MPN updates from iwMDS-iwMPN 2024 | Aiming to advance the diagnosis and treatment of CMML and BPDCN

Mrinal Patnaik:

Good afternoon everyone. I’m here with esteemed company. I’m Mrinal Patnaik from the Mayo Clinic. I’m with Dr. John Bennett from the University of Rochester and Dr. Dan Wiseman from Manchester.

So we just concluded a very interesting session that discussed a lot of nuances and advances in chronic myelomonocytic leukemia and blastic plasmacytoid dendritic neoplasm. So Dan, I’d just like to start off with you, and this is a great initiative, the ABNL-MARRO. These are rare diseases. I strongly believe that rare diseases are not rare for the people that are affected or afflicted by them, and it’s really time for academics and pharmaceuticals and industry in general to take notice of this. So could you just summarize briefly how important ABNL-MARRO is and where you see this moving forward in the next five to 10 years?

Daniel Wiseman:

Of course. I think ABNL-MARRO is transformative for this neglected group of diseases and it’s a soapbox I get on quite a lot about this. But prior to it, and to some extent still, pharma isn’t interested because it’s perceived to be a rare group of diseases. It’s a heterogeneous group of diseases. Trials have traditionally have been very difficult to do. It’s often a disease of elderly comorbid people as well, which doesn’t help. And over the years we’ve had lots of small, often single-center, early-phase studies that haven’t often pushed the dial very much.

And so I think this is a really innovative concept. And hats off to Michael Savona for leading this initiative. I know it’s not been easy, but it’s turning a difficult situation to our advantage because I think it is a small enough community, and I think there is recognition it’s difficult to do these things individually, so it’s almost forced, or it’s certainly allowed for, this collaborative effort which has given this platform. And I’m not really familiar with an example, quite like it. I mean there are basket trials, sure. But this has the potential to scoop up really all of the interested centers and so many of the patients around the world with this rare disease, and to just streamline multiple trials.

And I think that’s the thing I like most about it is that this isn’t just one trial with multiple drugs. This is a platform where you can have multiple combinations that it’s operating in parallel but with consistent… single sponsor, across countries, across regulatory agencies with consistent elegibility criteria and the ability to move across. And, as with my academic hat on, the ability to do good correlative science is helped as well. You’ve got an instant collaborative network ready to go, able to exploit the relative strengths of different groups. We all know each other and work together, but this is once the samples are all centrally collected and the questions are posed, different people can lead on different parts of it. So I think it goes beyond just the ability to recruit. I think it’s a great initiative.

Mrinal Patnaik:

I completely agree, Dan. And I think the collaborative nature, and to my knowledge, the first in this space to simultaneously open studies on both sides of the Atlantic. So, traditionally studies have been done in the US or Europe and here we have this opportunity. And as Dr. Bennett was alluding to, we have central bio repositories, investigators are free to reach out with their ideas, and it would lead to a lot of fruitful research, not just in therapy that we are obviously interested in, but even for biology. And this would help the overall population.

You know, Dr. Bennett, you’ve been classifying heme malignancies for decades now, many decades, and one of the things that’s changed in CMML is the absolute monocyte count threshold. So just to remind our viewers, traditionally you had to have an absolute monocyte count greater than or equal to 1,000 with more than 10% relative monocytosis. But in the last year, two different classifications have agreed that the monocyte count threshold will be lowered to 500. And it has nuances, it needs some molecular signature and clonality ascertainment. So Dr. Bennett, how do you view this? Is this a good thing? How does it impact MDS and your thoughts on that?

John Bennett:

It’s sort of a mixed blessing. The program that was just described primarily is for the proliferative patients with CMML or CMML-like diseases. What we’re talking about is sort of the MDS type of CMML in which the white count is not elevated. And there are many, many patients fall in this category. And we don’t know at this point whether these patients should be managed with traditional MDS treatment like azacitidine, et cetera. Or whether they should be offered the opportunity, since they’re untreated, with a new agent. And I think that remains to be seen.

But it does produce sort of a dilemma for patients as to what they’re being called or what their doctors say they have. In fact, for years, the whole term leukemia frightens a lot of people. So when you have a patient you say, “You have MDS, no, you don’t really have MDS, you have CMML.” “But isn’t that a form of leukemia?” It can be really very confusing. But I think at the basis of this whole new study is the fact that two major international groups of hematopathologists have basically agreed on a common terminology, which is reproducible. And that will then allow patients to enter these trials with a known diagnosis that is reasonably sound and secure.

Mrinal Patnaik:

No, that’s fantastic. And it segues well into what I had summarized as Dr. Bennett and Dr. Wiseman have pointed out, CMML is not one entity. You can subclassify it, but broadly speaking, there’s a myeloproliferative subtype, Dr. Bennett.

John Bennett:

Correct.

Mrinal Patnaik:

Very symptomatic, short survival. And then the myelodysplastic do a little bit better, but have their own unique problems with cytopenias. And one of the areas that I’ve been interested in is the RAS pathway mutations. They seem to define this myeloproliferative subtype. And Dr. Bennett, for years, RAS mutations have not been-

John Bennett:

Right. In fact, when I was growing up as a young hematologist, RAS proteins were the first ones to be found to be related to chronic myelomonocytic leukemia. There’s a long track history. And now for the first time, there are agents that can target specifically on this pathway.

Daniel Wiseman:

It also highlights there’s still a lot we need to learn because RAS pathway involves many different genes that are currently mutated. And I think there are differences between them. And I think it’s not just what mutation. I think that SIBL mutations do something slightly different from NRAS, KRAS. Perhaps even the different residues that are mutated in some of these, and also the hierarchical placement that you mentioned in your talk. Sometimes it’s a much earlier family event. Sometimes because as you know, there’s a subgroup of CMMLs that seem to only have a RAS mutation. And these are, again, different beasts from the more canonical epigenetic background with a subclone that becomes proliferative. And so knowing how to use it i’s really exciting. We’re suddenly having options to target the RAS pathway. I mean, it’s been a challenge.

Mrinal Patnaik:

It has.

Daniel Wiseman:

How to deploy them I think is going to be the next.

Mrinal Patnaik:

Absolutely. And we’re learning a lot from more common cancers like non-small cell lung cancer, ovarian and pancreatic. And as you can see, this has really opened up the opportunity for personalized medicine and precision medicine. So we may have to look at this in a more nuanced way.

Daniel Wiseman:

And we have to be vocal as the overlapped community. Because as you say, KRAS, NRAS mutations have much bigger homes than CMML, at least in the opinion of pharma. And there are examples. We were working with an interesting drug, I won’t say which, but it was hitting a target in that pathway that was taking it out from its main indication space, solid cancers. And for reasons in that area, the program was discontinued. And of course I think that would’ve been a really good drug for CMML. And so we need to get in early and we need platforms like ABNL-MARRO to make a compelling case to pharma that this is worth exploring.

John Bennett:

I was with, from NIH-

Daniel Wiseman:

Fauci-

John Bennett:

… with Tony Fauci the other day. He has just written a memoir. His book is published. And he was talking about the AIDS problem as he saw it at NIH, and the reluctance of his program to listen to the AIDS laypeople and what they were trying to encourage NIH to do, to be more flexible, to introduce agents earlier, and to relax some of the guidelines that had been so rigid. That same thing applies here. And what we really need is more flexibility from the agencies and from the pharmaceutical industry to allow a free flow of these agents without the roadblocks that are enormous. And in some way, conquer this burden of financial issues that say, oh, well, you’re only talking about a few thousand patients a year. Lung cancer, we have 150,000 in the US per year. That’s where the money is. Okay. But hopefully discussions like this and small groups like this will move in that direction.

Mrinal Patnaik:

So thank you all. And on that end, we note with great optimism, I think we are making progress, and with consortiums and alliances and meetings such as this, we hope we can bring a better tomorrow for our patients. So thank you.