Part 2 of 3
In Part 1, we looked at how molecular response – the extent to which BCR-ABL transcripts are suppressed – has become the new benchmark of treatment success. The key milestone to achieve is a 3-log reduction (a major molecular response, or MMR), which has been shown to significantly reduce a person’s risk of progression to accelerated-phase or blast-crisis CML (Hughes and colleagues. N Engl J Med 2003;349:1423-1432).
While these standards were being developed, new laboratory techniques were enabling even more sensitive PCR testing for BCR-ABL transcripts. This opened up a new world beyond MMR – to a 4-log reduction, a 4.5-log reduction, and even a 5-log reduction (abbreviated as MR4, MR4.5 and MR5; MR is molecular response). MR5 meant that BCR-ABL transcripts were reduced to 1/100,000th of what they had been before, and was the lowest limit of disease that could be detected (depending on the lab). This improvement in technology raised two important questions. First, is MR4.5 or MR5 better than MMR (a 3-log reduction) in terms of reducing the risk of disease progression and improving survival? Because tailoring treatment to a laboratory test isn’t the same as tailoring treatment to a person. Secondly, MR4.5 is considered to be a “complete molecular response” (CMR) or “molecularly undetectable leukemia”. So if leukemia is no longer detectable, does this mean that the person has been cured of CML?
First of all, is MR4.5 better than MR3? This is an area of considerable research and considerable controversy. Most research thus far has used CCyR as the benchmark for assessing outcomes such as the risk of progression or long-term survival. When MMR started to be used, it wasn’t that different from CCyR, so it was unlikely that it would be found to be much better. But MR4.5 represents more than twice the degree of leukemia suppression compared to CCyR, so this should theoretically translate to better outcomes for people.
Several studies have now shown this. In one study of 266 people with CML, 98% of people with CMR did not experience disease progression compared to 82% who achieved MMR but not CMR (Etienne and colleagues. Haematologica 2014;99:458-464). However, this did not translate to better overall survival. A second study was more encouraging. The CML-Study IV found that among those who achieved MR4.5, no one suffered progression of their leukemia (Hehlmann and colleagues. J Clin Oncol 2014;32:415-423). Indeed, those who achieved MR4 or MR4.5 and maintained this level of suppression for 3-4 years had the same life expectancy as people without CML.
If people with CML live as long as those without CML, can their treatment be considered a “cure”?
“Cure” is a surprisingly slippery concept. It can mean that there is some residual disease but the person never suffers a relapse and never gets worse (a “clinical cure”), with some maintaining this status even without treatment. Or it can mean that a person has undetectable leukemia and remains leukemia-free no matter how much better the testing gets for detecting disease (a “biological cure”). A biological cure is what most people would consider to be a true cure, and efforts are being made to achieve this. But in the meantime, a clinical cure – undetectable leukemia, no relapses, and a life expectancy that is the same as anyone else’s – would probably be satisfactory enough for most people. And it’s the reality that many people now live: in many cases, CML can be thought of as a chronic illness (like diabetes) rather than a fatal one.
If living with MMR or beyond is the new goal of treatment, how achievable is it with the current array of TKI medications? We’ll look at this issue in Part 3.