Place du ruxolitinib dans la stratégie thérapeutique des syndromes myéloprolifératifs

The discovery of the JAK2V617F mutation in 2005, present in 95% of polycythemia vera (PV) and in 55% of myelofibrosis (MF) patients, opened the way for a new era of targeted therapies for myeloproliferative neoplasms. Ruxolitinib was the first-in-class Janus Kinase (JAK) inhibitor approved for the management of these diseases. In PV patients, conventional treatment strategies including aspirin, phlebotomy, cytoreductive agents such as hydroxyurea and interferon, clearly provide clinical benefits. However, some patients develop resistance or intolerance to these treatments. Ruxolitinib has been approved for PV patients who are resistant to or intolerant of hydroxyurea, based on the results of the phase 3 RESPONSE study. This study showed that ruxolitinib improves hematocrit control, reduces splenomegaly, and ameliorate disease-related symptoms as compared with best available therapy. In MF patients, the only curative treatment is allogeneic stem cell transplantation, but it remains restricted to a limited group of patients with poor prognosis and who are eligible for such procedure associated with non-negligible transplant-related mortality. Other treatments are palliative and unlikely to prolong survival. Ruxolitinib has been approved in the United States for MF patients with intermediate or high-risk disease, and in Europe for disease-related splenomegaly or symptoms in adults with MF, based on phase 3 COMFORT-I and COMFORT-II studies. These studies showed that ruxolitinib was able to reduce splenomegaly, ameliorate symptoms, and improve survival. However, the journey is not finished yet since there are still important unmet needs for MF patients, including improvement in cytopenias, and significant modification of disease natural history.