Myelofibrosis is a chronic bone marrow disorder where scar tissue builds up, disrupting normal blood cell production. This can lead to an enlarged spleen, fatigue, and night sweats. Targeted therapies, particularly JAK inhibitors, are important for managing myelofibrosis. Ruxolitinib and fedratinib are two such treatments.
Understanding Myelofibrosis and How These Drugs Work
Myelofibrosis involves fibrous scar tissue accumulating in the bone marrow, displacing normal blood-forming cells. This scarring leads to ineffective blood cell production, causing anemia, low platelet counts, and an enlarged spleen. Common symptoms include fatigue, night sweats, unexplained weight loss, bone pain, and itching, which impact quality of life.
The progression of myelofibrosis is linked to abnormal signaling within the JAK-STAT pathway. This pathway regulates blood cell formation and immune responses. In myelofibrosis, mutations, most commonly in the JAK2, CALR, or MPL genes, cause continuous overactivity. This promotes inflammation, scar tissue formation, and abnormal blood cell production, contributing to disease symptoms.
Janus kinase (JAK) inhibitors block the overactive JAK-STAT pathway. By inhibiting specific JAK enzymes, these drugs reduce the excessive signaling that drives the disease. This approach alleviates myelofibrosis-related symptoms, such as reducing spleen size and improving systemic symptoms like fatigue and night sweats.
Ruxolitinib’s Role in Treatment
Ruxolitinib primarily inhibits two Janus kinase enzymes: JAK1 and JAK2. These enzymes are involved in signaling pathways that regulate blood cell production and immune responses. By blocking both JAK1 and JAK2, ruxolitinib reduces the excessive signaling that contributes to myelofibrosis symptoms and progression.
Ruxolitinib’s efficacy was established through clinical trials, including COMFORT-I and COMFORT-II. The COMFORT-I trial, a placebo-controlled study, showed ruxolitinib significantly reduced spleen volume (41.9% of patients achieved a 35% or greater reduction at 24 weeks vs. 0.7% with placebo). It also improved total symptom scores (45.2% of ruxolitinib-treated patients experienced a 50% or greater reduction vs. 5.3% with placebo). The COMFORT-II trial, comparing ruxolitinib to best available therapy, similarly confirmed its ability to reduce spleen size and improve symptom burden.
Ruxolitinib also demonstrated a survival benefit in these studies. Common side effects include anemia and thrombocytopenia. These blood count reductions generally occur early and are managed by dose adjustment. Other non-hematologic side effects include bruising, dizziness, and headaches. Ruxolitinib is commonly used as a first-line treatment for individuals with intermediate-2 or high-risk myelofibrosis.
Fedratinib’s Place in Therapy
Fedratinib primarily inhibits Janus kinase 2 (JAK2). It also inhibits FMS-like tyrosine kinase 3 (FLT3) and bromodomain-containing protein 4 (BRD4). These additional targets distinguish its action from other JAK inhibitors.
Fedratinib’s efficacy was demonstrated in the JAKARTA and JAKARTA2 clinical trials. The JAKARTA trial, a placebo-controlled study, showed fedratinib achieved a 35% or greater reduction in spleen volume at 24 weeks in 36% of previously untreated patients. It also led to a 50% or greater reduction in total symptom scores at 24 weeks in 40% of these patients.
The JAKARTA2 trial focused on patients previously treated with ruxolitinib who were resistant or intolerant. This study showed fedratinib achieved a 35% or greater spleen volume reduction at 24 weeks in 31% of these patients. Additionally, 27% experienced a 50% or greater reduction in total symptom scores at 24 weeks. This trial established fedratinib as a second-line treatment option for myelofibrosis.
Like ruxolitinib, fedratinib can cause anemia and thrombocytopenia. A distinct side effect is Wernicke’s encephalopathy, a neurological disorder caused by thiamine (vitamin B1) deficiency. Thiamine levels must be monitored before and throughout treatment, and supplementation is often recommended to mitigate this complication. Other common non-hematologic side effects include gastrointestinal issues such as diarrhea, nausea, and vomiting. Fedratinib is approved for adults with intermediate-2 or high-risk myelofibrosis, including those who have previously received ruxolitinib.
Key Differences and Considerations
Both ruxolitinib and fedratinib reduce spleen volume and improve systemic symptoms associated with myelofibrosis. Ruxolitinib is established as a first-line therapy, demonstrating efficacy in previously untreated patients and showing an overall survival benefit. Fedratinib, while also effective in previously untreated patients, mainly serves as a second-line option for patients resistant or intolerant to ruxolitinib. Neither drug offers a cure.
The mechanisms of action differ. Ruxolitinib’s inhibition of both JAK1 and JAK2 is effective for many patients by broadly targeting the overactive signaling pathway. Fedratinib, with its JAK2 inhibition and additional activity against FLT3 and BRD4, may benefit patients whose disease has developed resistance to ruxolitinib.
The safety profiles also present distinct considerations. Both commonly cause anemia and thrombocytopenia. The incidence and severity of these blood count abnormalities can differ and require careful monitoring throughout treatment. Dose adjustments are often necessary to manage these side effects.
Their non-hematologic side effects vary. Ruxolitinib’s common non-hematologic adverse events include bruising, dizziness, and headache. Some patients may also experience weight gain or elevated cholesterol levels. Fedratinib is associated with more common gastrointestinal issues, such as diarrhea, nausea, and vomiting. Its distinct side effect is the risk of Wernicke’s encephalopathy. Thiamine level monitoring and supplementation are crucial before and during fedratinib treatment to mitigate this risk.
The choice between ruxolitinib and fedratinib depends on several factors, including the patient’s treatment history and disease characteristics. Ruxolitinib is the initial choice for eligible patients due to its established efficacy, demonstrated survival benefit, and manageable side effect profile. Fedratinib is an option for patients who have lost response to ruxolitinib or experienced intolerable side effects, serving as a second-line therapy. The decision often hinges on the reason for ruxolitinib failure.
Patient-specific factors, such as baseline blood counts, pre-existing medical conditions (e.g., gastrointestinal problems or neurological disorders), and predominant symptoms, influence therapy selection. For example, a patient with pre-existing anemia might require closer monitoring or different dose adjustments. Regular monitoring of blood counts is important for both drugs, and for fedratinib, consistent thiamine level checks are also important. Clinical decision-making involves balancing potential symptom improvement and spleen reduction against each drug’s unique risks and management strategies.
References
Verstovsek, S., et al. (2012). A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis. New England Journal of Medicine, 366(9), 799-807.
Incyte Corporation. (2011). Jakafi (ruxolitinib) prescribing information.
Harrison, C., et al. (2012). Ruxolitinib versus Best Available Therapy for Myelofibrosis. New England Journal of Medicine, 366(9), 787-798.
Pardanani, A., et al. (2015). JAKARTA: a phase 3, double-blind, placebo-controlled study of fedratinib in patients with intermediate-2 or high-risk myelofibrosis. Journal of Clinical Oncology, 33(15_suppl), 7027-7027.
Harrison, C. N., et al. (2017). Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: an updated analysis of the JAKARTA2 study. Blood, 130(Supplement 1), 416-416.
Celgene Corporation. (2019). Inrebic (fedratinib) prescribing information.