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Sequenta Readies ClonoSight for 2013 Launch with CLIA Certification and Clinical Validation Studies

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With CLIA certification and several validation studies under its belt, Sequenta is gearing up for the 2013 launch of its sequencing-based test to detect minimal residual disease in cancer patients.

The company plans to launch its test, which it has named ClonoSight, as a service from its CLIA-certified laboratory in South San Francisco. It will initially focus on patients with acute lymphocytic leukemia, mantle cell leukemia, and chronic lymphocytic leukemia, but plans to expand to all blood cancers.

Previously, the company had referred to the assay as LymphoSight, but has named the commercial test ClonoSight, and is calling the sequencing-based method LymphoSight.

Malek Faham, Sequenta's chief scientific officer, told Clinical Sequencing News that the company will offer the assay on either the Illumina HiSeq 2000 or the MiSeq instrument, depending on the customer's needs.

"The HiSeq gives you lots of information, but it takes some time. The MiSeq gives you quick information, but it's [lower] throughput," Faham said.

He said that the company has not yet settled on a price or pinned down a turnaround time for the assay.

The company has been collaborating with several academic groups, including St. Jude Children's Research Hospital and Stanford University, recently publishing two studies in the journal Blood demonstrating the assay's ability to monitor disease.

Earlier this year, the company announced that it would run its test alongside two clinical trials — a 180-patient phase II clinical trial being run by SWOG and a 322-patient phase II trial run by the Eastern Cooperative Oncology Group (CSN 8/15/2012).

In its most recent study with St. Jude's, published earlier this month, the company tested its assay in 106 pediatric patients with B-cell acute lymphocytic leukemia and compared its ability to detect residual disease with the current standard techniques: flow cytometry and allele-specific PCR.

The assay was tested as part of a clinical trial to evaluate survival of children treated with "risk-directed therapy" and to monitor the "molecular remission induction rate."

The assay detected disease in all 28 samples that were deemed positive by flow cytometry, and in 35 of the 36 samples deemed positive by PCR. Additionally, it detected disease in 10 and three samples that were deemed negative by flow cytometry and PCR, respectively. Additionally, the researchers determined that the assay could detect one leukemic cell present in more than one million normal leukocytes. Flow cytometry and PCR can detect leukemic cells present at concentrations of one in 10,000 and one in 100,000, respectively.

The discrepancy between the 10 samples that were positive with the LymphoSight technology but negative by flow cytometry can be attributed to the sensitivity limitations of flow cytometry, according to the study's authors. MRD levels ranged between 0.00004 percent and 0.011 percent for nine of those samples.

The discrepancy between the discordant samples with PCR can again be primarily explained by the lower sensitivity of PCR compared to sequencing. Those samples had MRD levels between 0.00004 percent and 0.0014 percent.

In one sample, PCR detected MRD at a level of 0.002 percent, but sequencing did not detect MRD. The researchers said that the reasons for this discrepancy were "unclear," but could be due to the PCR method being inaccurate, which tends to be common at such lowconcentrations, or to an artifact of the PCR method.

These data are consistent with other results that the company presented last year at the American Society of Hematology meeting in San Diego (CSN 12/14/2011).

Collaborators at Stanford University, led by Charles Gawad, a clinical instructor and oncologist, are also using the technology to measure IgH clonotypes in pediatric patients with B-cell ALL. The IgH locus, in particular, is useful for diagnosis and monitoring treatment response.

Currently, Gawad said, flow cytometry is commonly used to monitor patient response to therapy, but "about half the patients that relapse are negative by flow cytometry."

Studies with PCR have confirmed that there are rare rearrangements present in some of these patients that appear to be driving the relapse, he said.

Sequenta's technology is promising because it can "assay for all the possible rearrangements at the same time," rather than designing a PCR test for a specific rearrangement, he added.

In the Blood study, the Stanford team used the method to characterize the IgH locus of 51 patients with B-ALL at the time of diagnosis. They found clonal rearrangements in 43 of 51 cases, with the number of rearrangements per patient ranging from 0 to more than 4,000.

Gawad said the extent of evolution in the IgH locus was "surprising," and could help in understanding the biology of the disease. The team was also able to analyze samples from four patients who relapsed to see how the IgH rearrangements changed over time and to see whether there were markers present in the diagnosis sample that would be predictive of relapse.

Of the four evaluable relapse patients, "all showed high levels of evolution at diagnosis," the authors wrote, with a statistically significant association between evolution and relapse.

Gawad said the team now plans to use the assay to evaluate around 100 more relapse patients.

The assay "has major implications for disease monitoring," he said. "Patients with higher levels of evolution may be more prone to relapse, but we need to validate it in a larger cohort."

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