| Popis: |
Cladribine indirectly downregulates methylation of DNA, RNA, and histones by blocking the transfer of methyl groups from S-adenosyl-methionine. The cladribine and rituximab combination showed a synergetic effect in treating B-cell lymphomas. Bortezomib (Velcade) is a Food and Drug Administration (FDA)-approved proteasome inhibitor for treating mantle cell lymphoma (MCL). In this single-arm, phase I study, the safety, dose-limiting toxicity, and clinical activity of bortezomib, cladribine, and rituximab (VCR) combination treatment were evaluated in elderly MCL patients. Potential DNA methylation biomarkers for VCR treatment were also proposed. A standard 3 + 3 dose-escalation scheme was designed to determine the maximum tolerated dose of cladribine. The therapy consisted of six 28-day cycles. Most patients tolerated this regimen well. The overall response (OR) rate was 84.6%, and the complete remission (CR) rate was 84.6%. In the newly diagnosed subject cohort, the OR and CR were 100%, the 2-year overall survival rate was 84.6%, and the progression-free survival rate was 76.9%. The median age was 64 (54–81). The median time to first response was 3 (2.1–7.4) months. The median follow-up time was 43 (9–60) months. 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, the VCR combination is a well-tolerated, low-toxicity, and highly effective regimen for the elderly with untreated MCL.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT01439750. |
