Myelofibrosis (MF), a Philadelphia chromosome-negative myeloproliferative neoplasm, is marked by progressive bone marrow fibrosis and ineffective hematopoiesis, leading to splenomegaly, anemia, and debilitating symptoms. Two phase III trials, COMFORT-I and COMFORT-II, have demonstrated that the JAK1/JAK2 inhibitor ruxolitinib significantly improves splenomegaly and MF-related symptoms compared to placebo or best available therapy (BAT) in intermediate-2 or high-risk MF patients.
Aberrant JAK-STAT Signaling in Myelofibrosis
A key characteristic of MF is the dysregulation of JAK-STAT signaling, often driven by somatic mutations in hematopoietic stem cells. The JAK2 V617F mutation, present in approximately 60% of PMF and ET patients and over 95% of PV patients, contributes to the disease phenotype. This dysregulation is implicated in both myeloproliferation and the excessive production of inflammatory cytokines, which are linked to MF-related symptoms.
Ruxolitinib's Impact on Symptoms and Quality of Life
Ruxolitinib has shown significant improvements in MF-related symptoms, with COMFORT-I demonstrating a mean decrease of 46% in Total Symptom Score (TSS) compared to a 42% increase with placebo. Patients treated with ruxolitinib also experienced improvements in measures of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30), including global health status/quality of life and physical, role, emotional, and social functioning. Symptom improvements were accompanied by decreases in the plasma levels of pro-inflammatory biomarkers.
Long-Term Efficacy and Safety
Long-term follow-up data from the COMFORT trials and clinical experience in unselected patient populations have confirmed the sustained improvement of splenomegaly and symptoms with ruxolitinib. Analyses suggest that patients benefit from ruxolitinib therapy across subgroups defined by age, MF type, risk category, performance status, JAK2 V617F mutation status, extent of splenomegaly, or presence of cytopenias. While ruxolitinib is associated with dose-dependent anemia and thrombocytopenia, these adverse events are generally manageable and rarely lead to treatment discontinuation. Furthermore, data suggest that with dose adjustments, platelet counts stabilized, and hemoglobin gradually recovered to levels slightly below baseline after the first 8–12 weeks of therapy. After initial increases, the need for red blood cell transfusions decreased to a level similar to placebo.
Survival Benefits
Two-year follow-up data from the COMFORT trials suggest that patients with intermediate-2 or high-risk MF receiving ruxolitinib therapy may have improved survival compared with those receiving no (placebo) or traditional therapy.
