Impact of venetoclax monotherapy on the quality of life of patients with relapsed or refractory chronic lymphocytic leukemia: results from the phase 3b VENICE II trial

Cochrane, Tara; Enrico, Alicia; Gómez‐Almaguer, David; Hadjiev, Evgueniy; Lech-Maranda, Ewa; Masszi, Tamás; Nikitin, Eugene; Robak, Tadeusz; Weinkove, Robert; Wu, Shang‐Ju; Sail, Kavita; Pesko, John C.; Pai, Madhavi; Komlósi, Viktor; Anderson, Mary Ann

doi:10.1080/10428194.2021.1986217

Cited by 10 publications

(6 citation statements)

References 30 publications

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“…Patient samples. Patients treated with venetoclax monotherapy (VENICE study; NCT02980731 18 ), venetoclax-ibrutinib (CAPTIVATE; NCT02910583 19 ) or combination timelimited venetoclax-obinutuzumab 7 were recruited from the Department of Clinical Haematology Royal Melbourne Hospital and Peter MacCallum Cancer Centre (Victoria, Australia) (Supplementary Table 1); healthy donors were from the Victorian Blood Donor Registry. All donors provided written informed consent and the research was approved by Human Research Ethics Committees/Institutional Review Boards.…”

Section: Methodsmentioning

confidence: 99%

“…To assess the impact of venetoclax on CLL heterogeneity and survival, we assayed peripheral blood (PB) from 18 relapse/refractory CLL patients receiving venetoclax monotherapy 18 , healthy donor and two treatment naïve CLL patients receiving venetoclax-ibrutinib after ibrutinib run-in 7 (Supplementary Table 1). PB samples were drawn before each weekly venetoclax dose- In addition, we detected minor CLL sub-populations, including pRB high TACI high BAX high (C2.9) and pH2AX high (C2.10) subsets (Fig.…”

Section: Mass Cytometry Resolves Heterogeneity Among Cll Cellsmentioning

confidence: 99%

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Early cytokine-driven adaptation of survival pathways in lymphoid cells during targeted therapies

Luo,

Tan,

Trussart

et al. 2024

Preprint

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Venetoclax, a first-in-class BH3 mimetic drug targeting BCL-2, has improved outcomes for patients with chronic lymphocytic leukemia (CLL). Early measurements of the depth of the venetoclax treatment response, assessed by minimal residual disease, are strong predictors of long-term clinical outcomes. Yet, there are limited data concerning the early changes induced by venetoclax treatment that might inform strategies to improve responses. To address this gap, we conducted longitudinal mass cytometric profiling of blood cells from patients with CLL during the first two months of venetoclax monotherapy. At baseline, we resolved CLL heterogeneity at the single-cell level to define multiple subpopulations in all patients distinguished by proliferative, metabolic and cell survival proteins. Venetoclax induced significant reduction in all CLL subpopulations coincident with rapid upregulation of pro-survival BCL-2, BCL-XL and MCL-1 proteins in surviving cells, which had reduced sensitivity to the drug. Mouse models recapitulated the venetoclax-induced elevation of survival proteins in B cells and CLL-like cells that persistedin vivo, with genetic models demonstrating that extensive apoptosis and access to the B cell cytokine, BAFF, were essential. Accordingly, analysis of patients with CLL that were treated with a different targeted therapy, the anti-CD20 antibody obinutuzumab, also exhibited marked elevation of BAFF and increased pro-survival proteins in leukemic cells that persisted. Overall, these data highlight the rapid adaptation of CLL cells to targeted therapies via homeostatic factors and support co-targeting of cytokine signals to achieve deeper and more durable long-term responses.Key pointsLeukaemic cells rapidly adapt to targeted therapy by elevating pro-survival protein expression.Cell attrition and increased bioavailability of homeostatic cytokines drive this heightened survival, highlighting avenues for more potent combination therapies.

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Section: Methodsmentioning

confidence: 99%

Section: Mass Cytometry Resolves Heterogeneity Among Cll Cellsmentioning

confidence: 99%

Early cytokine-driven adaptation of survival pathways in lymphoid cells during targeted therapies

Luo,

Tan,

Trussart

et al. 2024

Preprint

Self Cite

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“…Venetoclax monotherapy has also demonstrated efficacy in the context of BCRi resistance or intolerance [ 55 , 56 ], although refractoriness to BCRis is associated with inferior response rates and disease control after venetoclax on multivariate analyses [ 44 ]. Venetoclax monotherapy was also associated significantly improved quality of life among patients with R/R CLL in the single-arm VENICE II study [ 57 ].…”

Section: Efficacy Of Venetoclax In Chronic Lymphocytic Leukemia/small...mentioning

confidence: 99%

“…Venetoclax monotherapy was also associated significantly improved quality of life among patients with R/R CLL in the single-arm VENICE II study [ 57 ].…”

Section: Efficacy Of Venetoclax In Chronic Lymphocytic Leukemia/small...mentioning

confidence: 99%

Clinical experiences with venetoclax and other pro-apoptotic agents in lymphoid malignancies: lessons from monotherapy and chemotherapy combination

Lew

Seymour

2022

J Hematol Oncol

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BH3-mimetics are a novel drug class of small molecule inhibitors of BCL2 family proteins which restore apoptosis in malignant cells. The only currently approved BH3-mimetic, the selective BCL2 inhibitor venetoclax, is highly efficacious in chronic lymphocytic leukemia and has rapidly advanced to an approved standard of care in frontline and relapsed disease in combination with anti-CD20 monoclonal antibodies. In this context, tumour lysis syndrome and myelosuppression are the most commonly encountered toxicities and are readily manageable with established protocols. Venetoclax is active in other lymphoid malignancies including several B cell non-Hodgkin lymphomas, acute lymphoblastic leukemia and multiple myeloma, with the highest intrinsic sensitivity observed in mantle cell lymphoma and Waldenstrom macroglobulinemia. Venetoclax combination with standard regimens in follicular lymphoma, multiple myeloma and aggressive B cell neoplasms has shown some promise, but further studies are required to optimize dose and scheduling to mitigate increased myelosuppression and infection risk, and to find validated biomarkers of venetoclax sensitivity. Future research will focus on overcoming venetoclax resistance, targeting other BCL2 family members and the rational design of synergistic combinations.

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“…Notably, the dysregulation of the Bcl-2 family of anti-apoptotic proteins, including Bcl-2, Bcl-xL and Mcl-1, permits escape from intrinsic and extrinsic apoptosis (17). Targeting this anti-apoptosis pathway using Bcl-2 inhibitors such as venetoclax, is a faithful alternative for treatment of resistant and refractory CLL as well as other B cell malignancies (18,19). Along with identifying reliable signature mutations, continuous efforts have been made to analyze the leukemogenic potential of these sporadic mutations in genetically modified animals (20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

The Determinants of B Cell Receptor Signaling as Prototype Molecular Biomarkers of Leukemia

et al. 2021

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Advanced genome-wide association studies (GWAS) identified several transforming mutations in susceptible loci which are recognized as valuable prognostic markers in chronic lymphocytic leukemia (CLL) and B cell lymphoma (BCL). Alongside, robust genetic manipulations facilitated the generation of preclinical mouse models to validate mutations associated with poor prognosis and refractory B cell malignancies. Taken together, these studies identified new prognostic markers that could achieve characteristics of precision biomarkers for molecular diagnosis. On the contrary, the idea of augmented B cell antigen receptor (BCR) signaling as a transforming cue has somewhat receded despite the efficacy of Btk and Syk inhibitors. Recent studies from several research groups pointed out that acquired mutations in BCR components serve as faithful biomarkers, which become important for precision diagnostics and therapy, due to their relevant role in augmented BCR signaling and CLL pathogenesis. For example, we showed that expression of a single point mutated immunoglobulin light chain (LC) recombined through the variable gene segment IGLV3-21, named IGLV3-21R110, marks severe CLL cases. In this perspective, we summarize the molecular mechanisms fine-tuning B cell transformation, focusing on immunoglobulin point mutations and recurrent mutations in tumor suppressors. We present a stochastic model for gain-of-autonomous BCR signaling and subsequent neoplastic transformation. Of note, additional mutational analyses on immunoglobulin heavy chain (HC) derived from non-subset #2 CLL IGLV3-21R110 cases endorses our perspective. Altogether, we propose a model of malignant transformation in which the augmented BCR signaling creates a conducive platform for the appearance of transforming mutations.

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Impact of venetoclax monotherapy on the quality of life of patients with relapsed or refractory chronic lymphocytic leukemia: results from the phase 3b VENICE II trial

Cited by 10 publications

References 30 publications

Early cytokine-driven adaptation of survival pathways in lymphoid cells during targeted therapies

Early cytokine-driven adaptation of survival pathways in lymphoid cells during targeted therapies

Clinical experiences with venetoclax and other pro-apoptotic agents in lymphoid malignancies: lessons from monotherapy and chemotherapy combination

The Determinants of B Cell Receptor Signaling as Prototype Molecular Biomarkers of Leukemia

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