Fedratinib in combination with CC-486, an oral hypomethylating agent, in patients with accelerated phase myelofibrosis: Results from the phase I/II famy trial Free

About 20% of myelofibrosis (MF) patients (pts) progress to MPN-blast phase (MPN-BP) which is preceded by an accelerated phase (MPN-AP). Given the dismal prognosis of MPN-BP, therapeutic intervention of MPN-AP is needed but an optimal regimen is not established. Allogeneic stem cell transplant (SCT) is a curative option but is associated with significant morbidity/mortality/high relapse rates and infrequently utilized in practice. Combining a parentral hypomethylating agent (HMA) with the JAK inhibitor (JAKi) ruxolitinib is reported to be active in MPN-AP. Yet, leukemia cells have short half-lives and their exposure to HMAs is short potentially abrogating efficacy. Fedratinib (FED) an approved MF therapy, is an oral JAK2i and FLT3i, inhibits JAK-STAT signaling pathway and tumor cell proliferation. Yet, MPN-AP was excluded from trials. The oral HMACC-486 has distinct pharmacokinetics and dynamics from injectable azacitidine. Besides DNA and RNA hypomethylation, it has direct cytotoxicity and is administered in extended schedules ultimately prolonging therapeutic effect. CC-486 is approved as maintenance after chemotherapy in AML. The safety of combining FED with CC-486 in MF-AP was evaluated in a clinical trial.

FAMy (DRKS00030348) is a multicenter phase I/II trial of the East German Study Group (OSHO) and the German Study Group for MPN (GSG-MPN). Pts ≥18 years with MPN-AP, defined as 10-19% myeloid blasts in the blood or bone marrow, were eligible. Key inclusion criteria are platelets ≥50x10⁹/L, neutrophils ≥1.0x10⁹/L, normal blood thiamine levels, and no encephalopathy. Safety of FED in combination with CC-486 and week 24 response were key primary objectives of the phase I and II respectively. Pts were followed for survival for 24 months. Phase I followed a 3+3 design to determine the maximum tolerated dose defined as the highest dose at which <33% of pts experience a dose limiting toxicity (DLT). In a Run-in phase, the tolerability of FED 400mg QD monotherapy for ≥28 days (d) had to be confirmed. Thereafter combination therapy was started as 28d cycles consisting of a fixed dose of CC-486 300mg QD for 14d and FED for 28d [200mg QD in dose level 1, 300mg QD in level 2, and 400mg QD in level 3]. Driver mutations (mut) and mut associated with myeloid malignancies were centrally assessed. Approvals according to the EU Clinical Trials Regulation were granted and pts gave signed informed consent. The study is sponsored by the Martin-Luther-University Halle-Wittenberg, supervised by an Independent Safety Review Committee (SRC), and funded by Bristol Myers Squibb.

Between 03/Nov/2022 and 18/Dec/2024, 15 pts were screened, 6 were excluded [MPN-AP not confirmed (n=4); second malignancy (n=1), consent withdrawal (n=1)], and 9 pts [56% males; median age 63 years (IQR 9); 78% primary MF] received trial combination therapy. Driver mut (median VAF of 23.4%) were CALR type 1 (n=7) and MPL (n=2) mut. In 8/9 pts, high-risk mut were detected (ASXL1 mut in 67%). A history of MF therapy was documented in 89%. Median baseline blood values were: WBC 9x10⁹/L, Hb 5mmol/L, platelets 230x10⁹/L, and peripheral blasts 6% (IQR 5). Up to date, 74 (median=9; IQR 9.5) cycles were given. No DLT occurred in level 1 (n=3). In dose level 2 (n=6), one protocol defined DLT was documented [an asymptomatic thiamin level of 64nmol/L (normal range: 66.5-200)]. Median week 24 (n=7) blood values were: WBC 4.9x10⁹/L, Hb 5mmol/L, platelets 187x10⁹/L, and peripheral blasts 3% (IQR 11). After a median follow-up of 12.7 months, median survival time was not reached and 3 pts received SCT. No SUSAR was identified. Most common adverse events (AE) were cytopenia (38%) [neutropenia 19% (grade 3 in 4 pts); leukopenia 9% (grade 3 in 1 pt); thrombocytopenia 6% (grade 3 in 1 pt)], grade <2 gastrointestinal (21%) [diarrhoea 6%; nausea 5%] and infections (6%) [grade ≥3 in 3 pts]. Two grade 2 ALAT/ASAT elevations (1%) and 3 creatinine increases (1%) [grade 3 in 1 pt] were reported. Three pts were discontinued due to progression to MPN-BP and 1 pt due to AE. Though the SRC confirmed the safety of level 2, enrolment was ended in April/2025 due to slow recruitment.

For the first time, the feasibility of combining 300mg FED with CC-486 in MPN-AP is shown. Considering the dismal prognosis and lack of optimal therapies for MPN-AP, the preliminary but encouraging results of this regimen warrant further evaluation in an international trial.