Bortezomib Therapy in Patients With Relapsed or Refractory Lymphoma: Potential Correlation of In Vitro Sensitivity and Tumor Necrosis Factor Alpha Response With Clinical Activity

Strauss, Sandra J.; Maharaj, Lenushka; Hoare, Susan; Johnson, Peter; Radford, John; Vinnecombe, Sarah; Millard, Lynda; Rohatiner, A. Z. S.; Boral, Anthony; Trehu, Elizabeth; Schenkein, David P.; Balkwill, Frances R.; Joel, Simon P.; Lister, T. A.

doi:10.1200/jco.2005.04.6789

Cited by 160 publications

(105 citation statements)

References 30 publications

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“…The toxicity of the BORID regimen was limited in the series of patients in this study, and adverse events were manageable with routine clinical care. Notably, it was safe to combine bortezomib with rituximab and dexamethasone, and the side effects of bortezomib were similar to those reported in MCL [13][14][15][16][17][18] and multiple myeloma. 35,36 Besides hematologic side effects, including thrombocytopenia, peripheral neuropathy needs to be carefully monitored during treatment with bortezomib.…”

Section: Discussionmentioning

confidence: 57%

“…Bortezomib by itself may induce a remission in 29%-45% of previously treated MCL patients as reported in five phase II studies. [13][14][15][16][17][18] A complete remission following bortezomib treatment may be achieved in up to 8% of patients. 16,18 In these trials with bortezomib used as a single agent, the median progression-free survival was reported to range between 5.3 and 6.7 months.…”

Section: Discussionmentioning

confidence: 99%

“…Five phase II trials have now documented the activity of bortezomib, as a single agent, in relapsed MCL, with response rates ranging between 30% and 50%: some patients had a complete response. [13][14][15][16][17][18] Rituximab has been tested as a single agent for the treatment of previously untreated and relapsed MCL and was shown to induce partial remissions in 27% to 38% of patients. [19][20][21] In various preclinical studies, evidence was obtained for additive and possibly synergistic tumor cell killing of various combinations of bortezomib, dexamethasone, and rituximab.…”

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confidence: 99%

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Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma

Lamm¹,

Kaufmann²,

Raderer³

et al. 2011

Haematologica

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BackgroundBortezomib belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma and mantle cell lymphoma. Preclinical studies suggest that bortezomib has synergistic activity with rituximab, which provides a rationale for the exploration of treatment combinations. Design and MethodsThe activity and safety of bortezomib in combination with rituximab and dexamethasone were investigated in patients with relapsed or chemotherapy-refractory mantle cell lymphoma. A treatment cycle consisted of bortezomib (1.3 mg/m 2 on days 1, 4, 8, and 11; six 21-day cycles), rituximab (375 mg/m 2 , day 1) and dexamethasone (40 mg orally, days 1 to 4). Responding patients received four consolidating doses of rituximab. Sixteen patients with progressive mantle cell lymphoma after a median of three prior lines of therapy were enrolled. ResultsThe overall response rate was 81.3% (13 patients), with seven patients achieving a complete response (43.8%). Six of these patients were also negative for disease activity by positron emission tomography scanning. The median progression-free survival and overall survival were 12.1 and 38.6 months, respectively. In patients achieving a complete response, the median progression-free survival and overall survival have not yet been reached. Adverse events (greater than grade II) included thrombocytopenia (37.5%), fatigue (18.8%) and peripheral neuropathy (12.5%). Two patients discontinued bortezomib because of grade III neuropathy. ConclusionsBortezomib combined with rituximab and dexamethasone has promising activity and manageable toxicity in patients with heavily pretreated mantle cell lymphoma. Achievement of complete response emerged as an important factor for sustained disease control. This trial was registered at www.clinicaltrials.gov as #NCT00261612.Key words: bortezomib, rituximab, mantle cell lymphoma, relapse. Haematologica 2011;96(7):1008-1014. doi:10.3324/haematol.2011 Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma Citation: Lamm W, Kaufmann H, Raderer M, Hoffmann M, Chott A, Zielinski C, and Drach J. Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma

Lamm¹,

Kaufmann²,

Raderer³

et al. 2011

Haematologica

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“…3,4 Single-agent bortezomib demonstrated clinical activity in several other hematologic malignancies 5 with especially encouraging results in relapsed or refractory mantle cell lymphoma (MCL). [6][7][8] Objective response is achieved in 29-45% of MCL patients; however, complete remission rates are low and median duration of response short. These limitations may be overcome by combining bortezomib with conventional chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Sequence-dependent synergy of the proteasome inhibitor bortezomib and cytarabine in mantle cell lymphoma

Weigert

Pastore

Rieken³

et al. 2007

Leukemia

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Single-agent bortezomib, a potent, selective and reversible inhibitor of the 26S proteasome, has demonstrated clinical efficacy in relapsed and refractory mantle cell lymphoma (MCL). Objective response is achieved in up to 45% of the patients; however, complete remission rates are low and duration of response proved to be short. These limitations may be overcome by combining proteasome inhibition with conventional chemotherapy. Here we present two case reports and in vitro data suggesting synergistic efficacy of bortezomib combined with cytarabine in MCL. Interestingly, efficacy in vitro correlated with sequence of treatment, indicating that pretreatment with cytarabine, followed by proteasome inhibition, may be the preferred approach.

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“…Objective response is achieved with BTZ treatment in 29-50% of MCL patients; however, complete remission (CR) rates are low (about 20%) and duration of response is short (6-9 months). [9][10][11] Moreover, BTZ treatment is limited by severe toxic events in patients with relapsed or refractory MCL. 12,13 These limitations, however, may be overcome by strategically combining BTZ with other agents.…”

Section: Introductionmentioning

confidence: 99%

Bortezomib is synergistic with rituximab and cyclophosphamide in inducing apoptosis of mantle cell lymphoma cells in vitro and in vivo

et al. 2007

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Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor clinical outcome. Although front therapy induces a high rate of complete remission (CR), relapse is inevitable and new regimens are much needed for relapsed MCL. The proteasome inhibitor bortezomib (BTZ) induces apoptosis and sensitizes MCL cells to chemotherapy in relapsed MCL, but CR rates are low, with a short duration of response and severe toxicity. Here we evaluated whether BTZ is additive or synergistic with cyclophosphamide (CTX) and rituximab (RTX). Increasing doses of BTZ with a fixed dose of RTX and CTX (BRC regimen) resulted in markedly synergistic growth inhibition of MCL cells. BRC significantly enhanced apoptosis in MCL cell lines and primary tumor cells compared with singleagent treatment. Furthermore, western blotting analysis indicated that BRC induces apoptosis earlier via activation and cleavage of caspases-8, -9 and -3, and poly (ADP-ribose) polymerase, than single-agent treatment. The pan-caspase inhibitor completely blocked apoptosis induced by BRC. In vivo studies showed that BRC eradicated subcutaneous tumors in MCL-bearing SCID mice and significantly prolonged the longterm event-free survival in 70% of the mice. Hence, our study demonstrates that cytoreductive chemotherapy with both BTZ and anti-CD20 antibody may offer a better therapeutic modality for relapsed MCL.

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Bortezomib Therapy in Patients With Relapsed or Refractory Lymphoma: Potential Correlation of In Vitro Sensitivity and Tumor Necrosis Factor Alpha Response With Clinical Activity

Abstract: Bortezomib demonstrates encouraging efficacy in MCL in heavily pretreated individuals. Response was associated with a reduction in plasma TNF-alpha and in vitro sensitivity in a small number of patients.

Cited by 160 publications

References 30 publications

Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma

Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma

Sequence-dependent synergy of the proteasome inhibitor bortezomib and cytarabine in mantle cell lymphoma

Bortezomib is synergistic with rituximab and cyclophosphamide in inducing apoptosis of mantle cell lymphoma cells in vitro and in vivo

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