Ruxolitinib, a selective oral Janus kinase (JAK) 1/2 inhibitor, has emerged as a pivotal therapy in the management of myelofibrosis (MF), a rare and progressive myeloproliferative neoplasm characterized by bone marrow fibrosis, anemia, splenomegaly, and systemic symptoms. Since its approval by the U.S. Food and Drug Administration (FDA) in 2011 for the treatment of adults with intermediate- and high-risk MF—including primary MF, post-polycythemia vera (PV) MF, and post-essential thrombocythemia MF—ruxolitinib has become the standard of care in this patient population. The drug’s approval was based on the robust results from the COMFORT-I and COMFORT-II phase 3 trials, which demonstrated significant improvements in spleen volume reduction, symptom alleviation, and overall survival. Over the subsequent decade, its efficacy and safety have been consistently affirmed by numerous large-scale studies, including JUMP, ROBUST, EXPAND, and REALISE, and through extensive postmarketing surveillance covering more than 256,000 patient treatment years globally.
Hematologic adverse events (AEs), particularly anemia and thrombocytopenia, are the most common side effects associated with ruxolitinib, largely due to its JAK2-inhibitory mechanism that disrupts erythropoietin and thrombopoietin signaling. These cytopenias typically manifest within the first 8 to 12 weeks of therapy but are usually transient and manageable through dose adjustments or red blood cell transfusions. Notably, only a small proportion of patients discontinue treatment due to these effects. Real-world evidence, including from the expansive JUMP trial, has further validated the manageable nature of these events and the sustained clinical benefit of ruxolitinib, even in patients with pre-existing cytopenias.
Nonhematologic AEs are generally mild to moderate in severity and include fatigue, dizziness, diarrhea, and headaches. The incidence of serious infections such as pneumonia and herpes zoster remains low, and no significant increase in the risk of major adverse cardiovascular events (MACE) has been observed in comparison with control arms in pivotal studies. Moreover, despite the theoretical concerns related to JAK inhibition, long-term data show no elevated risk of secondary malignancies, including nonmelanoma skin cancers or lymphomas, when compared to background rates in MF populations or those treated with older therapies such as hydroxyurea. Importantly, the presence of baseline anemia is not a contraindication to ruxolitinib therapy and does not negatively affect treatment outcomes. Patients with anemia have shown similar spleen responses and symptom improvements as those without, and overall survival is not compromised.
In terms of dosing, individualized strategies based on platelet count, anemia status, and comorbidities are essential to optimizing outcomes. Findings from the REALISE and EXPAND studies support initiating therapy at lower doses in patients with low hemoglobin or platelet levels, followed by cautious uptitration based on response and tolerability. Adjunctive therapies such as erythropoiesis-stimulating agents, anabolic steroids like danazol, and thalidomide derivatives may further support hematologic parameters when necessary. Additionally, the management of ruxolitinib discontinuation is crucial. Abrupt cessation has been associated with symptom exacerbation due to inflammatory cytokine rebound. Hence, gradual tapering, often supplemented with corticosteroids, is recommended to minimize the risk of clinical deterioration during treatment interruption.
Postmarketing surveillance over ten years has reinforced the consistent safety profile of ruxolitinib observed in clinical trials. The majority of reported AEs were non-serious, and no new safety signals were identified. Ongoing monitoring, including real-world studies and registry data, continues to provide valuable insights into long-term use. The role of ruxolitinib during the COVID-19 pandemic has also been noteworthy. Evidence suggests that continuation of therapy during SARS-CoV-2 infection is advisable, as discontinuation has been associated with increased mortality in patients with MF.
In conclusion, more than a decade after its FDA approval, ruxolitinib continues to be an indispensable therapy for patients with myelofibrosis. Its ability to control symptoms, reduce spleen size, and potentially extend survival, combined with a well-characterized and manageable safety profile, underscores its significance in clinical practice. As research advances, further optimization of dosing strategies and combination therapies may enhance its utility, but its foundational role in the treatment of MF is firmly established.
Reference: https://pmc.ncbi.nlm.nih.gov/articles/PMC10373260/
