Myelofibrosis (MF) is a rare but aggressive myeloproliferative disorder, characterized by bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis, and a host of constitutional symptoms such as weight loss, pruritus, and fatigue. Activating mutations in Janus kinase 2 (JAK2) are found in approximately 50% to 60% of patients. Additionally, some patients may also show mutations in the thrombopoietin receptor (MPL) and in the endoplasmic reticulum chaperone protein, calreticulin (CALR).1,2
The identification of driver mutations (JAK2, MPL, and CALR) has helped in the understanding of the pathophysiology of disease. JAK-STAT is a key pathway associated with hematopoietic cell growth, differentiation, and death, and JAK1/2 are intracellular, nonreceptor, tyrosine kinases that mediate signal transduction.3-6 The driver mutations identified in MF keeps the JAK-STAT pathway in overdrive, which results in many of the disease-associated symptoms.
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The Landscape of JAK Inhibitors
The identification of the activating JAK2 V617F mutation in approximately 50% of patients with MF advanced the use of targeted therapies for its treatment. The JAK1/2 inhibitor, ruxolitinib, was the first JAK inhibitor approved in 2011 for the treatment of intermediate or higher-risk MF based on data from two phase 3 studies — COMFORT-I and COMFORT-II.7-9
Ruxolitinib
COMFORT-I and COMFORT-II were both phase 3 studies comparing ruxolitinib to placebo and best available therapy (BAT).8,9
COMFORT-I was a double-blind, placebo-controlled study, randomly assigned 309 patients to receive either ruxolitinib (15 to 20 mg twice daily) or placebo. Half the patients had primary myelofibrosis, 31% had post-polycythemia vera MF, and 18% had post-essential thrombocythemia MF.10
COMFORT-II was an open-label study that randomly assigned 219 patients (2:1) to either ruxolitinib (15 to 20 mg orally twice daily) or BAT. In this study, 53% of patients had primary MF, 31% post-polycythemia vera MF, and 16% post-essential thrombocythemia MF .10
The primary end point was determining at least a 35% spleen volume reduction (SVR) after 24 weeks in COMFORT-I or after 48 weeks in COMFORT-II.
COMFORT-I and -II achieved the prespecified primary end points. In COMFORT-I, 42% of patients in the ruxolitinib group and 1% of patients in the placebo group experienced at least a 35% SVR at 24 weeks (P < .0001). In COMFORT-II, 29% of patients in the ruxolitinib and 0% of patients on BAT experienced at least a 35% SVR at 48 weeks (P < .0001).8,9
The secondary end point was at least a 50% reduction (week 24 compared with baseline) in the myeloproliferative neoplasm (MPN) symptom assessment form total symptom score (MPN SAF TSS), which evaluates abdominal discomfort, pain under left ribs, night sweats, itching, bone/muscle pain, and early satiety. TSS improved by at least 50% in 46% of patients on ruxolitinib compared with 5% of patients receiving placebo (P < .0001).8 Similarly, in COMFORT-II patients in the ruxolitinib group showed improved reductions in myelofibrosis-related symptoms of anorexia, dyspnea, fatigue, insomnia, and pain.9
The recommended starting dose of ruxolitinib is based on platelet count: 20 mg orally twice daily for patients with a platelet count of more than 200 × 109/L and 15 mg orally twice daily for patients with a platelet count between 100 and 200 × 109/L.
