The genetic hallmark of chronic myeloid leukemia (CML) is the Philadelphia chromosome (Ph), the reciprocal translocation between chromosomes 9 and 22, which occurs in at least 90% of CML cases. This translocation leads to the production of functional BCR-ABL fusion tyrosin kinase, conferring a proliferative advantage to the tumor cells. Prior to the introduction of Gleevec in 2001, the first tyrosine kinase inhbitor (TKI), the only cure for CML was hematopoetic stem cell transplantation, and the median survival of all patients was 4-5 yrs. Since the introduction of Gleevec, ~87% of patients are expected to be alive at 8 yrs of follow up. CML patients are recommended to continue TKI therapy indefinitely, despite significant side effects associated with long-term use of TKI and financial burden on the US health care system. Several small clinical studies suggest that about 50% of CML patients can maintain complete molecular response (CMR) even after discontinuing TKIs; patients who relapse after discontinuation can restart with TKI to achieve CMR. With annual costs of $100,000 per patient, an estimated prevalence of 70,000 patients in 2010 alone, and with an estimated 36% of patients in stable CMR, a discontinuation rate of 50% could lead to savings of over $500 million to the US health care system each year. However, it is not possible to predict the cohort of patients who may have recurrence after TKI discontinuation. This is caused in part by the inability of current assay based on real-time PCR for accurately assessing BCR-ABL transcripts when they are present at very low levels. Preliminary studies suggest low levels of BCR-ABL transcripts present in CML patient samples that are undetectable by real-time PCR (polymerase chain reaction) may be detected and quantified by digital PCR, which in turn can be used to differentiate recurring from non-recurring patients after discontinuation of TKIs. To confirm this hypothesis, we propose to develop a new digital PCR platform with the requisite workflow and minimal user interference, thus improving reliability and accuracy of the results. With this new capability, we will analyze archived CML samples with linked clinical outcome data. This project therefore has the potential to provide a molecular diagnostic assay capable of predicting recurrence after TKI discontinuation. In addition to enabling monitoring of BCR-ABL transcripts from CML patients with minimal residual disease, this new digital PCR technology will advance current PCR measurements, especially in the clinical setting, so digital PCR will be adopted for use in a wide range of clinical diagnostic and prognostic tests.

Public Health Relevance

Project Summary Patients with chronic myeloid leukemia (CML) are recommended to continue TKI (tyrosine kinase inhibitor) therapy indefinitely, despite significant side effects associated with long-term use of TKI and financial burden on the US health care system. To address this issue, we propose to develop a new digital PCR system for the molecular analysis of archived CML patient samples with linked clinical outcome towards predicting recurrence after TKI discontinuation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
1R01EB021878-01A1
Application #
9184091
Study Section
Instrumentation and Systems Development Study Section (ISD)
Program Officer
Lash, Tiffani Bailey
Project Start
2016-07-01
Project End
2020-03-31
Budget Start
2016-07-01
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
$372,954
Indirect Cost
$113,185
Name
University of Washington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195