Tagraxofusp Shows Manageable Safety, Modest Activity in Myelofibrosis
Key Clinical Summary
- Population and design: Nonrandomized, open-label, multicenter phase 1/2 trial of tagraxofusp monotherapy in myelofibrosis (MF); 5 treatment-naïve and 25 JAK inhibitor (JAKi)–refractory/resistant patients were efficacy-evaluable at the recommended phase 2 dose (RP2D).
- Safety: RP2D was 12 μg/kg/day on days 1–3 per cycle; no dose-limiting toxicities. Grade ≥3 events included anemia (22%), thrombocytopenia (19%), and dyspnea (11%); capillary leak syndrome occurred in 11% (all cycle 1) with resolution.
- Efficacy signals: Among relapsed/refractory patients, 40% achieved ≥50% total symptom score (TSS) reduction at any time; spleen volume reduction ≥35% occurred in 2/18 evaluable patients with baseline splenomegaly; median overall survival (OS) 19.3 months.
A phase 1/2 study evaluated the CD123-targeted agent tagraxofusp—approved for blastic plasmacytoid dendritic cell neoplasm—as monotherapy in myelofibrosis, including patients resistant/refractory to JAK inhibitors. The trial determined an optimal dose and characterized safety and efficacy using IWG-MRT/ELN criteria and symptom endpoints (ClinicalTrials.gov NCT02268253).
Study Findings
Dose escalation identified 12 μg/kg/day (days 1–3 per cycle) as the RP2D, with no dose-limiting toxicities. In the safety population treated at this dose (n = 36), the most frequent grade ≥3 treatment-emergent adverse events were anemia (22%), thrombocytopenia (19%), and dyspnea (11%). Capillary leak syndrome (CLS) occurred in 11%, exclusively in cycle 1, with resolution in all cases; 2 patients discontinued because of CLS.
Thirty patients treated at the RP2D were efficacy-evaluable. Among 18 patients with baseline splenomegaly (2 treatment-naïve, 16 relapsed/refractory), 2 relapsed/refractory patients achieved spleen volume reduction ≥35%. In relapsed/refractory MF, 40% achieved TSS ≥50% at any time, and median OS was 19.3 months. In treatment-naïve patients, 40% achieved TSS ≥50%, and median OS was 26.6 months. The investigators reported no cumulative myelotoxicity and noted platelet stability over time.
The authors conclude that tagraxofusp monotherapy was well tolerated with modest clinical activity, supporting further study—particularly in combinations.
Clinical Implications
Patients with MF who fail or cannot tolerate JAK inhibitors have limited options and poor prognoses. The safety profile observed here—especially manageable early CLS and limited cumulative cytopenias—suggests tagraxofusp could be a bone-marrow–sparing partner in combination regimens for high-risk, cytopenic populations. Symptom improvements (TSS ≥50% in 40% of relapsed/refractory patients) and isolated spleen responses indicate biologic activity against CD123-expressing disease, although traditional endpoints (SVR35 at fixed time points) were infrequent.
Given median OS of 19.3 months in the relapsed/refractory cohort, outcomes appear within the expected range for this difficult-to-treat setting, underscoring the need to optimize combinations and refine clinically meaningful endpoints beyond JAKi-centric measures. Ongoing studies exploring tagraxofusp with JAK inhibitors (eg, pacritinib) may clarify its role in symptom, spleen, and survival benefits while maintaining tolerability.
Conclusion
In this phase 1/2 trial, tagraxofusp demonstrated a predictable safety profile and modest efficacy signals in MF, including JAKi-refractory disease. The results support combination strategies to enhance clinical benefit and further evaluate CD123 targeting as part of the evolving therapeutic landscape in myelofibrosis.
Reference
Yacoub A, Ali H, Gupta V, et al. Final safety and efficacy results from a phase 1/2 study of tagraxofusp, a CD123-targeted therapy, for myelofibrosis. blood neoplasia. 2025;2(4):100165. doi:10.1016/j.bneo.2025.100165
