Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial

Stilgenbauer, Stephan; Eichhorst, Barbara; Schetelig, Johannes; Hillmen, Peter; Seymour, John F.; Coutré, Steven; Jurczak, Wojciech; Mulligan, Stephen P.; Schuh, Anna; Assouline, Sarit; Wendtner, Clemens‐Martin; Roberts, Andrew W.; Davids, Matthew S.; Bloehdorn, Johannes; Munir, Talha; Böttcher, Sebastian; Zhou, Lang; Salem, Ahmed Hamed; Desai, Monali; Chyla, Brenda; Arzt, Jennifer A.; Kim, Su Young; Verdugo, Maria; Gordon, Gary; Hallek, Michael; Wierda, William G.

doi:10.1200/jco.2017.76.6840

Cited by 275 publications

(230 citation statements)

References 11 publications

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“…Interestingly, reflecting pre-clinical data showing a TP53-independent induced apoptosis of CLL cells [11], venetoclax then showed a potent activity in high-risk CLL harboring a 17p deletion in a phase II study [12], leading to US Food and Drug Agency (FDA) approval in this setting in 2016. The updated results of this study [13] showed an overall response rate (ORR) of 77% and minimal residual disease (MRD) negativity of 30% with a sensitivity of 10 −4 , in a population of CLL patients with 17p deletion, mostly in the relapse setting.…”

Section: Clinical Activity Of Venetoclax In Chronic Lymphocytic Leukemiamentioning

confidence: 86%

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: Clinical Activity Of Venetoclax In Chronic Lymphocytic Leukemiamentioning

confidence: 86%

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

Jullien

Gomez‐Bougie

Chiron

et al. 2020

Cells

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“…Because of the striking improvement in clinical outcomes among patients with del17p using ibrutinib and venetoclax, we expect that CLL FISH testing will continue to increase in the future. 20, 21 …”

Section: Discussionmentioning

confidence: 99%

“…Because of the striking improvements in clinical outcomes noted among patients with del17p treated with ibrutinib and venetoclax, we expect that FISH testing for CLL will continue to increase in the future. 20,21 In contrast, IgV H mutation analysis has remained prognostic and has not been incorporated into guideline treatment algorithms since 2009. Now that FCR also has been found to demonstrate a progression-free survival of >10 years in a sizeable percentage of patients with mutated IgV H status, 22,23 there may be an increase in the use of this test in the future.…”

Section: Discussionmentioning

confidence: 99%

Real‐world testing and treatment patterns in chronic lymphocytic leukemia: A SEER patterns of care analysis

Seymour

Ruterbusch

Beebe‐Dimmer

et al. 2018

Cancer

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Background: Laboratory testing and treatments have changed dramatically in chronic lymphocytic leukemia (CLL) within the last decade. We evaluated changes in patterns of real-world testing and treatment over time by comparing two population-based cohorts. Methods: The National Cancer Institute (NCI) sponsored Patterns of Care study was conducted among CLL patients sampled from 14 Surveillance, Epidemiology, and End Results (SEER) program registries. Demographics, testing, and treatment data were abstracted from medical records within 24 months of diagnosis. Results: 1,008 patients diagnosed in 2008 and 1,367 patients diagnosed in 2014 were included. There was a significant increase in fluorescence in situ hybridization (FISH) testing, IgVH mutation analyses, and lymph node biopsies between 2008 and 2014. FISH testing was performed in the majority of, but not all, treated patients (53% in 2008, increased to 62% in 2014). Some differences in receipt of FISH testing by age and insurance status were observed over time (older patients and Medicare patients without private insurance were less likely to be tested in 2014). There were contrasting testing patterns by practice type and year, with non-teaching hospitals more likely to perform bone marrow biopsies in 2008, and teaching hospitals more likely to perform FISH and IgVH testing in 2014. There were also differences in treatments over time, with the use of bendamustine and rituximab (BR) being more common in 2014 at the expense of fludarabine, cyclosporine, and rituximab (FCR). Conclusions: There are been rapidly changing practices of testing and treatment patterns for CLL patients in the last decade.

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“…Venetoclax (ABT-199/GDC-0199) is a potent, selective B-cell lymphoma-2 (BCL-2) inhibitor 8 that was first indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. 9,10 Venetoclax demonstrated modest single-agent activity in patients with relapsed or refractory AML 11 and synergistic activity with HMAs and LDAC in preclinical models of AML. 12 These findings prompted evaluation of venetoclax in combination with an HMA (azacitidine or decitabine; NCT02203773) or LDAC (NCT02287233) in patients 65 years of age or older newly diagnosed with AML and not eligible for standard induction therapy.…”

Section: Introductionmentioning

confidence: 99%

Optimizing venetoclax dose in combination with low intensive therapies in elderly patients with newly diagnosed acute myeloid leukemia: An exposure‐response analysis

Agarwal

Gopalakrishnan

Mensing

et al. 2019

Hematological Oncology

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The objective of this research was to characterize the venetoclax exposure‐efficacy and exposure‐safety relationships and determine its optimal dose in elderly patients with newly diagnosed acute myeloid leukemia (AML) receiving venetoclax in combination with low intensity therapies (hypomethylating agent [HMA; azacitidine or decitabine] or low‐dose cytarabine [LDAC]). A total of 212 patients from the HMA study and 92 patients from the LDAC study were included in the exposure‐safety analyses. Those who received at least one dose of venetoclax and had at least one measurable response (201 and 83 in the HMA and LDAC studies, respectively) were included in the exposure‐efficacy analyses. The probability of response based on International Working Group (IWG) for AML response criteria, adverse events of grade 3 or worse neutropenia or infection or a serious adverse event was modeled using logistic regression analyses to characterize the venetoclax exposure‐response relationships. In combination with an HMA, increasing concentrations of venetoclax, up to those associated with a less than or equal to 400‐mg once daily (QD) dose, were associated with a higher probability of response, with a trend for flat or decreasing probabilities of response thereafter. In combination with LDAC, increasing concentrations of venetoclax were associated with higher probabilities of response, with no plateau observed. Increasing concentrations of venetoclax were not associated with increasing probability of any safety event except for a slight increase in grade 3 or worse infections with HMAs; however, tolerability issues were observed at doses of greater than or equal to 800 mg QD in each study. Exposure‐response analyses support the use of venetoclax 400 mg QD in combination with an HMA and 600 mg QD in combination with LDAC (ie, the next highest dose evaluated below 800 mg in each combination) to safely maximize the probability of response in elderly patients with newly diagnosed AML.

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Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial

Cited by 275 publications

References 11 publications

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

Real‐world testing and treatment patterns in chronic lymphocytic leukemia: A SEER patterns of care analysis

Optimizing venetoclax dose in combination with low intensive therapies in elderly patients with newly diagnosed acute myeloid leukemia: An exposure‐response analysis

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