Seventy-Two Hour Continuous Infusion Flavopiridol in Relapsed and Refractory Mantle Cell Lymphoma

Abstract

The cell cycle regulatory protein cyclin D1, which is over-expressed in 95-100% of mantle cell lymphomas (MCL), is a potential therapeutic target. Flavopiridol inhibits the cyclin-dependent kinase (CDK)4-cyclin D1 complex and induces apoptosis in lymphoma cell lines. Previous phase I clinical studies had demonstrated that this drug could be safely administered in humans, prompting further evaluation of flavopiridol as a single agent in MCL. Ten patients with relapsed or refractory MCL, who had received one prior chemotherapy regimen, were treated with flavopiridol 50 mg/m 2 /day given as a 72 h continuous intravenous infusion every 14 days. Treatment was well tolerated, and only one patient developed grade III-IV non-hematologic toxicity. However, there were no clinical responses; despite therapy, three patients maintained stable disease, and seven patients demonstrated progressive disease within two months. In relapsed and refractory MCL, flavopiridol is ineffective as a single agent given by 72 h continuous infusion at 50 mg/m 2 /day. Recent in vitro studies using human plasma suggest that higher plasma drug levels may be necessary to achieve clinical efficacy. In vitro studies of flavopiridol indicate that the agent is synergistic with DNA-damaging compounds. Further investigation into flavopiridol as a clinical agent should focus on alternative dosing schedules and the compound's potential use in combination chemotherapeutic regimens.