Background
Phase 2, single-arm, open-label, multicentre study. 97 patients with intermediate or high-risk primary MF, post-PV MF, or post-ET MF, who were ruxolitinib-resistant or ruxolitinib-intolerant after ≥14 days of treatment. Palpable splenomegaly ≥5 cm required. 31 sites in 9 countries. The study was terminated early due to suspected Wernicke encephalopathy in other fedratinib trials.
Interventions and follow up
Regimen: Fedratinib 400 mg orally once daily, 28-day cycles, until progression or intolerance (myelofibrosis previously treated with ruxolitinib)
Population: n=97; ruxolitinib-resistant/intolerant; palpable splenomegaly ≥5 cm
Primary endpoint: Spleen response (≥35% reduction in spleen volume by MRI/CT)
mFollow up: Not stated
Population: n=97; ruxolitinib-resistant/intolerant; palpable splenomegaly ≥5 cm
Primary endpoint: Spleen response (≥35% reduction in spleen volume by MRI/CT)
mFollow up: Not stated
Results
Spleen response (per-protocol, n=83 evaluable): 55% (46/83; 95% CI 44–66%)
Symptom response: meaningful TSS reduction reported in responders
Discontinuation due to AEs: 19% (18/97)
Deaths during study: 7 (none drug-related)
Symptom response: meaningful TSS reduction reported in responders
Discontinuation due to AEs: 19% (18/97)
Deaths during study: 7 (none drug-related)
Adverse events
Hematologic (grade 3–4): anemia 38% (37/97), thrombocytopenia 22% (21/97)
Tolerability: AE-related discontinuation in 19% of patients
Deaths/neurologic: 7 on-study deaths, all unrelated to fedratinib; suspected Wernicke encephalopathy in other fedratinib trials led to premature termination, with no WE confirmed in this study
Tolerability: AE-related discontinuation in 19% of patients
Deaths/neurologic: 7 on-study deaths, all unrelated to fedratinib; suspected Wernicke encephalopathy in other fedratinib trials led to premature termination, with no WE confirmed in this study
Conclusions
Fedratinib 400 mg achieved a 55% spleen response rate in post-ruxolitinib patients, meeting its primary endpoint and demonstrating clinically meaningful activity in a population with limited options. These data, combined with JAKARTA, contributed to the FDA approval of fedratinib with mandatory thiamine monitoring.
Key Limitations
Single-arm phase II with no comparator; the 55% response rate is from the per-protocol evaluable population (n=83), which can overestimate effect versus intention-to-treat. Early termination (due to Wernicke encephalopathy concerns in other fedratinib studies) limited follow-up and data maturity. Heterogeneous reasons for prior ruxolitinib discontinuation (resistance vs intolerance) complicate interpretation. No long-term OS or duration-of-response data. Wernicke encephalopathy risk requires thiamine monitoring despite no confirmed cases here.
Clinical Context
JAKARTA-2 provided the key second-line evidence supporting fedratinib (Inrebic) for MF after ruxolitinib failure, contributing with JAKARTA to its August 2019 FDA approval at 400 mg daily with mandatory thiamine replacement. It established fedratinib as an active option in the post-ruxolitinib setting, where pacritinib (especially for thrombocytopenic patients) and momelotinib (for anemia-predominant disease) are also used. ESMO and ELN guidance recognize fedratinib among second-line JAK inhibitor options for symptomatic intermediate/high-risk MF.