieved a partial response (PR). Given the encouraging clinical results with flavopiridol in combination with ara-C and mitoxantrone, further studies are needed to dissect the molecular pathways disrupted by flavopiridol and should facilitate the development of better therapeutic approaches in adult AML. Our results also indicate that targeting Bcl-2 anti-apoptotic pathways could enhance cytotoxicity and improve outcomes in patients treated with flavopiridol.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4713. doi:10.1158/1538-7445.AM2011-4713