A Phase I Study using Bortezomib (Velcade), Cladribine, and Rituximab (VCR) in Treating Elderly Patients with Mantle Cell Lymphoma

Abstract

Abstract Cladribine indirectly downregulates methylations of DNA, RNA and histone by blocking transferring methyl groups from S-adenosyl-methionine. Cladribine and Rituximab combination showed a synergetic effect in treating B cell lymphomas. Bortezomib (Velcade) is a FDA approved proteasome inhibitor for treating mantle cell lymphoma (MCL). In this single arm phase I study, we evaluated the safety, dose limiting toxicity, and efficiency of Bortezomib, Cladribine, and Rituximab (VCR) combination treatment in elderly MCL patients. We also proposed potential DNA methylation biomarkers for VCR treatment. A standard 3+3 dose escalation scheme was designed to determine the maximum tolerable cladribine dose. The therapy consisted of 6 28-day cycles. Most patients tolerated this regimen well. The overall responding (OR) rate was 84.6% and complete remission (CR) rate was 84.6%. In newly diagnosed subject cohort, the OR and CR was 100% respectively, 1 year overall survival rate was 90%, and progression free survival rate was 80%. Low grade hematological toxicity and mild fatigue were observed. No severe systemic toxicity was observed. Five hypermethylated regions located at gene promoters were identified as potential biomarkers for an effective treatment response. In conclusion, VCR combination is a well-tolerated, low toxicity and effective regimen for elderly untreated MCL. Clinicaltrials.gov #: NCT01439750.