Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma.
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/m(2) rituximab on Days 1 and 8 and 1.3 to 1.5 mg/m(2) 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.
Division of Hematology, Ohio State University, Columbus, Ohio.
Robert A
RA
Baiocchi
Lapo
L
Alinari
Mark E
ME
Lustberg
Thomas S
TS
Lin
Pierluigi
P
Porcu
Xiaobai
X
Li
Jeffrey S
JS
Johnston
John C
JC
Byrd
Kristie A
KA
Blum
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017452:Receptors, IgG / Q000235:genetics; D012008:Recurrence; D000069283:Rituximab; D016896:Treatment Outcome
D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D017452:Receptors, IgG; D000069283:Rituximab; D000069286:Bortezomib
bortezomib; follicular lymphoma; mantle cell lymphoma; neuropathy; rituximab