Excessive Neurotoxicity in a Phase II Trial of Combined Bortezomib and Rituximab in Patients with Relapsed/Refractory Mantle Cell (MCL) and Follicular (FL) Non-Hodgkin’s Lymphoma.
Authors: Blum Kristie A. , Lucas Margaret S. , Johnston Jeffrey S. , Dalton James , Young Donn , Baiocchi Robert A. , Lin Thomas S. , Porcu Pierluigi , Byrd John C. 
Published: October 2019

Background: Preliminary data from our institution has demonstrated synergistic apoptosis and enhanced NFkB depletion in MCL patient (pt) samples and cell lines treated with combination bortezomib and rituximab (Baiocchi, et al., 2005 ASH abstr. 2407). On the basis of these in vitro results, we initiated a phase II trial of combination bortezomib and rituximab in pts with relapsed/refractory MCL and FL beginning in 12/2004.

Methods: Histologically confirmed MCL or FL (grade 1 or 2), > 1 prior therapy, age ≥ 18, ECOG performance status 0–3, measurable disease, signed informed consent, and creatinine clearance > 30 ml/min were required. Pts with pre-existing peripheral neuropathy ≥ grade (gr.) 2 were not eligible. Treatment consisted of rituximab 375 mg/m2 d 1 & 8 immediately followed by bortezomib 1.5 mg/m2 d 1, 4, 8, & 11 every 21 d for 6 cycles. Rituximab was started on d 1 of cycle 2 to permit assessment of the effect of rituximab on bortezomib-induced proteasome inhibition.

Results: Nine pts (6 MCL and 3 FL), with a median age of 66 (range 55–81), completed a median of 3 cycles (range, 1–5). The median number of prior therapies was 3 (range, 1–3), 5 pts had stage IV disease, and 3 pts were refractory. 7 pts were evaluable for response, 2 pts discontinued therapy due to toxicity (ileus and orthostatic hypotension) prior to response evaluation. Of the 7 evaluable pts, the overall response rate was 42.9% (1 CR, 1 CRu, 1 PR), with 14.3% stable disease (1). Responses were observed in 1 MCL and 2 FL pts. In 9 pts, the median progression-free survival (PFS) was 1.7 mos (range, 1–12.9+ mos), with a median PFS of 5.5+ mos (range, 5.5–12.9+ mos) in the responders. The median overall survival was 5.3 mos (range, 2.8 – 12.9+ mos). Gr. 3 and 4 toxicities consisted of thrombocytopenia (4 pts), sensory neuropathy (3 pts), constipation (2 pts), motor neuropathy (1pt), orthostatic hypotension (1 pt), neutropenia (1 pt), rash (1 pt), myositis with creatinine kinase elevation (1 pt), and ileus (1 pt). 5 pts stopped protocol therapy due to toxicity: 1 pt with CR stopped after cycle 3 due to gr. 3 sensory/motor neuropathy and myositis, 1 pt with CRu stopped after cycle 4 due to gr. 3 sensory neuropathy, 1 pt with SD stopped after 5 cycles due to gr. 3 sensory neuropathy, 1 pt stopped therapy after 3 doses of bortezomib due to a gr. 3 ileus, and 1 pt stopped after 4 doses of bortezomib due to gr. 3 orthostatic hypotension. All pts with neurotoxicity had received prior vincristine. In the 8 pts with available pharmacodynamic data, the peak percent proteasome inhibition was observed 30 min after bortezomib treatment, with a median percent inhibition of 60.8% (44.7–72.1%) on d1 and 69.4% ( 63.9–85.6%) on d8 cycle 1. No difference was observed in peak proteasome inhibition with the addition of rituximab during cycle 2 (p=0.65), with peak levels reaching 64.2% (56.9–67.5%) and 67% (55.5–74.5%) on d1 and 8. Finally, no differences in peak proteasome inhibition were observed in patients with response (p=0.34) or excessive toxicity (p=0.64).

Conclusions: Although preliminary efficacy has been observed in this combination trial of bortezomib and rituximab, 71.4% (5 pts) experienced gr. 3 autonomic, sensory, or motor neuropathy. The frequency of neuropathy observed in this trial exceeds that observed with single agent bortezomib, warranting additional caution in the use of this combination.