Ultraprecision Targeting of CALR Mutations Signals a New Era in Myelofibrosis Treatment

Emerging research suggests a new class of ultraprecision therapies may fundamentally change how MF is treated, particularly for patients harboring calreticulin (CALR) mutations.^1-3

Limitations of Current Treatment Approaches

Myelofibrosis (MF) is a rare, chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, cytopenias, splenomegaly, and a substantial symptom burden that significantly affects quality of life. Despite therapeutic advances over the past decade, most available treatments focus on symptom control rather than selectively targeting the malignant clone driving disease progression.^1-3

Janus kinase (JAK) inhibitors such as ruxolitinib (Jakafi; Incyte) and fedratinib (Inrebic; Celgene) are considered the standard-of-care therapies for many patients with MF. These drugs can shrink the spleen and alleviate various symptoms related to the disease. However, JAK inhibitors do not directly target malignant hematopoietic stem cells and thus have little effect on disease modification or long-term survival.³ Consequently, the majority of patients end up with disease progression, become intolerant to treatment, or lose their response to drugs over time.

“People with myelofibrosis are often treated with therapies that help control symptoms, but they don’t selectively target the abnormal cells driving the disease,” Professor Daniel Thomas, director of SAHMRI’s Blood Cancer program, said.¹ This limitation underscores a major unmet need in MF therapies that precisely distinguish malignant cells from healthy hematopoietic tissue.

CALR Mutations as a Therapeutic Target

Approximately 20-30% of MF patients carry CALR gene mutations, which lead to an abnormal mutant protein that stimulates the oncogenic signaling pathway through the thrombopoietin receptor.² Notably, the CALR mutations are categorized into different structural classes­­—type 1 and type 2—which vary in their biologic characteristics and clinical outcomes.

The latest data published in Blood reveal that mutant CALR generates a novel neoantigen that the immune system can detect, suggesting the possibility of highly selective immunologic targeting.² The findings indicate that CALR mutant cells could potentially be overwhelmed by treatments that focus on the recognition of mutation-specific molecular characteristics rather than the general suppression of hematopoiesis.

Precision Immunology and Ultraprecision Therapies

The SciMex-reported research highlights a novel ultraprecision immunotherapy approach that exploits the structural differences between mutant and normal CALR proteins.¹ By focusing on what differentiates malignant cells from healthy tissue, researchers aim to eliminate disease-driving cells while minimizing off-target toxicity.

“Our research shows that by focusing on what makes these cells different, it may be possible to develop treatments that are both more effective and more targeted. This is part of a major paradigm shift in the treatment of myelofibrosis and related diseases,” Professor Thomas said.¹

This strategy exemplifies the growing field of precision immunology, in which therapies are engineered to recognize specific disease-causing molecular signatures. “This work shows the power of precision immunology, where treatments are designed to recognize disease-causing cells with extraordinary specificity while sparing healthy tissue,” Angel Lopez, Head of Human Immunology at SA Pathology, said.¹

Clinical and Pharmacist Implications

When ultraprecision CALR-targeted therapies are effectively applied in clinical settings, they could drastically reshape the way MF is treated. For pharmacists, the changes could entail new considerations, including patient selection, biomarker testing, monitoring for immune-related adverse events, and long-term disease management.

Pharmacists working in oncology, specialty pharmacy, or hematology clinics are likely to be crucial in guaranteeing that CALR mutation molecular testing is done correctly, informing patients about novel mechanisms of action, and coordinating care with hematologists. As MF treatment becomes increasingly tailored, pharmacists’ drug expertise and patient education skills will be necessary to achieve the best possible outcomes.

Conclusion

The promise of CALR-directed ultraprecision therapy reflects a broader shift toward disease-modifying treatments in hematologic malignancies. “The future of cancer treatment lies in understanding disease at a molecular and immune level and then translating that knowledge into therapies that are potent, long-lasting, and precise,” Lopez said.¹ While additional clinical validation is needed, these findings represent an important step toward therapies that move beyond symptom relief and directly address the root causes of myelofibrosis.

REFERENCES

1. New targeted treatment offers hope for people with myelofibrosis. Scimex. Published January 12, 2026. Accessed February 3, 2026. https://www.scimex.org/newsfeed/new-targeted-treatment-offers-hope-for-people-with-myelofibrosis

2. Thompson-Peach CA, Thomas D, Dottore M, et al. Ultraprecision Therapy for Type 1 vs Type 2 CALR+ MPN by Dual Epitope Targeting that Restores Ruxolitinib Sensitivity. Blood Journal. Published online January 2, 2026. doi:https://doi.org/10.1182/blood.2024027897

3. Tefferi A, Guglielmelli P, Pardanani A, Vannucchi AM. Myelofibrosis Treatment Algorithm 2018. Blood Cancer J. 2018;8(8):72. Published 2018 Jul 31. doi:10.1038/s41408-018-0109-0

4. Passamonti F, Mora B. Myelofibrosis. Blood. Published online November 23, 2022. doi:https://doi.org/10.1182/blood.2022017423