In patients with CALR exon 9–mutated myelofibrosis who were resistant or intolerant to prior Janus kinase (JAK) inhibitor therapy or ineligible for such treatment, the first-in-class mutant calreticulin–specific monoclonal antibody INCA033989 as monotherapy or in combination with ruxolitinib appeared to be well tolerated and resulted in spleen and anemia responses and symptom improvements, based on preliminary data from dose escalation of two global phase I studies (INCA033989-101 and INCA033989-102).1
“Current treatments for myelofibrosis are not mutant-targeted and have limited efficacy in reducing the mutant CALR variant allele frequency,” commented presenting author John O. Mascarenhas, MD, Professor of Medicine, Icahn School of Medicine at Mount Sinai, New York, at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition. “INCA033989 has a unique mechanism of action…, selectively targeting and binding the mutant CALR protein in complex with the thrombopoietin receptor, thereby internalizing the complex for lysosomal degradation and abrogating oncogenic JAK–STAT signaling…, leading to selective death of CALR-mutant cells and sparing wild-type cells.”
Study Details
Data were from two ongoing phase I, first-in-human, multicenter, open-label studies (INCA033989-101 [outside the U.S.] and -102 [U.S. only]) evaluating INCA033989 in patients with certain classic myeloproliferative neoplasms harboring CALR exon 9 mutations. The presentation focused on those with myelofibrosis; results from the essential thrombocythemia cohort were presented separately during the meeting.2
Eligible patients were aged at least 18 years with primary or post–essential thrombocythemia myelofibrosis, a CALR exon 9 mutation, and splenomegaly of at least 450 mL by imaging or 5 cm by palpation. The monotherapy cohort was either intolerant or resistant to JAK inhibitor therapy after at least 12 weeks, or ineligible for such treatment, while those in the combination therapy cohort had received ruxolitinib for at least 12 weeks with a suboptimal response.
INCA033989 was administered intravenously every 2 weeks, with dose escalation from 24 to 2,500 mg, either as monotherapy or in combination with ruxolitinib. Dose expansion was evaluated in patients receiving monotherapy and combination therapy, as well as in JAK inhibitor–naive patients within these cohorts. The myelofibrosis analysis included 52 and 20 patients in the monotherapy and combination therapy cohorts, respectively.
Dose-limiting toxicities and treatment-emergent adverse events were identified as the primary endpoints. The key secondary endpoints were spleen volume reduction of 25% (SVR25) or 35% (SVR35) or more at weeks 12 and 24; anemia response; symptom improvement (per the MPN Symptom Assessment Form Total Symptom Score [MPN-SAF TSS]); and changes in mutant CALR allele burden.
Monotherapy: Safety
Monotherapy with INCA033989 was “super well tolerated,” as described by Dr. Mascarenhas. Any-grade treatment-emergent adverse events were seen in 96.2% of patients, with treatment-related treatment-emergent adverse events reported in 57.7%. A total of 30.8% of patients experienced a treatment-emergent adverse event of grade 3 or higher. Serious treatment-emergent adverse events occurred in 9.6% of the cohort and included abdominal pain with tendonitis, monoclonal B-cell lymphocytosis (progressed to Mantle cell lymphoma) with small intestinal obstruction, arthritis, basal cell carcinoma, and pyrexia.
Dose reductions (3.8%) and interruptions (5.8%) were “infrequent,” according to Dr. Mascarenhas, and 23.1% of patients had dose delays because of treatment-emergent adverse events. No dose-limiting toxicities were observed, so no maximally tolerated dose was identified. A total of 86.5% of patients remained on treatment, which, in a first-in-human phase I study, is “a testament to its tolerability and safety,” he said.
Increases in aspartate aminotransferase (AST) were reported in 11 patients; nearly half (n = 5 [45%]) had grade 1 elevation at baseline. This treatment-emergent adverse event resolved in nine patients, with the remaining cases being grade 1. One patient required a dose reduction because of grade 3 AST elevation, which resolved, and a subsequent increase was tolerated, “so this was not a major obstacle for treatment with this antibody,” Dr. Mascarenhas explained.
No association between treatment-emergent adverse events and dose was observed.
Monotherapy: Efficacy
Monotherapy with INCA033989 resulted in an SVR25 at week 24 in 41.7% of patients (overall n = 36), while 33.3% achieved SVR35 at the same time point. A total of 47.9% and 31.3% of patients achieved SVR25 and SVR35, respectively, as best SVR. Dr. Mascarenhas added, “In [JAK inhibitor–naive] patients [n = 7]…, the spleen responses were better” compared with those who had previously received such therapy (n = 29) at 24 weeks (SVR25: 71.4% vs 34.5%; SVR35: 57.1% vs 27.6%).
A total of 93.3% of evaluable patients (overall n = 45) experienced symptom improvement, and 60.0% achieved a TSS reduction of at least 50% (TSS50). The TSS50 rate was 39.4% at 24 weeks (overall n = 33); the rates were 60.0% and 35.7% in JAK inhibitor–naive (n = 5) and previously treated (n = 28) patients, respectively.
Improvements in hemoglobin levels were observed in both patients with (defined as hemoglobin < 10 g/dL for men, < 11 g/dL for women) and without anemia “but really impressively in [the former population],” Dr. Mascarenhas stated. Among evaluable patients with anemia (n = 25), 56.0% achieved an anemia response, including major responses in 40.0% and minor responses in 16.0%.
Combination Therapy: Safety
“Similar in many ways to what we saw with monotherapy,” said Dr. Mascarenhas, INCA033989 was well tolerated in combination with ruxolitinib. Treatment-emergent adverse events occurred in all patients, with 65.0% experiencing treatment-related treatment-emergent adverse events and 55.0% having treatment-emergent adverse events classified as grade 3 or higher. He noted that serious treatment-emergent adverse events were reported in 25.0% of patients and included acute myocardial infarction, anemia, basal cell carcinoma, diffuse large B-cell lymphoma (DLBCL), and stomatitis. Regarding the DLBCL case, he noted, “We see increased risk of second primary malignancies, including lymphomas, in this patient population, so I don’t read much into that.”
Dose reductions and interruptions because of treatment-emergent adverse events occurred in 5.0% of patients each, and 40.0% experienced a dose delay. As with monotherapy, no dose-limiting toxicities were observed, so a maximum tolerated dose was not reached. A total of 85.0% of patients were still receiving treatment, again highlighting its tolerability, Dr. Mascarenhas said.
Four patients experienced elevations in AST and/or alanine aminotransferase (ALT), but all events were grade 1 or 2. Two events remain ongoing.
Combination Therapy: Efficacy
Among evaluable patients at week 24 (n = 12), the SVR25 rate was 50.0% and the SVR35 rate was 25.0%. A best SVR of SVR25 and SVR35 occurred in 11 and 8 patients, respectively.
Symptom improvements were observed in 81.3% of patients (overall n = 16), and 33.3% of those with available percentage change in MPN-SAF TSS from baseline (overall n = 9) achieved TSS50 at week 24.
In evaluable patients (n = 14), 86% had stable anemia during the study. One achieved a major anemia response.
Other Findings
“One of the things that makes this antibody really interesting and very exciting is that it is very selective,” said Dr. Mascarenhas. Exploratory analyses appeared to support the potential of INCA033989 to modify the disease and suggest that “we’re really getting to [its] core.”
Immunohistochemistry demonstrated a reduction in mutated CALR–positive megakaryocytes from screening to the first day of the seventh cycle of treatment. This decrease was found to be accompanied by a corresponding increase in their wild-type counterparts.
Dr. Mascarenhas noted a “very significant” decline in total megakaryocytes in aggregated data from 23 patients, “being driven by a reduction in mutant CALR–positive megakaryocytes.” He added that there was an increase in wild-type CALR megakaryocytes, which “speaks to the normalization of hematopoiesis in the bone marrow.”
Bone marrow fibrosis was found to decrease in 40.0% of patients (overall n = 30). “Very interestingly,” CD71 staining indicated improved erythropoiesis in a population with anemia (n = 14), Dr. Mascarenhas noted, adding that this correlated with anemia responses.
Additionally, among patients who received INCA033989 monotherapy and had at least one postbaseline variant allele frequency measurement (n = 47), 89.4% experienced a reduction, with 10.6% achieving a best reduction of at least 25%.
Clinical Implications
The investigators concluded, “As monotherapy in patients with myelofibrosis intolerant, resistant, or ineligible for JAK inhibitor treatment, and in combination with ruxolitinib, [INCA033989] was well tolerated, with no dose-limiting toxicities and few treatment discontinuations. Promising spleen and anemia responses and symptom improvements occurred in both cohorts despite advanced disease and limited follow-up. Variant allele frequency reductions and single-cell analyses further support the potential disease modifying impact of [INCA033989].”
“These data are clear and robust,” Dr. Mascarenhas stated, “enabling a pivotal registration study in the near future.” The development of a subcutaneous formulation is ongoing, which may “make this easier for the patients,” he added.
DISCLOSURE: Dr. Mascarenhas has received research funding from Incyte, PharmaEssentia, Geron, Ajax, Novartis, Italfarmaco SpA, Sobi, AbbVie, BMS, Kartos, Disc, and Karyopharm; and has served as a consultant (including giving expert testimony) for Incyte, Novartis, BMS, Geron, Kartos, Karyopharm, AbbVie, Sobi, MorphoSys (now Novartis), Roche, Merck, Keros, Disc, PharmaEssentia, Italfarmaco SpA, Sumitomo, GSK, Galecto, Pfizer, and Blueprint Medicines.
REFERENCES
1. Mascarenhas J, Al-Ali HK, Gupta V, et al: Safety and efficacy of the mutant calreticulin-specific monoclonal antibody INCA033989 as monotherapy or in combination with ruxolitinib in patients with myelofibrosis: Preliminary results from dose escalation of two global phase 1 studies. 2025 ASH Annual Meeting & Exposition. Abstract 484. Presented December 7, 2025.
2. Gupta V, Mascarenhas J, Ali H, et al: Safety and efficacy of INCA033989, a novel first in class mutant calreticulin-specific monoclonal antibody, in patients with essential thrombocythemia. 2025 ASH Annual Meeting & Exposition. Abstract 1024. Presented December 8, 2025.
EXPERT POINT OF VIEW
Prithviraj Bose, MD, Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, commented on the preliminary data on myelofibrosis from the phase I INCA033989-101 and INCA033989-102 studies of the mutant calreticulin–specific monoclonal antibody INCA033989 in an interview with The ASCO Post.
“I can say, without hesitation, the results were very, very positive, and [INCA033989] was extremely well tolerated. I was very impressed with what I saw in myelofibrosis, and we saw even better results in essential thrombocythemia, which you’d expect because it’s a less genomically complex disease,” Dr. Bose said.
Dr. Bose spoke about the need to identify agents that can effectively target mutant CALR: “This is the driver mutation in 25% to 30% of patients with primary myelofibrosis and essential thrombocythemia. Currently, our treatment landscape consists of JAK inhibitors, which are not specific to this driver mutation and do not eradicate the underlying malignant clone. They make patients feel better and even live longer, shrink spleens, and some improve anemia, but they don’t really modify the underlying disease to a major degree. That’s where a drug that selectively targets the driver mutation, such as this one, clearly has appeal.”
In the study, treatment with INCA033989 also resulted in a reduction in mutant CALR variant allele frequency, and this might be a signal of early disease modification, though this remains to be seen, Dr. Bose added. He said that the addition of a disease-modifying agent to the treatment armamentarium would be a true treatment advance.
DISCLOSURE: Dr. Bose has received research support from Incyte, BMS, CTI (now Sobi), Geron, Janssen, Ionis, Disc, Sumitomo, Karyopharm, Kartos, Telios, MorphoSys (now Novartis), Ajax, Merck, Blueprint Medicines, and Cogent; and has received honoraria/consulting fees from Incyte, BMS, Sobi, GSK, AbbVie, PharmaEssentia, Geron, Ionis, Disc, Sumitomo, Karyopharm, Novartis, Merck, Takeda, Morphic, Jubilant, RayThera, Blueprint Medicines, and Cogent.
