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Phase Ib/II Study of Azacitidine, Venetoclax and Magrolimab in Adult Patients with Newly Diagnosed and Relapsed Refractory Acute Myeloid Leukemia

ABSTRACT: Phase Ib/II Study of Azacitidine, Venetoclax and Magrolimab in Adult Patients with Newly Diagnosed and Relapsed Refractory Acute Myeloid Leukemia

PROVIDER: PRJNA1123202 | ENA |

REPOSITORIES: ENA

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Phase Ib/II Study of Azacitidine, Venetoclax and Magrolimab in Adult Patients with Newly Diagnosed and Relapsed Refractory Acute Myeloid Leukemia

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Improved Prediction of Venetoclax and Azacitidine Efficacy in Acute Myeloid Leukemia through Machine Learning

Project description:Despite the transformative impact of venetoclax-azacitidine in treating acute myeloid leukemia (AML), reliable markers for accurately predicting patient responses remain urgently needed. To address this challenge, we employed a multidisciplinary approach that combined transcriptomic profiling, ex vivo drug sensitivity testing, functional assays, and clinical data to identify robust predictors of venetoclax-azacitidine response. We pinpointed a set of core genes linked to both ex vivo and in vivo drug responsiveness, validated through CRISPR-Cas9 screens in the setting of both venetoclax and azacitidine therapies. In particular, silencing BCL2L1 and PINK1 preferentially enhanced response to the venetoclax-azacitidine treatment. Building on these insights, we further developed and validated an 8-gene random forest model (RF8) that demonstrated high specificity and sensitivity in four independent cohorts comprising 498 patients. This model was capable of distilling downstream effects of genetic alterations to assist in predicting treatment response and outperformed existing genetic mutation-based signatures. Furthermore, the RF8 score demonstrated a nearly monotonic relationship with venetoclax-azacitidine response probabilities and patient outcomes, enabling precise stratification of patients. These findings illustrated the feasibility of translating integrated transcriptomic and drug-response profiling data into more refined risk stratification approaches, offering a new avenue for optimizing clinical decision-making in AML.

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IMPRINTS-CETSA Venetoclax in Kasumi-1 cells, 6h incubation

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The clonal basis of either resistance or response to ivosidenib and venetoclax ± azacitidine is established early in IDH1-mutated myeloid malignancies

Project description:A recent phase Ib/II trial of ivosidenib and venetoclax ± azacitidine in patients with IDH1-mutated myeloid malignancies showed a promising 94% response rate. However, relapse was still common. To define the clonal and cellular basis of acquired resistance and sustained response, we performed single-cell studies on longitudinal samples from 8 patients. Whilst all 8 patients initially responded to treatment, 6 relapsed and 2 remained in sustained remission for > 4 years. Therapy-resistant clones were selected early, within 3 treatment cycles, preceding relapse by months or years. Treatment failure was associated with either emerging genetically evolved clones or acquired differentiation arrest of pre-existing clones; in both cases, within small immunophenotypic leukemic stem cell (LSC) populations. In sustained response, all leukemic clones were eradicated and rapidly replaced by clonal and wild type hematopoiesis. If validated in larger cohorts, early clonal assessment of LSCs may be predictive of long-term outcome, providing a clinically relevant endpoint.

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Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia

Project description:Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Leukemia stem cells (LSCs) drive the initiation and perpetuation of AML, are quantifiably associated with worse clinical outcomes, and often persist after conventional chemotherapy resulting in relapse1-5. In this report, we show that treatment of older patients with AML with the B cell lymphoma 2 (BCL-2) inhibitor venetoclax in combination with azacitidine results in deep and durable remissions and is superior to conventional treatments. We hypothesized that these promising clinical results were due to targeting LSCs. Analysis of LSCs from patients undergoing treatment with venetoclax + azacitidine showed disruption of the tricarboxylic acid (TCA) cycle manifested by decreased α-ketoglutarate and increased succinate levels, suggesting inhibition of electron transport chain complex II. In vitro modeling confirmed inhibition of complex II via reduced glutathionylation of succinate dehydrogenase. These metabolic perturbations suppress oxidative phosphorylation (OXPHOS), which efficiently and selectively targets LSCs. Our findings show for the first time that a therapeutic intervention can eradicate LSCs in patients with AML by disrupting the metabolic machinery driving energy metabolism, resulting in promising clinical activity in a patient population with historically poor outcomes.

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Azacitidine Plus Venetoclax for the Treatment of Relapsed and Newly Diagnosed Acute Myeloid Leukemia Patients.

Project description:Venetoclax (VEN) belongs the BH3-mimetic class that selectively targets BCL-2, activating apoptosis. The combination of VEN and azacitidine (AZA) has changed the paradigm of treatment of newly diagnosed (ND) acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy. There is scarce evidence for the use of VEN-AZA for relapsed or refractory (R/R) AML. We compared the outcome of 39 R/R AML and 38 ND AML patients treated between 01/20 and 12/21. The median age was 69 (22-86) and 73 (61-81) in the R/R and ND groups, respectively. Adverse cytogenetics were found in 36% of patients in the R/R group and 59% of patients in the ND group. Overall response rate was 37% in R/R AML, including 13% CR, 8% CRi, 3% PR and 13% MLFS, and 58% in the ND AML, including 32% CR, 13% CRi and 13% MLFS. Adverse cytogenetics was associated with treatment failure in the R/R group (Relative Risk = 0.13, p = 0.005). Median overall survival (OS) was 5.9 months in the R/R group and 9.4 months in the ND group. Median OS was 2.2 months in the adverse cytogenetics group versus 8.7 months in the intermediate cytogenetics group in the R/R group (p = 0.02). Median leukemia-free survival was not different between the two groups (9.4 months and 10.3 months), indicating that VEN-AZA can be an efficient salvage treatment for selected R/R AML patients. In conclusion, VEN-AZA is a promising treatment for ND AML and for selected R/R AML patients.

| S-EPMC9028084 | biostudies-literature

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