Fedratinib is best therapy for ruxolitinib-refractory myelofibrosis

Fedratinib is superior to the best available therapy (BAT) in terms of spleen volume reduction (SVR) and symptom response rates in patients with myelofibrosis (MF) treated with the Janus kinase inhibitor (JAKi) ruxolitinib, as shown in a study presented at ASH 2023.

In addition, “[m]ost patients on BAT received ruxolitinib, highlighting a clinical need for an alternative JAKi,” according to the investigators, led by Claire N Harrison of Guy’s and St Thomas’ NHS Foundation Trust in London, England, UK.

Harrison and her team randomized a total of 201 patients with primary, postpolycythemia vera, or postessential thrombocythemia MF with Dynamic International Prognostic Scoring System (DIPSS) score ≥intermediate-2, splenomegaly (≥450 cm³), platelets ≥50 x 10⁹/L, peripheral blood myeloblasts <5 percent, and normal baseline thiamine, relapsed/refractory (R/R) or intolerant to ruxolitinib to receive either fedratinib 400 mg/day (n=134) or BAT (n=67) in 28-day cycles.

Participants were stratified according to spleen size, platelet count, and ruxolitinib R/R vs intolerance. The investigators allowed switching to fedratinib for patients with progressive disease or after cycle 6 (EOC6) response assessment. Patients were treated until intolerance or lack of efficacy and followed-up every 3 months until death, withdrawal of consent, or study closure.

SVR ≥35 percent (SVR35) at EOC6 served as the primary endpoint. Secondary endpoints were symptom response (≥50 percent reduction in total symptom score measured by Myelofibrosis Symptom Assessment Form), SVR ≥25 percent (SVR25), durability of SVR and symptom response, and safety.

Of the patients (median age 70 years), 52.2 percent were male, 54.7 percent had primary MF, and 76.1 percent had intermediate-2 DIPPS risk. Forty-six (68.7 percent) patients treated with BAT crossed over to fedratinib. Most patients in the BAT arm received ruxolitinib (70.1 percent), hydroxyurea (10.4 percent), or ruxolitinib plus hydroxyurea (7.5 percent). [ASH 2023, abstract 3204]

At the data cutoff (27 December 2022; median follow-up, 15 months), patients treated with fedratinib showed a significantly higher rate of SVR35 at EOC6 than did those on BAT (35.8 percent vs 6.0 percent; p<0.0001). Fedratinib also exhibited superior SVR25 at EOC6 and SVR35 during the full treatment course.

The SVR35 benefit derived from fedratinib was found across subgroups. Patients treated with fedratinib also had higher rates of symptom response at EOC6 than those who received BAT (34.1 percent vs 16.9 percent; p=0.0033).

Adverse events

The median duration of treatment was 43 weeks with fedratinib and 24.7 weeks with BAT. During the first 6 cycles in the safety population, 70 (52.2 percent) patients on fedratinib and 20 (29.9 percent) on BAT had dose interruption/reduction, with median time to first reduction/interruption of 44.0 and 56.5 days, respectively.

Moreover, treatment-emergent adverse events (TEAEs) that led to permanent treatment discontinuation occurred in 13 (9.7 percent) patients in the fedratinib arm and 4 (6.0 percent) in the BAT arm. At least one TEAE occurred in 132 (98.5 percent) patients on fedratinib and 65 (97.0 percent) on BAT.

The most common TEAEs were diarrhoea (38.1 percent with fedratinib vs 0.0 percent with BAT) and nausea (32.1 percent vs 1.5 percent). Most cases were grade 1 or 2.

Grade 3 or 4 TEAEs occurred in 52 (38.8 percent) and eight (11.9 percent) patients in the fedratinib and BAT arms, respectively, with thrombocytopenia (11.9 percent vs 3.0 percent) and anaemia (9.0 percent vs 9.0 percent) being the most frequent.

One patient on fedratinib had suspected Wernicke’s encephalopathy during cycle 3, but this resolved fully 24 hours after thiamine supplementation. In addition, two patients each in both treatment arms had an infection.

“Differences in AE and discontinuation rates in the first 6 cycles are consistent with other studies comparing JAKi with BAT,” the investigators said. “AE mitigation strategies were effective and no new safety concerns for fedratinib were identified.”