Long-Term Safety of Fedratinib in Patients with Intermediate- or High-Risk Myelofibrosis (MF)

INTRODUCTION: Fedratinib is an oral, selective inhibitor of Janus kinase 2 (JAK2) approved in the United States for treatment of adult patients (pts) with intermediate-2 or high-risk MF. A clinical hold placed on fedratinib development in November 2013 related to suspected Wernicke’s encephalopathy (WE), which was later lifted, limited long-term follow-up from fedratinib studies. The longest follow-up for pts treated with fedratinib is available from a phase I/II extension study (TED12015; NCT00724334) that followed a 6-cycle dose-finding study in 59 pts with intermediate- or high-risk MF (TED12037; NCT00631462) (Pardanani, JCO, 2011).

OBJECTIVE: Report long-term safety of fedratinib in pts with MF who received > 24 treatment cycles in the TED12037 and TED12015 studies.

METHODS: These open-label, dose-finding and extension studies included pts with intermediate- or high-risk primary, post-polycythemia vera, or post-essential thrombocythemia MF. During the TED12037 dose-finding study, pts received continuous fedratinib at doses ranging from 30–800 mg/day for up to 6 28-day treatment cycles. The maximum tolerated dose was 680 mg/day. Pts with stable disease, clinical improvement, or complete or partial remission (IWG-MRT response criteria) after 6 cycles could enter the TED12015 extension study at the last fedratinib dose they received in the dose-finding study. During the extension study, site visits occurred every 3 cycles until cycle 13 and then every 6 cycles. Here, we report long-term safety of fedratinib in pts who received > 24 total treatment cycles in TED12037 and TED12015, as assessed by treatment-emergent adverse event (TEAE) reporting, summarized in 6-cycle intervals up to cycle 36 and collectively after 36 cycles. Late-emerging TEAEs of special interest were cardiac, infectious, and neurologic events. TEAEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA; version 11.0) and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE).

RESULTS: In all, 59 pts enrolled in the TED12037 dose-finding study; 43 of those pts (73%) entered the TED12015 extension study, and 28 pts (47%) received > 24 cycles of fedratinib across both studies and comprise the Long-term (LT) Cohort. 11 of 59 pts (19%) discontinued before cycle 24 due to a TEAE.

In the LT Cohort, median age at study entry was 62.5 years (range 43–82). Pts received fedratinib for a median of 46 cycles (range 25–72) for a total of 100.6 pt-years of exposure. The median average fedratinib dose per pt was 462 mg/day (range 283–800), and overall treatment compliance rate was 98% (80%–100%). Reasons for fedratinib discontinuation in > 1 pt in the LT Cohort were investigator decision (n = 10), TEAEs (n = 5), study termination (n = 5), and disease progression (n = 4).

TEAE frequencies were highest during treatment cycles 1–6 and generally decreased or remained stable in later cycles (Table). The most common TEAEs after > 24 cycles of fedratinib were hematologic and gastrointestinal (GI) events, reported at rates lower or similar to those in early treatment cycles. Grade 3–4 TEAEs reported in > 1 pt after cycle 24 were thrombocytopenia, anemia, neutropenia, and pneumonia.

Few pts experienced late-emerging cardiac events or severe/opportunistic infections. The only cardiac event of interest was 1 case of congestive cardiac failure (grade 1) during cycle 7. The only infectious event observed in > 1 pt after cycle 24 was pneumonia; of 5 events reported in 4 pts, all were grade 3 or grade 4, and 2 were considered possibly related to treatment. Three grade 3–4 serious neurologic events were reported at any time: post-herpetic neuralgia (in 2 pts, at cycle 10 and cycle 36) and cerebrovascular accident (in 1 pt during cycle 1). No suspected cases of WE were reported.

CONCLUSIONS: Fedratinib remained well tolerated in pts who stayed on treatment for >24 cycles. TEAE frequencies generally decreased or remained stable after cycles 1–6. Among TEAEs of interest, pneumonia was the only event reported in > 1 pt (n = 4) after cycle 24. Although limited to a small pt population, these findings provide valuable information to guide clinical practice for pts who require long-term therapy. The ongoing phase III FREEDOM (NCT03755518) and FREEDOM2 (NCT03952039) studies include assessment of long-term outcomes with fedratinib in pts with MF previously treated with ruxolitinib.