New Essential Thrombocythemia Treatment Appears to Address Underlying Disease

The monoclonal antibody INCA44989 is the first-ever treatment for essential thrombocythemia (ET) that may alter the underlying mechanism of disease for patients with mutations of calreticulin (mutCALR), according to a recent phase 1 study. The majority of patients achieved a swift and durable response.

The research outcomes were presented at a late-breaking session during the 2025 European Hematology Association Congress. Notably, the medication also has a very low toxicity profile.

“The overall response rate of roughly 70% is pretty remarkable,” notes Aaron Gerds, MD, study co-author and a hematologist with Cleveland Clinic Cancer Institute. “It’s also very advantageous to have a therapy with a side effect profile like this, as it’s likely to also work well in combination with other medications.”

Background

ET is a myeloproliferative neoplasm with increased risk of thrombosis, hemorrhage and progression to myelofibrosis (MF) or acute myeloid leukemia. Patients with ET often suffer from extreme fatigue, night sweats, fevers, itchy skin, unintentional weight loss and/or enlarged spleen. “Controlling patients’ blood counts is very important to reduce the risk of bleeding or clotting,” explains Dr. Gerds. “However, we not only need therapies that control blood counts and improve symptoms but modify the course of disease and reduce the risk of progression to post-ET myelofibrosis or acute leukemia.”

In recent years, researchers discovered that ET was caused by threedistinct driver mutations: JAK II, MPL and mutCALR. Roughly a quarter of patients with ET have mutCALR, which is associated with lower rates of response to treatment as well as higher risk of transformation to MF. Current treatments control blood counts and mitigate vascular complications for a certain percentage of patients, but don’t address the underlying disease and are not targeted at driver mutations.

“All the existing treatments are non-specific in that they can’t target specific mutations, and most have considerable toxicities,” explained Dr. Gerds. “Hydroxyurea and interferons can achieve disease control in between 30-60% of patients, but they’re accompanied by hair thinning, mouth sores, and in the case of interferons, liver enzyme elevation. They’re also not appropriate for patients with auto immune disorders, as they can lead to depression and other mental health issues.”

Study concept

The mutCALR protein is unique in that it’s actually external to the cell so it’s susceptible to targeting. (JAK II and MPL don't act in that manner.) Researchers sought to target mutCALR with a monoclonal antibody, which would be expected to have a minimal side effect profile.

Several years ago, researchers conducted preclinical work in that space, deploying INCA33989 to go after mutCALR mutations. They found the therapy had a fairly remarkable response in terms of selectively targeting the mutation.

Study design

Building on the preclinical work, researchers at Cleveland Clinic Cancer Institute participated in a multisite, first-in-human study evaluating INCA33989 for patients with the CALR exon-9 mutation with high-risk ET or MF. Patients received INCA33989 as a monotherapy via IV every two weeks.

Primary endpoints were dose-limiting toxicities or treatment-emergent adverse events. Secondary endpoints included symptom improvement (based on MPN-SAF TSS), treatment response using European LeukemiaNet response criteria and changes in allele burden of mutCALR.

In the ET cohort, there were 49 patients enrolled, with a median age of 60. Initially, patients received a very low dose (24 mg) and over time titrated up to 1,500 mg.

Study outcomes

Sixty-six percent of patients achieved a complete response in terms of normalization of platelet count. “Even for those starting at an incredibly low dose, we were seeing transient responses,” says Dr. Gerds. Eight-nine percent of evaluable patients also had a reduction in mutCALR VAR from their baseline, with 47% achieving a reduction of 20% or more and 21% achieving a reduction of 50% or more.

Perhaps even more importantly, the therapy seems to reduce disease burden. In the trial, a significant number of patients also achieved reductions in allele rates (a rough approximation of disease burden in ET) at a median follow-up of seven weeks. “By comparison, we don’t typically see allele burden reductions with interferons for one to two years,” says Dr. Gerds.

Higher doses of INCA33989 correlated with improved responses. Fortunately, increasing the dose did not seem to cause many adverse events. There were no dose-limiting toxicities found, and only one patient stopped treatment due to side effects. Of the side effects observed, the most common were asymptomatic lipase, visceral venous thrombosis and diverticulitis, all of which were minimal. The medication also appears to be well tolerated by patients with ET who could not take cytoreductive therapy.

Dr. Gerds is quick to point out that this is very preliminary study data that needs correlating with improvements in myelofibrosis-free survival, clot-free survival and overall survival. However, these early results are quite encouraging. “Given the favorable toxicity profile of INCA44989, the world is our oyster in terms of where we can take this therapy. We’re not limited by additive or combinatorial toxicities, so that broadens the possibilities for how this treatment can be developed,” Dr. Gerds says.

What’s next

This monoclonal antibody is just one example of how to treat somewhat rare myeloproliferative neoplasms like ET and MF. The field is rapidly evolving.

The myelofibrosis cohort study is still enrolling, with top-line results expected around the end of the year. A parallel study outside of Cleveland Clinic is also underway investigating INCA44989 in combination with ruxolitinib. “As we bring these findings together over the next year or so, that will help identify what direction this therapy will take next,” says Dr. Gerds.

“There is also ongoing research into bispecific antibodies as well as engineered cells like CAR T-cell therapy that may build on top of a monoclonal antibody. I expect there will be a huge wave of change in this area over the next five to ten years,” explains Dr. Gerds.