Twenty-four or more cycles of fedratinib was well-tolerated in patients with intermediate- or high-risk myelofibrosis treated in either the phase 1/2 TED12015 study or the phase 1 TED12037 study. The long-term safety and tolerability results of fedratinib.
Twenty-four or more cycles of fedratinib (Inrebic) was well-tolerated in patients with intermediate- or high-risk myelofibrosis (MF) treated in either the phase 1/2 TED12015 study (NCT00724334) or the phase 1 TED12037 study (NCT00631462). The long-term safety and tolerability results of fedratinib were recently presented during the 2020 American Society of Hematology (ASH) Annual Meeting.
Fedratinib is an FDA-approved oral, selective JAK2 inhibitor indicated for use in adults with intermediate- to high-risk disease. With reduced survival as well as issues like cytopenia, marrow fibrosis, and splenomegaly which are associated with MF, in addition to a prior FDA clinical hold on fedratinib due to suspected Wernicke’s encephalopathy (WE), researchers found it necessary to investigate the safety of fedratinib long-term.
The patients assessed were 18 years of age or older with primary, post-polycythemia vera (PV), post-essential thrombocythemia (ET) MF with intermediate or high-risk disease, and an ECOG performance status of 0–2. Patients who were treated in the TED12037 dose-finding study received between 30 to 800 mg of fedratinib daily for up to 6 cycles. In the TED12015 extension study, patients were enrolled after achieved a complete response, partial response, clinical improvement, or stable disease during the prior dose-finding study. For this extension study, patients were treated at whatever dose they were last receiving in the dose-finding study.
Fedratinib was administered in these studies for continuous 28-day cycles. All patients remained in fedratinib until MF relapse or unacceptable toxicity. Safety was determined by treatment-emergent adverse events (TEAEs) with late-emerging TEAEs, like cardiac failure, cardiomyopathy, severe or opportunistic infection, and neurologic toxicities, being of special interest to the investigators led by Animesh Pardanani, MBBS, PhD, of the Mayo Clinic of Rochester.
Of the 59 patients in the dose-finding study and 43 patients in the extension study, a cohort of 28 patients received 24 cycles of fedratinib. Investigator decision was the most common reason for treatment discontinuation in the cohort, but 5 patients did also discontinue due to AEs. The remaining patient who discontinued either had disease progression, underwent transplant, experience treatment failure, withdrew consent, or the study was terminated at their site.
Notably, some patients in the cohort went on to receive more than 24 cycles of fedratinib. The median treatment duration of the cohort was 46 cycles (range, 25-72). The total exposure to fedratinib was 100.6 patients-years. Combined, patients received a median of 462 mg of fedratinib per day (range, 283-800). The median dose at cycle 24 was 440 mg daily (range, 200-680).
Comparing the patients in the long-term fedratinib cohort to those previously enrolled in dose-finding study, no recognizable differences were seen in the baseline characteristics. All patients had comparable MF subtypes, risk classification, laboratory values, spleen size, and JAK2 mutation positivity. Patients were also around the same age.
In terms of the frequency of TEAEs, Pardanani et al noted that many of the events occurred early on in treatment during the first 1–6 cycles of the dose-finding study. Fewer TEAS were observed in the extension cohort and the long-term cohort. Overall TEAES of any-grade were reported in 25% or fewer patients during any cycle interval. The most common TEAEs of any-grade were thrombocytopenia (35%), fatigue (29), nausea (18%), diarrhea (12%), and vomiting (12%). The most common hematologic and gastrointestinal TEAEs occurred after cycle 24.
Grade 3/4 TEAEs were reported in ≥ 10% of patients during any cycle interval. The most common TEAEs at any interval and of any grade were thrombocytopenia (18%) and pneumonia (18%). Notably, pneumonia was the sole grade 3/4 TEAE with first onset in more than 1 patient. Specifically, 5 pneumonia events were observed in patients received ta 440 mg to 600 mg daily dose of fedratinib. Two of the pneumonia events were deemed fedratinib-related.
In regard to AEs of special interest, the events were rare. Neurologic events were the most frequent of the special interest AEs, with any-grade AEs occurring in 29% of patients at any interval. In addition, 12% of patients experienced severe or opportunistic infection of any grade, and 6% had any-grade cardiac failure or cardiomyopathy.
Importantly, there were no suspected cases of WE in this analysis.
Taken together, the findings from these clinical trials of fedratinib provide valuable insight on the long-term use of fedratinib, which can be used to guide clinical practice, Pardanani et al concluded. Long-term fedratinib use is now being explored in 2 phase 3 clinical trials (FREEDOM, NCT03755518, and FREEDOM 2, NCT03952039).
Pardanani A, Stone R, Talpaz M, et al. Long-term safety of fedratinib in patients with intermediate- or high-risk myelofibrosis (MF). Presented at: 2020 American Society of Hematology (ASH) Annual Meeting and Exposition; December 4-8, 2020; virtual. Abstract 3006.