New Assay Paves Way for 'Personalized' Therapy in AML
NEW ORLEANS—A clinical trial has enrolled nine patients with relapsed or refractory acute myeloid leukemia (AML) for “personalized” therapy based on results of a high-throughput sensitivity assay, attendees at the 55th American Society of Hematology Annual Meeting and Exposition were told.
“This new personalized approach to individualized therapy for refractory AML may provide novel drugs to patients and new insights into leukemia drug resistance,” said Pamela S. Becker, MD, PhD, of the University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA.
The study (NCT01872819) is testing multiple drugs simultaneously against a patient's own donated blood sample, best matching the drug most effective in killing leukemia cells, according to ClinicalTrials.gov. Most patients with AML have multiple unique mutations that cause them either to relapse or fail to respond to initial therapy. The primary objective of the study is to demonstrate feasibility of the assay as a potential means to predict response; the secondary objective is cytoreduction with selected agents.
The high-throughput sensitivity assay has been devised for 160 drugs that represent multiple mechanisms of action and signaling pathways. The U.S. Food and Drug Administration has approved 45 of the drugs and 115 are investigational; the latter include kinase inhibitors.
Dr. Becker reported on 30 primary patient blood marrow samples and 15 acute leukemia cell lines analyzed to date. Peripheral blood blasts from individual patients were thawed and viable cells were isolated and purified to higher than 80% using magnetic bead separations. Gene expression microarrays were also performed.
Assays of the 30 patients revealed more than 50 drugs “exhibited cytotoxicity in at least some patients,” Dr. Becker said. “There was wide variation in the drug sensitivity patterns exhibited by the patient blasts samples, and each was unique. Notably, all patient samples were susceptible to several drugs with IC50s in the range that might predict clinical response.”
For patients who achieved complete remission with a clinical regimen, a statistically significant association with cytotoxicity in assay was observed in response to several drugs commonly used to treat AML, including clofarabine, mitoxantrone, daunorubicin, and cladribine. Multivariate analysis to identify drug combinations effective in predicting complete remission found that in vitro cytotoxicity data of a combination of three drugs (BAY 11-7085, TPCA-1, ON 01910.Na), for example, was more predictive compared with using each of these drugs individually (ie, 91.2% accuracy vs. 84.8%, 84.2%, and 79.1%, respectively).
Dr. Becker presented data on seven of the nine enrolled patients with multiply relapsed or refractory AML who completed treatment to date. The feasibility of the ongoing study is to use the assay to identify a drug within 10 days, obtain a drug within 14 days, and treat within 21 days (time concurrent, not sequential).
In actual practice, drug sensitivity test results were obtained in 5 to 7 days (mean, 5.2 days), and all patients were treated within seven to 21 days. A decrease in blasts was observed in the patients given drugs selected by the assay, she said.
For example, selected results of the high throughput screen for patient 1, a 67-year-old male with relapsed/refractory disease who had five prior regimens, demonstrated a decline in bone marrow blasts following treatment with cladribine.
Future work will combine genetic and chemosensitivity testing data to optimize drug choice for patients, Dr. Becker concluded.