Ruxolitinib. Bone marrow fibrosis: theory versus practice.

Currently, the only curative treatment for bone marrow fibrosis is haematopoietic stem cell transplantation, but it is only feasible in a minority of patients. Ruxolitinib (Jakavi, Novartis) inhibits Janus kinases, enzymes necessary for haematopoiesis. Many cases of bone marrow fibrosis appear to be due to mutations that interfere with the expression of these kinases. Clinical assessment of ruxolitinib is based on a randomised placebo-controlled trial in 309 patients in whom conventional treatments had failed, and on a randomised, unblinded trial versus standard management in 219 patients. The patients enrolled in the placebo-controlled trial had a poor prognosis. Mortality appeared to be lower in the ruxolitinib arm after 24 and 51 weeks, but not in the trial versus standard management. Ruxolitinib had a short-lived symptomatic effect, but almost all patients enrolled in a non-comparative study discontinued ruxolitinib because of inadequate efficacy or adverse effects. Discontinuation often led to symptom rebound. The primary endpoint in these trials was the reduction in spleen volume, a surrogate outcome measure. Ruxolitinib was effective on this endpoint, but it is unclear whether reduction in spleen volume correlates with symptoms. Ruxolitinib aggravates haematological disorders associated with bone marrow fibrosis (anaemia, thrombocytopenia) and also causes neurological disorders (headache, dizziness, confusion). In practice, ruxolitinib appears to have an unfavourable harm-benefit balance in most patients. It is therefore better to avoid using this drug. Additional clinical trials are needed in patients for whom haematopoietic stem cell transplantation is not feasible, especially those with a large, expanding spleen.