Acute myeloid leukemia (AML) is a morbid condition, with over 20,000 new cases and 10,000 deaths annually in the U.S. While the majority of patients achieve remission, most harbor minimal amounts of residual disease (MRD) that will ultimately lead to relapse. The ability to detect MRD is important as its presence is associated with increased risk of relapse and death, and there is considerable interest in modulating treatment intensity based on the presence or absence of MRD. Unfortunately, current MRD detection methods suffer from variable sensitivity, non-uniform performance across laboratories, and lack of broad applicability to all patients. There is an urgent, unmet need for a better MRD detection method, which could substantially benefit patients as well as other stakeholders. Next generation sequencing (NGS) permits detection of genetic aberrations on the subclonal level. As virtually all AML harbors mutations, NGS could be a platform for a ?universal? MRD assay. Unlike other detection methods, NGS would reveal specific mutations and could suggest targeted therapies. Enthusiasm for NGS for MRD detection has, until now, been tempered by the relatively poor sensitivity of this method. Duplex Sequencing, the most accurate NGS technology, can change the paradigm for MRD detection. Members of our team pioneered this proprietary technology and demonstrated in proof-of-principal studies that it can accurately detect leukemic clones at extremely low levels. In Phase I of this Fast Track application, we will refine steps in our sequencing procedures to facilitate industrial-scale deployment of our MRD assay and validate analytical performance. In Phase II, we assess our assay's performance based on banked AML samples.
In Aim 1, we focus on whether our assay is prognostic of disease relapse.
In Aim 2, we compare our assay to flow cytometry, the current gold standard for MRD detection.
In Aim 3, we compare performance of our assay on paired bone marrow and peripheral blood samples to determine if we can achieve comparable results less invasively. The final product will be a robust, cost-effective, and implementable Laboratory Developed Test (LDT) ready for commercial deployment. This product will be widely useful for patients, oncologists, and payers alike by helping direct cutting-edge therapies to the patients most likely to benefit, while sparing others unnecessary medical and financial toxicities. It will allow researchers and pharmaceutical companies to rapidly evaluate novel therapies, permitting future clinical trials to be smaller and less costly. AML takes the lives of thousands of patients every year. Patients die both from the disease and from the aggressive treatment. Having an ultra-accurate ?universal? test to detect MRD would allow for improved prognostication and would pave the way for more efficacious personalized treatment. We fundamentally believe that such a test is necessary and well within our reach, and that our team is positioned better than any other in the world to bring this advance to patients.

Public Health Relevance

Despite the fact that most patients with acute myeloid leukemia receiving intensive chemotherapy are able to achieve a remission, many have residual disease below the level of morphological detection (so-called `minimal residual disease', or MRD), which eventually leads to relapse and ultimately death. Current methods of MRD detection are limited in sensitivity, are not applicable to all AML patients, and are challenging to perform and interpret. This project proposes to develop an ultra-sensitive, broadly-applicable, and easily implementable MRD assay for patients with acute myeloid leukemia based on Duplex Sequencing, the most sensitive DNA sequencing technology available.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44CA233381-04
Application #
10076806
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Evans, Gregory
Project Start
2018-07-16
Project End
2021-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
4
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Twinstrand Biosciences, Inc.
Department
Type
DUNS #
080451837
City
Seattle
State
WA
Country
United States
Zip Code
98121