Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia

DiNardo, Courtney D.; Jonas, Brian A.; Pullarkat, Vinod; Thirman, Michael J.; Garcia, Jacqueline S.; Wei, Andrew H.; Konopleva, Marina; Döhner, Hartmut; Letaï, Anthony; Fenaux, Pierre; Koller, Elizabeth A.; Havelange, Violaine; Leber, Brian; Esteve, Jordi; Wang, Jianxiang; Pejša, Vlatko; Hájek, Roman; Porkka, Kimmo; Illés, Árpád; Lavie, David; Lemoli, Roberto M.; Yamamoto, Kazuhito; Yoon, Sung‐Soo; Jang, Jun‐Ho; Yeh, Su‐Peng; Turğut, Mehmet; Hong, Wan‐Jen; Zhou, Ying; Potluri, Jalaja; Pratz, Keith W.

doi:10.1056/nejmoa2012971

Cited by 1,702 publications

(1,931 citation statements)

References 26 publications

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“…The confirmatory international phase 3 placebo-controlled randomized trial (VIALE-A; NCT02993523) of azacitidine +/venetoclax in a similar patient population was just presented at the European Hematology association (EHA) 2020 virtual meeting with positive results and then published in the New England New Journal of Medicine (34). Among 431 patients treated (286 with AZA + venetoclax, and 145 with azacytidine), the median age was 76 years; 25% had s-AML.…”

Section: Venetoclax-based Combinations Hypomethylating Agents (Hma)mentioning

confidence: 99%

Venetoclax-Based Combinations in Acute Myeloid Leukemia: Current Evidence and Future Directions

Samra

Konopleva

Isidori³

et al. 2020

Front. Oncol.

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The past decade has witnessed major advances in our understanding of molecular biology, which led to breakthrough novel therapies, importantly including the B-cell lymphoma-2 (BCL-2) inhibitor venetoclax. Notably, venetoclax-based combinations have improved outcomes, including both remission rates and overall survival, of older patients with acute myeloid leukemia (AML) deemed "unfit" for intensive chemotherapy due to age or comorbidities. This has translated into a rapid and widespread use of venetoclax-based combinations in both academic and community-based settings. Other venetoclax-based combinations are being investigated in AML with the ultimate goal of improving cure rates across many subgroups; frontline and relapsed/refractory, in combination with intensive chemotherapy, in the post-transplant setting, or as maintenance strategy. In this article, we summarize the current available data on venetoclax-based combinations. We also highlight areas of unmet medical need, and we offer practical clinical pearls for management of patients receiving such therapy.

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Section: Venetoclax-based Combinations Hypomethylating Agents (Hma)mentioning

confidence: 99%

Venetoclax-Based Combinations in Acute Myeloid Leukemia: Current Evidence and Future Directions

Samra

Konopleva

Isidori³

et al. 2020

Front. Oncol.

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“…Venetoclax, a selective BCL-2 inhibitor that was approved by the FDA for treatment-naïve elderly AML patients, has shown potential to be further explored. According to a recent study, previously untreated patients aged 75 years or older who were ineligible for intensive chemotherapy experienced a longer overall survival and a higher incidence of remission after treatment with azacitidine plus venetoclax than patients who received azacitidine alone (116). In addition, venetoclax+HMA has also been confirmed to be safe and effective in younger patients (117).…”

Section: Conclusion and Prospectsmentioning

confidence: 99%

Targeting Bcl-2 Proteins in Acute Myeloid Leukemia

et al. 2020

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B cell lymphoma 2 (BCL-2) family proteins play an important role in intrinsic apoptosis. Overexpression of BCL-2 proteins in acute myeloid leukemia can circumvent resistance to apoptosis and chemotherapy. Considering this effect, the exploration of anti-apoptotic BCL-2 inhibitors is considered to have tremendous potential for the discovery of novel pharmacological modulators in cancer. This review outlines the impact of BCL-2 family proteins on intrinsic apoptosis and the development of acute myeloid leukemia (AML). Furthermore, we will also review the new combination therapy with venetoclax that overcomes resistance to venetoclax and discuss biomarkers of treatment response identified in early-phase clinical trials.

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“…An analogous advantage was not highlighted in other AML categories [32] and was not demonstrated in patients for whom MRC is defined by morphologic dysplasia, who were excluded from the phase 3 trial [33]. In this view, a more reliable, MFC-based appraisal of dysplasia might aid at identifying patients that potentially benefit from the adoption of CPX-351, as well as other emerging treatment combinations (i.e., BCL2 inhibitors plus hypomethylating agents) [34], in the scarcity of genetic predictors of response.…”

Section: Discussionmentioning

confidence: 99%

Multilineage Dysplasia as Assessed by Immunophenotype in Acute Myeloid Leukemia: A Prognostic Tool in a Genetically Undefined Category

Mannelli

Bencini

Piccini

et al. 2020

Cancers

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Acute myeloid leukemia (AML) “with myelodysplasia-related changes (MRC)” is considered a separate entity by the World Health Organization (WHO) classification of myeloid neoplasms. While anamnestic and cytogenetic criteria provide objective attribution to this subset, with clear unfavorable prognostic significance, the actual role of multi-lineage dysplasia (MLD) as assessed by morphology is debated. The aim of our work was to study MLD by a technique alternative to morphology, which is multiparameter flow cytometry (MFC), in a large series of 302 AML patients intensively treated at our Center. The correlation with morphology we observed in the unselected analysis reiterated the capability of the MFC-based approach at highlighting dysplasia. MLD data, estimated through an immune-phenotypic score (IPS), provided no insight into prognosis when considered overall nor within well-defined genetic categories. Of interest, IPS-related dysplasia conveyed significant prognostic information when we focused on genetically undefined patients, triple-negative for NPM1, FLT3 and CEBPA (TN-AML). In this context, the lack of dysplastic features (IPS_0) correlated with a significantly higher CR rate and longer survival compared to patients showing dysplasia in one or both (neutrophil and erythroid) cell lineages. The impact of IPS category maintained its validity after censoring at allogeneic HSCT and in a multivariate analysis including baseline and treatment-related covariates. In a subgroup featured by the lack of genetic determinants, our data could help address the relative unmet needs in terms of risk assessment and treatment strategy, and provide insight into prediction of response in the rapidly evolving therapeutic scenario of AML.

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Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia

Cited by 1,702 publications

References 26 publications

Venetoclax-Based Combinations in Acute Myeloid Leukemia: Current Evidence and Future Directions

Venetoclax-Based Combinations in Acute Myeloid Leukemia: Current Evidence and Future Directions

Targeting Bcl-2 Proteins in Acute Myeloid Leukemia

Multilineage Dysplasia as Assessed by Immunophenotype in Acute Myeloid Leukemia: A Prognostic Tool in a Genetically Undefined Category

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