Ruxolitinib, a JAK1/JAK2 inhibitor (2011) [45] and fedratinib, a JAK2/FLT3 inhibitor (2019) [46] are approved in the USA for MF patients with splenomegaly and/or constitutional symptoms regardless of the presence of mutated JAK2. Although long-term follow-up studies have validated the sustained benefit of ruxolitinib in MF patients in terms of improvement in splenomegaly, symptom burden, and quality of life with an increase in overall survival (OS), a subset of patients are intolerant or refractory to JAK inhibitor therapy. The gene discussed is JAK2; the disease is Splenomegaly.