Tagraxofusp Shows Manageable Safety Profile, Modest Activity as Monotherapy in Myelofibrosis

Myelofibrosis (MF) is a difficult-to-treat myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, cytopenias, symptomatic splenomegaly, and a high symptom burden that severely affects the patient's quality of life. Janus kinase (JAK) inhibitor therapies constitute a basis for symptom and spleen size control in many patients. Treatment choices are often limited due to patients having baseline cytopenias, comorbidities, and loss of response over time; hence, there remains a need for new drugs that work differently, especially after the failure of a JAK inhibitor. Against this backdrop, study investigators evaluated tagraxofusp—an IL-3–diphtheria toxin fusion protein that targets CD123—in patients with MF, based on the biologic rationale that CD123 is expressed in MF-relevant malignant and microenvironmental cell populations.^1,2

Rationale for CD123 Targeting in MF

Tagraxofusp is a first-in-class CD123-targeted cytotoxin currently approved for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).³ Due to CD123 expression in MF, along with preclinical evidence of malignant-cell sensitivity, it is thought that CD123-directed therapy could deliver clinical benefits without the cumulative myelosuppression that often limits such therapies. In fact, CD123 targeting might provide a “therapeutic window” in MF by having a greater effect on the malignant hematopoietic populations than on normal hematopoiesis, a notion that is especially significant in a condition where anemia and thrombocytopenia are frequently present at baseline.¹

Phase 1/2 Study Design and Key Outcomes

In final results from a nonrandomized, open-label phase 1/2 trial, tagraxofusp monotherapy was studied in patients with treatment-naive MF (n = 5) and in patients with MF resistant or refractory to prior JAK inhibitor therapy and who were transplant-ineligible (n = 25). Dose escalation identified 12 μg/kg per day for 3 consecutive days per cycle as the recommended phase 2 dose, with no dose-limiting toxicities reported. Among the patients treated at this dose, 30 were evaluable for efficacy.¹

Efficacy signals were modest but clinically notable in symptom improvement: 40% of patients achieved a 50% or greater reduction in Total Symptom Score (TSS). Spleen responses were limited; among patients with baseline splenomegaly, 2 with relapsed/refractory disease achieved a 35% or greater reduction in spleen volume. Median overall survival was 19.3 months in the relapsed/refractory cohort and 26.6 months in the small treatment-naive cohort, showing the limitations of a small sample size and single-arm design.¹

Safety Findings and What Pharmacists Should Watch For

The safety profile in MF was described as manageable and predictable, with the most frequent grade 3 or higher treatment-emergent adverse events including anemia (22%), thrombocytopenia (19%), and dyspnea (11%).¹ A key toxicity associated with tagraxofusp across indications is capillary leak syndrome (CLS), which carries a boxed warning in the BPDCN label and can be life threatening if not properly managed.³ In the MF study, CLS occurred in 11% of patients, all during cycle 1, and resolved in all affected patients.¹

For pharmacists, these data highlight several actionable care points, especially when tagraxofusp is used in clinical trials or future combination strategies. Pharmacist-led monitoring protocols should emphasize early-cycle vigilance for CLS (eg, rapid weight gain, edema, hypotension, hypoalbuminemia), prompt escalation pathways, and supportive care coordination aligned with institutional policies and labeling precautions for tagraxofusp.³ Pharmacists also play a central role in managing cytopenias (dose holds, transfusion support, growth factor considerations per protocol), evaluating dyspnea etiologies (anemia, fluid shifts, infection), and ensuring accurate symptom assessment using standardized tools (eg, Myeloproliferative Neoplasm Symptom Assessment Form TSS) to contextualize benefit in a disease where symptom control is a primary treatment goal.²

REFERENCES

1. 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

2. Helwick C. Understanding the assessment and treatment of high-risk myelofibrosis. The ASCO Post. December 10, 2024. Accessed February 18, 2026. https://ascopost.com/issues/december-10-2024/understanding-the-assessment-and-treatment-of-high-risk-myelofibrosis/

3. Elzonris. Prescribing information. Stemline Therapeutics, Inc; 2018. Accessed February 18, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761116s000lbl.pdf