Bortezomib: A Review in Mantle Cell Lymphoma in Previously Untreated Patients Unsuitable for Stem-Cell Transplantation
Bortezomib (Velcade®) is a proteasome inhibitor that is approved for the treatment of multiple myeloma and mantle cell lymphoma (MCL). This article reviews the efficacy and tolerability of bortezomib in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (VR-CAP) in the treatment of previously untreated MCL unsuitable for stem-cell transplantation, and overviews the pharmacology of bortezomib. In the large, randomized, assessor-blinded, multinational LYM-3002 trial, induction therapy with VR-CAP improved progression-free survival significantly more than R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) after a median follow-up of 40 months in patients with newly diagnosed MCL ineligible or not considered for stem-cell transplantation. Complete response and certain other secondary endpoints were improved significantly more with VR-CAP than R-CHOP. Overall survival data were not mature at the time of assessment. The improved efficacy with VR-CAP was accompanied by an increased incidence of grade 3 or higher adverse events, particularly haematological adverse events.
The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit. Paul L. McCormack is a salaried employee of Adis/Springer.
- 3.Dreyling M. Mantle cell lymphoma: biology, clinical presentation, and therapeutic approaches. In: American Society of Clinical Oncology educational book. 2014. p. 191–8.Google Scholar
- 4.Dreyling M, Geisler C, Hermine O, et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):iii83–92.Google Scholar
- 5.National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guildelines®): non-Hodgkin’s lymphomas, version 2.2015. 2015. http://www.nccn.org/. Accessed 2 June 2015.
- 6.European Medicines Agency. Velcade (bortezomib): summary of product characteristics. 2015. http://www.ema.europa.eu/. Accessed 2 June 2015.
- 7.US FDA. Velcade (bortezomib): US prescribing information. 2014. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed 2 June 2015.
- 8.Till BG, Li H, Bernstein SH, et al. Phase II trial of R-CHOP plus bortezomib induction therapy followed by bortezomib maintenance for previously untreated mantle cell lymphoma: SWOG 0601 [abstract no. 149]. Blood. 2014;124(21).Google Scholar
- 11.Schwartz RN, Davidson T. Pharmacology, pharmacokinetics, and practical applications of bortezomib. Oncology (Williston Park, NY). 2004;18(14 Suppl 11):14–21.Google Scholar
- 25.LoRusso PM, Venkatakrishnan K, Ramanathan RK, et al. Pharmacokinetics and safety of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction: phase I NCI Organ Dysfunction Working Group Study NCI-6432. Clin Cancer Res. 2012;18(10):2954–63.PubMedCrossRefGoogle Scholar
- 26.Leal TB, Remick SC, Takimoto CH, et al. Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study. Cancer Chemother Pharmacol. 2011;68(6):1439–47.PubMedCentralPubMedCrossRefGoogle Scholar
- 27.Venkatakrishnan K, Rader M, Ramanathan RK, et al. Effect of the CYP3A inhibitor ketoconazole on the pharmacokinetics and pharmacodynamics of bortezomib in patients with advanced solid tumors: a prospective, multicenter, open-label, randomized, two-way crossover drug-drug interaction study. Clin Ther. 2009;31:2444–58.PubMedCrossRefGoogle Scholar
- 28.Quinn DI, Nemunaitis J, Fuloria J, et al. Effect of the cytochrome P450 2C19 inhibitor omeprazole on the pharmacokinetics and safety profile of bortezomib in patients with advanced solid tumours, non-Hodgkin’s lymphoma or multiple myeloma. Clin Pharmacokinet. 2009;48(3):199–209.PubMedCrossRefGoogle Scholar
- 31.Drach J, Huang H, Samoilova OS, et al. Efficacy and safety of frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) vs R-CHOP in a subset of newly diagnosed mantle cell lymphoma patients medically eligible for transplantation in the randomized phase 3 LYM-3002 study (NCT00722137) [abstract no. 3064 plus poster]. Blood. 2014;124(21).Google Scholar
- 32.Robak T, Huang H, Jin J, et al. Bortezomib(Btz) dose intensity is the strongest predictor of overall survival in mantle cell lymphoma patients not considered for transplantation, receiving frontline Btz plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) therapy in the phase 3 LYM-3002 study [abstract no. 4412]. Blood. 2014;124(21).Google Scholar
- 33.European Medicines Agency. MabThera (rituximab): summary of product characteristics. 2015. http://www.ema.europa.eu/. Accessed 2 June 2015.
- 34.US FDA. Rituxan (rituximab): US prescribing information. 2014. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed 2 June 2015.
- 36.van Keep M, Gairy K, Seshagiri D, et al. Cost effectiveness of bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisone for the first-line treatment of mantle cell lymphoma patients not eligible for stem cell transplantation [abstract no. P420 plus poster]. In: 20th Congress of the European Hematology Association. 2015.Google Scholar
- 37.Houot R, Le Gouill S, Ojeda Uribe M, et al. Combination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: results of a phase II trial from the GOELAMS. Ann Oncol. 2012;23(6):1555–61.PubMedCrossRefGoogle Scholar
- 40.Gressin R, Callanan M, Daguindau N, et al. Frontline therapy with the RiBVD regimen elicits high clinical and molecular response rates and long PFS in elderly patients mantle cell lymphoma (MCL); final results of a prospective phase II trial by the LYSA group [abstract no. 148]. Blood. 2014;124(21).Google Scholar