How to define treatment failure for JAK inhibitors

Therapy with Janus kinase-2 (JAK2) inhibitors generally provides substantial clinical benefit in patients with myelofibrosis, particularly with regard to reduction of splenomegaly and constitutional symptoms. Many JAK inhibitors have entered clinical testing; however, only ruxolitinib, a dual JAK1 and JAK2 inhibitor, is currently approved. Although the COMFORT-I 1 Verstovsek S Mesa RA Gotlib J et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012; 366: 799-807 Crossref PubMed Scopus (1469) Google Scholar and COMFORT-II 2 Harrison C Kiladjian JJ Al-Ali HK et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012; 366: 787-798 Crossref PubMed Scopus (1332) Google Scholar studies showed that clinical benefits were generally maintained, it is becoming increasingly evident that ruxolitinib is discontinued in more than 50% of patients with myelofibrosis after 3 years due to adverse events, loss of response, or disease progression. 3 Harrison CN Vannucchi AM Kiladjian JJ et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016; 30: 1701-1707 Crossref PubMed Scopus (304) Google Scholar , 4 Verstovsek S Mesa RA Gotlib J et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017; 10: 55 Crossref PubMed Scopus (234) Google Scholar Patients with ruxolitinib resistance or intolerance have a dismal prognosis with a very short overall survival after discontinuation. In this context, the efficacy of post-ruxolitinib salvage therapies is not well established. Consequently, a critical need exists to clarify the causes of discontinuation and to define a working consensus of treatment failure that allows a meaningful comparison of treatment results across different clinical trials. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre studyThis phase 2 study met its primary endpoint, suggesting that patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis might achieve significant clinical benefit with fedratinib, albeit at the cost of some potential toxicity, which requires further evaluation. Fedratinib development in this setting is currently being assessed. Full-Text PDF