Combination treatments for myelofibrosis in JAK inhibitor-naive patients: evidence, rationale, and clinical direction

ABSTRACT Introduction Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by splenomegaly, constitutional symptoms, cytopenias, bone marrow fibrosis. Frontline therapy relies upon Janus kinase (JAK) inhibition improving symptoms and spleen size, though limited durability and disease modification. Prompting interest in combination strategies. Areas covered This review focuses on combination therapies in patients with MF who are naive to JAK inhibitors. We summarize the available clinical evidence from phase 2 and particularly 3 studies that evaluate combinations of JAK inhibitors with agents that target epigenetic regulation, apoptosis, inflammation, and fibrogenesis. A pubmed search was conducted. Selected combination therapies show promise for improving the depth and durability of response compared with JAK inhibitor monotherapy. Expert opinion Beyond higher rates of spleen and symptom responses, emerging signals suggest combination may deliver reductions in mutant variant allele frequency and improvements in bone marrow fibrosis, supporting a potential shift toward disease modification. However, important gaps remain regarding long-term outcomes, safety, and optimal patient selection, which could range from all, to high risk to those planned for transplant, and these signals require confirmation with longer follow-up and standardized assessment methods including those for toxicity to define the role of combination therapy in the evolving management of MF.