How could calreticulin-targeting therapies change the myelofibrosis transplant paradigm?

Myelofibrosis (MF), the most severe Philadelphia chromosome-negative myeloproliferative neoplasm, is driven by mutations in JAK2, CALR, or MPL, with CALR mutations accounting for 30-35% of cases. Mutant CALR forms an aberrant complex with the thrombopoietin receptor, resulting in constitutive JAK-STAT signalling and is expressed on the malignant cell surface as a tumour-specific neoantigen absent from normal tissues, making it an attractive therapeutic target. Allogeneic haematopoietic cell transplantation (allo-HCT) remains the only curative treatment but is limited to selected patients with adequate fitness and a suitable donor. This review summarises the rapidly evolving landscape of CALR-directed therapies, including peptide vaccines, the Fc-silenced monoclonal antibody INCA033989, bispecific T-cell engagers, antibody-drug conjugates, and the CAR T-cell therapy RPG4, and explores their potential impact on transplant decision-making. INCA033989 has generated the most mature clinical data, demonstrating improvements in splenomegaly, constitutional symptoms, anaemia and early markers of disease modification, whereas cytotoxic approaches such as CAR T-cell therapy offer the prospect of deeper clonal eradication. Collectively, these therapies have the potential to redefine the role and timing of allo-HCT and expand treatment opportunities in the peri-transplant setting, including the targeted eradication of measurable residual disease following transplantation.