Safety and efficacy of fedratinib, a selective oral inhibitor of Janus kinase-2 (JAK2), in patients with myelofibrosis and low pretreatment platelet counts.

Abstract

Fedratinib, an oral Janus kinase-2 (JAK2) inhibitor, is approved for patients with myelofibrosis (MF) and platelet counts ≥50 × 109 /l, based on outcomes from the phase 3, placebo-controlled JAKARTA trial in JAK-inhibitor-naïve MF, and the phase 2, single-arm JAKARTA2 trial in patients previously treated with ruxolitinib. We evaluated the efficacy and safety of fedratinib 400 mg/day in patients with baseline platelet counts 50 to <100 × 109 /l ("Low-Platelets" cohorts), including 14/96 patients (15%) in JAKARTA and 33/97 (34%) in JAKARTA2. At 24 weeks, spleen response rates were not significantly different between the Low-Platelets cohort and patients with baseline platelet counts ≥100 × 109 /l ("High-Platelets" cohort), in JAKARTA (36% vs. 49%, respectively; p = 0.37) or JAKARTA2 (36% vs. 28%; p = 0.41). Symptom response rates were also not statistically different between the Low- and High-Platelets cohorts. Fedratinib was generally well-tolerated in both platelet-count cohorts. New or worsening thrombocytopaenia was more frequent in the Low-Platelets (44%) versus the High-Platelets (9%) cohort, but no serious thrombocytopaenia events occurred. Thrombocytopaenia was typically managed with dose modifications; only 3/48 Low-Platelets patients discontinued fedratinib due to thrombocytopaenia. These data indicate that fedratinib 400 mg/day is safe and effective in patients with MF and low pretreatment platelet counts, and no initial fedratinib dose adjustment is required for these patients.

• Authors: Claire N Harrison, Nicolaas Schaap, Alessandro M Vannucchi, Jean-Jacques Kiladjian, Francesco Passamonti, Sonja Zweegman, Moshe Talpaz, Srdan Verstovsek, Shelonitda Rose, Jun Zhang, Oumar Sy, Ruben A Mesa
• Journal: British journal of haematology (Br J Haematol) Vol. 198 Issue 2 Pg. 317-327 (07 2022) ISSN: 1365-2141 [Electronic] England
• PMID: 35476316 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

Chemical References

• Nitriles
• Protein Kinase Inhibitors
• Pyrrolidines
• Sulfonamides
• fedratinib
• JAK2 protein, human
• Janus Kinase 1
• Janus Kinase 2

Topics

• Double-Blind Method
• Humans
• Janus Kinase 1
• Janus Kinase 2
• Nitriles (therapeutic use)
• Platelet Count
• Primary Myelofibrosis (diagnosis, drug therapy)
• Protein Kinase Inhibitors (adverse effects)
• Pyrrolidines
• Sulfonamides
• Thrombocytopenia (chemically induced, drug therapy)