Clinical Summary: 

• Design/Population: The phase 1 INCA033989-101 and INCA033989-102 studies evaluated the mutant CALR-specific monoclonal antibody INCA033989 as monotherapy or in combination with ruxolitinib in patients with CALR-mutant myelofibrosis who were JAK inhibitor–intolerant, relapsed or refractory, ineligible for JAK inhibitor therapy, or had a suboptimal response to ruxolitinib.
• Key Outcomes: INCA033989 produced clinically meaningful spleen, symptom, and anemia responses as both monotherapy and combination therapy, accompanied by reductions in mutant CALR variant allele frequency and mutant CALR-positive cell populations. The therapy demonstrated a favorable safety profile, with no dose-limiting toxicities or maximum tolerated dose identified.
• Clinical Relevance: These findings provide early evidence that mutant CALR-directed therapy may modify disease biology while improving clinical outcomes, supporting the planned phase 3 development of INCA033989 in myelofibrosis.

Claire Harrison, MD, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom, discusses updated results from a phase 1 study evaluating INCA033989, a first-in-class monoclonal antibody targeting mutant calreticulin in patients with CALR-mutant myelofibrosis. The studies enrolled patients across multiple treatment settings, including those who were JAK inhibitor naïve, relapsed or refractory, intolerant to JAK inhibitors, or receiving combination therapy with ruxolitinib.

In addition to improvements in conventional clinical endpoints, INCA033989 demonstrated molecular activity through reductions in mutant CALR allele burden and circulating mutant cell populations, supporting its potential as a disease-modifying therapy. These results, together with the favorable safety profile, provide the rationale for ongoing phase 3 development in patients with CALR-mutant myelofibrosis.

Dr Harrison presented these results at the European Hematology Association (EHA) Congress in Stockholm, Sweden.

Transcript:

Hi, my name is Claire Harrison, I'm a professor of hematology at Guy's Hospital in London, UK.

I'm going to talk to you about a study that I presented at the EHA meeting in Stockholm evaluating the mutant CALR-specific monoclonal antibody INCA033989, which I'll refer to as 989 for short, and the latest response data in patients with myelofibrosis. 

Just as a reminder about CALR mutations and 989, calreticulin mutations are seen in approximately 30% of patients with essential thrombocythemia and myelofibrosis and have a very unique biology. The mutant CALR protein is processed through the Golgi apparatus, associates with the thrombopoietin receptor MPL, and is then expressed on the cell surface. Importantly, only the mutant form of CALR is expressed on the cell surface in this way, and only on cells carrying the mutation. That makes it a very attractive mutation-specific therapeutic target.

INCA033989 is an Fc-silenced monoclonal antibody that selectively targets mutant CALR in complex with MPL. The data we presented in Stockholm focused on patients with myelofibrosis. 

We have now treated a substantial number of patients—83 patients with monotherapy and approximately 20 additional patients receiving the combination of 989 with ruxolitinib. Within the monotherapy cohort, 21 of the 83 patients had not previously received a JAK inhibitor because they were considered ineligible. So, we now have data across the spectrum of JAK inhibitor–naïve patients, JAK inhibitor–relapsed, refractory or intolerant patients, and patients receiving combination therapy. Patients in the monotherapy cohorts have now been followed for well over 800 days.

Looking first at our traditional myelofibrosis efficacy end points, namely spleen volume reduction, it's important to remember how these patients entered the study. Baseline spleen imaging was often performed while patients were still receiving a JAK inhibitor. They then discontinued the JAK inhibitor before starting 989. Therefore, baseline spleen size may actually have been somewhat smaller because of the residual effects of prior JAK inhibitor therapy. Despite that, we observed encouraging spleen responses across the monotherapy cohorts, both in the frontline JAK inhibitor–ineligible population and in the second-line setting, regardless of CALR mutation subtype.

In the second-line setting, we generally focus on a spleen volume reduction of at least 25%, and overall just over half of patients achieved that end point. Approximately 40% of patients achieved an SVR35, which is generally considered the gold standard endpoint in frontline myelofibrosis studies. 

Among JAK inhibitor–ineligible patients treated in the frontline setting, approximately 47% achieved SVR35, which compares favorably with some of the newer frontline combination studies. Symptom improvement was also encouraging. Overall, just over half of patients achieved at least a 50% reduction in total symptom score. 

I also want to highlight several findings that, in my view, suggest that this agent may truly be disease modifying. 

First, we observed robust and durable improvements in anemia, both in patients who were anemic at baseline and in those previously treated with JAK inhibitors. Among the patients who were transfusion dependent at study entry, three of six achieved a major anemia response by becoming transfusion independent. 

We also observed reductions in circulating blast cells and circulating mutant hematopoietic progenitor cells. Looking at whole-blood CALR variant allele frequency, approximately 89% of patients demonstrated some reduction in variant allele frequency, and approximately 12% achieved reductions of at least 25%.

When we specifically examined circulating peripheral blood mononuclear cells carrying the CALR mutation, responses were even deeper, with approximately 81% of patients achieving at least a 25% reduction.

Perhaps most exciting are the bone marrow findings. Because mutant CALR can be detected on the surface of megakaryocytes, we were able to demonstrate reductions in mutant megakaryocytes together with the reappearance of mutation-negative megakaryocytes. We also observed improvements in bone marrow fibrosis in approximately 40% of patients, and overall the bone marrow appeared more histologically normal. In addition, erythroid progenitors, assessed using CD71 staining, increased during treatment. 

All of these findings occurred with a therapy that has been very well tolerated. Approximately 84% of patients receiving monotherapy remain on treatment, with follow-up approaching three years, and approximately three-quarters of patients receiving combination therapy also remain on treatment, despite having substantially higher disease burden. No dose-limiting toxicities were observed, and the maximum tolerated dose has not been reached. We did observe some cytopenias, but these generally occurred in patients who already had baseline cytopenias.

Overall, I believe these data support the disease-modifying potential of INCA033989 and support the initiation of the planned phase III clinical program.

In addition to these myelofibrosis data, we also presented translational analyses and updated data in patients with essential thrombocythemia at EHA, so I would encourage you to take a look at those presentations as well. 

Source: 

Harrison C, Gupta V, Al-Ali HK, et al. Mutant calreticulin–specific monoclonal antibody, INCA033989, is well tolerated and achieves robust spleen, anemia, and molecular responses in patients (pts) with myelofibrosis (MF). Presented at EHA 2026 Congress; June 11-14, 2026; Stockholm, Sweden. Abstract EHA-2822.