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Cepheid Developing New Target for BCR-ABL Test for Leukemia Patients

NEW YORK – Cepheid has been receiving significant attention for its SARS-CoV-2 diagnostic products during the COVID-19 pandemic, but it is continuing to develop and improve tests it offers for other conditions including oncology.  

The Sunnyvale, California-based firm's Xpert BCR-ABL Ultra test was cleared a little more than a year ago by the US Food and Drug Administration for monitoring disease burden in patients with chronic myeloid leukemia (CML). At the Association for Molecular Pathology's annual meeting this week, the Danaher subsidiary unveiled a new prototype application for the test, which will detect the p190 gene fusion in leukemia patients. Measuring BCR-ABL gene transcript levels can help indicate how treatment is working and predict disease relapse.

According to Grace Macauley, Cepheid's senior director of medical affairs in oncology, the breakpoint in the BCR gene can happen at different points, with the major p210 breakpoint in e13a2 and e14a2 transcripts occurring in 95 percent of CML patients and 5 percent of acute lymphocytic leukemia (ALL) patients. The minor p190 breakpoint in e1a2 transcripts occurs in 75 percent of ALL patients. 

The BCR-ABL Ultra test uses EDTA whole blood to detect p210 transcripts and runs on Cepheid's GeneXpert platform, delivering results in less than three hours, said SVP and GM of Oncology Scott Campbell. The p190 target application will have the same workflow as the p210 test with 30 minutes of sample prep and is being designed to have a turnaround time under three hours as well, Campbell added. 

The Cepheid managers didn't provide any actual sensitivity data, presumably because the test is still in development, but Campbell said the test is targeting a limit of detection of less than .01 percent and linearity between .01 percent and 12 percent. 

The shorter sample preparation time was a major focus for the company, with six steps needed to run the test. The BCR-ABL Ultra test and other hematological assays in Cepheid's pipeline have also been designed to share the same primary lysate to improve ease of use, Macauley said.

Michelle McBean, the scientist-in-charge in the molecular haematology laboratory at Peter Maccallum Cancer Centre in Melbourne, Australia, has been using the BCR-ABL test since September 2018, and her lab conducted a validation study for it. The lab performs more than 10,000 tests per year and receives 3,000 requests for BCR-ABL1 testing each year, she said. 

Cepheid's BCR-ABL test was compared to an undisclosed RT-PCR assay made by a different company or lab that the lab had used between 2002 and 2018 that had a much more intensive workflow and a longer turnaround time, McBean said. Routine turnaround time on the old assay was approximately three weeks, with priority results returned in one week, she said. In contrast, the turnaround time for the Xpert BCR-ABL Ultra test is about three days, with priority results returned in 24 hours.

That reduced turnaround time can lead to better patient outcomes, since patients can be diagnosed with CML within 24 hours, McBean said. There can also be reduced staffing requirements due to the shorter sample prep time, allowing staff to be reallocated.

Using 112 samples, the lab found 84 percent of the samples were concordant between both tests, with 15 samples testing negative by the old test and positive by Cepheid's test. The 15 samples had BCR-ABL levels between .00023 percent and .011 percent, McBean said. She added that the discrepancy was associated with increased sensitivity of the BCR-ABL Ultra test.

Cepheid's test had a sensitivity of molecular response 5.0 for all samples, while the old test didn't meet the clinically significant value of MR 4.5 in about 30 percent of samples.  Reproducibility in Cepheid's test was also equivalent to the old assay, although the values were reproduced from a smaller number of replicates, McBean said. 

The improved sensitivity of Cepheid's test "is useful to be able to determine which patients have had a deep molecular response," McBean said. 

Currently, for patients with suspected CML, McBean's lab performs the Xpert BCR-ABL Ultra test, but if the suspicion of CML is particularly strong, they also perform the old assay for the p190 gene fusion, which takes more time. For patients with suspected ALL, both tests are performed. For minimal residual disease monitoring, patients with BCR-ABL1 e13a2 or e14a2 fusions, the Xpert test is used, and for patients with BCR-ABL1 e1a2 the old test is used. 

McBean said her lab needs a test to more quickly determine p190 fusions with a shorter turnaround time, which Cepheid could provide with its new p190 assay.