# 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

> **NIH NIH UM1** · YALE UNIVERSITY · 2021 · $108,302

## Abstract

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

## Key facts

- **NIH application ID:** 10337831
- **Project number:** 3UM1CA186689-06S2
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Patricia M. LoRusso
- **Activity code:** UM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $108,302
- **Award type:** 3
- **Project period:** 2021-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10337831

## Citation

> US National Institutes of Health, RePORTER application 10337831, 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 (3UM1CA186689-06S2). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10337831. Licensed CC0.

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