fedratinib for treating disease-related splenomegaly or symptoms in myelofibrosis

Last edited 12/2021 and last reviewed 01/2022

NICE have stated (1):

Fedratinib is recommended for use within the Cancer Drugs Fund as an option for treating disease-related splenomegaly or symptoms of primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis in adults. It is recommended only if:

  • they have previously had ruxolitinib and
  • the conditions in the managed access agreement for fedratinib are followed

Fedratinib is a selective oral JAK2 inhibitor approved in the United States for treatment of adult patients with intermediate-2 or high-risk MF (2)

  • in mouse models of JAK2V617F-driven myeloproliferative disease, fedratinib
    • blocked phosphorylation of STAT5,
    • increased survival,
    • and improved MF-associated disease features, including reduction of white blood cell counts, hematocrit, splenomegaly, and fibrosis
  • exerts off-target inhibitory activity against bromodomain-containing protein 4 (BRD4); combination JAK/STAT and BRD4 inhibition was shown to synergistically block NF-kB hyperactivation and inflammatory cytokine production, attenuating disease burden and reversing bone marrow fibrosis in animal models of MPNs
  • is rapidly absorbed and dosed once daily (effective half-life 41 h)
  • showed robust clinical activity in JAK-inhibitor-naive patients and in patients with MF who were relapsed, refractory, or intolerant to prior ruxolitinib therapy
  • is effective regardless of JAK2 mutation status
  • onset of spleen and symptom responses are typically seen within the first 1-2 months of treatment
  • most common adverse events (AEs) with fedratinib are grades 1-2 gastrointestinal events, which are most frequent during early treatment and decrease over time

Notes (1):

  • most people with higher-risk myelofibrosis have ruxolitinib, and continue having it even if their disease does not fully respond, or stops responding. After ruxolitinib is stopped, people can have best available therapy, which includes chemotherapy, radiation therapy, splenectomy or red blood cell transfusion. The company proposes that fedratinib would only be used after ruxolitinib, which is more restrictive than its marketing authorisation
  • clinical trial evidence for people who have stopped ruxolitinib suggests that fedratinib improves myelofibrosis symptoms and reduces spleen size. However, this evidence is uncertain because fedratinib was not compared with best available therapy and some people did not finish the trial. Fedratinib has been compared indirectly with best available therapy using evidence from other studies. There is further uncertainty because of some differences between the trial populations in the indirect comparison
  • it is unclear how much longer people having fedratinib live compared with best available therapy, and this has a large effect on the cost-effectiveness results. There is also uncertainty around how many people would continue having fedratinib if their disease does not fully respond, or stops responding.

Reference:

Related pages:

myelofibrosis