Venetoclax resistance and acquired <i>BCL2</i> mutations in chronic lymphocytic leukemia

Tausch, Eugen; Close, William; Dolnik, Anna; Bloehdorn, Johannes; Chyla, Brenda; Bullinger, Lars; Döhner, Hartmut; Mertens, Daniel; Stilgenbauer, Stephan

doi:10.3324/haematol.2019.222588

Cited by 174 publications

(174 citation statements)

References 9 publications

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“…In vitro experiments on CLL cell lines demonstrated that the cells harboring G101V were approximately 30-fold less sensitive to venetoclax, due to a 180-fold reduction of venetoclax binding. This mutation was independently reported by another team, along a second one (D103Y) [37]. Additional BCL2 mutations acquired in parallel with BCL-2 G101V were recently reported in patients with progressive CLL on venetoclax [38].…”

Section: Mechanism Of Acquired Intrinsic Resistancementioning

confidence: 69%

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

Jullien

Gomez‐Bougie

Chiron

et al. 2020

Cells

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Apoptosis is a highly conserved mechanism enabling the removal of unwanted cells. Mitochondrial apoptosis is governed by the B-cell lymphoma (BCL-2) family, including anti-apoptotic and pro-apoptotic proteins. Apoptosis evasion by dysregulation of anti-apoptotic BCL-2 members (BCL-2, MCL-1, BCL-X L ) is a common hallmark in cancers. To divert this dysregulation into vulnerability, researchers have developed BH3 mimetics, which are small molecules that restore effective apoptosis in neoplastic cells by interfering with anti-apoptotic proteins. Among them, venetoclax is a potent and selective BCL-2 inhibitor, which has demonstrated the strongest clinical activity in mature B-cell malignancies, including chronic lymphoid leukemia, mantle-cell lymphoma, and multiple myeloma. Nevertheless, mechanisms of primary and acquired resistance have been recently described and several features such as cytogenetic abnormalities, BCL-2 family expression, and ex vivo drug testing have to be considered for predicting sensitivity to BH3 mimetics and helping in the identification of patients able to respond. The medical need to overcome resistance to BH3 mimetics supports the evaluation of innovative combination strategies. Novel agents including MCL-1 targeting BH3 mimetics are currently evaluated and may represent new therapeutic options in the field. The present review summarizes the current knowledge regarding venetoclax and other BH3 mimetics for the treatment of mature B-cell malignancies.

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Section: Mechanism Of Acquired Intrinsic Resistancementioning

confidence: 69%

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

Jullien

Gomez‐Bougie

Chiron

et al. 2020

Cells

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“…The mutation, which reduces the affinity of venetoclax for BCL2 and confers acquired resistance in vitro and in vivo, was present in 7 of 15 paired samples at progression but not at treatment initiation [127]. Moreover, multiple novel BCL2 mutations have been recently identified in parallel with BCL2 Gly101Val during venetoclax therapy [128,129].…”

Section: Bcl2 Mutationsmentioning

confidence: 99%

An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

Cohen

Bomben

Pozzo

et al. 2020

Cancers

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Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. Novel biomarkers discovered over the past 20 years have revolutionized the way clinicians approach prognostication and treatment especially in the chemotherapy-free era. Herein, we review the best established prognostic and predictive biomarkers in the setting of chemoimmunotherapy (CIT) and novel targeted therapy. We propose that TP53 disruption (defined as either TP53 mutation or chromosome 17p deletion), unmutated immunoglobulin heavy chain variable region gene status (UM IGHV), NOTCH1 mutation, and CD49d expression are the strongest prognosticators of disease progression and overall survival in the field of novel biomarkers including recurrent gene mutations. We also highlight the predictive role of TP53 disruption, UM IGHV, and NOTCH1 mutation in the setting of CIT and TP53 disruption and CD49d expression in the setting of novel targeted therapy employing B-cell receptor (BCR) and B-cell lymphoma-2 (BCL2) inhibition. Finally, we discuss future directions in the field of biomarker development to identify those with relapsed/refractory disease at risk for progression despite treatment with novel therapies.

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“…1 We had identified mutations in BCL2 as a resistance mechanism characterizing patients with slowly outgrowing, refractory CLL after at least 3 years of continuous therapy with venetoclax. 2 Correspondingly, Blomberry et al had previously identified BCL2 variants up to 25 months before progressive disease in patients with CLL on long-term treatment with venetoclax. 3 In contrast, the patient cohort studied by Herling et al progressed after 4-22 months with CLL characterized by genomic features of Richter transformation.…”

Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia

Cited by 174 publications

References 9 publications

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

Response to Comment by Jonathan Weiss et al.

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