Claire Couty: No financial relationships to disclose
Objectives: Combining Venetoclax (VEN, Bcl-2 inhibitor) and Azacitidine (AZA, hypomethylating agent) has recently become the standard of care for newly diagnosed acute myeloid leukemia (AML) in patients unfit for intensive chemotherapy. Nevertheless, challenges remain to describe heterogeneity in response and development of relapse. This study aimed to develop a QSP model to study the effect of relative levels of Bcl-2 family members on patient response to VEN and VEN-AZA.
Methods: We developed a QSP model of VEN pharmacodynamics (PD), including representations of cellular uptake, binding to Bcl-2 and intrinsic apoptosis through mitochondrial outer membrane permeabilization. We combined it with a cell line model and a phenomenological model for AZA PD to obtain a model for in vitro viability assays. Including a mechanistic model of AML proliferation and a simple PK model for both treatments yielded a model for human AML treated with VEN-AZA. We derived sensitivity to relative levels of Bcl-2 family members from basic assumptions and informed variability in cell lines/population using recent clinical results on quantifying Bcl-2 sensitivity by MAC score [1]. We then integrated in vitro viability assay data for VEN [2] (ML-2 cells) and the combination of VEN and AZA [3] (Oci-AML5 cells) to inform the corresponding model. Lastly, we used clinical trial data from VEN and AZA monotherapy trials [4,5] in order to translate our in vitro model to an in vivo human model for AML treatment. Simulations were run on the collaborative QSP simulation platform jinkō.
Results: Our model of intrinsic apoptosis captures single drug and drug-drug interaction data for VEN and AZA in vitro viability assays. Clinical translation of the model allowed to successfully match response variability in the context of VEN monotherapy (bone marrow blast count changes after four weeks) and long term behavior in AZA monotherapy (mean blast and white blood cell counts). In silico trials coupled with sensitivity analysis and stratification then allowed to study model predictions, showing qualitative agreement for dependence of response markers on MAC score with clinical observations.
Conclusions: We present, to our knowledge, the first QSP model for VEN-AZA that reproduces in vitro viability and clinical trial data for VEN and AZA monotherapy while deriving variability in response from quantitative clinical data on Bcl-2 sensitivity. This paves the way towards an AML QSP platform including additional treatment combinations targeting intrinsic apoptosis.
Citations: [1] Waclawiczek et al. (2023), Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax [2] Seipel et al. (2022), Rationale for Combining the BCL2 Inhibitor Venetoclax with the PI3K Inhibitor Bimiralisib in the Treatment of IDH2- and FLT3-Mutated Acute Myeloid Leukemia [3] Cojocari et al. (2021), Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia [4] Konopleva et al. (2016), Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia [5] PMDA of Japan, CTD Azacitidine 2.7.6
