Emerging Treatment Strategies in Acute Myeloid Leukemia

Transcript:

Jorge E. Cortes, MD:We have a lot of hope in the upcoming agents that are in development. Some of them already have attractive data and some are for populations where we have an important need. One category of drugs are the inhibitors, which are still in clinical trials and not yet approved, but they developed a good amount of data. We had good updates at ASH [American Society of Hematology annual meeting]. Margie, what’s your take on these drugs and any differences that you see between the 2? We shouldn’t compare the 2 studies too much, but they give us some interesting items for discussion.

Margaret T. Kasner, MD:Absolutely. I’ll start by saying something that we’ve echoed here a few times already, which is this is an interesting area of up-and-coming research. I think people are really interested in Menin inhibitors, but there certainly is a question about where they’ll be best used. NPM1 mutated plus or minus the MLL [mixed-lineage leukemia] arranged AMLs [acute myeloid leukemias] versus…there’s some data in neither of those 2 categories. I find the data very promising, but I’m eager to see larger studies. If you look at the KO-539, which they presented at this ASH, and looked at both patients with MLL rearranged leukemias and NPM1 mutated leukemias, and it was a small group of patients, but it was promising that these were patients that had been exposed to venetoclax [Venclexta] and were relapsed. We just mentioned Dr Jonas is going to run for the hills when he sees those patients who are relapsed/refractory in that setting, and it’s a particularly important area where we need new data. This is a very small percentage of patients that fit into those categories, at least the MLL rearranged patients, so I think the mechanism is quite interesting. How many patients ultimately will benefit from it? I’m not sure. But I am excited to think how these will be studied in much bigger settings. There’s multiple phase 3 trials that are upcoming, and it’s going to be a couple of ASHs until we see the results of those, but I think that they’re very promising.

Jorge E. Cortes, MD:Two interesting populations, the MLL as you mentioned, not a very high percentage of patients, but the patients with prognosis that we’ve been searching for something targeted for a long time. NPM1 a larger patient population, perhaps the most common mutation, not necessarily with a prognosis, but certainly having something that’s targeted if it gets us away from using chemotherapy or at least reducing the need for chemotherapy would be welcome. In these studies that were presented, there were some differences, and again, not trying to draw any conclusions, but just to brainstorm a little bit about what we saw. For example, the scene that seemed to have similar efficacy between the 2 subsets, whereas with the [INAUDIBLE] there was good responses in the NPM1 not so much in the MLL patients. I know we’re all-timers because it’s not supposed to be MLL, but that’s how I grew up, so it’s going to be MLL until I die. Then there was a bit of difference in terms of the QTC prolongation, a slight difference in terms of the frequency and severity of the differentiation. Hetty, what’s your take about these? What did you make out of these contrasts? Again, not comparing them, but do they tell us anything about the drugs?

Hetty E. Carraway, MD:These oral agents are of interest in this patient population that have either the KMT2A rearranged or the NPM1 positivity. These are a relapsed/refractory subset patient population that would otherwise have poor outcomes as we described. The SNDX-5613 Menin inhibitor had some amount of QTC prolongation; I think it was noted to be a grade 3 QTC prolongation, about 10% of patients in the RP2D dose. This patient population that they described isn’t a huge number of patients; I think in that study, they had a total of 37 patients that they were talking about. I think the best response with the SNDX agent was in that MLL patient population, and again, the CRCRH rates around 30%. What was interesting, or what was highlighted, is the degree of MRD [minimal residual disease] negativity in those patients where the ability to eradicate disease was quite impressive. With the other Menin inhibitor, ziftomenib, this one is also an oral agent studied in both the KMT2 rearranged patient population and the NPM1 population; the adverse event didn’t describe much in the way of QTC prolongation, but the differentiation syndrome is going to be something that we need to be mindful of with both of these Menin inhibitors. The FDA was interested in the differentiation syndrome that happened with the IDH [isocitrate dehydrogenase] agents, and with this agent they’ll be mindful of capturing the frequency and the management needs for patients that are showing differentiation syndrome. With the ziftomenib agent, it seemed that the NPM1 population did the best in terms of response with about a 30% CRCRH rate. Interestingly, even though these are small numbers, there were 2 patients that had concurrent IDH1 or [IDH]2 mutations, and those patients had a nearly 60% likelihood of complete remission. There’s more to be told with these agents, and we’ll have to learn more about the co-mutations and why they will or won’t be likely to respond to Menin inhibition. But it’s nice to see that we may have interesting agents in this space.

Jorge E. Cortes, MD:One interesting thing, and an important lesson, is that we must better get our minds around the issue of these drugs. We first learned with the IDH inhibitors and now with the Menin inhibitors, that these drugs are not chemotherapy. With the IDH2 inhibitor, which was the first of these drugs that gave differentiation syndrome where we didn’t expect, we took patients off therapy way too early and thought they were progressing, and then we learned that this is differentiation. We talked earlier about how you must be patient with these drugs, it’s not chemotherapy and it’s not 1 cycle; You’re nonresponding, you move on. Patients can have stable disease for a few cycles and eventually move on to respond. So this completely changes the way we manage these patients. These differentiation syndrome, no question that it’s important and needs attention and to be managed properly, but it is something that little by little, we’ve started to recognize and manage better, and if you do that, patients tend to do well.

Transcript edited for clarity.