Serial monitoring of circulating cell-free tumor DNA as measured by duplex sequencing in older patients with acute myeloid leukemia who receive azacitidine+venetoclax +/- immune checkpoint blockade

摘要

ABSTRACT IDH1 and IDH2 mutations are present in 15 to 20% of newly diagnosed cases of AML. They are associated with the production of the onco-metabolite 2-Hydroxyglutarate and a distinctive clonal landscape. IDH targeted inhibitors have been developed with success over the last decade but primary or secondary resistances remain extremely common. Resistance is driven by a variety of mechanisms including isotype switch, IDH secondary point mutation, acquisition of RTK mutation (such as RAS), or the development of IDH negative clones. Identifying the mechanisms driving resistance in a patient is crucial to be able to develop strategies to prevent and treat progressions. Our group has demonstrated that the presence IDH mutation induces a “BRCAness phenotype” in cells and a sensitivity to PARP inhibitors. These in vitro and in vivo findings were translated in a phase 2 study of Olaparib in IDH mutated AML and MDS (the PRIME study, CTEP #10264). For patients treated with Olaparib, we expect to see a similar pattern of resistance mechanisms as the one seen with IDH inhibitors and in order to optimize our therapies, we need to have a clear picture of the clonal complexity at the different points of the treatment. Conventional “Bulk sequencing” can provide some information but the level of granularity of the data may not be sufficient in all cases. Single cell sequencing may overcome these limitations and the new generation of platforms, such as the Tapestri platform, allow integrated and reliable workflows that can process a large volume of samples. More recently, multi-omics approaches have been developed with concomitant immunophenotyping and this allows to refine even more the results by allowing to focus on different cellular subsets. In this proposal, we use Single Cell DNA Sequencing and multi-omics approach to evaluate the clonal architecture before and during treatment with olaparib. Besides giving us more insights on the mode of action of olaparib, this approach will help us define the mechanisms of primary and secondary resistance to olaparib in this population. Consequently, this will guide our future strategies to overcome these resistances. Second, we will correlate SCS data with clinical response and evaluate if SCS has the potential to be used as a biomarker of response in a multicenter trial setting. 2