Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study

Goy, André; Bernstein, Steven H.; Kahl, Brad S.; Djulbegoviĉ, Benjamin; Robertson, Michael J.; Vos, Sven de; Epner, Elliot; Krishnan, Amrita; Leonard, John P.; Lonial, Sagar; Nasta, Sunita Dwivedy; O’Connor, Owen A.; Shi, Hongliang; Boral, Anthony; Fisher, Richard I.

doi:10.1093/annonc/mdn656

Cited by 307 publications

(195 citation statements)

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“…A second investigated strategy to overcome Mcl-1 is to modify Mcl-1 complexes and its protein network. Bortezomib is among the most promising compounds in the treatment of MCL (25). Interestingly, the mixture of ABT-737 with bortezomib shows a synergistic effect, although no decrease of Mcl-1 protein expression is observed in the presence of bortezomib for up to 24 hours.…”

Section: Discussionmentioning

confidence: 99%

“…ABT-737 synergizes with ara-C or bortezomib in ABT-737-resistant MCL cell lines ara-C and, more recently, bortezomib have been shown to be 2 important compounds in the treatment of MCL patients (24)(25)(26). ara-C exposure can induce a rapid decrease of Mcl-1 that occurs independently of caspase 3 (Fig.…”

Section: Combination Of Abt-737 and Flavopiridol Overcomes The Mcl-1-mentioning

confidence: 99%

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ABT-737 Induces Apoptosis in Mantle Cell Lymphoma Cells with a Bcl-2high/Mcl-1low Profile and Synergizes with Other Antineoplastic Agents

Touzeau

Dousset

Bodet

et al. 2011

Clinical Cancer Research

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Purpose: Mantle cell lymphoma (MCL) is considered to be incurable. ABT-737 is a BH3 mimetic that targets Bcl-2, which is overexpressed in MCL and implicated in drug resistance. The present work investigated the antitumor effect of ABT-737. Experimental Design: Six MCL cell lines and primary MCL cells (n = 13) were used. Sensitivity to ABT-737 was assessed, and expression levels of Bcl-2 and Mcl-1 were analyzed. Finally, ABT-737 was combined with other cytotoxic agents to promote tailored therapy. Results: MINO and GRANTA-519 cell lines were highly sensitive to ABT-737 [the median lethal dose (LD50) = 20 and 80 nmol/L, respectively], whereas other cell lines were resistant. In primary MCL cells, 46% of patients' samples were sensitive to ABT-737. The analysis of protein expression levels revealed that both sensitive cell lines and primary MCL cells could be characterized by a Bcl-2high/Mcl-1low profile, whereas resistant MCL cells contained high levels of Mcl-1. ABT-737 induced a rapid disruption of both Bcl-2/Bax and Bcl-2/Bik complexes. In addition, silencing of Mcl-1 by siRNA sensitized MCL cell lines to ABT-737. Similarly, flavopiridol, which induces Mcl-1 downregulation, in combination with ABT-737 led to a synergistic anti-MCL effect in ABT-737–resistant cell lines. This synergy was also observed when ABT-737 was combined with either bortezomib or cytarabine. Conclusions: The present work shows that ABT-737 induces strong apoptosis in MCL cells expressing a Bcl-2high/Mcl-1low profile. In ABT-737–resistant MCL cells, downregulation of Mcl-1 overcomes Mcl-1–induced resistance and synergizes ABT-737 effects. Our results strongly support the use of ABT-737 according to the Bcl-2/Mcl-1 tumor cell profiles in the treatment of MCL. Clin Cancer Res; 17(18); 5973–81. ©2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Combination Of Abt-737 and Flavopiridol Overcomes The Mcl-1-mentioning

confidence: 99%

ABT-737 Induces Apoptosis in Mantle Cell Lymphoma Cells with a Bcl-2high/Mcl-1low Profile and Synergizes with Other Antineoplastic Agents

Touzeau

Dousset

Bodet

et al. 2011

Clinical Cancer Research

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“…44 The use of bortezomib, both as a single agent or in combination with a wide range of agents, is currently under investigation to improve survival in aggressive lymphomas. 6,9,14,47 Although bortezomib monotherapy is mainly ineffective in DLBCL cell lines, 29 the combination with immunochemotherapy has been shown to benefit a selected group of patients with relapsed or refractory ABC DLBCL 7 and in previously untreated patients with advance disease. 6 We have demonstrated that almost all of the DLBCL cell lines studied were primary resistant to bortezomib monotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…6,8 -10 Bortezomib induces cell death by disrupting the endoplasmic reticulum (ER) stress responses in multiple myeloma 11,12 and in mantle cell lymphoma. [13][14][15] Moreover, preclinical studies demonstrate that bortezomib induces apoptosis and sensitizes tumor cells to chemotherapy and radiation. 16 The ER stress response is involved in aggressive phenotype and chemoresistance in many tumor types, including B-cell lymphomas.…”

mentioning

confidence: 99%

The Expression of the Endoplasmic Reticulum Stress Sensor BiP/GRP78 Predicts Response to Chemotherapy and Determines the Efficacy of Proteasome Inhibitors in Diffuse Large B-Cell Lymphoma

Mozos

Roué

López‐Guillermo

et al. 2011

The American Journal of Pathology

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Activation of the endoplasmic reticulum (ER) stress pathway is associated with poor response to doxorubicin-containing regimens, such as rituximab, cyclophosphamide, hydroxydaunorubicin (doxorubicin), vincristine and prednisone (R-CHOP), in patients with diffuse large B-cell lymphoma (DLBCL). Bortezomib, a proteasome inhibitor, interferes with ER responses and improves survival in patients with aggressive hematologic malignant tumors, although its use in DLBCL patients remains controversial. The 78-kDa glucose-regulated protein (GRP78), also known as immunoglobulin heavy chain binding protein (BiP), is an ER stress sensor involved in the resistance to doxorubicin and bortezomib, but its role in the response to chemotherapy in DLBCL has not been explored before. We show that high BiP/GRP78 expression is related to worse overall survival (median overall survival, 5.2 versus 3.4 years). Moreover, cell death after R-CHOP in DLCBL cell lines is associated with decreased BiP/GRP78 expression. Conversely, DLBCL cell lines are primarily resistant to bortezomib, probably owing to BiP/GRP78 overexpression. Small-interfering RNA silencing of BiP/GRP78 renders all cell lines sensitive to bortezomib. R-CHOP with bortezomib (R-CHOP-BZ) reduces BiP/GRP78 expression and overcomes bortezomib resistance, mimicking the small-interfering RNA silencing of BiP/ GRP78. Accordingly, R-CHOP-BZ is the most effective treatment, providing a rationale for the use of this combinational therapy to improve DLBCL patient survival. Moreover, this study provides preclinical evidence that the germinal center B-cell-like subtype DLBCL is sensitive to bortezomib combined with immunochemotherapy.

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“…The first 'new drug' to be registered in relapsed MCL in the United States is bortezomib, since the first demonstrations of this selective and reversible proteasome 26S inhibitor's efficacy [22][23][24][25]. Even though the combination of bortezomib with rituximab and chemotherapy showed high response rates (up to 60-70%), the majority of these studies consists of small series of heavily pretreated patients and often comprises other histologies.…”

Section: Proteasome Inhibitorsmentioning

confidence: 99%

The current therapeutic scenario for relapsed mantle cell lymphoma

Ferrero

Dreyling

2013

Current Opinion in Oncology

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Purpose of reviewPatients with relapsing mantle cell lymphoma (MCL) still represent a demanding challenge for the hematooncologist. The dismal prognosis and the absence of generally accepted therapeutic standards hamper the clinical management of such cases. Moreover, the availability of many targeted approaches, in a field so far missing efficient salvage regimens, challenges current therapeutic algorithms in these patients. Recent findingsMolecular targeted drugs provide unprecedented response rates in relapsed and even chemorefractory MCL. Many phase II studies demonstrated impressive antilymphoma activity of compounds such as bortezomib, lenalidomide and temsirolimus, whereas ongoing phase III trials currently assess the 'real world' benefit and the impact on survival, both alone and in combination with chemotherapy or monoclonal antibodies. Recently, the Bruton's tyrosine kinase inhibitor ibrutinib, targeting the B-cell receptor cascade, showed impressive response rates and will be soon available in phase III trials. SummaryIn the present review we focus on the major therapeutic discoveries of the last few years to offer a practical algorithm to select the appropriate treatment in patients with relapsed MCL.

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Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study

Abstract: Single-agent bortezomib is associated with lengthy responses and notable survival in patients with relapsed or refractory MCL, with considerable TTP and TTNT in responding patients, suggesting substantial clinical benefit.

Cited by 307 publications

References 31 publications

ABT-737 Induces Apoptosis in Mantle Cell Lymphoma Cells with a Bcl-2high/Mcl-1low Profile and Synergizes with Other Antineoplastic Agents

ABT-737 Induces Apoptosis in Mantle Cell Lymphoma Cells with a Bcl-2high/Mcl-1low Profile and Synergizes with Other Antineoplastic Agents

The Expression of the Endoplasmic Reticulum Stress Sensor BiP/GRP78 Predicts Response to Chemotherapy and Determines the Efficacy of Proteasome Inhibitors in Diffuse Large B-Cell Lymphoma

The current therapeutic scenario for relapsed mantle cell lymphoma

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