A Phase II Trial of Bortezomib and Vorinostat in Mantle Cell Lymphoma and Diffuse Large B-cell Lymphoma

• Published in: Clinical lymphoma, myeloma and leukemia myeloma and leukemia, 2018-09, Vol.18 (9), p.569-575.e1
• Main Authors: Yazbeck, Victor, Shafer, Danielle, Perkins, Edward B., Coppola, Domenico, Sokol, Lubomir, Richards, Kristy L., Shea, Thomas, Ruan, Jia, Parekh, Samir, Strair, Roger, Flowers, Christopher, Morgan, David, Kmieciak, Maciej, Bose, Prithviraj, Kimball, Amy, Badros, Ashraf Z., Baz, Rachid, Lin, Hui-Yi, Zhao, Xiuhua, Reich, Richard R., Tombes, Mary Beth, Shrader, Ellen, Sankala, Heidi, Roberts, John D., Sullivan, Daniel, Grant, Steven, Holkova, Beata
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bortezomib - administration & dosage; Clinical trial; DLBCL; Drug Resistance, Neoplasm - drug effects; Female; Follow-Up Studies; Histone deacetylase inhibitor; Humans; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - pathology; Lymphoma, Mantle-Cell - drug therapy; Lymphoma, Mantle-Cell - pathology; Male; MCL; Middle Aged; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - pathology; Prognosis; Prospective Studies; Proteasome inhibitors; Salvage Therapy; Survival Rate; Vorinostat - administration & dosage
• ISSN: 2152-2650; 2152-2669
• DOI: 10.1016/j.clml.2018.05.023

Patients with relapsed/refractory non-Hodgkin lymphoma remain a population with an unmet medical need. Histone deacetylase inhibitors and proteasome inhibitors have shown synergistic interactions preclinically in several B-cell malignancies. The present phase II trial examined the combination of the proteasome inhibitor bortezomib and the histone deacetylase inhibitor vorinostat in patients with relapsed/refractory diffuse large B-cell lymphoma or mantle cell lymphoma. The results of the present trial revealed a modest overall response rate. The proteasome inhibitor bortezomib has demonstrated marked preclinical activity when combined with the histone deacetylase inhibitor vorinostat in leukemia, multiple myeloma, and mantle cell lymphoma (MCL) cells. The present study evaluated the efficacy and safety of the combination in patients with relapsed or refractory MCL and diffuse large B-cell lymphoma (DLBCL). The present multicenter, nonrandomized phase II trial used a Simon 2-stage design with 3 cohorts: cohort A, MCL with no previous bortezomib (including untreated MCL); cohort B, MCL with previous bortezomib; and cohort C, relapsed or refractory DLBCL with no previous bortezomib. Vorinostat (400 mg) was administered orally on days 1 to 5 and 8 to 12 before bortezomib (1.3 mg/m2), which was administered intravenously on days 1, 4, 8, and 11 of each 21-day cycle. For the 65 treated patients (22 in cohort A, 4 in cohort B, and 39 in cohort C), the overall response rate was 31.8%, 0%, and 7.7%, respectively. The median progression-free survival was 7.6 months for cohort A and 1.8 months for cohort C. In cohort A, 7 patients had a partial response (PRs), 5 had stable disease (SD), 7 had progressive disease (PD), 1 was not assessed, and 2 were not evaluable. In cohort B, 2 had SD and 2 had PD. In cohort C, 3 had a PR, 8 had SD, 23 had PD, and 5 were not assessed. Baseline NF-κB activation, measured as nuclear RelA by immunohistochemistry, did not correlate with clinical response. The combination of bortezomib and vorinostat is safe and has modest activity in MCL and limited activity in DLBCL.