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. Treatment in both phases to maximum 6 cycles of chemotherapy, continued until disease progression, or severe toxicity. The primary endpoint was overall response. The secondary 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. Results 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 phase 1) in phase 2. In phase 1, we identified the MTD as 250 mg/m2 cyclophosphamide. In phase 2, grade 3–4 hematological toxicities included thrombocytopenia, leucopenia, neutropenia, and lymphopenia. Among 32 patients in phase 2, 23 (72%) had an overall response: 10 (31%) had a complete response and 13 (41%) had a partial response. The median follow-up time was 31.6 months. The median response duration was 26.3 months. 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). Conclusions Bortezomib in combination with fludarabine and cyclophosphamide is highly effective and well tolerated for patients with relapsed or refractory MCL. Trial registration ClinicalTrials.gov NCT01322776 (Registered on March 25, 2011)