The presentation was given by Dr. Robert Arceci, MD, PhD, PH, director of the Children’s Center for Cancer and Blood Disorders Hematology/Oncology at Phoenix Children’s Hospital and the University of Arizona College of Medicine, as well as co-director of the Ron Matricaria Institute of Molecular Medicine.
He argued that the treatment and cure of childhood cancer “might be looked upon as one of the greatest accomplishments in the past 100 years.” The cure rate exceeds 75 percent.
But, he said, clinicians and scientists are correct only half the time in predicting whether a new treatment will improve outcomes.
And, he said, research illustrates a significant survival gap between children in high-income vs. low- and middle-income countries.
Arceci’s work has focused on acute myeloid leukemia (AML), which physicians commonly treat with Anthracycline and Cytarabine. The tactic of simply intensifying the timing and dosing of cancer drugs is a blunt-force approach with limited efficacy.
The advent of molecular diagnosis and biologically targeted therapy holds promise of better outcomes. He set out four overall goals and possibilities:
- Every patient will have full molecular analysis of tumor and germ line defined in real time followed by computational decision making that leads to an effective and non-toxic treatment
- Molecular analysis will be able to predict the best types of preventive interventions
- Points 1 and 2 will provide more effective and tolerable approaches for patients in low-income countries
- Points 1 and 2 will transform issues of survivorship
But, he said, the experience with Mylotarg illustrates the “trials and tribulations of targeted therapy.”
Starting out as CMA-676, the drug has had dramatic results in children and adults. However, in a finding he attributed to a statistical anomaly, SWOG Trial 0106 found that patients treated with Mylotarg and conventional chemotherapy had a fatal induction toxicity rate of 5.7 percent, which was higher than the patients treated only with conventional chemotherapy.
Given that finding, the Food and Drug Administration banned Mylotarg from the U.S. market.
However, the MRC 15 trial found Mylotarg to be beneficial among patients with good-risk AML. That study has its critics as well, but Mylotarg is now standard of care in Europe for patients with good-risk AML.
Targeting tyronine kinases is one therapy now showing promise. Trials with Lestaurtinib have had good results in China, France and North America among a certain subset of patients – those with high serum levels had good remission rates.
The drug disrupts PML/RAR, a fusion protein unique to this tumor, so that you can break the link, repressed genes become expressed, and you get differentiation – a “huge advance.”
He also noted that Tarceva has been successful in a small group of patients with lung cancer.
But, he argued, all those efforts amounted to targeted therapy – not personalized medicine.
He discussed a project he’s working on that aims to bring genomic methods to bear on identification of novel therapeutic targets for patients with AML, a complex and heterogeneous disease with over 300 reported translocations.
The project initially focused on established hybridization-based technologies, but it is transitioning to sequence-based characterization. The study looked at Methylation probe variability: AML vs. remission marrow – autosomes.
- Epigenetic marks in pediatric AML are strongly associated with other known molecular classifiers (cytogenetics, mutations)
- Epigenetic differences that associate with and may predict (or impact) response to treatment are readily identifiable, but rarely withstand rigorous statistical correction for multiple testing
- Outlier analysis identified some key “pan-AML” pathways marked by genomic DNA methylation changes
He said many factors stand in the way of achieving truly personalized medicine for every patient. Those include the fact that as advances increase, it’s getting harder and harder to make breakthroughs. Because the bar for success is so high, he said, regulators are becoming less tolerant of toxicity.
Research will likely never reach the point where physicians can predict with 100 percent accuracy whether a particular drug will work in an individual patient. But, Arceci said, perhaps the field can get to a point where a doctor can tell a relapsed patient that a drug has a 90 percent chance of working vs. maybe 20 percent or 5 percent.
“So to finish here,” he said, “personalized medicine – absolutely critical. This is the tsunami that is going to change healthcare in hospitals from treatment centers to prevention centers.”