A Phase II Trial of Induction Plus Maintenance Rituximab and Bortezomib in Patients with Relapsed/Refractory Mantle Cell (MCL) and Follicular (FL) Non-Hodgkin’s Lymphoma
Authors: Blum Kristie A. , Baiocchi Robert A. , Alinari Lapo , Lin Thomas S. , Porcu Pierluigi , Jones Jeffrey , Flynn Joseph , Hicks William , Lucas Margaret S. , Wei Lai , Johnston Jeffrey S. , Byrd John C. 
Published: April 2020

Background: On the basis of in vitro data demonstrating synergistic apoptosis and enhanced NFkB depletion in MCL with combination rituximab (R) and bortezomib (Baiocchi, et al., 2005 ASH abstr. 2407), we conducted a phase II trial of R-bortezomib in patients (pts) with relapsed/refractory MCL and FL to determine overall response rate (ORR) and 2-year progression-free survival (PFS).

Methods: Pts with histologically confirmed MCL or grade 1–2 FL, ≥ 1 prior therapy, age ≥ 18, ECOG performance status 0–3, and peripheral neuropathy ≤ grade (gr.) 1 were enrolled. Induction therapy consisted of R 375 mg/m2 d 1 on weeks 4, 5, 7, 8, 10, 11, 13 and 14 and bortezomib 1.5 mg/m2 d 1 & 4 on weeks 1, 2, 4, 5, 7, 8, 10, 11, 13, and 14. In responding pts, maintenance R-bortezomib was planned d 1 & 8 every 6 months starting week 20. After 7 of the first 11 pts experienced gr. 3 neurologic toxicities, bortezomib was decreased to 1.3 mg/m2 for induction and maintenance cycles and pts with ≥ gr. 1 neuropathy pre-treatment were excluded.

Results: Twenty-three pts (10 FL; 13 MCL) were enrolled, with 11 pts receiving 1.5 mg/m2 and 12 pts receiving 1.3 mg/m2 bortezomib. Median age was 66 years (range, 35–81), 18 pts had stage III–IV disease, 7 FL pts had 2–4 FLIPI risk factors, median number of prior therapies was 2 (range, 1–9), and 8 pts were refractory. Pts completed a median of 9 weeks of therapy (range, 1–15). ORR was 39.1%, with complete responses (CR) in 5 pts (4 MCL; 1 FL) and CR unconfirmed (CRu) in 4 FL pts. CR or partial responses (PR) were evident in all responders after 9 weeks; however, the response improved from PR to CR/CRu in 5 FL pts over 3–9 months. Median follow-up is 13.4 months. Median PFS was 5.9 months (range, 1.7–36.4 + months). In the responders, PFS was 7.8–13.8+ months in FL pts and 3.8–36.4+ months in MCL pts. Three responding pts (1 MCL; 2 FL) underwent autologous or allogeneic stem cell transplant (SCT) following R-bortezomib, with PFS censored at the time of SCT. None of the responding pts received maintenance R-bortezomib due to gr. 3–4 neurotoxicity. Reasons for study removal included SCT in 1 pt, disease progression in 8 pts, and gr. 3–4 toxicity in 14 pts. Gr. 3–4 toxicities consisted of fatigue (9 pts), sensory neuropathy (9 pts), thrombocytopenia (4 pts), neutropenia (4 pts), orthostatic hypotension (3 pts), constipation/ileus (3 pts), diarrhea (3 pts), motor neuropathy (1 pt), rash (1 pt), and myositis with creatinine kinase elevation (1 pt). Gr. 3–4 neurotoxicity occurred in 64% and 50% of pts receiving 1.5 mg/m2 and 1.3 mg/m2 bortezomib, respectively. In 5 pts, gr. 1 sensory neuropathy preceded the development of gr. 3 neurologic events despite bortezomib dose reductions. Maximal proteasome inhibition occurred 30 min after bortezomib, and no difference was observed in peak proteasome inhibition with the addition of R during week 4. Mean percent proteasome inhibition was 57.7% +/− 7.7% d1 week 1 and 61.3% +/− 6.8% d1 week 4. In univariate analysis, neurotoxicity was not associated with age, gender, diagnosis, history of diabetes mellitus, number of prior therapies, weeks of bortezomib, or pre-existing neuropathy. However, CR or PR (p=0.029), previous vincristine (p=0.068), maximal proteasome inhibition during week 1 (0.082), and development of gr. 1–2 neuropathy on protocol (p=0.099) may increase the risk for ≥ gr. 3 neurologic complications.

Conclusions: R-bortezomib was active in pts with relapsed FL and MCL with a 39.1% ORR, but gr. 3 autonomic, sensory, or motor neuropathy occcurred in 56.5% pts despite dose reduction of bortezomib.