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Phase II trial of R-CHOP plus bortezomib induction therapy
Mantle cell lymphoma (MCL) is a distinct subtype of B cell non-Hodgkin lymphoma characterised by the CCND1/IGH (t[11;14]) translocation leading to overexpression of cyclin D1. Although the survival of patients with MCL has improved over the last decade, much of this benefit is associated with selected populations of younger patients receiving intensive therapy (Delarue et al., 2013; Geisler et al., 2008; Hermine et al., 2010). Unfortunately, aggressive therapies are not feasible for many patients with MCL, and in population-based studies, where the median age at diagnosis is 70 or older, the median overall survival (OS) remains 3–5 years (Abrahamsson et al., 2014; Leux et al., 2014; van de Schans et al., 2010). The regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a standard induction therapy for MCL that is associated with high response rates, but remissions are not durable, with a median progression-free survival (PFS) of 14 to 22 months (Howard et al., 2002; Lenz et al., 2005; Robak et al., 2015; Rummel et al., 2013). Thus, improved therapies are clearly needed, especially for the growing population of patients with MCL not eligible for intensive regimens (Aschebrook-Kilfoy et al., 2013).
Bortezomib is a low-molecular weight compound that inhibits the protease activity of the 26S proteasome, leading to important regulatory changes in many intracellular proteins relevant to MCL biology, including inhibition of NF-κB activity (Pham et al., 2003), increased levels of p21 and p27, which regulate cyclin/cdk activity, resulting in cell cycle arrest (Bogner et al., 2003), and cleavage of the anti-apoptotic protein Bcl-2 via caspase 3 activation, leading to apoptosis (Bogner et al., 2006). The clinical activity of bortezomib in MCL has been demonstrated in several phase II trials, in which bortezomib as a single agent produced response rates ranging from 30–50% in patients with relapsed disease (Belch et al., 2007; Fisher et al., 2006; Gerecitano et al., 2009; Goy et al., 2009; Goy et al., 2005; O’Connor et al., 2005; Strauss et al., 2006), and a phase III trial recently showed a progression-free survival (PFS) benefit for bortezomib combined with frontline chemotherapy (Robak et al., 2015). Based on these studies, it is approved in the U.S. and Europe for the treatment of MCL in both the relapsed and upfront settings. The anti-CD20 antibody rituximab has been shown to be synergistic in vitro with bortezomib (Wang et al., 2008). Additionally, anthracyclines induce NF-κB in malignant cells, thus potentially increasing cellular dependency on NF-κB for survival and sensitising cells to proteasome inhibition (Guzman et al., 2002). Combining bortezomib with R-CHOP is therefore a promising strategy to improve the frequency and quality of remissions with induction therapy for MCL.
The pattern of continuous relapse despite initial response that is characteristic of MCL has led to the hypothesis that maintenance therapy may be beneficial in prolonging remissions. A randomised phase III intergroup trial comparing two different maintenance approaches in elderly patients with MCL showed that rituximab maintenance after CHOP-based induction improved both progression-free and overall-survival compared to interferon maintenance (Kluin-Nelemans et al., 2012); thus, several recent or ongoing trials have incorporated a maintenance component to therapy. Given the single-agent activity of bortezomib and relatively low toxicity, maintenance therapy with this drug may be an effective approach to improve PFS duration. S0601 was therefore designed with the goal of testing the feasibility and efficacy of adding bortezomib to an R-CHOP backbone, and prolonging PFS by incorporating a bortezomib maintenance strategy for patients with newly diagnosed MCL. The objective of this study was to estimate the 2 year PFS, with the goal of improving the rate and duration of remissions for patients with MCL without serious additive toxicity.
