Essential thrombocythemia (ET) is a common myeloproliferative neoplasm characterized by elevated platelet counts, thrombotic and hemorrhagic events, and significantly impaired quality of life. At the 2025 European Hematology Association (EHA) Congress, Professor John Mascarenhas from the Icahn School of Medicine at Mount Sinai (New York, USA) presented a first-in-class study of INCA33989—a monoclonal antibody specifically targeting mutant calreticulin (CALR) in ET. This groundbreaking study was selected for the prestigious “Late-Breaking Abstract” (LBA) session. The trial explored the safety, efficacy, and disease-modifying potential of INCA33989 in patients with ET. In an exclusive interview with Oncology Frontier - Hematology Frontier, Professor Mascarenhas elaborated on the study’s key findings and shared insights into future research directions.Oncology Frontier – Hematology Frontier: Could you briefly explain the mechanism of action of INCA33989 in ET patients, and what the current study has shown in terms of safety and efficacy?
Professor John Mascarenhas: INCA33989 is a monoclonal antibody that selectively targets the mutant CALR protein in complex with the thrombopoietin (TPO) receptor on the surface of malignant cells. It offers a highly selective therapeutic approach by specifically recognizing mutant CALR-positive clones in ET while sparing healthy cells. Preclinical studies have shown that the antibody induces cell death by inhibiting the JAK-STAT signaling pathway.
Importantly, INCA33989 lacks an Fc region, which prevents immune activation and reduces the risk of cytokine release syndrome and off-target toxicity. It also does not carry a cytotoxic payload, meaning it is not expected to produce significant toxicity—something that has been confirmed in clinical testing.
Oncology Frontier – Hematology Frontier: Do you believe the current data is sufficient to support INCA33989 as a potential standard of care in ET? What additional research is needed to validate its efficacy and safety?
Professor John Mascarenhas: We’re still in the early stages. The data we presented come from a Phase 1 trial involving 49 patients globally. In this trial, we escalated the dose from 24 mg to 2500 mg via intravenous infusion every two weeks, without encountering dose-limiting toxicity or identifying a maximum tolerated dose. This suggests a favorable safety profile, with minimal adverse effects.
Clinically, we observed normalization of platelet and white blood cell counts, as well as biologic activity evidenced by a reduction in the mutant CALR variant allele frequency. Sequencing of peripheral blood cells indicated a decrease in mutant CALR expression in hematopoietic stem and progenitor cells, suggesting clonal modulation. In the bone marrow, there was a reduction in abnormal megakaryocytes and a corresponding increase in normal megakaryocytes.
These results demonstrate not only that the antibody is safe but also that it has meaningful biologic and clinical activity. The next steps will involve expanding the study population, evaluating different dosing strategies, and collecting additional biomarker data to better assess the depth and durability of response.
Oncology Frontier – Hematology Frontier: Given the tolerability and efficacy of INCA33989 at various doses, how do you envision optimizing its dosing and treatment schedule in future clinical practice?
Professor John Mascarenhas: Optimizing the drug’s dosing schedule will be a key focus going forward. The current results give us confidence in its tolerability, but we’re still in the early phases of development and don’t yet know the optimal administration strategy. It’s possible that biweekly infusions may not be necessary. Monthly dosing—or even less frequent schedules—could potentially maintain efficacy while enhancing convenience.
There are many important and exciting questions to explore. The most critical ones have been answered so far: Is it safe? Yes. Is it effective? The data says it is. Now, the focus shifts to determining how best to deliver the therapy to achieve the most robust and durable responses. Fine-tuning the dosing schedule will be central to this goal.
About the Expert
Professor John Mascarenhas Director, Center of Excellence for Blood Cancers and Myeloid Disorders, Tisch Cancer Institute Director, Adult Leukemia Program, Mount Sinai Hospital Lead Investigator for Clinical Research in Myeloproliferative Neoplasms Icahn School of Medicine at Mount Sinai, New York, USA
Professor Mascarenhas specializes in translational research in myeloproliferative neoplasms and leads clinical trials sponsored by the National Cancer Institute within the Myeloproliferative Neoplasm Research Consortium (MPN-RC).
