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

Abstract

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.

Keywords: bortezomib; follicular lymphoma; mantle cell lymphoma; neuropathy; rituximab.

Copyright © 2010 American Cancer Society.

Figures

Figure 1

Kaplan Meier Curve of survival in a preclinical model of human MCL treated with combination Bortezomib + Rituximab.

Figure 2A

Kaplan-Meier Curve of PFS in patients (n=25) receiving R-bortezomib.

Figure 2B

Kaplan-Meier Curve of PFS in patients with follicular (n=11, solid line) and MCL (n=14, dashed line).

Figure 3

Percent proteasome inhibition achieved in 25 patients on days 1, 8 of cycle 1 (bortezomib alone) and cycle 2 (R-bortezomib). No significant difference was observed in bortezomib-induced peak proteasome inhibition with the addition of rituximab to cycle 2.

Figure 4

Kaplan Meier curve correlating CD32a SNP and PFS in 22 patients treated with R-bortezomib.