Sylvester Researchers Conduct Promising Pilot Study of Precision Medicine for AML

A team of researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine has obtained promising results with patients who have acute myeloid leukemia that has not responded well to prior standard treatments.

Acute myeloid leukemia (AML) is a blood cancer characterized by rapid growth of abnormal white blood cells most commonly found in older patients; the average age of a patient with AML is 67, and the five-year survival rate is only 27 percent. It is a serious disease with very few treatment options and the standard of care has not changed much in decades. Survival is especially low in older AML patients who are less able to tolerate aggressive chemotherapy. Reducing side effects to normal tissues and limiting unsuccessful treatment attempts are therefore major concerns in the treatment of these patients.

The Food and Drug Administration has approved a large number of anti-cancer drugs over the past decade, although only a small number of them are routinely used in AML therapy. However, it remains possible that individual AML patients could benefit from existing drugs.

“A precision, highly personalized, medicine approach is appealing for use in AML due to ease of access to tumor samples and the significant variability in the patients’ response to treatment,” said Claes Wahlestedt, M.D., Ph.D., professor of psychiatry and behavioral sciences, associate dean for therapeutic innovation, and director of the Center for Therapeutic Innovation. “Nonetheless, prior attempts to establish a precision medicine platform for AML have been largely unsuccessful, at least in part due to the use of small compound panels, non-optimized data analysis capabilities, and having relatively slow turnover rates, which restricts the scope of treatment and delays its onset.”

Wahlestedt and the researchers in his laboratory, spearheaded by Ines Lohse, Ph.D., and working in partnership with Sylvester clinicians, notably Ronan T. Swords, M.D., Ph.D., and Justin M. Watts, M.D., decided to take a different approach. In a pilot study they evaluated a cohort of 12 patients with refractory AML — those having residual cancer cells in their marrow even after intensive treatment — using an ex vivo drug sensitivity testing (DST) platform.

Purified AML blasts were screened against a panel of all 215 FDA-approved compounds, and the treatment response was evaluated after 72 hours of exposure. The cancer cell response to each drug was compared to responses from non-cancerous blood cells to find anticancer agents that particularly affect cancer cells, thus significantly reducing side effects. Drug sensitivity scoring was reported to the treating physician, and the patients were then treated with either DST- or non-DST-guided therapy. The results were dramatic. Three out of four DST-guided patients displayed treatment response, while all of the non-DST-guided patients failed the assigned treatment.

“These were patients who had no other treatment option,” said Wahlestedt. “By performing the drug screening, we were able to suggest drugs that otherwise would not have been used, and which, in some cases, resulted in a marked clinical improvement. This is arguably one of the best cases ever for actionable personalized medicine. Still, our pilot study had only 12 patients, so we are now writing grant applications to enable a scale-up to studies of approximately 300 patients.”

An article reporting the researchers’ initial findings, “Ex-vivo Sensitivity Profiling to Guide Clinical Decision Making in Acute Myeloid Leukemia: A Pilot Study,” was recently published in the journal Leukemia Research. Additional Miller School investigators/coauthors were Diana Azzam, Ph.D., Hassan Al-Ali, Ph.D., Claude-Henry Volmar, Ph.D., Aymee Perez, Ph.D., Ana Rodriguez, Fernando Vargas, Roy Elias, Francisco Vega, Arthur Zelent, Ph.D., Shaun P. Brothers, Ph.D., and Jonathan Trent, M.D., Ph.D.

Tags: Claes Wahlestedt, Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami