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BC Cancer Agency Developing Sequencing-Based AML Test to Stratify Patients for Different Treatments


By Monica Heger

This story was originally published Sept. 13.

In order to guide treatment for acute myeloid leukemia patients who have received an uncertain prognosis, researchers at the British Columbia Cancer Agency are developing a sequencing-based test to determine which patients should receive chemotherapy and which should receive stem cell transplantation.

The team is currently in the first phase of its project, in which it is testing both exome and transcriptome sequencing retrospectively on 184 banked samples. As the costs of whole-genome sequencing decline, they plan to also test that approach.

The team is currently doing the sequencing on the Illumina HiSeq 2000, but it is evaluating the Ion Torrent PGM and plans to also evaluate the MiSeq when it becomes available.

The goal is to develop a fast, effective, and low-cost method to make sure AML patients receive the most appropriate treatment.

Currently, patients with AML are stratified according to their cytogenetic profiles. Patients with good prognosis are started on chemotherapy, while those with a poor prognosis, typically determined by cytogenetic profiling, qualify for stem cell transplants.

However, there are also a number of patients for whom existing diagnostic tests do not provide a definitive answer, and it is "unclear whether to give them chemotherapy or a stem cell transplant," said Aly Karsan, the head of clinical diagnostic genomics at the Michael Smith Genome Sciences Center at the BC Cancer Agency.

Karsan and his team think that a sequencing-based test would be a better way to stratify patients because all possible molecular markers would be interrogated.

For example, a team at the Genome Institute of Washington University recently used whole-genome sequencing on an AML patient whose prognosis was unclear. The patient's cytogenetic profile indicated a poor prognosis, but a fluorescence in situ hybridization test suggested she had a possible gene fusion that could be treated with existing drugs, though the fusion could not be confirmed with either FISH testing or RT-PCR. The patient had already been approved for stem cell transplantation, but whole-genome sequencing clarified that she in fact had a rare gene fusion that could be treated with available drugs and would not need a stem cell transplant (CSN 4/26/2011).

For the BC Cancer Agency's pilot study, the team is evaluating 184 samples retrospectively to see if the sequencing test is as accurate as karyotyping in determining the right course of treatment. The researchers also hope to see if sequencing can provide further clarity on patients in the intermediate risk category, for whom it is not clear what type of treatment they should receive.

Karsan said that that the team wants to use a comprehensive sequencing approach, rather than sequencing a panel of genes, because the number of mutations that are clinically actionable is continuing to increase.

Currently there are about four to five point mutations that can be used to stratify AML patients. Within a year, "I easily see that going up to six or seven and in a few years to ten," Karsan said. Additionally, there are also gene fusion events and copy number changes that have been validated as predictive of risk and could be used to guide treatment.

Rather than develop a test that would only screen for currently validated markers, "if we have a whole-transcriptome, whole-exome, or whole-genome approach, it's possible to capture all the molecular variants in one shot," he said. "We'd deliver only the variants that are currently clinically validated as being markers we should use in stratifying, but as new markers are identified we'll report on those because presumably we'll have all that information."

The team will be targeting a two-week turnaround time from sample collection to generating a report for the physician, a time frame that would be adequate for the clinician to prepare the patient for a transplant if required, said Karsan.

The initial retrospective analysis will use patient samples "where we know what the molecular findings are, and we know how those patients have done." Both transcriptome sequencing and exome sequencing will be tested for their ability to detect four to five different point mutations, as well as gene fusions and copy number changes.

The goal is to develop one test that will be able to detect all the changes, said Karsan. The center has also developed bioinformatics tools to do de novo assembly of transcriptomes, which enables the detection of gene fusions, Karsan said.

Whether the team uses transcriptome, exome, or whole-genome sequencing will be based on which method can detect the relevant changes in a cost-effective and timely manner, said Karsan. As part of the study, a health economist will be determining the price point for which a test would make sense.

While only a few genomic changes will be reported back to the physician, the data from the patients will be stored, said Karsan, so there could potentially be the opportunity for discovery if a large enough cohort was established or if the team collaborated with other groups.

Karsan stressed, however, that the focus of the project is not on discovery. "It's a very clinically oriented project," he said.

Additionally, as other research groups identify novel variants that predict prognosis, those could be added to the list of reported variants.

Karsan said he anticipates beginning a prospective study next summer in 50 to 100 patients and then making the test available after about a year of prospective study. He said the test would initially be offered in British Columbia, either through the BC Cancer Center or as part of clinical trials for AML drugs.

Eventually, though, the goal is to make the test standard of care for all AML patients, he said.

Have topics you'd like to see covered by Clinical Sequencing News? Contact the editor at mheger [at] genomeweb [.] com.

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