Experimental and Clinical Pharmacology:Janus kinase inhibitors in myeloproliferative neoplasms: Clinical applications

Janus kinase inhibitors in myeloproliferative neoplasms Clinical applications SUMMARYHyperactive Janus kinase 2 signalling is a key molecular event in polycythaemia, essential thrombocythaemia and myelofibrosis.This is associated with the V617F mutation in the Janus kinase 2 gene of many patients with myeloproliferative disease.Ruxolitinib is the first Janus kinase inhibitor to be licensed in Australia for the treatment of myelofibrosis.Ruxolitinib can cause rapid and sustained splenic shrinkage in up to 42% of patients with higher risk myelofibrosis, however it does not change the risk of leukaemic transformation.Treatment with ruxolitinib can be limited by significant anaemia.myeloproliferative neoplasms.It is also being assessed in combination with other therapies.Two randomised phase III trials of ruxolitinib -COMFORT-I and COMFORT-II -were completed in patients with higher risk myelofibrosis, including those with primary or secondary myelofibrosis, irrespective of whether they had the V617F mutation.6,7 Splenomegaly is a common cause of disability in patients with myelofibrosis.The primary end point of the studies was a 35% reduction in splenic volume on magnetic resonance imaging.Outcomes from both studies were remarkably similar.In COMFORT-I, patients with myelofibrosis received oral ruxolitinib 15 or 20 mg twice a day (155 patients) or placebo (154 patients).The starting dose was dependent on the patients' baseline platelet count.After 24 weeks, a 35% reduction in spleen size was achieved in 41.9% of ruxolitinib-treated patients versus 0.7% of placebo-treated patients (p<0.001).COMFORT-II compared ruxolitinib with best available therapy (2:1 ratio).After 48 weeks, 28% of the ruxolitinib-treated patients met the primary end point versus 0% in the best available therapy group (p<0.001).In both studies, 97% of patients experienced some degree of splenic shrinkage with ruxolitinib therapy.Responses were rapid and sustained and were irrespective of the type of myelofibrosis (primary vs post-polycythaemia vera or post-essential thrombocythaemia), mutation status, initial spleen size or baseline symptoms.Patients on ruxolitinib had an improved quality of life and reversal of disease-related weight loss.Ruxolitinib was effective in patients with