Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia

Blombery, Piers; Anderson, Mary Ann; Gong, Jianan; Thijssen, Rachel; Birkinshaw, R.W.; Thompson, Ella R.; Teh, Charis E.; Nguyen, Tamia; Xu, Zhen; Flensburg, Christoffer; Lew, Thomas E.; Majewski, Ian J.; Gray, Daniel H.D.; Westerman, David; Tam, Constantine S.; Seymour, John F.; Czabotar, P.E.; Huang, David C.S.; Roberts, Andrew W.

doi:10.1158/2159-8290.cd-18-1119

Cited by 340 publications

(221 citation statements)

References 27 publications

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“…Indeed, in CLL, two teams have reported the acquisition of point mutations in BCL-2 by analyzing paired pre-venetoclax and progression samples from patients enrolled on venetoclax clinical trials. Glycine substitution by Valin in position 101 (G101V) was firstly identified at progression in 7/15 patients (but not at study entry) [36]. 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.…”

Section: Mechanism Of Acquired Intrinsic Resistancementioning

confidence: 99%

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: 99%

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

Jullien

Gomez‐Bougie

Chiron

et al. 2020

Cells

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“…A recent study has also described the occurrence of the G101V mutation in BCL2 in approximately 50% of patients who progressed while on trial with venetoclax (Blombery et al ). The mutation was first apparent in patients 19 months after initiation of therapy and is believed to confer resistance to venetoclax by reducing the affinity of the BH3‐mimetic for BCL2 (Blombery et al , ).…”

Section: Clonal Evolution Treatment Resistance and Progression In Cllmentioning

confidence: 99%

Molecular pathogenesis of chronic lymphocytic leukaemia

Crassini¹,

Stevenson²,

Mulligan

et al. 2019

Br J Haematol

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Summary Chronic lymphocytic leukaemia (CLL) is characterised by the clonal expansion of mature, CD5 positive, B lymphocytes in the blood, marrow, lymph nodes and spleen. For the majority of patients, CLL follows an indolent clinical course, while a proportion of patients experience rapid disease progression. Despite the strong correlation between certain genetic defects and prognosis, there remains no single unifying pathogenic lesion in CLL. With recent advances in therapy it is increasingly important to stratify CLL patients according to risk. This has been highlighted by two recent studies, the first showing that immunoglobulin heavy chain mutational status predicts a durable response to frontline chemoimmunotherapy and the second showing that complex karyotype is a stronger predictor of poor response to ibrutinib and venetoclax therapy than TP53 deletion. In this review we discuss the molecular features of CLL and how technological advances can identify patient subsets and stratify them according to risk.

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“…10,39,40 However, the percentage of patients obtaining a complete response (a necessary condition to achieve undetectable MRD) on receipt of treatment with ibrutinib alone is small. 50,51 These mutations appear early and have the potential to be used as biomarkers for future disease recurrence, suggesting an opportunity for intervention. 11,41 Predicting outcomes other than PFS and overall survival, such as the likelihood of treatment failure and disease progression after treatment with BTK and BCL2 inhibitors, also could be clinically useful.…”

Section: Treatment-related Biomarkersmentioning

confidence: 99%

“…For example, BTK and PLCG2 mutations are correlated with resistance to ibrutinib and BCL2 mutations are correlated with resistance to venetoclax. 50,51 These mutations appear early and have the potential to be used as biomarkers for future disease recurrence, suggesting an opportunity for intervention.…”

Section: Treatment-related Biomarkersmentioning

confidence: 99%

Predicting the outcome of patients with chronic lymphocytic leukemia: Progress and uncertainty

Montserrat

Gale

2019

Cancer

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Because chronic lymphocytic leukemia is a heterogeneous disease, there are considerable efforts underway to develop increasingly accurate and precise analytics with which to estimate the probability of future events such as the need for and probability of response to therapy, progression‐free survival, and survival. These analytics typically are constructed from clinical and laboratory variables. These variables often are combined into scores or staging systems, some of which are prognostic (therapy‐independent), whereas others are predictive (therapy‐dependent). Predictive variables differ with different therapies. Because response to therapy is a necessary condition for the improvement of survival, predictive biomarkers are extremely important. However, despite some progress to identify new predictive biomarkers, del(17p)/TP53 mutation remains the only widely accepted variable used to guide therapy. New laboratory techniques and analytical tools may contribute to improvements in the precision and accuracy of outcome indicators. However, there are inherent limitations when applying cohort‐based estimates to individuals within the cohort. The accuracy and precision of prediction also are limited by measurement error and chance. Ultimately, estimating outcomes requires a careful balance between clinical experience, imperfect prediction, and uncertainty.

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Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia

Cited by 340 publications

References 27 publications

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

Molecular pathogenesis of chronic lymphocytic leukaemia

Predicting the outcome of patients with chronic lymphocytic leukemia: Progress and uncertainty

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