A New Era for ET: Targeting the CALR Mutation

Essential thrombocythemia (ET) is a challenging myeloproliferative neoplasm (MPN) characterized by megakaryocyte hyperplasia, thrombocytosis, vasomotor symptoms, in addition to an increased risk for thrombosis, hemorrhage, and transformation to myelofibrosis (MF) or acute myeloid leukemia.

However, new research is changing how oncologists approach it. In an interview, Aaron Gerds, MD, MS, an associate professor of medicine and deputy director for clinical research at the Cleveland Clinic Taussig Cancer Institute in Ohio, discussed research on a novel therapy.

CALR mutations in exon 9 are found in approximately 25% of patients with ET. Treatments aim to control blood counts, prevent vascular complications, and improve symptoms, but are not targeted to driver mutations.

INCA33989 is a first-in-class, mutation-specific therapy with a unique mechanism of action that directly targets the underlying CALR mutation, offering a promising path forward that may not only manage symptoms but also modify the disease course itself.

Targeted Oncology: What was the rationale for this research? What are the unmet needs in the space?

Aaron Gerds, MD, MS: Essential thrombocythemia has very few treatments commercially available today. In fact, there is only 1 drug that is approved by the FDA to treat essential thrombocythemia: anagrelide [Agrylin]. And it’s inadequate, right? There are prospective trials saying that even hydroxyurea is better than anagrelide. We also use interferons, but that's in an off-label manner.

[ET] is a less-studied disease because it's not very common, and [patients] have very good survival [rates]. For most patients, their survival approaches that of the normal population, which is a good thing, but it still doesn't mean that this disease is without risk. Within this disease, you can progress to what is essentially acute leukemia, also known as blast phase MPN. This disease can progress to myelofibrosis, with an enlarging spleen, increasing symptom burden, and cytopenias. ET itself can lead to a lot of symptoms for our patients; particularly those patients with higher platelet counts tend to have more symptoms [and] constitutional symptoms [such as] headaches, fevers, night sweats, [and] weight loss. They can also have an increased risk of bleeding events known through a mechanism known as acquired von Willebrand syndrome.

Effective therapies are lacking, and there are consequences for this disease that need to be addressed. Most importantly, what we really need in the field are therapies that turn the course of disease in a different direction. If we can develop new therapies that can truly modify disease and either eliminate or at least lengthen that runway for those patients, I think that would be really, really important.

As we learn more about these diseases, we're thinking less and less in terms of morphologic features and thinking more and more about the driver mutation, and that's because in these patients, they typically have 1 of 3 driver mutations: JAK2, CALR, or NPL. We know clinically that these 3 entities behave differently. In particular, for the mutant calreticulin protein, it's different than the others. It is external to the cell. So, what happens when the protein becomes mutated? It gets stuck on the thrombopoietin receptor, and as the thrombopoietin receptor is being built and then pushed out to the surface of the cell, it stays on there, activating the pathway. Being external to the cell in that nature, it lends itself to attack in different ways, like with a monoclonal antibody, bispecific antibody, cellular therapy, CAR [chimeric antigen receptor] T cells, or even vaccine therapy.

With this discovery, there's been a clear and obvious pivot toward these types of treatments for this subset of patients with MPNs. A pretty straightforward thing to do is develop a monoclonal antibody that targets this external protein to the cell, like we have monoclonal antibodies for almost everything else. We know that this monoclonal antibody can disrupt that JAK-STAT signaling, starving these cells of the signal that they need to divide and grow and survive. It may also recruit immune cells similar to what rituximab [Rituxan] can do and lead to some [cellular] death via the immune system as well. But clearly, we want to show that the theory of the external protein can be targeted by external means. That’s the exciting part about this abstract. It proved that, yes, we can. We can target this in a very, very different way than what we have in the past.

Could you give some background on INCA33989 and the objectives of this study?

This is a fully humanized monoclonal antibody directed against mutant calreticulin protein. That’s important because, of course, it won't work in JAK2- or NPL-mutated disease. [The study] is a phase 1 trial looking at what dose we can get to without incurring excess toxicity as well as getting a look at the efficacy. It was a safety-first protocol, and being such, it was a 3 + 3 design. We enroll 3 patients at a dose level, monitor for [adverse] effects, then the next 3 patients at the next dose level, and so on and so forth.

We started off, quite frankly, at an incredibly low dose of 24 mg per dosing, which is very small. Within the protocol, the plan is to escalate all the way up to potentially a dose of 1500 mg, so it’s a very cautious approach. But even at those really tiny doses of 24 mg, we were seeing some responses, which is really exciting.

Could you go into the safety findings?

I think the ultimate take-home point is that this monoclonal antibody was safe in this report. That is what we expected, having a lengthy experience with monoclonal antibodies and hematologic malignancies. That’s important, obviously, for the patients on the study right now and for the patients who may receive this therapy in the future, but also in terms of planning where to go next with this. It lends itself to combination with other things, so you can then start to envision combinations with, say, ruxolitinib and other JAK inhibitors, with a BET inhibitor, or maybe even triplet therapy. That's the nature of the oncologist. We like to stick all these things together.

The safety profile was really impressive. There were some potentially immune-related adverse events. There were a couple of cases of pancreatitis that were identified. There were some lower blood counts in a few patients. You get in there, you start killing off hematopoietic cells, and even if they're cancerous, you can see those low blood counts. So, anemia and neutropenia were reported in a small number of patients. There was only 1 grade 3 neutropenia, and that was the only grade 3 event throughout the whole study. All the rest were grade 1 or grade 2.

What were some of the efficacy findings?

The simplest thing to measure in patients with essential thrombocythemia is whether platelets come down. Given the inclusion criteria of this trial, you can really see them drop nicely, and that's really what we saw. First and foremost, those platelet counts came down significantly and stayed down for those patients over time. We had data through cycle 6, and there was really an impressive dropping of those platelet counts for those patients.

Some other data really point to the deeper effect. We were observing, in some patients, molecular responses. So not only were the counts being controlled, but we're actually seeing the measurable amount of mutant calreticulin protein go down, which we think is a very valuable end point in MPNs. Reduction in driver mutational allele burden has been associated with better myelofibrosis-free survival, better thrombosis-free survival, and better overall survival. So, it does serve, in some part, as a surrogate.

We'll have to see if these responses, in terms of molecular responses, are durable. If I use hydroxyurea as an example, often we'll see a dip in the allele fraction with hydroxyurea, but then over time, it goes right back up. And if we look at a drug like interferon, we see it go down and stay down for those patients. So, where it does go down, it'll stay down as long as the patients continue on therapy. And I think that's what we're going to want to see with this therapy as we go along. Very early data, but encouraging to see at least a few of those responses occurring.

What are the next steps in this line of research?

This study is still ongoing and enrolling patients, and I think that's important. We want to get all the data from this. There's an expansion cohort planned as well. And then there's the companion for this trial, which is the myelofibrosis arm. So those patients are moving through the study, and we will hopefully have topline results from the initial patients treated on the myelofibrosis portion of this trial as well.

Outside the US, there is an ongoing study with combinations with ruxolitinib, particularly in patients with myelofibrosis. We'll want to see those data as well. Between these 3 components, the 2 arms of this particular study here in the US and the ex-US study, we get a pretty good sense of that safety profile as these studies come to completion.

For ET, I think there is a viable path forward with monotherapy, as we're seeing so far in this particular study in myelofibrosis. But we want to see more data. It hasn’t fully emerged yet, but you could rationalize a combination study there pretty easily.

I really think that this is the tip of the iceberg. After we establish the safety and efficacy of a monoclonal antibody, we can then turn to the other studies that are ongoing. There's an ongoing bispecific antibody study directed against mutant calreticulin protein. Groups are developing engineered CAR T cells that also target mutant calreticulin protein. There have been a number of vaccine studies that have been launched, as well. Across the board, this is just the beginning of the story. I look forward to seeing how this evolves over time.

This article was generated with assistance from NotebookLM. It was edited and reviewed by Targeted Oncology staff. If you have any questions about the use of AI, please contact us.

REFERENCE

Mascarenhas J, Ali H, Yacoub A, et al. INCA33989 Is a novel, first-in-class, mutant calreticulin-specific monoclonal antibody that demonstrates safety and efficacy in patients with essential thrombocythemia (ET). Presented at: European Hematology Association (EHA) Congress; June 12-15, 2025; Milan, Italy.