David Sallman:

My name is David Sallman from Moffitt Cancer Center in Tampa, Florida. It’s a privilege to be with my close colleague Dr. Brunner from Massachusetts General Hospital. So maybe I’ll start off with a question to you. I know you’re giving an oral presentation in high-risk MDS. So where are we at? Are we going to have new treatments? We’ve had some setbacks. Love to get your thoughts.

Andrew M. Brunner:

I hope so. I mean I think the exciting thing in MDS, especially in the higher risk space, is that we have a number of agents that have entered into these larger Phase III level of studies. And I think that one of the challenges in MDS is that there are a lot of things that we need to change. We need better response rates, we need more durable responses, we need better overall survival. And it’s hard to know at this moment where each of these agents may play a best role.

Andrew M. Brunner:

And so my hope is that we learn from each of these trials and we’re able to identify strengths of any of these agents, particularly if there really does seem to be a strength compare to monotherapy, and then utilize that to really develop a new approach to MDS, because what we’re lacking is any change in our approach. We basically have azacitidine monotherapy and we have a transplant decision point for some patients. And so I think that what’s exciting about some of these agents is that they don’t have overlapping toxicity. You can see them moving into even triplet-based therapy, and there seems to be varying characteristics of each drug combination that would have value for MDS care. And so I’m excited to see where some of the larger Phase studies show that.

David Sallman:

Yeah, and I think your point, I’m really interested in hearing the Panther presentation, which again is another setback of course for us, but how does azacitidine, decitibine long-term outcomes in the setting of potential salvage therapies? Of course we have venetoclax off-label, we’re maybe more aggressive with allogeneic transplant, is there a really key insight that we can look into even from the control arm that will help shape that? I think I completely agree with you. We have at least three exciting agents and potentially some others in the pipeline. How do these therapies work together? I feel like appropriately we need anything and everything is jumped into very large Phase III trials but is, can we turn on innate and adaptive immunity together?

David Sallman:

What is the synergy with each of these agents? What is the tolerability? Is there new safety signals elsewhere? But I think as you said, we are really desperate to have something that is not a inadequate standard of care therapy. And I think there’s some really interesting data to be presented at least with the three agents that are farthest along and actually, I think it may be a little bit interesting shift. There’s some CPX studies looking at frontline therapy for fit patients to transplant. I think that’s its own separate discussion. What is the depth of response, which with inadequate therapies, we’ve not been able to report, but can we start to use MRD, maybe MRD by sequencing? Something that a lot of us have a lot of interest in.

Andrew M. Brunner:

Absolutely. I think that, one of the highlights of this ASH was the advancement ongoing advance and of the use of molecular classification and risk stratification. And hopefully that translates into understanding patient outcomes, which patients might be most beneficial for certain therapeutics or others. And I think that one of the questions that I hope, regardless of how the trials go in high-risk disease that we learn is suddenly we will have a new modern cohort of patients treated with MDS with more sequencing with features that we didn’t have 15 years ago when many of the prior studies were done. And so hopefully this at least lets us understand who may benefit from a different treatment approach and really where are therapies that are borrowed from AML. For an instance, there may be certain subgroups that are most likely to respond and should we really be treating those patients differently if they have AML like mutations compared to other MDS subgroups?

David Sallman:

Yeah, no, completely agree. I guess maybe we could probably switch gears. So maybe to stick with somewhat higher risk in this group of patients. They fail our one standard of care therapy. Their past azacitidine, decitibine. What are our next best options? Unfortunately, it’s rare to have targetable mutations, IDH1/2 is about half the prevalence, NPM1 and FLT3 essentially don’t occur. But what about splicing? Splicing is 50% of our patient populations for main splicing targets. I know you’re involved in some, I think, exciting trials focused on this group. Where do you think we can go from just anemia improving to maybe ideally having disease modification?

Andrew M. Brunner:

Absolutely. I think that splicing, targeting splicing is so enticing in MDS-

David Sallman:

Yeah.

Andrew M. Brunner:

… Because most patients have it unlike the 5%-

David Sallman:

Yeah.

Andrew M. Brunner:

… Or, what we saw this morning, 1% with three mutations.

David Sallman:

Exactly.

Andrew M. Brunner:

So if you’re looking for that needle in a haystack for a targetable mutations so hard, I think that we’re really moving forward in understanding how splicing creates vulnerabilities in cells. And I think that the trials that we’ve had so far have demonstrated, A. Our ability to start targeting splicing. So we are able to introduce agents that do alter splicing, which I think as an intermediate pharmacodynamic endpoint, we are seeing some activity, but then how do we move that to understand those interactions and how we can actually target splicing the same way we might target IDH-mutated cell? Because I think that’s the overall goal, right. Would be to try to identify this abnormal splicing phenotype and then target it with perhaps multiple agents to kind of take it hold of this vulnerability and really kill these cells.

Andrew M. Brunner:

And so we’ve worked with a number of agents, both that target directly the spliceosome, also that target some downstream effects of splicing. I have a poster I’m presenting tonight looking at how ATR signaling is involved in splicing. And can we take advantage of the DNA damage response to actually also kind of look at these synthetic vulnerabilities. So I think we’re still fairly early. I think we’ve at least shown that we can’t alter splicing with splicing modifying agents and how we combine these really will be kind of the next step and hopefully be able to see synergy in targeting cells.

David Sallman:

No, I think that’s great. Yeah. I think from my standpoint, we still have half of patients that may not have that targetable mutation. And like you said, we’re still in our infancy, CAR-T and other novels. IO therapy has led to a paradigm shift in, in patients with other hematologic malignancies. Can we get there? A lot of trials are in AML. And unfortunately I think MDS is being left out too much. I really hope now that we establish some safety and a lot of the targets, there’s a high degree of overlap between MDS and AML, maybe a sicker, older group of patients. But as we understand more, I’m really hoping that say by ASH of next year, we’re starting to see dedicated cohorts for some of our CARs, whether or not it’s 33, 123, CLL-1 or others, and really open up some other avenues for our patients, because we need to get responses particularly when they failed our standard of care.

Andrew M. Brunner:

Absolutely. I think the appeal of cellular therapy, which also, transplant you could put under that umbrella.

David Sallman:

Sure.

Andrew M. Brunner:

Is that it is a little agnostic of the mutation profile to some degree of the cells that it’s attacking. You have to be able to identify them and eradicate those malignant precursors, but it’s less dependent on intracellular activity. I think case in point TP53-mutated MDS, which has a lot of overlap with AML, that is a space where we need a dynamic paradigm shift and is remains, has been and remain such a challenging group of diseases. Do some of these immuno-oncologic therapies have a better role in targeting TP53-mutated disease because of that different mechanism?

David Sallman:

Yeah, I think, I agree. I think maybe, in conclusion really, we’re going to have to personalize our care, both frontline salvage settings. I think it’s an exciting time in that there are options for trials for most of our patients, independent of the COVID pandemic. I think we really need to highly support the recruitment on all of these studies so that we can really change the standard of care and quality of life for our patients. Any other thoughts in conclusion.

Andrew M. Brunner:

I think that, what ASH 2021 to me symbolizes in MDS is an excitement for the future and a desire to push what has been the standard of care and change it. And I think that there are a number of efforts from many angles that really seek to provide definitive evidence of that change. And if you look at that number of Phase III trials that are finally moving through, I think that really symbolizes how MDS has a huge unneed, but people are working hard to make that different treatment.

David Sallman:

Well, thanks for talking with me.

Andrew M. Brunner:

Yeah. Great to see you.