Editor's Note: The 2025 European Hematology Association (EHA) Annual Meeting was recently held, bringing together top global experts in the field of hematologic malignancies to discuss the latest research findings and future directions. In the highly anticipated "Late-Breaking Abstract" session, Professor John Mascarenhas from the Icahn School of Medicine at Mount Sinai presented clinical study data on INCA33989, a novel, first-in-class monoclonal antibody specific to mutant calreticulin (CALR). The study results showed that INCA33989 demonstrated excellent safety and revolutionary therapeutic potential in previously treated patients with Essential Thrombocythemia (ET), with the potential to change the current treatment landscape.

The Therapeutic Dilemma in ET: Clinical Challenges and Unmet Needs of Mutant CALR

Essential Thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) characterized by abnormal proliferation of megakaryocytes in the bone marrow and a persistently elevated platelet count. It is associated with vasomotor symptoms, a risk of thrombosis or hemorrhage, and the risk of progression to myelofibrosis (MF) or acute myeloid leukemia (AML). Professor Mascarenhas first pointed out that approximately 25% of patients with ET carry a CALR gene mutation, with type 1 (a 52-bp deletion) and type 2 mutations being the most common.

Compared to patients with the JAK2 V617F mutation, patients with CALR-mutant ET have lower response rates to various existing treatment options and a higher risk of disease progression to myelofibrosis. Currently, the treatment goals for ET primarily focus on controlling blood cell counts to prevent vascular complications and improve symptoms. However, existing therapies (such as hydroxyurea, anagrelide, etc.) are often limited by side effects or inadequate efficacy and do not directly target the driver mutations of the disease. There is an urgent clinical need for an innovative therapy that can precisely target the mutant protein and modify the course of the disease.

INCA33989: A First-in-Class Antibody Precisely Targeting the Mutant Protein

To address this clinical gap, INCA33989 was developed. Professor Mascarenhas explained that INCA33989 is a high-affinity, fully humanized IgG1 monoclonal antibody with a first-in-class mechanism of action. It selectively recognizes and binds to the complex formed by mutant CALR and the thrombopoietin (TPO) receptor, thereby inhibiting the dimerization of the receptor and blocking the aberrant activation of the downstream JAK-STAT signaling pathway. In preclinical models, this precise targeted inhibition selectively induces apoptosis in cells carrying mutant CALR, thus eliminating the malignant clone at its source.

The data reported at this conference are from an ongoing Phase Ib clinical study. The study enrolled high-risk ET patients diagnosed according to World Health Organization (WHO) criteria, carrying a CALR exon 9 mutation, and having failed at least one prior line of therapy. The study aims to evaluate the safety and tolerability of INCA33989 and to determine the Recommended Phase 2 Dose (RP2D). Notably, in the initial phase of the study, patients were allowed to continue using hydroxyurea or anagrelide for platelet control while receiving INCA33989.

Excellent Safety: No Dose-Limiting Toxicities and Generally Well-Tolerated

Safety was the primary endpoint of the Phase I study. Professor Mascarenhas emphasized that across a wide dose-escalation range from 25mg to 2500mg, INCA33989 demonstrated an excellent safety profile. No Dose-Limiting Toxicities (DLTs) were observed, and the Maximum Tolerated Dose (MTD) was not reached.

Among the 49 enrolled patients, 85.7% experienced a Treatment-Emergent Adverse Event (TEAE), of which 61% were considered by investigators to be related to the study drug. The incidence of Grade 3 or higher TEAEs was 26%. Notably, transient, asymptomatic elevations in lipase were observed, but their occurrence was not clearly dose-related, was not associated with any imaging abnormalities, and typically resolved before the next dose. Professor Mascarenhas stated that while the exact mechanism is still unclear, it did not pose a clinical risk. Throughout the study, only one patient required a dose modification due to a TEAE, and no patients discontinued treatment due to adverse events. As of the reporting date, 98% of patients were still on treatment, with a median exposure duration of 22 weeks, demonstrating the drug’s long-term safety.

[High and Durable Hematologic and Molecular Responses] In terms of efficacy, the performance of INCA33989 was equally impressive. Data showed a rapid decrease in platelet counts within the first cycle of treatment. Particularly in the 400mg and higher dose cohorts, platelet counts quickly normalized and remained stable. A strong piece of evidence is that among the 31 patients who were on concomitant cytoreductive therapies, as many as 65% were able to discontinue their prior therapy due to effective platelet control. In terms of overall response, the Overall Response Rate (ORR) in the 400mg to 2500mg dose cohorts was as high as 86%, with an astounding Complete Response (CR) rate of 82%. This rate is unprecedented in previously treated ET patients. Deeper molecular analysis revealed the potential of INCA33989 to alter the biological behavior of the disease. Monitoring of the mutant CALR Variant Allele Frequency (VAF) showed a decrease in VAF levels in nearly all patients. 47% of patients achieved a VAF reduction of ≥20%, and 21% achieved a deep molecular response with a VAF reduction of ≥50%. All patients who achieved a molecular response also achieved a hematologic response (CR or partial response), strongly demonstrating the direct link between clinical benefit and the molecular targeting effect.

[Deep into the Bone Marrow: Biological Evidence of Restoring Normal Hematopoiesis] To further investigate the mechanism of action of INCA33989, the research team performed single-cell RNA sequencing on peripheral blood samples from seven patients in clinical response. The results showed that INCA33989 could precisely eliminate mutant CALR-expressing hematopoietic stem cells and myeloid/erythroid progenitors while promoting the proliferation of wild-type (i.e., non-mutant) cells. This finding indicates that INCA33989 not only controls blood cell counts but also remodels the patient’s hematopoietic system from the source, shifting it toward a normal hematopoietic state. Evidence from the bone marrow level also supports this conclusion. Analysis of post-treatment bone marrow samples revealed a significant reduction in the number of mutant CALR-expressing megakaryocytes (stained yellow), while the number of wild-type megakaryocytes (stained blue) correspondingly increased. Quantitative analysis showed that the reduction in mutant megakaryocytes was the primary driver of the overall decrease in megakaryocyte count (by approximately 75%). This again confirms that INCA33989 is driving a benign transformation of the hematopoietic pattern within the bone marrow.

[Expert Conclusion and Future Outlook] In his conclusion, Professor Mascarenhas stated: “As a first-in-class, mutant CALR-specific targeted therapy, INCA33989 has demonstrated unparalleled safety and efficacy in previously treated, high-risk ET patients. It not only provides rapid and durable control of hematologic parameters but also induces deep molecular responses and modulates the biological course of the disease by clearing the mutant stem/progenitor cell pool.” These encouraging early data mark a major leap forward in the targeted treatment of ET. The success of INCA33989 not only brings a new, potentially disease-modifying treatment option to patients with CALR-mutant ET but also highlights the enormous potential of precisely targeting driver mutations in the field of MPN therapy. The continued progress of this research gives us reason to believe that the treatment of hematologic malignancies is entering a new era of greater precision, efficacy, and safety. Contribution/Interview Source: Onco-Vision, Oncology Express