iwAL 2024 | The treatment landscape and challenges in rare diseases: BPDCN, CMML, MPN-AP/BP, and VEXAS

Anand Patel:

Hi, my name’s Anand Patel. I’m an assistant professor of medicine at the University of Chicago and a member of our acute leukemia and myeloid malignancy group.

Marina Konopleva:

Hi, I’m Marina Konopleva. I’m a director of leukemia at Montefiore Cancer Center in Bronx, New York.

Guillermo Montalban-Bravo:

Hi, I am Guillermo Montalban-Bravo. I’m an assistant professor at the leukemia department of the University of Texas MD Anderson Cancer Center.

Emma Groarke:

And hello, my name is Emma Groarke. I’m an associate research physician at the National Heart, Lung, and Blood Institute of the NIH.

Anand Patel:

So in the last session, I focused on how we manage myeloproliferative neoplasms in the accelerated and blast phase. So despite several novel therapies being approved for acute myeloid leukemia, when we’ve retrospectively looked and seen if that’s impacted outcomes in an appreciable way in accelerated/blast-phase disease, we haven’t really seen that. Median overall survival is still less than a year.

And really, the goal being if you are able to achieve disease control, taking patients to an allogeneic stem cell transplant if they are eligible. Some therapeutic strategies that I think hold merit or promise could be IDH inhibition. As about 25% of these patients will have a mutation in IDH1 or IDH2.

And then there’s also compelling preclinical rationale for using LSD1 inhibitors in this space. And we can… Again, borrowing from the AML landscape, we do have data demonstrating efficacy of LSD1 inhibition plus azacitidine in AML. So perhaps that could translate to therapeutic benefit in MPN accelerated phase and blast phase.

Marina Konopleva:

In this last session, I focused on the rare disease called blastic plasmacytoid dendritic cell neoplasm, which we abbreviate as BPDCN. It’s really an orphan disease with the incidence of 0.04 of patients, 400,000, but it is quite aggressive.

It involves skin and in many patients, also bone marrow, spleen, and extramedullary sites, including CNS in about 20% to 30% of patients. Historically, the outcomes have been extremely poor. The chemotherapy was the only choice using either AML or ALL-based therapies with median overall survival of less than two years.

In the last few years, we have received the approval for the first target therapy using the CD123 as a target. CD123 is a receptor for interleukin 3 and is highly over-expressed in BPDCN tumor cells in 100% of patients. So the first agent that was approved, it’s called tagraxofusp. It’s interleukin 3, conjugated to diphtheria toxin, and it selectively more or less kills the BPDCN cells.

It was approved based on the large multi-center Phase I/II study in relapsed/refractory and newly diagnosed BPDCN, where it showed quite high response rate, especially in newly diagnosed patients, about 70%. And respectable duration of responses, although our final overall survival was still about only 15 months.

With that said, patients who were able to transition towards allogeneic stem cell transplantation, they actually… A number of them were within cured with about 50% of patients alive at two years mark and median overall survival about 38%.

Since then, we have several other agents that are in the pipeline. One of them is PVEK (Pivekimab sunirine), which is an antibody conjugated to alkylating payload, which has gone through the initial Phase I/II studies. And is currently being evaluated for approval in BPDCN, especially in patients who fail tagraxofusp or intolerant to tag.

We also know that BCL-2 inhibitors are quite efficacious in BPDCN cells that have high levels of BCL-2. And the use of HMA/venetoclax, as well as chemotherapy with venetoclax has been reported as efficacious, although there are no formal trials that has demonstrated survival benefit.

And then we also are hoping to get the CAR T-cells against CD123, which we think will be highly effective in this disease. But ultimately, the goal again is to get patients into remission with either the targeted therapies or chemotherapy. And perhaps a combination of these targeted agents and the chemotherapy will be the best approach and get them to transplant and also prevent CNS relapses using intrathecal chemotherapy.

Guillermo Montalban-Bravo:

So in this session, I highlighted what are the novel targets or novel therapies that are currently being developed for chronic myelomonocytic leukemia. And one of the key aspects that I think we had to pay attention to and I tried to deliver is that one of the essential problems we have is in defining what the unmet needs are.

And how do we overcome some of the challenges that this disease essentially represents. Not just because of how clinically diverse it is, but also genetically diverse, and what are the aspects that we want to try and ask out of novel therapeutics for these patients.

Because evidently, some patients have very prolonged survival in which the major disease are derived from cytopenias, or the symptoms are derived from their chronic line of inflammatory condition. While other patients have very high comorbidity where they can easily progress to AML and they can have extramedullary disease, and that’s associated with a high morbidity.

So I outlined some of the novel therapeutics that I think could have a therapeutic impact in different subsets of the disease, be it low-risk disease with TET2 mutations, where certain interventions could be helpful, aside of HMAs like ascorbic acid for example.

But also high-risk genomic subsets like RAS-mutant disease, which we know is inherently resistant to available therapies, including HMA. And where distinct interventions could be useful, not just targeting specific pathways, but even cellular subsets like mature monocyte populations, or progenitor populations, or PDCs.

And to that end, there’s certain immunotherapies or immunoconjugates that we could use, but also treatments that are directed towards inhibiting inflammatory signals or RAS signals.

And also other epigenetic mechanisms in certain subsets like ASXL1 mutant disease, which is also a high risk of progression. And in that aspect, BET inhibitors or in the setting of CMML, also LSD1 inhibitors could be potential of use and are actually currently being investigated.

So it’s thankfully a field in which, despite the lack of effective approved therapies, there’s a huge increasing effort from the scientific community to develop novel therapies and do cooperative efforts to try and have clinical trials to demonstrate if any of these agents could be efficacious in CMML.

Emma Groarke:

What I spoke about was VEXAS. So VEXAS is a pretty recently described disease just back in 2020, and it’s caused by somatic mutations in a gene called UBA1. And these occur in hematopoietic stem progenitor cells.

And patients with VEXAS have two main issues. One is rheumatologic, so they have a lot of inflammatory symptoms, and it’s going to include things like fevers, night sweats, lung involvement, arthritis, rashes, and much more. And as hematologists, we’re particularly interested in the hematologic aspects.

So patients also develop pretty significant cytopenias. About 10% to 15% will develop myelodysplastic syndrome and about 10% will also develop MGUS. So I went through a bit about the clonal landscape of VEXAS.

So co-mutations with VEXAS most commonly are DNMT3 and TET2. And this is more analogous to age-related clonal hematopoiesis than was seen in a typical MDS patient. However, it occurs at a higher rate and frequency than what’s seen in the general population when age-matched.

I also spoke a bit about a large MDS cohort that was sequenced for mutations in UBA1. And what was found is that patients who were pre-selected to likely have VEXAS, so these were males who were older and had MDS-U or MDS/MPN crossover, there is a 7% pick-up rate for UBA1.

While in a general MDS cohort, it’s about 1%. And most of the MDS that we see is lower-risk MDS with the WHO subtype of MDS-SLD or MLD. But there are some cases of higher-risk MDS with excess blasts and AML.

I then spoke a little bit about therapy. So there’s really three main ways that we try to tackle this. One is trying to control the inflammation, and this is primarily done with steroids. So VEXAS patients are very steroid-responsive, but unfortunately are also steroid-dependent. So when you try and taper the steroids, their VEXAS will flare.

There are different steroid-sparing agents that are used. The most common are JAK inhibitors and IL-6 inhibitors. There are other therapies that are being developed in terms of trying to get rid of the UBA1 clone. One is allogeneic stem cell transplant and also hypomethylating agents.

And also really important to keep in mind is supportive care. So this is things like transfusion support, infection prophylaxis as patients are at high risk of infection and also dropper prophylaxis. I then spoke a little bit about data on IL-6 and JAK inhibitors, which seem to be the best out of anti-inflammatory therapies that a large study that the French group recently published.

And this is in comparison to things like TNF inhibitors and IL-1 inhibitors. And that there are data that azacitidine when used in patients with VEXAS can actually control both the MDS and the inflammatory symptoms in over 50% of patients. And actually does have a direct effect on the clonal burden of the VEXAS.

And finally, I spoke very briefly about allogeneic transplant and the fact that at the NIH, we have a trial open for this. And what we’ve seen so far is that we can eradicate the UBA1 and patients do not have symptoms of VEXAS after transplant.

However, what we are seeing is high rates of inflammatory complications, such as GvHD, which seem to be the primary complications. So we’re making some changes to conditioning in GvHD prophylaxis to try and mitigate this.

Anand Patel:

So Emma, every time I hear you talk about VEXAS, I feel like I learned so much about this disease. And one thing that really struck me was the potential role for allotransplant. Is there work being done or are there efforts to develop risk stratification tools in VEXAS to identify lower risk versus higher risk patients, and then use those to potentially inform that decision around transplant versus not?

Emma Groarke:

Yeah, I think that’s a really good question. So at the moment, we don’t have a good risk score. I think that that will probably be a collaborate effort because we’ll need large numbers of patients. But when we are considered and the risk score we use going into transplant is kind of standard scoring, so HCT-CI.

However, when we’re thinking about trying to select patients for transplant, really what we think about is how bad is their disease? So patients who are earlier on in the disease, who’ve only tried one or two agents or who are not very highly steroid dependent, they’re the ones we tend to just watch and wait and just see how they get on with medical therapy.

And the patients who we bring to transplant tend to be the ones who have pretty significant inflammation that’s really not being well-controlled or who end up being hospitalized due to their VEXAS.

And some of the really severe complications patients get particularly are like the lung involvement and other organ involvement, or else patients who have significant cytopenias or actually develop MDS. So they’re the two that we’re targeting at moment.

But I agree, this is an older and comorbid population. So I think a tool to try and select out patients who will benefit from this is really key. And what we see in our clinic is that really the majority of patients we’re seeing in clinic probably are not fit for allotransplant. So I think that it is an effective therapy, but this is a high risk population and it’s not going to be a therapy that’s available for all of our patients.

Anand Patel:

No, I think that makes perfect sense. And I think so much of what we do in myeloid malignancies is really identify those patients that benefit the most from transplant, or potentially can be cured or have durable disease control without transplant. So very interested to hear how that work evolves.

Emma Groarke:

And I think it’s so far, I mean, it’s not technically a malignant disorder. It is caused by a somatic mutation, but we don’t consider it a malignant disease. So I think the standards are high that you also don’t want to harm patients by performing a transplant in a non-malignant disease.

But we also don’t really have to deal with relapse as an issue. And so far, we have patients over a year out where we’re still not detecting the UBA1. Now, obviously we’ll need to track that long term and see that’s the case long term.

But so far, we have been successful in getting rid of the VEXAS phenotype and the genetic mutation. But as I said, we have had complications and I think GvHD has been our main issue. And obviously, that’s quite serious in an older population. We’ve had a couple of deaths related to that.

Anand Patel:

Got it. And Guillermo, you provided a wonderful overview about CMML, what we know and a lot of what we don’t know or what we need to discover. When thinking about trial design in this population, ultimately from your standpoint, do you think it needs to primarily be driven by what we would think of as lower risk CMML versus higher risk, much like we do for MDS?

Do you think it needs to be more molecularly driven in identifying molecular targets and then testing targeted therapies, whether it’s in small pilot studies or randomized fashion? Or somewhere where you’re integrating both where you have your high-risk CMML studies with specific molecular subsets and then something similar for low risk?

Guillermo Montalban-Bravo:

Yeah, I think it’s a good question, and I think one of the major challenges we have is that I think in any situation in any myeloid disorder or cancer in general, when we’re trying to identify and develop normal therapeutics and clinical trials with a potential for approval.

We always face a question of do we try and identify specific therapy that we could try and treat large numbers of patients with, to try and have a greater end to be able to more easily demonstrate efficacy with a potential loss of unique biologically driven effect?

Or do we focus in subsets where we might be more able to have a unique effect to then lead to approval? And I think that CMML is a disease where this question is particularly relevant because evidently, even though we have examples, for example, like BPDCN, where if you have a… Even if it’s a ultra-rare disease, if you know it’s driven or exclusively sensitive to a specific agent, then it is going to be much more easy to demonstrate efficacy.

But the question is, then in those settings, do we really want to conceive that it would be likely to be able to take that agent to approval in a randomized fashion? Probably not. So it’s all very much dependent on what the path of approval for a specific agent is going to be.

So I think both options have merit. And I do think that the field now is moving in such a way that we’re not being exceedingly restrictive or very specific for certain subsets outside of perhaps more genomically driven agents. But I think how we define or design those clinical trials is going to probably be very dependent on how initial results of preliminary studies are going to demonstrate efficacy or not.

So I think the upcoming Phase I/II studies are going to be very important for us to be able to define that kind of selection. Because it is possible that there might be therapies that could be effective for a large expanse of our patients, but other ones for which the specific biology or genotype may be very important.

Anand Patel:

And Marina, a key part of your talk that stood out to me was the different compartments where BPDCN can be: the bone marrow, the skin, the CSF.

In terms of clinical evaluation of patients, does the predominant site of disease, whether it be marrow involvement, predominantly skin involvement, plus or minus the CSF, does that influence your therapeutic decision-making?

Assuming that a patient is well enough to receive any of the therapies that we have, whether it’s something like Hyper-CVAD, something like tagraxofusp. Does the site of disease or predominant site of disease influence where you think the most promising therapeutic is for that patient?

Marina Konopleva:

Yeah, that’s a great question. In general, no, because we know that patients with skin-only disease, they’re also doing quite poorly. And again, there’s a debate where it originates. We think it still maybe originates in bone marrow and that migrates to the skin.

Although there’s some data now that published by Andy Lane in nature recently that there’s a UV signature in the skin, and so there’s PTC that are transformed perhaps by the UV light, and then they can migrate back to the bone marrow and come back to skin.

So I think that’s not very well-understood, but we think it is a systemic disease. So we use that sort of assessment more for the staging and for response criteria to make sure that we cleared all the sites. But in general, the therapies are fairly similar.

So even the patient who has skin-only disease, we treat with systemic therapy or with tag, and we also think that they should be candidates for the stem cell transplant to be cured.

I think where it makes a difference perhaps for all the patients who may not be able to undergo allogeneic stem cell transplantation. So there’s some data that autologous stem cell transplant in skin-only disease could be an option. It’s mainly Japanese data.

Again, the number of patients are so limited that there are no randomized studies. But certainly, there are some patients who are just going through the autologous stem cell transplant and they seem to be doing well long term. And those are the patients who don’t have any other sites of disease. It just skin only.

So I think that there’s a difference there. But overall for younger patients, even with skin-only disease, you still treat it as a systemic disease for the most part.

Anand Patel:

Got it. No, that’s very helpful because I think knowing that ultimately our therapy needs to be systemic no matter where the compartment of disease is, is I think such a critical part of the management of disease.

Maybe to wrap up, we’ll do a rapid fire where we’re just talking about in 30 seconds or so, what’s the most exciting thing about what you’ve spoken about that you’re looking to or future direction? So let’s start with VEXAS and you Emma.

Emma Groarke:

Yeah. So I think the key thing in VEXAS is it’s still very new. We still have a lot to learn about really what’s driving this inflammation and how we can effectively treat it. But I do think that the main medical unmet need is medical therapies for these patients.

So as I said, I don’t think allogeneic transplant is going to be a good therapy for most patients with VEXAS. So we really need to be able to try and develop probably more targeted therapies that will be able to control inflammation and maybe more direct targeted therapies on the UBA1 pathway as well.

Anand Patel:

Guillermo, how about you and CMML?

Guillermo Montalban-Bravo:

So I think for me, one of the most exciting prospects moving forward is I really think that in the last five, six years, there’s been a humongous increase in our knowledge about CMML biology. It used to be a disease where we didn’t even know where to classify it, not so recently.

And this has been progressively advancing. And I think part of what echoes what I wanted to reiterate in the presentation that I gave is that our understanding of how the complex biology of this disease is being dissected, not just at the genetic level, but even in distinct cell populations and what their contribution to the disease is.

To me, it’s really exciting because I think that’s what’s going to allow us to really translate that into novel therapeutics for our patients. Because we lack any real disease biologically driven disease therapy to date.

Like HMAs we know are useful, but I think for me, that’s a major area of excitement, how our understanding of the biology that is increasing so rapidly may translate in treatment for our patients.

Anand Patel:

And Marina, how about with BPDCN, what’s exciting you?

Marina Konopleva:

Yeah, I think BPDCN, I really love BPDCN because it has such a great target. So this is like a poster child, almost like a CMML that responds to [unintelligible]. So it has the CD123. So it’s super responsive to these drugs like Tagraxofusp or PVEK, but we’re still not curing majority of our patients.

But fortunately, we also know BCL-2 inhibitors work, we know chemotherapy works. So I think for these aggressive diseases, we probably need to do our triplets and quadruplet combinations.

And fortunately, we have tools now that we can play with. And then we still have allo transplant because the patients are… Generally, the median age is still 65 plus. But we do see young kids and we have younger patients who we can channel towards stem cell transplant.

But I think the potential for cure will be higher. The other thing that I didn’t get a chance to emphasize that it’s very important because it’s such a rarity of the disease that there are consortiums, international consortiums, that collect information on these patients, similar to VEXAS perhaps.

So there are two of those, for example, that I know of. The one is in US that is led by Naveen Pemmaraju and Andy Lane, and they wrote this consensus paper on the diagnostics and treatment. And the other one is actually in Armenia by our former fellow.

And they’re collecting international data on BPDCN patients, their genetics, how they’re being treated, and what are the outcomes, and they’re presenting some of the data. I think we really need this real-world experience to standardize the therapy for this pretty aggressive and lethal disease.

Anand Patel:

And I think for me, when thinking about accelerated and blast-phase MPNs, what’s exciting to me is I think we as a community are acknowledging that just utilizing AML-based therapies in this disease space isn’t enough. That we really need to think about what is different molecularly and biologically.

And I think there are promising targets that are coming to light, BCLxL, LSD1. Perhaps some of these phase III drugs that are being looked at in myelofibrosis, whether it’s a telomerase inhibition or otherwise, may have a role in accelerated or blast-phase disease.

So I think having that kind of critical mass of acknowledgement that we need to move beyond AML therapies and really think about rational design for prospective studies in this space is something that really has me excited about where the field’s going.

So with that, thanks so much for a great discussion, everyone. I really learned so much from all of you and what a great session.

Emma Groarke:

Thank you.

Guillermo Montalban-Bravo:

Thank you.

Marina Konopleva:

Thank you.