BCL2 Inhibition: A New Paradigm for the Treatment of AML and Beyond

Wei, Andrew H.; Roberts, Andrew W.

doi:10.1097/hs9.0000000000000912

Cited by 6 publications

(6 citation statements)

References 98 publications

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“…The BCL-2 family includes multiple proteins (e.g., BCL2, BCL-XL, MCL1, BCL2A1) specifically involved in the intrinsic mitochondrial apoptotic pathway. As inappropriate cell survival and dysregulated apoptotic processes are one of the hallmarks of malignancies, this family of proteins has become a promising therapeutic target for cancer since its discovery more than 30 years ago [ 10 ]. The mechanism of action of venetoclax includes its binding to the BH3 domain of the BCL-2 protein, with subsequent release of proapoptotic proteins that cause death cell induction [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Venetoclax with Hypomethylating Agents in Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Survival Data from Real-World Studies

Ucciero,

Pagnoni,

Scotti

et al. 2023

Cancers

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In recent years, the association of venetoclax (VEN) with hypomethylating agents (HMAs) significantly improved the outcome of patients with newly diagnosed acute myeloid leukemia (AML) who were unfit for intensive chemotherapy and became the standard of care after the publication of the pivotal RCT VIALE-A. However, it is still not clear to what extent the results observed in the VIALE-A apply to a real-world setting. For this reason, we carried out a systematic review and meta-analysis of real-world studies on newly diagnosed patients with AML, ineligible for intensive induction chemotherapy, receiving first-line VEN+HMA. We then compared their results in term of survival with those from the VIALE-A. Kaplan-Meier curves were extracted from all included studies and individual survival data was reconstructed. We then estimated a pooled survival curve and compared it with the results of the VIALE-A using the log-rank test. We also conducted a secondary analysis including only studies considering VEN plus azacytidine (AZA) as treatment, as this was the schedule originally used in the VIALE-A. Nineteen real-world studies met the inclusion criteria and were included in the systematic review. Most of them reported a worse survival than the VIALE-A. The pooled survival curve was similar to that reported in the VIALE-A during the first three months of treatment but diverged thereafter (p-value = 0.0001). The pooled median survival among the real-world studies was 9.37 months (95%CI 8.81–10.5), substantially lower than that reported in the VIALE-A (14.7 months; 95%CI 11.9–18.7). Results slightly increased when the analysis was restricted to the studies using VEN+AZA as treatment (median survival: 11.5 months; 95%CI 10.2–14.8). Survival of newly diagnosed AML patients treated with VEN+HMAs in a real-world setting seems to be lower than previously reported in the VIALE-A, while the effect of VEN+AZA is more in line with expected results. Future studies are needed to evaluate whether this apparent discrepancy is due to the different characteristics of enrolled patients or to a non-optimal adherence to therapy, and whether alternative regimens can provide better results in terms of safety and effectiveness.

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Section: Introductionmentioning

confidence: 99%

Venetoclax with Hypomethylating Agents in Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Survival Data from Real-World Studies

Ucciero,

Pagnoni,

Scotti

et al. 2023

Cancers

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“…An increased level of BCL-2 expression is associated with poor outcomes in patients receiving intensive chemotherapy for AML. For this reason, venetoclax has gained approval as a targeted therapy for AML [ 6 , 19 , 21 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

“…Despite its efficacy in achieving remission, the current approach often results in short-lived responses, leading to an unfavourable overall prognosis with a five-year survival rate of around 40–45% in adults below sixty and less than 10% in elderly patients. The addition of the BCL-2 inhibitor, venetoclax, to either zacytidine or low-dose cytarabine has emerged as a standard treatment for older patients [ 6 ], but the improvement in median survival with this approach was <6 months [ 7 ]. The persistence of leukemic stem/progenitor cells (LSPCs) that are resistant to therapy leads to relapse, necessitating the development of innovative approaches for AML treatment to improve longer-term outcomes.…”

Section: Introductionmentioning

confidence: 99%

Combating Acute Myeloid Leukemia via Sphingosine Kinase 1 Inhibitor-Nanomedicine Combination Therapy with Cytarabine or Venetoclax

Nguyen,

Joyce,

Ross

et al. 2024

Pharmaceutics

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MP-A08 is a novel sphingosine kinase 1 (SPHK1) inhibitor with activity against acute myeloid leukemia (AML). A rationally designed liposome-based encapsulation and delivery system has been shown to overcome the physicochemical challenges of MP-A08 and enable its effective delivery for improved efficacy and survival of mice engrafted with human AML in preclinical models. To establish therapies that overcome AML’s heterogeneous nature, here we explored the combination of MP-A08-loaded liposomes with both the standard chemotherapy, cytarabine, and the targeted therapy, venetoclax, against human AML cell lines. Cytarabine (over the dose range of 0.1–0.5 µM) in combination with MP-A08 liposomes showed significant synergistic effects (as confirmed by the Chou–Talalay Combination Index) against the chemosensitised human AML cell lines MV4-11 and OCI-AML3. Venetoclax (over the dose range of 0.5–250 nM) in combination with MP-A08 liposomes showed significant synergistic effects against the chemosensitised human AML cell lines, particularly in venetoclax-resistant human AML cells. This strong synergistic effect is due to multiple mechanisms of action, i.e., inhibiting MCL-1 through SPHK1 inhibition, leading to ceramide accumulation, activation of protein kinase R, ATF4 upregulation, and NOXA activation, ultimately resulting in MCL-1 degradation. These combination therapies warrant further consideration and investigation in the search for a more comprehensive treatment strategy for AML.

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“…Some of these interventions include inhibitors targeting IDH1/2, [5,6] FLT3, [7,8] and BCL2. [9] Venetoclax, an orally administered selective small molecule inhibitor targeting BCL2, [10] has garnered considerable scientific interest. In a recent phase 2 clinical trial, we embarked on meticulously evaluating the therapeutic efficacy of the DAV regimen (a composite of intravenous daunorubicin and cytarabine in combination with venetoclax) in a cohort of adult patients with AML (n = 33).…”

Section: Introductionmentioning

confidence: 99%

“…Some of these interventions include inhibitors targeting IDH1/2, [ 5 , 6 ] FLT3, [ 7 , 8 ] and BCL2. [ 9 ]…”

Section: Introductionmentioning

confidence: 99%

Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia

Jin,

Hou,

Yao

et al. 2023

Advanced Science

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Resistance to chemotherapy remains a formidable obstacle in acute myeloid leukemia (AML) therapeutic management, necessitating the exploration of optimal strategies to maximize therapeutic benefits. Venetoclax with 3+7 daunorubicin and cytarabine (DAV regimen) in young adult de novo AML patients is evaluated. 90% of treated patients achieved complete remission, underscoring the potential of this regimen as a compelling therapeutic intervention. To elucidate underlying mechanisms governing response to DAV in AML, quantitative phosphoproteomics to discern distinct molecular signatures characterizing a subset of DAV‐sensitive patients is used. Cluster analysis reveals an enrichment of phosphoproteins implicated in chromatin organization and RNA processing within DAV‐susceptible and DA‐resistant AML patients. Furthermore, kinase activity profiling identifies AURKB as a candidate indicator of DAV regimen efficacy in DA‐resistant AML due to AURKB activation. Intriguingly, AML cells overexpressing AURKB exhibit attenuated MCL‐1 expression, rendering them receptive to DAV treatment and maintaining them resistant to DA treatment. Moreover, the dataset delineates a shared kinase, AKT1, associated with DAV response. Notably, AKT1 inhibition augments the antileukemic efficacy of DAV treatment in AML. Overall, this phosphoproteomic study identifies the role of AURKB as a predictive biomarker for DA, but not DAV, resistance and proposes a promising strategy to counteract therapy resistance in AML.

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BCL2 Inhibition: A New Paradigm for the Treatment of AML and Beyond

Cited by 6 publications

References 98 publications

Venetoclax with Hypomethylating Agents in Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Survival Data from Real-World Studies

Venetoclax with Hypomethylating Agents in Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Survival Data from Real-World Studies

Combating Acute Myeloid Leukemia via Sphingosine Kinase 1 Inhibitor-Nanomedicine Combination Therapy with Cytarabine or Venetoclax

Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia

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