The question of timing of response has become an important question in the field since the adoption of venetoclax plus HMA as a standard regimen after its approval. There’s a lot of historical experience using the hypomethylating agents, one of the chemo drugs, for the last several years and clinicians are used to how to manage that, how many cycles to give before assessing a response or how many cycles to give before maybe moving on to try something else if they don’t feel like it’s working. So that led us to ask the question of how that appears to be in the setting of venetoclax based combinations. What we did was we combined data from two clinical trials using venetoclax combinations, one which was in combination with a hypomethylating agent, the other was in combination with low dose cytarabine.
We were looking to see whether patients should continue for several cycles or if one should stop after a certain amount of cycles. We were looking to see if there was any baseline data that could help us guide those decisions clinically. We found that actually, as expected, most patients achieved remissions fast, which is what we all knew from the manuscripts that have been presented, the data that has been presented from the two trials. In most cases remissions are achieved in the first cycle or two cycles. What we also found was that about a third of remissions occurred after cycle 2 and to some degree that was a surprising finding, at least to me, as my thought had been that a higher percentage of patients were achieving the response early. So that was quite interesting.
We also did an analysis looking at maybe baseline features that could help predict who would maybe benefit from additional cycles of treatment after cycle 2 and that was also informative.
We looked at some subsets of disease and maybe which subsets might be more likely to achieve a response early. That was useful data; certain mutations like IDH and NPM1, these have performed very well on the parent studies, so this would be the phase I and the I/II, the LODAC and the hypomethylating agent studies. So no surprise here, we saw that patients tended to achieve robust complete remissions and quick in those contexts.
The other analysis showing that patients who had a secondary AML and those that didn’t achieve blast clearance early were less likely to achieve a later remission was perhaps the more relevant piece of information.
This is certainly an intriguing dataset. It’s obviously a dataset that’s derived from two controlled clinical trials. So they are definitely not real world populations, so to speak, and I think that would be interesting to start looking into, whether or not you see similar things or what we’re seeing in the real world evidence side of things where a lot of these practice patterns can be tested. It would be interesting to see if this is more generalizable because I think this has the potential to impact how we give the regimen and that’s important to disseminate to clinicians.
What really this data shows us is that you have to take the patient on an individual level and you need to think about the patient’s baseline disease characteristics as well as their response to treatment when you’re thinking about how long to give them venetoclax based regimens in order to get a response. So, in other words, personalise these decisions as to when do you either decide to move on to something else if you don’t think treatment is working well enough or to continue and push to try to get a response at a later time. This is really pertaining to those third of patients that are not achieving a response within the first two cycles like you see in the majority of the remission.