VcR-CVAD (rituximab, bortezomib, modified hyper-CVAD) induction chemoimmunotherapy and maintenance rituximab (MR) was evaluated for efficacy and safety in ECOG protocol E1405. Patients with previously untreated mantle cell lymphoma (MCL) received VcR-CVAD chemotherapy every 21 days for 6 cycles, followed by MR for 2 years. Transplant eligible patients had the option of autologous stem cell transplantation (ASCT) consolidation instead of MR. The primary end point was the complete response (CR) rate to VcR-CVAD. The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicities. Seventy-five eligible patients with a median age of 62 (range 40-76) were enrolled. The ORR was 95% and a CR was achieved in 68% of patients. After a median follow-up of 4.5 years, 3-year PFS and OS were 72% and 88%, respectively. No substantial difference in PFS or OS was observed between patients treated with MR (n=44) versus ASCT (n=22). There were no unexpected toxicities. VcR-CVAD produced high ORR and CR rates in MCL. MR after VcR-CVAD induction performed similarly to ASCT and may improve response duration. Randomized clinical trials (RCTs) comparing MR against ASCT should be considered and RCTs evaluating bortezomib's contribution to conventional therapy are underway. This study was registered with clinicaltrials.gov (identifier NCT00433537).
[Show abstract][Hide abstract] ABSTRACT: Mantle cell lymphoma is a heterogeneous subtype of non-Hodgkin lymphoma. Conventional treatment with immunochemotherapy followed by autologous stem cell transplantation or intensive immunochemotherapy alone has improved outcomes, but the disease remains incurable. Recent advances in basic and translational research have significantly enhanced our understanding of disease pathogenesis and have sparked the development of novel therapies. Novel agents include the proteasome inhibitor bortezomib, the immunomodulatory agent lenalidomide, the phosphatidylinositol-4,5-bisphosphate 3-kinase pathway inhibitor idelalisib and the Bruton tyrosine kinase inhibitor ibrutinib. Preliminary results from clinical trials, especially from studies of ibrutinib, have proven these agents to be effective. In ongoing studies, these agents are being integrated into conventional immunochemotherapy regimens to hopefully improve patient outcomes.
British Journal of Haematology 06/2014; 167(1). DOI:10.1111/bjh.13000 · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mantle cell lymphoma (MCL) is an uncommon, incurable B-cell non-Hodgkin's lymphoma that afflicts the elderly. There is no standard course of treatment, with options varying from observation in asymptomatic patients to aggressive induction/consolidation regimens in younger patients with rapidly progressive disease. Emerging data regarding the role of the ubiquitin-proteasome system, B-cell receptor and mTOR signaling pathways, cell cycle regulation, and epigenetic and immune-modulation in the pathogenesis of MCL have resulted in the development of novel therapies, with a shift away from conventional cytotoxic chemotherapy to relatively less toxic, more targeted treatment. The challenge now is to determine the optimal sequence and combination of the various available and emerging therapies for use in patients with MCL.
[Show abstract][Hide abstract] 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).
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.
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.
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