Bortezomib in combination with fludarabine and cyclophosphamide for patients with relapsed or refractory mantle-cell lymphoma: results of the LYM-4003 study

Background: The LYM-4003 study was initiated to identify the maximum tolerated dose (MTD) of cyclophosphamide when combined with bortezomib and fludarabine in a phase 1b trial, and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL. Methods: Patients with relapsed or refractory MCL who had received at least one previous lines of treatment were enrolled in this single-arm, open-label, phase 1/2 trial at six major cancer centers in China. In phase 1, to identify the MTD of cyclophosphamide, 3 patient cohorts received escalating doses (150, 200, and 250 mg/m2) of intravenous cyclophosphamide on days 1, 2 of each 28-day cycle. Patients also received bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11, fludarabine 25 mg/m2 on days 1, 2, 3 of each 28-day cycle. In phase 2 study, patients received bortezomib and fludarabine plus the MTD of cyclophosphamide, following the same cycles as for phase 1. Treatment in both phases to maximum 6 cycles of chemotherapy, continued until disease progression, or severe toxicity. The primary efficacy endpoint was overall response (complete or partial response). The secondary efficacy endpoint was survival. We used the Kaplan-Meier method to estimate response duration, progression-free survival, and overall survival. Analysis was by intention to treat population. Findings: 40 patients were enrolled between April 8, 2011 and October 10, 2015, 9 in phase 1 and 34 (including three patients who received the MTD of cyclophosphamide in the phase 1 portion) in phase 2. In phase 1, we identified the MTD as 250 mg/m2 cyclophosphamide. In the phase 2 portion of the study, grade 3-4 hematological toxicities included thrombocytopenia, leucopenia, neutropenia, and lymphopenia. Among 32 patients in phase 2, 23 (72%, 95% CI 57-87) had an overall response: 10 (31%, 95%CI 16-46) had a complete response and 13 (41%, 95% CI 25-57) had a partial response. The median follow-up time was 31·6 months (IQR 13·5- 47·4). The median response duration was 26·3 months (IQR 11·8-33·9). The median progression-free survival was 21 months (95% CI 7·3-34·7), and the median overall survival was 32·4 months (95% CI 17·8-47·0). Interpretation: Bortezomib in combination with fludarabine and cyclophosphamide is highly effective and well tolerated for patients with relapsed or refractory MCL. Further investigation is needed. Trial Registration: (ClinicalTrials.gov identifier: NCT01322776). Funding Statement: This research was supported by Xian-Janssen Pharmaceutical Ltd. Xian-Janssen provided free bortezomib and financial support. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. Institutional Review Board approval was obtained at each study site. Informed written consent was obtained from all participants before enrollment.