AT THE EPIGENETIC CORE OF MYELOFIBROSIS COULD BET LEAD TO to groundbreaking discoveries?

Hi, my name is Dr Andrew Kuykendall, and I have been a clinical researcher specializing in myeloproliferative neoplasms for the past 7 years.

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So, oftentimes, patients with myelofibrosis present with enlarged spleens or these things we call constitutional symptoms.

So, fever, chills, night sweats, bone pain, weight loss.

These are inflammatory symptoms, and both the spleen and the symptoms are critically tied.

Oftentimes, patients have both of these to some extent, and these associate with a poor quality of life and decreased overall survival.

The other concern that we have is ultimately patients may deal with other changes in their blood counts, and so they may notice that their white blood cell count is elevated with hemoglobin being low.

So, if you have moderate to marked fibrosis, patients have a much different prognosis than if they have minimal to mild fibrosis.

Additionally, the more scar tissue in fibrosis you get actually probably influences the ability to have normal erythropoiesis.

And so, oftentimes this fibrosis level is linked to the degree of anemia, the need for transfusions.

So, when you think about myelofibrosis, I think you can consider this and really focus in on 4 different hallmarks of the disease: splenomegaly or spleen enlargement, constitutional symptoms, anemia, and bone marrow fibrosis.

Certainly, the first 3 when we talk about symptoms, spleen, and anemia, these are often reasons that the patients present to the clinic.

And then bone marrow fibrosis is something that’s inherently linked to the disease.

Historically, we’ve had JAK inhibitors, which have been approved for the indication of myelofibrosis, and they’re very effective at attacking the splenomegaly and the constitutional symptoms.

I think that one thing we know is that patients who receive JAK inhibitor therapy don’t typically do so for an extended period of time.

Half of patients will be off of a JAK inhibitor at about 3 years. This is what long-term follow-up with some of these critical studies has shown us.

And we know that outcomes after JAK inhibitor therapy discontinuation are quite poor.

So, we need to be thinking about how do we extend the durability of our responses with these agents and get patients to stay on therapy with controllable disease for a longer period of time?

So, as we mentioned, bone marrow fibrosis is a hallmark of the disease. I think that this is diagnostically linked to myelofibrosis.

It’s something we know we have to look at when we’re looking at clinical trials if we want to achieve disease modification.

As you get more fibrosis, more scar tissue in the marrow, it becomes more of an inhospitable environment to have normal hematopoiesis, and that’s where we start to see a link with more anemia, more difficulty in making red blood cells.

I think if we truly think we’re getting rid of the disease we would expect bone marrow fibrosis to change.

What JAK inhibitors are able to do is reduce spleen volume and improve symptoms.

And they do this pretty much for all patients; however, there are some limitations to JAK inhibitors.

I would say first and foremost these do not get rid of the underlying disease, so when we look at the bone marrow oftentimes we still see disease that’s there.

We still see a hypercellular marrow, megakaryocytic atypia, and the mutations that drive the disease are usually still present, right? They may shift in how often they're there, but they're usually still present.

So, we’re not having a lot of disease response and, unfortunately, we’re not talking about complete or partial responses when we use JAK inhibitors.

We’re talking about clinical improvements.

Overall, the limitations to me are lack of a disease-modifying effect, the fact that it actually worsens other cytopenias and the inability to give it to some patients that have preexisting cytopenias, and overall a lack of duration or durability as far as treatment goes.

And so I think those are the things we are looking to improve when we’re trying to treat our myelofibrosis patients in a better way.

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This is a very heterogeneous disease, and there’s probably multiple different inflammatory pathways that are being utilized within this.

And so while many of the characteristic signs and symptoms and hallmarks of the disease come from activation of JAK-STAT, the complexity probably comes from utilization of other inflammatory pathways.

And that’s where BET inhibition really comes into focus.

We know that JAK inhibitors help to block that pathway, the JAK-STAT pathway, and thereby lead to clinical efficacy from that standpoint; however, we’ve also learned that there’s other pathways that are included.

And oftentimes those may be critical for some of these underserved aspects of the disease that are ineffectively impacted by JAK inhibitors.

One idea has been to target these epigenetic modulators such as BET proteins.

So, BET proteins have many different target genes that they help to regulate, some of which are involved with the NF-kappa-B pathway.

And this NF-kappa-B inflammatory pathway has come into critical focus over the last few years.

This is part of the innate immune system but activation of some of these NF-kappa-B pathway genes has really shown to have clinical impact within patients with myelofibrosis.

Some of the key upregulated genes within myelofibrosis are shown not to be part of the JAK-STAT pathway.

And here we can see that potentially by impacting the NF-kappa-B pathway by targeting BET proteins, we may be able to have more substantial control or impact upon this disease process.

At least that’s what preclinical models would suggest, and certainly further investigation is warranted.

We believe that in preclinical models that by blocking the NF-kappa-B pathway by targeting BET proteins, or supplying BET inhibition, we may be able to achieve control of 4 different hallmarks of this disease.

We’ll be able to improve megakaryocyte differentiation, thereby reducing bone marrow fibrosis.

We may be able to improve effective hematopoiesis and improve anemia, while also being able to downregulate some of these inflammatory cytokines that lead to an increased symptom burden and prolonged splenomegaly.

So, BET inhibition is very exciting in terms of what it can potentially bring to the table for myelofibrosis.

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And so, when we think about the future of myelofibrosis therapy, I think many people are talking about the potential for combination therapy.

Right now, we largely use single-agent approaches, mainly JAK inhibition.

But we know that that’s not enough, right?

We know that comprehensively we may need more than 1 agent to do that, and so when we think about the idea of combination therapy, it has to be leveraged in a way that makes sense.

So, the question is why would we do this?

And I think that we have to fall back on those unmet needs.

The unmet needs of cytopenias, durability of response, and the fact that it’s only a minority of patients that are achieving these spleen volume and symptom response rates.

And so, a combination therapy would need to bring to the table the ability to augment those responses, to really provide more substantial improvement in disease-related symptoms, more substantial improvement in organomegaly, more substantial improvement at the bone marrow level of changing the underlying biology of the disease.

The way I like to think about this is almost like a highway or an interstate or some sort of road system, and so if you’re thinking about the disease process as maybe the JAK-STAT pathway would form that interstate, right? The main thoroughfare to get from 1 place to another.

And JAK inhibitors have disrupted the therapeutic landscape by being able to block that pathway.

And if you block an interstate, you’re going to block a lot of the traffic from 1 area to another and a lot of the inflammation.

However, we know that by blocking that interstate we’re not getting disease responses.

We’re not getting eradication of the disease.

We’re not getting a ton of changes in bone marrow fibrosis or morphologic changes.

So, people are still getting around that interstate block, right, and so that’s where you have to think about state roads, alternative routes, and these are other inflammatory pathways that are overutilized and activated as well in myelofibrosis, but perhaps to a lesser extent.

And that’s where I think the shift has been more recently is focusing on these alternative strategies, these alternative pathways, that may need to be focused upon if we’re going to get meaningful disease responses. And so, one of these critical pathways is the NF-kappa-B pathway.

One of the ways in which we can target this NF-kappa-B pathway is by utilizing BET inhibitors.

So, BET inhibitors we know have many different target genes in and of themselves, but many of those are associated with this NF-kappa-B pathway.

And so, it may be by targeting both these pathways together with JAK inhibitors and BET inhibitors we can potentially achieve better responses.

And so, rationally, it makes sense to think about leveraging our ability to block 2 different inflammatory pathways and use those together.

And preclinically what we see when you combine BET and JAK inhibition is the ability to further improve spleen volume enlargement symptoms and erythroid differentiator or megakaryocyte differentiation leading to more erythrocyte production, more so than you’d see with either agent individually.

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