The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism

Anderson, Mary Ann; Deng, Jing; Seymour, John F.; Tam, Constantine S.; Kim, Su Young; Fein, Joshua; Yu, Lingling; Brown, Jennifer R.; Westerman, David; Ghigo, Éric; Majewski, Ian J.; Segal, David; Enschede, Sari L. Heitner; Huang, David C.S.; Davids, Matthew S.; Letaï, Anthony; Roberts, Andrew W.

doi:10.1182/blood-2016-01-688796

Cited by 263 publications

(246 citation statements)

References 36 publications

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“…In contrast, venetoclax (ABT-199), another selective inhibitor of BCL2, was not associated with thrombocytopenia. 22 Several studies have already demonstrated the clinical benefit of venetoclax in relapsing chronic lymphocytic leukemia patients, whereas studies in patients with DLBCL are still ongoing. 23 Several agents aimed at modulating MYC expression or activity are presently undergoing clinical development.…”

Section: Strategies For Refractory Patientsmentioning

confidence: 99%

Diffuse large B-cell lymphoma: R-CHOP failure—what to do?

2016

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Although rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment for patients with diffuse large B-cell lymphoma (DLBCL),~30% to 50% of patients are not cured by this treatment, depending on disease stage or prognostic index. Among patients for whom R-CHOP therapy fails, 20% suffer from primary refractory disease (progress during or right after treatment) whereas 30% relapse after achieving complete remission (CR). Currently, there is no good definition enabling us to identify these 2 groups upon diagnosis. Most of the refractory patients exhibit double-hit lymphoma (MYC-BCL2 rearrangement) or double-protein-expression lymphoma (MYC-BCL2 hyperexpression) which have a more aggressive clinical picture. New strategies are currently being explored to obtain better CR rates and fewer relapses. Although young relapsing patients are treated with high-dose therapy followed by autologous transplant, there is an unmet need for better salvage regimens in this setting. To prevent relapse, maintenance therapy with immunomodulatory agents such as lenalidomide is currently undergoing investigation. New drugs will most likely be introduced over the next few years and will probably be different for relapsing and refractory patients. Learning Objectives• To be able to determine at diagnosis which DLBCL patients will likely experience treatment failure with R-CHOP • To understand the mechanisms that underlie resistance to standard treatments • To be able to assess the new proposed drugs, along with their efficacy for specific lymphoma populations such as those with double-hit lymphoma or double-protein-expression lymphoma • To learn more about potential solutions for refractory or relapsing patients

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Section: Strategies For Refractory Patientsmentioning

confidence: 99%

Diffuse large B-cell lymphoma: R-CHOP failure—what to do?

2016

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“…The clinical responses of CLL patients were also independent of del17p, TP53 mutation, and TP53 function. 39 Recently, a phase II, open label, two-arm study reported the outcome of venetoclax monotherapy in 64 CLL patients who relapsed after, or were refractory to, ibrutinib or idelalisib, of whom 43 were on prior ibrutinib (Arm A) and 21 (Arm B) on prior idelalisib. ORR by an independent review for Arm A and Arm B was 70% and 48%, respectively.…”

Section: The Development Of Venetoclax As Monochemotherapymentioning

confidence: 99%

Development of venetoclax for therapy of lymphoid malignancies

Zhu

Almasan

2017

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B-cell lymphoma-2 (BCL-2) family dysfunction and impairment of apoptosis are common in most B-cell lymphoid malignancies. Venetoclax (Venclexta™, formerly ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor, which mimics its BCL-2 homology 3-domain to induce apoptosis. It was approved for treatment of previously treated chronic lymphocytic leukemia (CLL) patients with 17p deletion early in 2016. It has also been in clinical trials for other B-cell lymphoid malignancies. Unlike the other recently approved targeted agents idelalisib and ibrutinib, so far there has been no relapse reported in some patients. Also, unlike the other targeted agents, it is effective against tumor cells that reside in the blood marrow. Despite its promising outcome in CLL, preclinical data have already uncovered mechanistic insights underlying venetoclax resistance, such as upregulation of MCL-1 or BCL-xL expression and protective signaling from the microenvironment. In this review, we describe the role of the BCL-2 family in the pathogenesis of B-cell lymphoid malignancies, the development of venetoclax, and its current clinical outcome in CLL and other B-cell malignancies. We also discuss the resistance mechanisms that develop following venetoclax therapy, potential strategies to overcome them, and how this knowledge can be translated into clinical applications.

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“…Venetoclax specifically binds and inhibits Bcl-2, releasing BH3 proteins to activate Bax and/or Bak and cause mitochondrial outer membrane permeabilization. [8][9][10] Venetoclax has been recently approved for previously treated CLL patients. 9 However, despite an overall response rate of 71% to 79%, the complete remissions rate for venetoclax monotherapy was relatively low (20%).…”

Section: Introductionmentioning

confidence: 99%