Editor's Note: At the 2026 European Hematology Association (EHA) Annual Congress, Professor Claire Harrison from Guy's and St Thomas' NHS Foundation Trust, London, shared the latest research data on the mutation-specific monoclonal antibody INCA033989 (hereinafter referred to as "989") for the treatment of calreticulin (CALR)-mutated myelofibrosis (MF) patients. This study aims to evaluate the safety, tolerability, and preliminary efficacy of this first-in-class drug in monotherapy and combination regimens, providing a new path for precision treatment in this specific subpopulation of CALR-mutated patients. 01 Treatment Dilemma: Unique Biological Challenges of CALR-Mutated Myelofibrosis
CALR mutations account for approximately 25%-35% of MF patients. Professor Harrison pointed out that although CALR-mutated patients may outperform JAK2-mutated patients in certain prognostic indicators, they possess unique biological and clinical characteristics. These patients often respond poorly to existing standard treatments (such as JAK inhibitors), particularly in terms of Spleen Volume Reduction (SVR) and Total Symptom Score (TSS) relief, where response rates are typically lower than the overall level. Furthermore, CALR-mutated patients experience a higher incidence of anemia when receiving ruxolitinib treatment. The CALR-mutant protein has a unique pathogenic mechanism: the mutated CALR protein binds to the thrombopoietin receptor (MPL/TPO-R) and is secreted to the cell surface. This mutant protein exists only on mutated cells, providing an excellent “neoantigen” target for precision targeted therapy. As a novel, fully humanized, high-affinity, Fc-silent IgG1 monoclonal antibody, INCA033989 selectively targets the mutant CALR protein on the cell surface, thereby inhibiting oncogenic signaling and cell proliferation.
02 Safety Assessment: Excellent Tolerability Supports Continuous Dose Exploration
The data released at this congress included follow-up observations for up to 2.5 years. The study was divided into a monotherapy cohort (including patients who were intolerant to JAK inhibitors, relapsed/refractory, or unsuitable for JAK inhibitors due to reasons such as skin cancer or cytopenia) and an INCA033989 combined with ruxolitinib cohort. The safety data were extremely impressive. Professor Harrison emphasized that no dose-limiting toxicities (DLTs) were observed across all dose groups, and the maximum tolerated dose (MTD) has not yet been reached. • Monotherapy Cohort: 84% of patients remain on treatment, fully demonstrating the drug’s good long-term tolerability. • Adverse Events (AEs): Treatment-emergent adverse events (TEAEs) with an incidence exceeding 15% were almost entirely hematological toxicities (anemia, thrombocytopenia), and the vast majority occurred in patients with pre-existing cytopenia at baseline. More importantly, the occurrence of TEAEs did not show significant dose-dependency. • Combination Cohort: Safety when combined with ruxolitinib was equally good, with transient alanine aminotransferase (ALT) elevations observed in only a few patients, who recovered spontaneously without drug discontinuation.
03 Efficacy Analysis: Significant Benefits in Spleen and Symptom Relief
Regarding efficacy assessment, the study employed rigorous MRI monitoring. Notably, 61% of patients did not undergo a sufficient ruxolitinib washout period prior to baseline MRI, making the subsequent observed spleen reduction data even more significant. • Spleen Volume Reduction (SVR): o In the monotherapy cohort, 55% of patients achieved best SVR25 (spleen volume reduction ≥25%), and 39% achieved best SVR35. o In non-Type 1 CALR-mutated patients, even with a small sample size, 1/3 of patients still achieved SVR35. • Total Symptom Score (TSS): o The majority of patients achieved ≥50% TSS relief (TSS50). Professor Harrison specifically mentioned that as this is an open-label study, the objective data for spleen reduction and subjective symptom improvement were highly consistent, further validating the clinical benefit.
04 Hematopoietic Restoration: Breakthrough in Anemia Response and Transfusion Independence
Anemia is a major challenge in the treatment of myelofibrosis. INCA033989 demonstrated excellent erythropoietic potential by restoring the normal hematopoietic microenvironment. • Hemoglobin (Hb) Increase: Anemia response was observed in 60% of patients, the vast majority of which were Major Responses. Regardless of baseline Hb levels, patients showed a significant upward trend in Hb after receiving treatment. • Transfusion Independence: Among the 6 patients who were transfusion-dependent at baseline, 4 (approximately 66.7%) successfully achieved transfusion independence. This result suggests that INCA033989 is of great significance in improving the quality of hematopoiesis and patients’ quality of life.
05 Deep Response: Significant Reductions in Variant Allele Frequency (VAF) and Bone Marrow Morphological Modification
As a potential disease-modifying therapy, INCA033989 provided solid evidence at the molecular biological and histopathological levels. • Molecular Remission: o The study observed a significant decrease in the proportion of CALR mutation-positive cells among circulating progenitor cells via single-cell sequencing. o Variant Allele Frequency (VAF) analysis showed that in the PBMC analysis cohort, 81% of patients had a VAF reduction of ≥25%; among them, 62% were Type 1 mutations and 38% were Type 2/non-Type 1 mutations. • Bone Marrow Morphology: o Professor Harrison displayed landmark bone marrow comparisons: after 6 months of treatment, bone marrow cellularity tended to normalize, and histological features of megakaryocytes were significantly improved. o Quantitative analysis showed that 40% of patients achieved a reduction in bone marrow fibrosis grade, and CD71 staining indicated a significant increase in erythroid progenitors, which highly correlated with the clinically observed improvement in anemia.
Summary and Outlook:
Professor Claire Harrison concluded that INCA033989 (989), whether as a monotherapy or in combination with ruxolitinib, demonstrated excellent safety and significant clinical activity in CALR-mutated myelofibrosis patients. The drug is not only effective in reducing spleen volume, alleviating symptoms, and increasing hemoglobin but also demonstrates the potential for deep remission at the molecular and bone marrow pathological levels. Based on these positive results, the research team plans to launch a global multi-center Phase III clinical project to further validate its position in clinical practice.
Expert Profile: Professor Claire Harrison • Professor of Hematology, Guy’s and St Thomas’ NHS Foundation Trust, London. • Internationally renowned expert in Myeloproliferative Neoplasms (MPN), with profound academic expertise in the precision treatment of myelofibrosis, clinical evaluation of JAK inhibitors, and new drug development.
