On August 16, 2019, fedratinib was approved for the treatment of adults with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis.1,2
Supporting Efficacy Data
The approval was based on findings from the phase III double-blind JAKARTA trial (ClinicalTrials.gov identifier NCT01437787),2,3 in which 289 patients with intermediate-2 or high-risk myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis with splenomegaly were randomly assigned to receive fedratinib at 500 mg (n = 97), 400 mg (n = 96), or placebo (n = 96) once daily for at least six 28-day cycles. The primary efficacy outcome was the proportion of patients achieving at least a 35% reduction from baseline in spleen volume at the end of cycle six, measured by magnetic resonance imaging or computed tomography with a follow-up scan 4 weeks later. The efficacy analysis included the fedratinib group receiving the recommended starting dose of 400 mg/d vs placebo.
The median age of patients who received fedratinib at 400 mg was 65 years (range = 27–86 years), 59% were male, 90% were white, and 92% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Fedratinib has a boxed warning for severe and fatal encephalopathy, including Wernicke’s encephalopathy.
Among 96 patients receiving fedratinib at 400 mg, 35 (37%) achieved at least a 35% reduction in spleen volume vs 1 of 96 patients (1%) in the placebo group (P < .0001). The median duration of spleen response was 18.2 months in the fedratinib group. At least a 50% reduction in myelofibrosis-related symptoms (based on the modified Myelofibrosis Symptom Assessment Form v2.0) was observed in 40% of the fedratinib group vs 9% of the placebo group (P < .0001).
How It Works
Fedratinib is an oral kinase inhibitor with activity against wild-type and mutationally activated Janus-associated kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). It is a JAK2-selective inhibitor with higher inhibitory activity for JAK2 vs family members JAK1, JAK3, and TYK2.
Abnormal activation of JAK2 is associated with myeloproliferative neoplasms, including myelofibrosis and polycythemia vera. In cell models expressing mutationally active JAK2-V617F or FLT3-ITD, fedratinib reduced phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, inhibited cell proliferation, and induced apoptotic cell death. In mouse models of JAK2-V617F–driven myeloproliferative disease, fedratinib blocked phosphorylation of STAT3/5 and improved survival, white blood cell counts, hematocrit, splenomegaly, and fibrosis.
How It Is Used
The recommended dosage of fedratinib in myelofibrosis is 400 mg orally once daily for patients with a baseline platelet count ≥ 50 x 109/L. The starting dose is 200 mg/d in patients with severe renal impairment.
Administration with a high-fat meal may reduce the incidence of nausea and vomiting. Prophylaxis with antiemetics is recommended. Patients receiving ruxolitinib before initiation of fedratinib must taper and discontinue ruxolitinib, according to the product’s prescribing information.
The following blood tests must be obtained prior to starting treatment with fedratinib, periodically during treatment, and as clinically indicated: thiamine (vitamin B1) level; complete blood cell count with platelets; creatinine and blood urea nitrogen; hepatic panel; and amylase and lipase.
Fedratinib has a boxed warning for severe and fatal encephalopathy, including Wernicke’s encephalopathy. For management of thiamine and Wernicke’s encephalopathy, thiamine levels and nutritional status must be assessed prior to starting treatment in all patients, periodically during treatment, and as clinically indicated. Fedratinib should not be started in patients with thiamine deficiency; thiamine should be repleted prior to treatment and during treatment if thiamine levels are low. If Wernicke’s encephalopathy is suspected, fedratinib should be immediately discontinued and parenteral thiamine treatment started. Patients should be monitored until symptoms resolve or improve and thiamine levels return to normal.
Use of fedratinib should be avoided in patients with severe hepatic impairment. Product labeling provides dose modifications, including dose reduction, interruption, and discontinuation for adverse effects, including grade 4 thrombocytopenia or grade 3 thrombocytopenia with active bleeding; grade 4 neutropenia; grade ≥ 3 nausea, vomiting, or diarrhea; grade ≥ 3 elevations of alanine transaminase, aspartate transaminase, or bilirubin; and grade ≥ 3 other nonhematologic adverse effects. Dose reductions should be considered for patients who become transfusion-dependent during treatment.
Product labeling provides information on dose reduction with concomitant use of strong CYP3A4 inhibitors. Concomitant use of fedratinib with strong and moderate CYP3A4 inducers and with dual CYP3A4 and CYP2C19 inhibitors should be avoided.
The most common adverse events of any grade (≥ 20%) in patients who received fedratinib at 400 mg/d in the JAKARTA trial were diarrhea (66% vs 16% with placebo), nausea (62% vs 15%), anemia (40% vs 14%), and vomiting (39% vs 5%). The most common grade ≥ 3 adverse events included anemia, diarrhea, and fatigue/asthenia. The most common grade 3 or 4 laboratory abnormalities were anemia, thrombocytopenia, and increased lipase.
Serious adverse events occurred in 21% of patients in the fedratinib group, including cardiac failure and anemia. Adverse events led to discontinuation of fedratinib in 14%, with the most common causes being cardiac failure and thrombocytopenia, myocardial ischemia, diarrhea, and increased blood creatinine. Dose interruption and dose reduction occurred in 21% of patients (including diarrhea and nausea in > 3%) and in 19% of patients (including anemia in 6% and diarrhea and vomiting in 3% each). One patient in the fedratinib group had a fatal adverse event (cardiogenic shock).
As noted, fedratinib has a boxed warning for serious and fatal encephalopathy, including Wernicke’s encephalopathy (see section on How It Is Used). Fedratinib also has warnings/precautions for anemia and thrombocytopenia, gastrointestinal toxicity, hepatic toxicity, and amylase and lipase elevation. Patients should be advised not to breastfeed while receiving fedratinib. ■
1. U.S. Food and Drug Administration: FDA approves fedratinib for myelofibrosis. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fedratinib-myelofibrosis. Accessed October 3, 2019.
2. Inrebic (fedratinib) capsules prescribing information, Celgene, August 2019. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212327s000lbl.pdf. Accessed October 3, 2019.
3. Pardanani A, Harrison C, Cortes JE, et al: Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: A randomized clinical trial. JAMA Oncol 1:643-651, 2015.