<i>Ex vivo</i>activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies

Bogenberger, James M; Delman, Devora; Hansen, Nanna; Valdez, Riccardo; Fauble, Veena; Mesa, Ruben A.; Tibes, Raoul

doi:10.3109/10428194.2014.910657

Cited by 130 publications

(105 citation statements)

References 13 publications

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“…These results, along with preclinical data with venetoclax in combination with other agents (9, 37, 38) and observations that AML stem cells may be dependent on BCL-2 (7, 9, 10), support evaluating venetoclax in combination with other agents in patients with AML. Venetoclax is currently being investigated in phase 1 studies in combination with low-dose cytarabine (NCT02287233) and decitabine or azacitidine (NCT02203773).…”

Section: Discussionmentioning

confidence: 58%

Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia

et al. 2016

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We present a phase 2, single-arm study evaluating 800 mg daily venetoclax, a highly selective, oral small-molecule B-cell leukemia/lymphoma-2 (BCL-2) inhibitor in patients with high-risk relapsed/refractory acute myelogenous leukemia (AML) or unfit for intensive chemotherapy. Responses were evaluated following revised International Working Group (IWG) criteria. The overall response rate was 19%; an additional 19% of patients demonstrated anti-leukemic activity not meeting IWG criteria (partial bone marrow response and incomplete hematologic recovery). Twelve (38%) patients had isocitrate dehydrogenase 1/2 mutations, of whom 4 (33%) achieved complete response/complete response with incomplete blood count recovery. Six (19%) patients had BCL-2–sensitive protein index at screening, which correlated with time on study. BH3 profiling was consistent with on-target BCL-2 inhibition and identified potential resistance mechanisms. Common adverse events included nausea, diarrhea and vomiting (all grades), and febrile neutropenia and hypokalemia (grade 3/4). Venetoclax demonstrated activity and acceptable tolerability in patients with AML and adverse features.

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Section: Discussionmentioning

confidence: 58%

Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia

et al. 2016

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“…The Bcl-2-selective inhibitor ABT-199 has demonstrated promising preclinical results (10, 11, 26, 32), although it has limited efficacy in Bcl-xL- and Mcl-1-dependent malignancies (9, 33). Thus, it is important to understand the mechanisms of resistance and develop therapies to overcome resistance.…”

Section: Discussionmentioning

confidence: 99%

“…For example, ABT-199 was demonstrated to synergize with cytarabine in acute lymphoblastic leukemia (39) and lymphoma cell lines, though the mechanism was not investigated (40). It has also been demonstrated to synergize with 5-azacytidine in ex vivo AML and myelodysplastic syndrome/chronic myelomonocytic leukemia samples (32). In addition, synergistic interactions have been demonstrated for ABT-199 in combination with doxorubicin, bortezomib, and YM155 in lymphoma cell lines (40), though the mechanism of action for the combined treatments was not investigated in these studies.…”

Section: Discussionmentioning

confidence: 99%

Binding of Released Bim to Mcl-1 is a Mechanism of Intrinsic Resistance to ABT-199 which can be Overcome by Combination with Daunorubicin or Cytarabine in AML Cells

Niu

Zhao

et al. 2016

Clinical Cancer Research

191

181

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Purpose-To investigate the molecular mechanism underlying intrinsic resistance to Experimental Design-Western blots and real-time RT-PCR were used to determine levels of Mcl-1 after Conclusions-Our results demonstrate that sequestration of Bim by Mcl-1 is a mechanism of intrinsic ABT-199 resistance and supports the clinical development of ABT-199 in combination with cytarabine or daunorubicin for the treatment of AML. HHS Public AccessAuthor manuscript Clin Cancer Res. Author manuscript; available in PMC 2017 September 01.

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“…Subsequent ex vivo studies using primary AML samples demonstrated ABT-737 and venetoclax single agent activity as well as synergy with 5-Aza (100). In an earlier study, Tsao et al demonstrated synergistic AML cell killing by 5-Aza and ABT-737, in part through inhibition of MCL-1 by 5-Aza (22).…”

Section: Identifying Sensitive Tumor Types and Likely Respondersmentioning

confidence: 98%

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

Sampath²,

et al. 2017

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Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high priority goal for cancer therapy. After decades of effort, drug discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL-2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL-2 biology, were essential to the development of BH3 mimetics such as the BCL-2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL-2 biology and facilitated the clinical development of venetoclax.

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Ex vivoactivity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies

Cited by 130 publications

References 13 publications

Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia

Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia

Binding of Released Bim to Mcl-1 is a Mechanism of Intrinsic Resistance to ABT-199 which can be Overcome by Combination with Daunorubicin or Cytarabine in AML Cells

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

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