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More than a decade after ruxolitinib became the standard frontline therapy for intermediate- and high-risk myelofibrosis, clinicians still lack a reliable way to predict which patients will benefit most. A review published in Clinical Lymphoma, Myeloma & Leukemia as part of the Society of Hematologic Oncology's State of the Art Updates series, led by Francesca Palandri of the University of Bologna, summarizes the current evidence on clinical, molecular, cytogenetic, and dynamic predictors of response to the JAK1/JAK2 inhibitor.
Myelofibrosis is a biologically heterogeneous myeloproliferative neoplasm driven by constitutive JAK-STAT activation and characterized by progressive marrow fibrosis, cytopenias, splenomegaly, and systemic inflammation. Ruxolitinib delivers meaningful improvements in spleen size, constitutional symptoms, and survival, but responses vary widely. A substantial proportion of patients experience suboptimal benefit, early discontinuation, or disease progression, which is the gap the review sets out to address.
On the clinical side, the review and Palandri's accompanying SOHO discussion point to several baseline features associated with fewer responses and shorter overall survival: peripheral blast counts above 5%, higher overall disease burden, and a cytopenic rather than proliferative phenotype. Timing matters as well. Delaying ruxolitinib for more than a year after diagnosis has been linked to lower response rates and reduced survival, a finding that echoes pooled analyses of the COMFORT trials.
Dosing emerges as a modifiable predictor. Drawing on interim results from the Italian ROMEI observational study, Palandri notes that roughly 40% of patients receive ruxolitinib below the recommended dose, often to blunt early hematologic toxicity, and that underdosing substantially lowers the probability of spleen and symptom responses.
The review also covers dynamic assessment. The RR6 model, developed by Passamonti and colleagues, uses response at six months of therapy to identify patients headed for poor outcomes, allowing earlier consideration of alternative treatment. Molecular and cytogenetic findings, including high-molecular-risk mutations and unfavorable karyotype, add prognostic information but have not yet been integrated with clinical variables into a single predictive tool.
Palandri frames the next step as building an integrated clinical and molecular model to guide treatment decisions, together with attention to physician practice patterns so that patients receive ruxolitinib at the right stage and the right dose. The review is one of the series SOHO commissions for its annual meeting in Houston, where Palandri discussed the topic during the 2026 congress week.
