After 15 years of clinical experience with ruxolitinib in myelofibrosis, researchers have identified key predictive biomarkers that can optimize treatment decisions and improve patient outcomes. Despite demonstrating clear superiority over best available therapies like hydroxyurea and corticosteroids for controlling splenomegaly and symptoms, 40% to 70% of patients ultimately fail ruxolitinib therapy and discontinue treatment within 3 to 5 years.
Clinical Predictors of Treatment Response
Research has established several clinical variables that correlate with reduced treatment efficacy. Patients with peripheral blast counts exceeding 5%, cytopenic phenotype, and higher disease burden show significantly lower response rates and decreased overall survival. The cytopenic phenotype specifically includes transfusion-dependent anemia and platelet counts below 200 μL, which are associated with higher probability of early drug discontinuation.
"For example, for a patient with a high percentage of blasts, ruxolitinib therapy may not be optimal. Also, for patients who have a cytopenic phenotype, ruxolitinib may not be the go-to option," explained Dr. Francesca Palandri, adjunct professor in the Department of Medical and Surgical Sciences at the University of Bologna, during her presentation at the Society of Hematologic Oncology 2025 Annual Meeting.
Dosing Challenges in Real-World Practice
A critical finding from real-world studies reveals that over 40% of patients receive underdosed ruxolitinib compared to their baseline platelet counts. This practice, likely driven by concerns over early hematological toxicity, significantly compromises treatment outcomes. Patients who start ruxolitinib at underdoses experience much lower probability of spleen and symptom responses, higher discontinuation rates, and decreased overall survival.
"That's why it is very important to have an educational point recommending the use of the higher tolerated dose," Palandri emphasized, highlighting the need for clinicians to balance toxicity concerns with therapeutic efficacy.
Timing of Treatment Initiation
Both the real-world ROMEI study from Italy and prospective sub-cohort analyses of the COMFORT-I and COMFORT-II studies demonstrate that delaying ruxolitinib initiation by more than one year from myelofibrosis diagnosis significantly impacts outcomes. Patients who experience treatment delays show decreased probability of response and reduced overall survival, making timely treatment initiation a prognostic marker within clinicians' control.
Molecular Biomarkers for Treatment Selection
Emerging evidence supports the integration of molecular evaluation into treatment decision-making. Data from the COMFORT-I and COMFORT-II studies indicate that patients with more than one high molecular risk mutation experience decreased response probability and overall survival. More recently, alterations in the CBL/RAS pathway have been directly correlated with lower response probability.
"Having a RAS/CBL mutation, for example, should raise our alarm bells. We should seek additional combinational or alternative therapies regarding ruxolitinib alone," Palandri noted, suggesting that while molecular evaluation may not definitively determine whether to start ruxolitinib, it should influence treatment strategy considerations.
Implications for Clinical Practice
These findings underscore the importance of comprehensive patient assessment before initiating ruxolitinib therapy. The identification of predictive biomarkers enables clinicians to select the most appropriate frontline JAK inhibitor treatment and optimize dosing strategies. For patients with unfavorable predictive markers, alternative therapeutic approaches or combination strategies may be warranted to improve outcomes in this challenging hematologic malignancy.
