Schedule of bortezomib administration may be an important determinant of single-agent activity in patients with relapsed or refractory follicular (FL) lymphoma and mantle cell lymphoma (MCL)

Abstract

8051 Background: We previously demonstrated the significant activity of bortezomib for the treatment of FL and MCL. The activity in MCL has been confirmed in a multi-center study leading to the recent approval by the FDA. The demonstrated activity was observed on the twice weekly schedule. Recent data using bortezomib in combination with rituximab suggested that weekly bortezomib was less toxic and possibly equally as efficacious as twice weekly bortezomib. This study does not allow a determination of weekly single agent activity alone. We sought to evaluate the single agent activity of bortezomb in FL and MCL administered on a weekly schedule. Methods: Pts with FL and MCL were treated with bortezomib at a dose of 1.8 mg/m2 weekly for 4 of 6 consecutive weeks. To date, 20 pts (12 FL, 8 MCL) have been treated on this schedule, of which 18 are assessable for response. Two pts were inevaluable: 1 pt received steroids for bronchitis (MCL); and 1 pt (FL) with grade 2 diarrhea withdraw consent making her data inaccessible. Results: The range of cycles administered was 1 to 8, with a median of 2. The weekly dosing schedule was well tolerated with 1 pt. developing neuropathy (grade 3). Fourteen pts completed at least two cycles of therapy and underwent restaging. Two pts had a PR (both FL), 8 had SD (5 FL, 3 MCL) and 4 had POD (2 FL, 2 MCL). The other 4 evaluable patients are now being restaged. Conclusions: These data suggest weekly dosing with bortezomib may not be as effective as twice weekly. Typically, bortezomib administered on the twice weekly schedule has an ORR of 30% in MCL and 50% in FL. Additionally, the frequency of pts. experiencing POD appears to be less common on the twice weekly schedule. One difference in the schedules is the dose intensity and dose density. A cycle of twice weekly bortezomib administers 1.7 mg/m2/week, while a weekly schedule administers only 1.2 mg/m2/week, a 30% difference in dose intensity and a 100% difference in dose density (1.33 × per week vs. .67 × per week). What remains unclear from a pharmacologic perspective is the relative importance of high Cmax vs high AUC exposures, and their impact on both toxicity and efficacy. These data suggest that schedule is critical in the activity of bortezomib. No significant financial relationships to disclose.

Weekly versus twice weekly bortezomib given in conjunction with rituximab, in patients with recurrent follicular lymphoma, mantle cell lymphoma and Waldenström macroglobulinaemia

“…The incidence and severity of neuropathy were similar in the two groups of patients. Equivalent degrees of neurotoxicity have likewise been observed in other reports where bortezomib has been given once or twice weekly (Goy et al , 2005; O’Connor et al , 2005, 2007; Fisher et al , 2006; Strauss et al , 2006; Gerecitano et al , 2009; de Vos et al , 2009).…”

“…However, a subsequent multi‐centre trial (in MCL) suggested a rather lower response rate (31%), with a median duration of response of 9 months in a heavily pre‐treated population (Fisher et al , 2006). Again, the principal toxicities were gastro‐intestinal (GI) tract symptoms, peripheral neuropathy and thrombocytopenia (Goy et al , 2005; O’Connor et al , 2005, 2007; Fisher et al , 2006; Strauss et al , 2006; Gerecitano et al , 2009; de Vos et al , 2009).…”

Addition of bortezomib to standard dose chop chemotherapy improves response and survival in relapsed mantle cell lymphoma

“…Despite this, only 4 patients had a dose change in either bortezomib or vincristine solely due to neuropathy. The incidence of neuropathy (all grades and ≥grade3) reported in this trial is broadly similar to that reported in other trials of weekly bortezomib administration in MCL patients (De Vos et al , ), and is lower than that reported in some trials of biweekly bortezomib (Goy et al , ; O'Connor et al , , ; Fisher et al , ; Strauss et al , ; De Vos et al , ; Gerecitano et al , ). This conflicts with the results from a randomized phase II trial of bortezomib + RCHOP (Ribrag et al , ), which reported increased peripheral neuropathy when higher dose bortezomib (weekly dose 1·6 mg/m 2 ) was used, but acceptable toxicity with lower dose bortezomib (1·3 mg/m 2 bi weekly).…”

“…Recent data shows an improvement in survival of MCL patients when rituximab is added to fludarabine‐cyclophosphamide chemotherapy. (Rule et al , ) Given that bortezomib appears to have significant single agent activity in MCL (O'Connor et al , ; Goy et al , ) and has an acceptable toxicity profile when combined with CHOP chemotherapy, it is now being combined with RCHOP immunochemotherapy in trials. The PFS of CHOP‐bortezomib in a relapse setting is virtually identical to that of RCHOP given in a first line setting (Howard et al , ).…”

Patients with chemotherapy‐refractory mantle cell lymphoma experience high response rates and identical progression‐free survivals compared with patients with relapsed disease following treatment with single agent bortezomib: results of a multicentre phase 2 clinical trial

“…46%). Our experience with bortezomib in patients with follicular lymphoma clearly demonstrated that patients with refractory disease exhibited a much shorter PFS compared with patients with relapsed disease (7·5 months vs. 1·8 months) (O’Connor et al , 2007). Interestingly, in MCL it appears that bortezomib may be capable of overcoming both the intrinsic and acquired mechanisms of drug resistance in some relatively consistent fraction of patients.…”