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Testing response to treatment
Both ELNet and NCCN identify a major molecular response (MMR / MR3) within 12 months to be an optimal response and a realistic goal of TKI therapy.
Under the best lab conditions q-PCR can detect as little as 0.001%I.S. (MR5) BCR-ABL1 transcripts in a sample, allowing for better detection of residual disease as well as the identification of patients who may be at risk of treatment failure or suboptimal response. Consistently rising levels of BCR-ABL1 transcripts identifies a need to address a probable cause, such as primary or acquired resistance or the possible lack of adherence to therapy.
Regularly missing more than three daily doses in one month is likely to affect optimal responses to therapy. In patients whose adherence to therapy was monitored, those whose adherence rate was greater than 90%, meaning that they took more than 90% of their prescribed doses in a month, were more likely to achieve the lower molecular levels of remission required for optimal response, such as MR3; MR4.5 or lower.
Levels of Molecular Response
Until recently the ultimate goal for CML patients treated with TKI therapy was to achieve a ‘PCR negative’ result, also known as a Complete Molecular Response (CMR). However, the use of the word ‘complete’ is now considered to be misleading because it is often interpreted to mean that there has been a total eradication of disease. Recently, international CML experts and clinical groups have agreed to stop using the term CMR replacing it with MR followed by a log reduction number, as in the definition on the next page.
% of BCR-ABL1 detected
by qRT-PCR testing
reduction from 100% I.S.
Why results may differ between testing laboratories
In its present form, q-PCR testing is technically challenging to perform requiring a high level of skill, a consistent method of sample collection and timely delivery to the laboratory. Several factors can adversely influence a result, which often makes it difficult to be confident that it is an accurate reflection of the actual level of residual disease. Factors include:
- The quality of the sample, also related to time taken for the sample to
- reach the lab
- Adequate amounts of a control gene – there should be at least 10,000 transcripts in a sample
- The control gene used—ABL1, GUSB, BCR or other
- The method a lab uses to extract mRNA, related to the chemicals and type of equipment used
- Even if the method used is consistent, the quality of a sample and the efficient extraction of mRNA are variable. Results, even from the same laboratory, may fluctuate up as well as down. Doctors are only likely to recommend a change of treatment if there is a rise in the % of BCR-ABL1 transcripts from 2 or 3 consecutive q-PCR results generated from samples containing adequate numbers of control gene transcripts such as ABL1 or BCR.