From JAK to CALR: redefining therapeutic targets in myeloproliferative neoplasms.

This review highlights the emergence of CALR as a promising therapeutic target in CALR-mutated myeloproliferative neoplasms. While current JAK inhibitors alleviate symptoms and reduce thrombosis risk, they lack clonal specificity, have a limited impact on the natural history of disease, and are limited by toxicity and resistance. In contrast, CALR mutations generate a unique, disease-specific neoepitope that drives disease pathogenesis through aberrant MPL activation and is accessible on the cell surface, making it an ideal immunologic and antibody target. Preclinical and early clinical advances - including monoclonal antibodies, bispecific T-cell engagers, CAR-T therapies, antibody-drug conjugates, and peptide/viral vector vaccines - have demonstrated selective activity against CALR-mutant clones while sparing normal hematopoiesis, with encouraging evidence of molecular remissions and disease modification. Although challenges such as immune tolerance remain, mutant CALR-directed therapies represent a potential transformative shift in essential thrombocythemia, and primary myelofibrosis treatment.