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Background: Pre-clinical data suggests that bortezomib may have a suppressive effect on B-cell lymphoma 2 (bcl- 2), an anti-apoptotic protein over expressed in follicular lymphoma; therefore, the addition of bortezomib to standard chemotherapy may improve the treatment of follicular lymphoma. We conducted this prospective, single-arm, openlabel phase II trial of bortezomib combined with rituximab, fludarabine, mitoxantrone, and dexamethasone (R-VFND) to evaluate the efficacy and safety of this regimen in patients with relapsed/refractory advanced follicular lymphoma. Methods: Twelve patients with relapsed or refractory stage III or IV follicular lymphoma were treated with bortezomib 1.6 mg/m2 day 1 and day 8 in combination with R-FND (rituximab 375 mg/m2 day 1, fludarabine 25 mg/m2 iv days 1, 2, and 3; mitoxantrone 10 mg/m2 iv day 2; and dexamethasone 20 mg/m2 p.o. days 1, 2, 3, 4, and 5). Cycles were repeated every 28 days for a maximum of 8 cycles. Cycles were held for grade 3/4cytopenias and patients were withdrawn if drug was held for more than 2 weeks. Results: Of 11 evaluable patients, 7 had a response (64%) with 4 complete responses (CR) (36%). Two patients remain in CR after 43 months: on after four cycles with no further treatment, the other after three cycles followed by allogeneic hematopoietic stem-cell transplant. Cytopenias were significant: 55% of patients had grade 3-4 neutropenia and 55% had grade 3-4 thrombocytopenia. Four patients (36%) withdrew early due to hematologic adverse events and one patient (9%) due to neuropathy. Conclusion: The addition of bortezomib to R-FND for treatment of follicular lymphoma resulted in a high response rate, but it was not clearly higher than what is expected from R-FND and the cytopenias were severe. Therefore, while bortezomib’s role in the treatment of follicular lymphoma remains to be fully defined, we find it hard to justify further trials with the fludarabine based combination and suggest future studies focus on alternative combinations.