More than 120,000 people in the U.S. are living with acute lymphoblastic leukemia (ALL), and 6,000 new cases are diagnosed each year. Of those, more than 3,500 will be in children.
Responsible for 75% of all pediatric leukemia diagnoses, ALL is a rapid-onset blood cancer, preventing the body from producing mature, infection-fighting white blood cells, sometimes within a matter of months.
ALL requires immediate treatment, often a combination of chemotherapy, targeted therapy, immunotherapy and bone marrow transplants—but clinicians today have no way of knowing how specific drug combinations and dosages will impact the patient, or whether the treatment will be successful.
Currently, treatment strategies incorporate some degree of personalization based on leukemia subtype and risk classification. Despite this, most patients ultimately receive similar treatment regimens. While advances in genomic sequencing have raised the possibility of truly personalized therapy, new complementary functional assays are still necessary to test live cancer cells directly against treatments to see which interventions actually work. Two patients can have the same genetic mutation but have very different responses to targeted therapy.
To address this, a team of scientists and clinicians at Emory University, Children's Healthcare of Atlanta and Georgia Tech developed a groundbreaking new technology to help clinicians identify how children will respond to any given ALL treatment at the time of diagnosis, rather than after standard chemotherapy has been administered, saving invaluable time.
GradientScreen, a microfluidic assay or a "lab-on-a-chip," rapidly measures how patient's leukemia cells respond to drug combinations from a single blood or bone marrow sample. By complementing genomic and related data with direct measurements of drug sensitivity, GradientScreen provides an additional layer of information that can guide treatment decisions. Rather than testing each drug pair and dose ratio individually— which would be time-consuming and resource-intensive—the assay uses microfluidic technology to evaluate the full range of combination ratios within a three-drug regimen in a single, efficient experiment.
"One of the Holy Grails in oncology is the ability to identify which patient is likely to be unresponsive to standard treatment before initiation of therapy begins, and to personalize which combination of standard chemotherapies with newer targeted or biological agents would be most beneficial, and at which dosages, for that particular person," says Wilbur Lam, MD, PhD, professor of pediatrics and biomedical engineering at Emory University and Georgia Tech, and principal investigator on the study.
"This is a significant advancement in helping pediatric oncologists nationwide understand which drugs to administer to patients who are most likely to resist standard chemotherapy," adds Lam, also a pediatric oncologist at Children's Healthcare of Atlanta. In fact, roughly 50% of the adult ALL population will experience relapse or refractory disease, in which the cancer doesn't respond to or proliferates during the intervention, and in the pediatric population, roughly 15% experience relapse.
Developed in Atlanta by Kendall Williams, PhD, and Dan Zhang, PhD, graduates of Emory University and Georgia Tech's biomedical engineering and bioengineering programs, respectively, GradientScreen works by exposing leukemia cells to 3-drug combinations and measuring how many cancer cells survive. By comparing how cells respond to single drugs versus combinations, the assay can identify which drug combinations and ratios work better together. This results in detailed "response patterns" that reflect how a patient's type of leukemia might react to treatment. In this retrospective study of 17 leukemia cell and bone marrow samples of ALL patients, provided by The Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, results using this platform correlated with patient treatment outcomes, including the amount of residual disease after induction treatment, which is the first month of chemotherapy, as well as whether the patient relapsed.
"GradientScreen aims to improve as well as broaden access to precision medicine in leukemia treatment by helping clinicians identify harder-to-treat patients earlier in disease progression, and more precisely matching them with new, alternative treatment approaches," says Williams.
Initial next steps for the team include expansion to other leukemia types, including acute myeloid leukemia, to adult as well as pediatric patients, and establishment within the Emory Lab for Innovative Assay Development (ELIAD), a collaboration between Emory Healthcare and Emory University that supports diagnostic testing that can be immediately used for patient care.
This study was funded by the following awards: NSF GRFP No. 1937971 and NIH NHLBI grant R35HL145000.
