Molecular response criteria examined for CML

By Lynda Williams, Senior medwireNews Reporter

The limitations in determining molecular response (MR) in patients with chronic myeloid leukaemia (CML) treated with tyrosine kinase inhibitor (TKI) therapy have been reviewed in Cancer.

Joëlle Guilhot, from Poitiers University in France, and co-workers examined reports on issues associated with measuring the BCR–ALB1 tyrosine kinase transcript rate, noting that a conversion factor to give the result in an International Scale (IS) must be applied.

However, they highlight that the IS scale is not always sensitive enough for ratios below 0.01%, while high BCR–ABL1 ratios are not reliable when the ABL1 gene is used as the internal control, resulting in an underestimation of BCR–ABL1.

Thus, the International Standardization Group recommends that an IS ratio greater than 10% should not be used, the researchers report.

Use of other control genes, such as ß-glucuronidase (GUS), may also help accurately detect decline in BCR–ABL transcript levels, especially in the first 3 months of treatment, they add.

In addition to a major MR, defined as a 0.1% or less BRC–ABL1 ratio on the IS scale, several other molecular endpoints may be used to monitor patients on first- and second-line TKI regimens, with a MR of 10% or less after 3 months’ treatment considered an “optimal response”.

However, the researchers note that the BCR–ABL1 ratio must be measured accurately at TKI initiation for 3-month comparison to be possible and observe that further confounding occurs due to lack of knowledge about kinetics at the time of diagnosis.

“Thus a patient may be classified as a fast responder, slow responder, or merely in need of time to respond because of a very heavy BCR-ABL1 burden at the initiation of therapy with TKIs”, they explain.

Guilhot et al also highlight that measuring cumulative incidence of MR gives a higher rate than doing so at one specific time point.

“[T]his discrepancy is largely explained by the fact that patients may rapidly gain and lose their MR, usually for reasons of poor compliance or intolerance to treatment”, they write, also citing resistance as a factor.

Thus, MR-free survival is effectively a tool for short-term follow-up and not suitable for monitoring patients with multiple remissions, the researchers explain, suggesting the use of markers such as cumulative incidence of response or leukaemia-free survival as better alternatives.

Finally, the researchers discuss the difficulty in identifying surrogate markers for survival, focusing on early MR, how well the MR is sustained and how these factors can guide clinical decision-making, such as dose reduction.

“[Early] MR has been demonstrated to be prognostic of favorable late outcomes”, they conclude. “However, the consideration of [early] MR as a surrogate endpoint remains to be explored.”

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