Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma

• Published in: Cancer 2011-06, Vol.117 (11), p.2442-2451
• Main Authors: Baiocchi, Robert A., Alinari, Lapo, Lustberg, Mark E., Lin, Thomas S., Porcu, Pierluigi, Li, Xiaobai, Johnston, Jeffrey S., Byrd, John C., Blum, Kristie A.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Antibodies, Monoclonal, Murine-Derived - administration & dosage; Antibodies, Monoclonal, Murine-Derived - adverse effects; Antibodies, Monoclonal, Murine-Derived - therapeutic use; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Boronic Acids - administration & dosage; Boronic Acids - adverse effects; Boronic Acids - therapeutic use; Bortezomib; Disease Models, Animal; Drug Evaluation, Preclinical; Female; follicular lymphoma; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Follicular - drug therapy; Lymphoma, Follicular - mortality; Lymphoma, Follicular - pathology; Lymphoma, Mantle-Cell - drug therapy; Lymphoma, Mantle-Cell - mortality; Lymphoma, Mantle-Cell - pathology; Male; mantle cell lymphoma; Medical sciences; Mice; Middle Aged; Neoplasm Staging; neuropathy; Polymorphism, Single Nucleotide; Proteasome Inhibitors - administration & dosage; Proteasome Inhibitors - adverse effects; Proteasome Inhibitors - therapeutic use; Pyrazines - administration & dosage; Pyrazines - adverse effects; Pyrazines - therapeutic use; Receptors, IgG - genetics; Recurrence; Rituximab; Treatment Outcome; Tumors
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.25792

BACKGROUND: In vitro studies in mantle cell lymphoma (MCL) cell lines and patient‐derived cells have demonstrated synergistic apoptosis with combined rituximab and bortezomib (R‐bortezomib) compared with single‐agent bortezomib. Therefore, the authors of this report evaluated R‐bortezomib in a preclinical model and in a phase 2 clinical trial. METHODS: A Hu‐MCL‐severe combined immunodeficiency (SCID) model engrafted with the Jeko cell line was treated with R‐bortezomib, bortezomib, or rituximab. Twenty‐five patients with relapsed follicular lymphoma (n = 11) and MCL (n = 14) received 375 mg/m2 rituximab on Days 1 and 8 and 1.3 to 1.5 mg/m2 bortezomib on Days 1, 4, 8, and 11 every 21 days for a median of 3 cycles (range, 1‐5 cycles). RESULTS: R‐bortezomib resulted in a statistically significant improvement in overall survival in Hu‐MCL‐SCID mice. In the clinical trial, the overall response rate was 40% in all 25 patients, 55% in patients with follicular lymphoma, and 29% in patients with MCL. The estimated 2‐year progression‐free survival (PFS) rate was 24% (95% confidence interval [CI], 10%‐53%) in all patients and 60% (95% CI, 20%‐85%) in responding patients. Thirteen patients (52%) developed grade 3 neurotoxicity, which consisted of constipation/ileus, sensory or motor neuropathy, or orthostatic hypotension. Patients who were heterozygous for the CD32a (Fcγ receptor IIa) 131 histidine (H) to arginine (R) polymorphism had a significantly decreased PFS (P = .009) after R‐bortezomib compared with HH and RR homozygotes. CONCLUSIONS: R‐bortezomib had significant activity in patients with relapsed or refractory follicular lymphoma and MCL, although an unexpectedly high incidence of grade 3 neurologic toxicity was a potential limiting factor with this combination. Cancer 2011. © 2010 American Cancer Society. Encouraging preclinical data demonstrating that bortezomib in combination with rituximab (R‐bortezomib) leads to synergistic apoptosis in non‐Hodgkin lymphoma provided justification for a phase 2 combination trial of R‐bortezomib in patients with relapsed mantle cell and follicular lymphoma, who had response rates of 29% and 55%, respectively. However, grade 3 neurotoxicity that occurred in 52% of patients enrolled on the trial limited prolonged dosing with this combination.