Bortezomib for the treatment of non-Hodgkin’s lymphoma

Abstract

Introduction Bortezomib, the first proteasome inhibitor (PI) to be evaluated in humans, is approved in the USA and Europe for the treatment of patients with multiple myeloma, and in the USA for patients with relapsed mantle cell lymphoma (MCL). Areas covered This review examines the role of bortezomib in the therapy of non-Hodgkin’s lymphoma (NHL). Bortezomib may be particularly effective against the NF-κB-dependent activated B-cell subtype of diffuse large B-cell lymphoma. The combination of bortezomib with rituximab and dexamethasone represents a standard approach for the treatment of Waldenström’s macroglobulinemia, and that with bendamustine and rituximab has demonstrated excellent efficacy in follicular lymphoma. Combinations with other novel agents, such as inhibitors of cyclin-dependent kinases or histone deacetylases, also hold substantial promise in NHL. Unmet needs in NHL, competitor compounds, chemistry, pharmacokinetics, pharmacodynamics and safety and tolerability of bortezomib are also discussed. Expert opinion The success of bortezomib in MCL has validated the proteasome as a therapeutic target in NHL. Rational combinations, for example, with Bruton’s tyrosine kinase inhibitors or BH3-mimetics, may hold the key to optimizing the therapeutic potential of PIs in NHL. Future trials are likely to involve newer agents with improved pharmacodynamic (e.g., carfilzomib, marizomib) or pharmacokinetic (e.g., ixazomib, oprozomib) properties.

Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma

“…Success of the proteasome inhibitor bortezomib has established protein homeostasis as valid target in oncology, especially for lymphoid malignancies (11,36) but multiple myeloma remains incurable costing estimated 11,240 lives in 2015 in the United States (SEER). CCF642, consistent with its effect on proteostasis by PDI inhibition (Figs.…”

Pixantrone: a novel anthracycline-like drug for the treatment of non-Hodgkin lymphoma

“…Interestingly, liposomal Doxorubicin was also developed with the aim of reducing [40] Dawson et al [41] Faivre et al [35] Borchmann et al [31] Pettengell et al [29] cardiac toxicity. Although the results were encouraging in the upfront and relapsed setting in NHL, there is no evidence supporting the superiority of this drug in NHL in terms of efficacy or toxicity [37][38][39]. In summary, Pixantrone is a potential alternative agent with a favorable safety profile for the treatment of relapsed and refractory patients.…”

A phase 1 study of bortezomib and romidepsin in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, indolent B-cell lymphoma, peripheral T-cell lymphoma, or cutaneous T-cell lymphoma

“…Bortezomib is thought to act through inhibition of the NK-κB pathway, although some evidence argues that it may have the opposite effect [6]. Bortezomib is currently approved in mantle cell lymphoma [7] and has shown clinical activity in several NHLs [8]. …”