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Achieving an international scale for standardising and interpreting molecular response in Chronic Myeloid Leukaemia patients

4 May 2018

Advanced technology from Asuragen enables labs to reliably monitor leukaemia patients’ response to TKI therapy by reporting data on the international scale, ensuring effective CML treatment

Chronic Myeloid Leukaemia (CML) affects 1.2 people per 100,000 in the UK, with 624 newly-diagnosed cases in 2015. It represents less than one per cent of all cancer diagnoses in the UK.

CML was, at one stage, rapidly fatal, with a typically short prognosis. Five-year survival rate was once as low as 20 per cent. However, with early detection, it can now be managed as a chronic condition for many patients.

The cause of CML is a translocation between chromosomes 9 and 22, resulting in an abnormal chromosome known as the Philadelphia (Ph) chromosome. The Ph chromosome is composed of fused regions of chromosomes 9 and 22, causing a Leukemogenic BCR-ABL gene.

The BCR-ABL gene expresses BCR-ABL tyrosine kinase (TK) protein: this has unregulated activity and triggers a cascade of events, culminating in a malignant transformation.

The initial chronic phase of the disease is easiest to treat, therefore CML treatment focuses on eliminating the BCR-ABL protein and preventing transformation to the later stages of the disease.

The development in CML treatment was achieved through the use of a tyrosine kinase inhibitor (TKI) therapy, which targets the BCR-ABL protein kinase.

Molecular monitoring to prevent CML relapse

However, even with early detection and effective treatment, close monitoring and management is critical to prevent relapse.

It has been shown that increases in BCR-ABL transcript numbers may be a precursor to a loss of response, or to the emergence of a mutation. However, careful molecular monitoring enables clinicians to make necessary adjustments to treatment and increase the chances of long-term patient survival.

Molecular response has been found to provide information about the depth and stability of treatment response in CML patients. Patients who have demonstrated a certain reduction in BCR-ABL transcript level have minimal risk of progressing to the advanced stages of the disease.

Patient monitoring via Quantitative RT-PCR techniques (not qualitative, which is only useful for initial diagnosis and not response to treatment) is the widely recommended approach for tracking disease residuals. PCR is a very sensitive technique which permits the exponential reproduction of genetic material to enable detection of very low levels of DNA. We wrote in more depth about how to select the correct polymerase for PCR applications here.

Why is an international standard needed?

Differences in methods and procedures in laboratories worldwide have made it difficult to compare qRT-PCR results when monitoring CML patients. Likewise, it has been difficult to offer a benchmark to clinics that treated relatively few patients with CML.

For example, different techniques could produce varied results from the same patient, which in turn could indicate different molecular responses.

An increase in BCR-ABL transcripts could be attributed to a relapse, or it could be caused by different laboratory standards yielding different results. CML is never fully cured, and it’s likely that, through the lifespan of a patient, they may need to be treated, and have their disease monitored, by different clinics.

Therefore an agreed international standard was sought, and the International Scale (IS) has been developed. Anchored to two fixed values – a standardised baseline value of 100 per cent, which corresponds to the International Randomised Study of Interferon and STI571 (IRIS) study, and a standardised value for Major Molecular Response (MMR or MR) set at 0.1 per cent – the IS provides a common approach for reporting the results of qRT-PCR.

By reverting to the IS, the reasons for an increase in BCR-ABL transcript levels can be deduced, and it does not necessarily mean that treatment is failing or needs to be changed.

Is the IS sample exchange working?

Pilot studies have established that individual testing labs can align their reporting scale to the IS by exchanging samples with a reference laboratory and through the derivation of a lab-specific conversion factor (CF).

Although this works well, it is impossible to standardise all testing laboratories around the world and it remains an intensive and flawed solution – probably the best available for now, but still not as convenient as it could be for a lot of laboratories.

We may yet see regional or national reference laboratories, which will act as an effective ‘hub’ communicating and exchanging samples internationally, but then providing the link to local test centres.

In an ideal world, any testing laboratory would have access to the reference standards that would enable them to convert patient results to the International Standard quickly and easily.

The Asuragen BCR-ABL monitoring kit

There is solution to the problem: the Asuragen QuantideX BCR-ABL IS monitoring kit. Available exclusively in the UK through VHBio, the QuantideX BCR-ABL offers laboratories a robust and reliable method for monitoring leukaemia patients, while keeping in line with developments in TKI therapies.

The QuantideX BCR-ABL IS kit enables direct reporting on the IS, without labs having to participate in the lengthy/inconvenient sample exchange program.

It also offers a number of benefits to the user, including an optimised workflow, reduced ‘hands-on’ time, and increased sensitivity without loss of specificity.

For more information, you can read our product page here.

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