iwAL 2024 | Novel targets, combinations & treatments in AML: use of OGM, TP53 treatment strategies & ADCs

Dr. Andrew Wei:

Hello, my name is Dr. Andrew Wei from Melbourne, Australia. And with me today at the Acute Leukemia’s meeting number six, currently in Phoenix, Arizona, I have doctors Loghavi, and also Ravandi from MD Anderson, and also David Sallman from Moffitt.

So today we were talking through a variety of different topics today, and I’m just going to get each of our esteemed speakers just to briefly summarize the focus of their discussion. So Sanam.

Dr. Sanam Loghavi:

Thank you, Andrew. I spoke about the utility of optical genome mapping and RNA fusion sequencing, and the workup of newly diagnosed acute myeloid leukemia.

Of course, we know that there are several actionable targets now that may be cryptic and not identifiable on routine karyotype, including NUP98 rearrangements, a small fraction of KMT2A rearrangements, and other alterations that may become prognostically or of predictive value in the future.

So really the idea is to complement our current diagnostic workup with better methods that allow better classification and prognostication.

Dr. Andrew Wei:

Thank you. David.

Dr. David Sallman:

Yeah. So I talked about p53. And I think sort of the clear, or maybe the most important message is that it is a uniform group that can be defined. Specifically patients that have 5% blasts or greater, complex karyotype, or multi-hit status by a number of different definitions, really represents a uniform group that we should think about treating them collectively.

And I think really the summary is that our standard of care is clearly not adequate for this group of patients, and we should think about really highly prioritizing clinical trials for these patients really from the start.

And we know that we can do it. We’ve run now randomized trials both in MDS and AML specifically for p53, and these trials actually quite rapidly accrue. So I think we can do that now.

What is the answer from a novel therapy perspective? I think that’s a big question. I think maybe you’ll give us some highlights, and maybe on an attractive therapy that we could start testing.

But it’s really identifying these groups, highly prioritizing trials, thinking about unique concepts specifically for this group, and hopefully trying to change the standard of care for this very difficult to treat patient population.

Dr. Andrew Wei:

Thanks, David. Dr. Ravandi.

Dr. Farhad Ravandi:

I talked about antibody-drug conjugates, and their potential role in AML. We already have one such compound approved and in use, that’s gemtuzumab ozogamicin. But the history of that compound tells us what we should think about when we want to introduce these agents into our armamentarium. So I think dosing when used in combination is very important. The other thing about any immunotherapy in AML is whether we actually have the appropriate antigen to target. And I think that’s the question that has been the problem in the field, and will continue to be until we really totally find a target that’s highly generally applicable and can be used in a widespread manner.

Dr. Andrew Wei:

Thank you. And the focus of my discussion was on a new class of drugs called STING agonists and their potential role in AML in directly inducing apoptosis in combination with BH3-mimetics.

So Dr. Loghavi, can I just ask you, with respect to new technologies beyond conventional sequencing, how do these new technologies help us in our diagnosis and management of patients from your experience at MD Anderson?

Dr. Sanam Loghavi:

Right. So again, I think if we kind of lump conventional as a routine karyotype and then next-generation sequencing, which I think in most US and European and Australian centers is now the gold standard of routine diagnostics for AML. In a small subset of patients, but not trivial fraction of patients, we get additional information using methods like RNA sequencing, or optical genome mapping, or whole genome sequencing, that in the great scheme of things it may be 5% of patients, but I think if you are that individual patient that has a cryptic KMT2A rearrangement that may be amenable to menin inhibition, you want that to be identified. And I think it’s really important to think about patient level – individual patients that we’re trying to treat. So I think these are definitely helpful.

Dr. Andrew Wei:

Thank you.

Dr. David Sallman:

Can you talk a little bit about the real world applicability? So we actually don’t have these panels yet, we’ll have them by the end of the year. So is this something that you think community path labs can start to do? Is there any commercialization from that standpoint? Or is this even more reason that patients, at least from an initial diagnostic workup, are going to need to be in academic centers to really get this comprehensive and personalized workup? What’s your thoughts?

Dr. Sanam Loghavi:

Yeah. I mean, I’ll answer your second question first. I think really getting these comprehensive workups in big diagnostic academic centers is more feasible, of course, because of the resources that we have.

That being said, I think the example of optical genome sequencing, if you can afford to purchase the instrument, have the machine, Bionano, which is the vendor for this particular pipeline that we’re using, has been incredibly supportive in creating a custom pipeline for us, helping us with analysis. It’s still not perfect and it’s work in progress, but I think it’s something that can be done in any laboratory that does cytogenetics or does array. So it’s very similar to array.

Dr. Andrew Wei:

David, with respect to your discussion on p53-mutant AML, which is a really big problem, upwards of 20% of patients over the age of 60 and 70. You presented a really nice algorithm which hopefully will be published soon on how to treat patients with p53 mutant AML. Do you want to just go through that briefly for us?

Dr. David Sallman:

Yeah. So I think after you’ve identified this uniform patient population, again, our high priority really is clinical trial enrollment. But if trial’s not possible, again, many patients can’t travel, they may not be eligible for comorbidity or other issues, we kind of parse it then based on stem cell transplant status.

So particularly for patients that are not transplant-eligible, there’s really no role of the addition of venetoclax and single-agent hypomethylating agent, considering azacitidine, decitabine, oral decitabine are the options. We actually have some slight preference for the oral decitabine agent in that setting.

I think for patients that are eligible for transplant, given getting a rapid response may be valuable, we do still add venetoclax. We really favor non-intensive therapeutic strategies. And unfortunately in the salvage setting options are even worse, but can be considerations for intensive chemo in a small subset of people.

Dr. Andrew Wei:

Thank you. And Dr. Ravandi, I guess the one ADC we currently have at the moment is Mylotarg. And the data around its optimal use is obviously very complex. Do you want to summarize where you think Mylotarg is best used in the clinic in 2024?

Dr. Farhad Ravandi:

So I think the meta-analysis clearly showed, and that was supported by a number of the randomized studies, that favorable risk cytogenetics, that’s the core binding factor leukemias clearly do significantly benefit from the addition of Mylotarg to initial induction and at least one dose in consolidation.

So the dosing of Mylotarg, even in that setting, is still not fully established. The British group used only one dose, then the French used three doses. We tend to use just the one dose. And we clearly have seen the benefit in our center using the FLAG-GO regimen, which clearly is superior to our historical data with FLAG-Ida.

Now, there are other subsets that may benefit from Mylotarg, typically in the more favorable ELN group, perhaps NPM1 mutated. And even FLT3-ITD mutated patients, there have been studies that have suggested that addition of Mylotarg would be helpful.

The group that doesn’t benefit at all, in my opinion, is the adverse risk cytogenetics p53 mutated patients, but unfortunately they don’t benefit from much anyway. So that’s the group that I would definitely not use, because you’re just introducing toxicity.

Dr. Andrew Wei:

And last question, which I’ll just ask David, with respect to p53 mutation and transplant, that’s another big area and another clinical conundrum. What’s your view on how doctors should consider or maybe not consider allografting for their patients?

Dr. David Sallman:

Yeah. I mean, I think given how poor the survival in these patients, you can have long-term and the potential for cure with allogeneic stem cell transplant. And I think actually the field has shifted far too far one way, where many centers are actually not transplanting these patients given that their survival is poor. But again, the alternative is much worse.

I also find that with this sort of sentiment, there’s a lot of delays in actually getting these patients to transplant. And I think you have a very narrow window to really optimally transplant these patients.

So for us, ideally we would like to get patients in molecular response, but if you cannot after a couple cycles of therapy, really no matter what just bringing them to transplant. I think there’s a lot of translational work trying to better understand these mechanisms of why a majority of patients will relapse as high, as 70% to 80% of patients. And again, thinking about strategies in the post-transplant setting, anything to augment GVL, DLI, armored DLI, maybe some of these cellular therapy strategies, I think would be great. What we’re doing is very early HMA maintenance, and hopefully we’ll have data in the near future to kind of tease out the benefit of that group.

But at this point for your fit patients, I think really trying to get them there. I think the big challenge is there’s a lot of patients, I would say, on the borderline, there’s a lot of therapy related. They have very high transplant-related mortality scores from the same perspective, and so I think that’s its own challenge. But clearly for the patient that has really no other barriers, they should be getting to transplant.

Dr. Sanam Loghavi:

Can I ask you a question, David, for my education? When you say you have a narrow timeframe to get them to transplant, so what is the ideal condition in which you take them to transplant? Is it reduction of blasts, reduction of TP53? What is it?

Dr. David Sallman:

Yeah. So I think my optimal scenario would be after, let’s say, between two to four… We will definitely bone marrow patients at least after cycle two, cycle four of whatever we’re giving them, let’s say HMA or HMA combination. So best case, at any point if they achieve complete cytogenetic response with p53 clearance, that would be optimal.

I think sometimes what you can see is a nice reduction. Let’s say after cycle two, there’s 80% improvement both with VAF and let’s say metaphase, cleared from that perspective, we’ll kind of push and kind of green light to set up allo after that third or fourth cycle and really try to get them at that time point. But that’s just our approach.

Dr. Farhad Ravandi:

I would actually argue that maybe after one or two cycles, if you’re down to less than 10% blasts, you wouldn’t even aim to get any further reductions. Because in my experience, the more you wait, either the patient gets sick from something or they relapse. And so I think the ideal time is within the first couple of cycles actually.

Dr. David Sallman:

Yeah, I think there’s a fine line.

Dr. Farhad Ravandi:

Yeah.

Dr. Andrew Wei:

There’s a nice paper from Jennifer Marvin-Peek suggesting that patients given intensive chemotherapy with p53-mutant AML have a higher risk of bacterial and fungal infections. Have any of you observed this with respect to ven-aza type therapies?

Dr. David Sallman:

Yeah. I mean, just to comment, the treatment mortality with ven-HMA is as high as twenty-something percent in this patient group. There’s a very old paper from the GFM showing that there’s some intrinsic neutrophil dysfunction and some other reasons, why even independent of blood count from patient to patient these p53 patients do worse. And I think this has actually been a big challenge even as we get to more pivotal strategies, a very high mortality, we’re losing a lot of patients early, and maybe under-powering some of these trials. But it’s definitely a big issue, not just from an efficacy perspective, but from a side effect perspective.

Dr. Andrew Wei:

So perhaps another reason to avoid using perhaps myelosuppressive therapies in really older people not heading for transplant?

Dr. David Sallman:

Yeah, exactly. I mean, even as we kind of discussed in this session, even thinking about this metronomic dosing being led by the Montefiore group, again, you may get the same level of response without the toxicity from that perspective. I think how transplant fits into that sort of paradigm is an open question, though.

Dr. Andrew Wei:

Yeah. Any final comments from the talks today?

Dr. Sanam Loghavi:

Thank you. This was a wonderful session.

Dr. Andrew Wei:

If not, thanks everyone for listening. And hopefully we’ll see you next year at the International Workshop in Washington 2025. Thank you.

Dr. Sanam Loghavi:

Thank you.