Second-Line Fedratinib Produces Early Platelet Count Improvements in Myelofibrosis

Patients with myelofibrosis who received second-line fedratinib (Inrebic) experienced early increases in platelet count compared with those given best available therapy (BAT), and a higher magnitude of benefit was observed in patients with a low platelet count at baseline, according to findings from the phase 3 FREEDOM2 trial (NCT03952039) presented at the 2024 ASH Annual Meeting.

Findings showed that in the overall safety population, fedratinib generated improvements in mean platelet count and mean change from baseline platelet count, most noticeably in early treatment cycles.

In patients with a low platelet count at baseline, defined as at least 50 to less than 100 x 109/L, patients treated with fedratinib (n = 34) experienced a mean increase in platelet count of 45% on day 15 of cycle 1 compared with 11% for those given BAT (n = 21). Among patients with a high platelet count at baseline of at least 100 x 109/L, these rates were 27% for fedratinib (n = 85) and –6% for BAT (n = 39).

During a presentation of the data, lead study author Haifa Kathrin Al-Ali, MD, explained that increased platelet count was not correlated with changes in spleen size, pointing to a potential benefit for fedratinib on thrombopoiesis.

"These data suggest a platelet-sparing effect of second-line fedratinib vs BAT, and support fedratinib as a promising second-line treatment option for patient with myelofibrosis with low or high baseline platelet count,” said Al-Ali, who is a professor of translational oncology and head of the Krukenberg Cancer Center at the University Hospital of Halle (Saale) in Germany.

Patent Enrollment Criteria and Study Design

The global, open-label, FREEDOM2 trial enrolled patients at least 18 years of age with primary, post–polycythemia vera, or post–essential thrombocythemia myelofibrosis who had a Dynamic International Prognostic Scoring System score of at least intermediate-2 and were previously treated with ruxolitinib (Jakafi).

Additional eligibility criteria included a spleen volume of at least 450 cm³ and palpable spleen at least 5 cm below the left costal margin; a platelet count of at least 50 × 10⁹/L; an absolute neutrophil count (ANC) of at least 1 × 10⁹/L; peripheral blood blasts no more than 5%; and normal baseline thiamine levels.

Participants were randomly assigned 2:1 to receive 400 mg of oral fedratinib once daily or the BAT, which included ruxolitinib in 78% of patients in this arm. Crossover from the BAT arm to the fedratinib arm was permitted upon disease progression or intolerance. Treatment continued until lack of efficacy, disease progression, or unacceptable toxicity.

The primary end point was the rate of patients to experience a spleen volume reduction of at least 35% (SVR35) at the end of cycle 6 (EOC6). Key secondary end points included total symptom score improvement (TSS50) at EOC6, SVR25 at EOC6, and safety. Platelet analyses were conducted at screening, cycle 1 day 3, cycle 1 day 15, at the start of each subsequent cycle, at end of treatment, and at 30-day follow-up. Patients were stratified by low vs high baseline platelet count.

Exploratory end points included overall survival (OS), subsequent therapies, new malignancies, and progression of myelofibrosis to acute myeloid leukemia.

Baseline Patient Characteristics

The data cutoff date for the platelet analysis in the FREEDOM2 trial was May 10, 2023. Baseline demographics and disease characteristics were assessed by platelet levels, categorized as low (50 to < 100 × 10⁹/L) or high (≥ 100 × 10⁹/L). Median follow-up was 58 weeks (interquartile range [IQR], 37-93) for patients receiving fedratinib in the low platelet group and 43 weeks (IQR, 8-67) for those in the BAT cohort. In the high platelet group, median follow-up was 70 weeks (IQR, 43-109) with fedratinib and 74 weeks (IQR, 50-94) with BAT.

The median age in the low platelet cohort was 72 years (IQR, 69-76) with fedratinib vs 68 years (IQR, 63-71) with BAT. In the high platelet cohort, the median age was 69 years (IQR, 62-74) with fedratinib and 69 years (IQR, 64-73) with BAT. The majority of patients were male in both platelet subgroups (low: 58.8% with fedratinib vs 42.9% with BAT; high: 51.8% with fedratinib vs 46.2% with BAT). Most patients were White (low: 85.3% with fedratinib vs 100.0% with BAT; high: 77.6% with fedratinib vs 79.5% with BAT).

The median baseline platelet count in the low platelet cohort was 76.5 × 10⁹/L (IQR, 64.0-91.0) for patients receiving fedratinib vs 72.0 × 10⁹/L (IQR, 62.0-86.0) for those receiving BAT. In the high platelet group, median platelet counts were 170.0 × 10⁹/L (IQR, 124.0-317.0) with fedratinib vs 156.0 × 10⁹/L (IQR, 128.0-208.0) with BAT.

Primary myelofibrosis was the most common diagnosis in both platelet subgroups, occurring in 61.8% and 33.3% of patients with low platelet levels receiving fedratinib and BAT, respectively, and in 52.9% and 69.2% of patients with high platelet levels. Intermediate-2 risk status was observed in 70.6% and 81.0% of patients in the low platelet subgroup and in 81.2% and 76.9% of patients in the high platelet subgroup receiving fedratinib and BAT, respectively.

Median spleen volume at baseline was 2349.8 mL (IQR, 1609.5-3820.4) with fedratinib vs 3987.5 mL (IQR, 2488.4-4333.9) with BAT in the low platelet cohort. In the high platelet cohort, median spleen volume was 2622.3 mL (IQR, 1914.7-3818.4) with fedratinib vs 2349.3 mL (IQR, 1436.5-3204.0) with BAT.

The median Myelofibrosis Symptom Assessment Form (MFSAF) TSS was 26.0 (IQR, 19.0-44.0) with fedratinib vs 34.0 (IQR, 28.0-39.5) with BAT in the low platelet group. In the high platelet group, the median MFSAF TSS was 27.0 (IQR, 17.0-40.0) with fedratinib and 21.0 (IQR, 14.0-43.0) with BAT.

Safety Observations

Thrombocytopenia and hemorrhage were the most common treatment-emergent adverse effects (TEAEs) across baseline platelet levels. Grade 3/4 thrombocytopenia was observed in 29.4% and 9.5% of patients with low baseline platelet counts treated with fedratinib and BAT, respectively. Among patients with high baseline platelet levels, 10.6% of those receiving fedratinib developed grade 3/4 thrombocytopenia vs no patients in the BAT group.

Thrombocytopenia-related dose modifications occurred in 17.6% and 2.4% of patients in the low and high platelet cohorts receiving fedratinib, respectively; dose interruptions were required for 8.8% and 3.5% of patients, respectively. Permanent treatment discontinuation due to thrombocytopenia occurred in 2.9% of patients in the low platelet cohort.

Grade 3/4 hemorrhagic effects occurred in 5.9% of patients with low baseline platelet levels treated with fedratinib compared with none in the BAT group. Among patients with high baseline platelet counts, grade 3/4 hemorrhagic effects were observed in 3.5% of patients treated with fedratinib vs none for BAT.

The most frequently reported grade 3/4 TEAEs in the low platelet cohort receiving fedratinib included thrombocytopenia (29.4%), anemia (17.6%), renal and urinary disorders (14.7%), infections (14.7%), and gastrointestinal disorders (11.8%). In the BAT group, thrombocytopenia (9.5%), anemia (23.8%), and infections (4.8%) were the most common.

In the high platelet cohort, the most frequently reported grade 3/4 TEAEs in the fedratinib group included anemia (27.1%), thrombocytopenia (10.6%), renal and urinary disorders (11.8%), and gastrointestinal disorders (7.1%). In the BAT group, anemia (12.8%) and infections (10.3%) were the most prevalent.

Reference

Al-Ali HK, Harrison C, Mesa R, et al. Efficacy and safety of fedratinib in patients with myelofibrosis and low baseline platelet counts in the phase 3 randomized FREEDOM2 trial. Blood. 2024;144(suppl 1):482. doi:10.1182/blood-2024-193645