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Outside the Lab Oncology, Liquid biopsy, Screening and monitoring

A Drop of the Good Stuff

Chronic myeloid leukemia (CML) poses an interesting challenge for treating physicians. Though the advent of tyrosine kinase inhibitor therapy took CML from fatal to treatable, it is difficult to determine at what point (if at all) patients are able to discontinue chemotherapy without appreciable risk of recurrence. The ability to detect subtle increases in BCR-ABL fusion gene transcript levels early, reliably, and with minimal variation is critical for clinicians to make rapid treatment decisions. However, current monitoring methods lack sensitivity and are subject to high levels of variability both within and between laboratories. Effectively managing and monitoring CML patients requires a molecular test with high sensitivity, precision, and reproducibility.

Liquid biopsy offers several advantages over traditional tissue biopsies, including patient safety (because liquid biopsies are often minimally invasive) and speed (turnaround times are shortened because there’s no need for tissue processing or histopathology interpretation). It’s not just for solid tumors, though; other diseases that require quantitative monitoring, like CML, also benefit. Assessing disease status from plasma or other body fluids (representative of total disease burden) can provide a holistic view of cancer progression and resistance development, giving health care providers a better idea of what the patient may face and how best to approach treatment. Of course, the technique is not without its issues. The main disadvantage of liquid biopsy testing is that, if pathologists and researchers are to use it effectively in a wide range of situations, there’s a need for more sensitive analytical methods. That’s where a new droplet digital PCR (ddPCR) approach – the first of its kind to receive a CE mark – comes in.

At the moment, the primary method of monitoring CML status is the real-time PCR (qPCR) measurement of transcript levels of BCR-ABL and a reference gene, typically ABL, GUSB, or BCR. The main drawback of qPCR-based CML monitoring is reproducibility, both between operators and laboratories. When detecting very low levels of BCR-ABL, the sensitivity of qPCR can also be limiting. Finally, CML monitoring via molecular methods is standardized by referencing results to a certified calibrator, typically derived from World Health Organization reference standards. ddPCR technology has absolute quantitation and does not require use of these calibrators.

There are three primary response types for CML, listed below in order of better patient outcomes:

a) Hematologic responses are measured by assessing a patient’s white blood cell counts. Relying on hematologic responses is not widely accepted because of limited sensitivity and frequent relapse.
b) Cytogenetic response is typically measured by fluorescence in situ hybridization to interrogate the level of Philadelphia chromosome present in blood cells. This provides a more reliable, direct view of a patient’s response to therapy – but due to interpretation difficulties and reduced sensitivity, cytogenetic responses are not enough to manage CML patients.
c) Molecular responses are determined via qPCR. Enhanced sensitivity over other methods provides the most reliable information on disease status.

For patients on imatinib, over 95 percent will achieve complete hematologic response and 76 percent will have a complete cytogenetic response. Generally, it is estimated that patients with molecular response levels between 3.0 and 4.0 (determined through standard molecular testing methods) have approximately a 20 percent chance of relapse. Ongoing studies employing both standard monitoring methods and the new ddPCR test will address long-term patient outcomes for molecular responses greater than 4.0. Ultimately, the goal is to ensure that every patient – no matter what course their disease takes – receives the right treatment and achieves full remission from disease.

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About the Author
Michael Schubert

While obtaining degrees in biology from the University of Alberta and biochemistry from Penn State College of Medicine, I worked as a freelance science and medical writer. I was able to hone my skills in research, presentation and scientific writing by assembling grants and journal articles, speaking at international conferences, and consulting on topics ranging from medical education to comic book science. As much as I’ve enjoyed designing new bacteria and plausible superheroes, though, I’m more pleased than ever to be at Texere, using my writing and editing skills to create great content for a professional audience.

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