Laboratory criteria for CML deep molecular response reviewed
medwireNews: Laboratory recommendations for the detection and measurement of a deep response to chronic myeloid leukaemia (CML) treatment have been developed as part of the European Treatment and Outcome Study for CML.
The guidance follows the success of tyrosine kinase inhibitor therapy leading to low or undetectable disease levels, and in some cases sustained response after treatment withdrawal, explain Nick Cross, from the National Genetics Reference Laboratory in Salisbury, UK, and co-authors.
“Accurate definition of deep molecular responses (MRs) is therefore increasingly important for optimal patient management and comparison of independent data sets”, they write in a review published in Leukemia.
Cross et al explain that reverse transcriptase quantitative polymerase chain reaction is used to determine a patient’s BCR–ABL1 messenger RNA levels versus those of an internal reference gene. This is expressed as an International Scale (IS) percentage where a 0.1% BRC–ABLIS is the definition of a major molecular response.
While ABL1 is the most common reference gene, the team now reports the relationship between ABL1 and the alternative reference gene GUSB, finding the median ratio between the two to be 2:4.
This in turn allows the definition of the deep MR grades to 4.0, 4.5 and 5.0 log reductions (MR 4, MR4.5 and MR5) which can be used to derive independent laboratory cutoffs for MR, the researchers write.
The authors recommend using the Europe Against Cancer criteria for the definition of detectable and undetectable disease in amplification reactions and runs.
In addition, they advise on the optimal way of scoring MR for patients with measurable residual disease and recommend testing two or three replicates for MR testing in patients with undetectable disease.
“The recommendations described here are an attempt to develop standardized laboratory approaches that strike a reasonable balance between scientific accuracy and clinical reality”, the researchers summarise.
“It should be recognized that there is considerable inherent uncertainty in defining very low levels of disease and that it will be important to continue to look at trends over time to recognize sustained MR.”
They conclude: “It is obvious that future methodological improvements that increase the amount of sample tested (as determined by the number of reference gene transcripts) will increase the precision and accuracy of scoring MR4 or MR4.5, as well as enabling even deeper levels of MR to be determined.”
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By Lynda Williams, Senior medwireNews Reporter