First-in-Class CD123-Directed Therapy Shows Early Activity in MDS, CMML

An early study of tagraxofusp, a recombinant fusion protein consisting of human interleukin (IL)–3 conjugated to a truncated diphtheria toxin, demonstrated signs of clinical activity in myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML).

Mehmet Sevki Uyanik, MD, of the University of Texas MD Anderson Cancer Center, and colleagues recently presented a poster of a phase 1/2 dose escalation study of tagraxofusp at the American Society of Hematology Annual Meeting (Abstract 1842).

According to the study, patients with MDS and CMML have dismal clinical outcomes after failure of hypomethylating agent (HMA) therapy. Distinct hematopoietic populations that contribute to disease progression after HMA therapy—such as myeloid progenitors, myeloid-derived suppressor cells, or plasmacytoid dendritic cells—exhibit cell-surface expression of the IL-3 receptor alpha chain (IL3RA or CD123).

Therefore, this study was designed to see if tagraxofusp, a first-in-class CD123-directed therapy, would be active in this patient population.

The study enrolled 10 patients with high-risk MDS and CMML. Four dose levels of tagraxofusp administered on days one to three were planned: dose level 1 was 5 µg/kg/day; dose level 2, 7 µg/kg/day; dose level 3, 9 µg/kg/day; and dose level 4, 12 µg/kg/day. Six patients were treated at dose level 1 and four at dose level 2. The primary endpoint was the evaluation of safety, efficacy, and tolerability.

Dose reduction of decitabine was required for one patient treated at level 1. All patients had treatment-emergent adverse events (TEAEs); half of the patients had a grade 3 or worse TEAE. These included grade 3 capillary leak syndrome (CLS) with concurrent cytokine release syndrome (CRS) in two patients and grade 3 hemophagocytic lymphohistiocytosis in one patient.

Four-week and eight-week mortality was 10%. No patients died during the  study.

The researchers noted that “although tagraxofusp at low doses is associated with no new safety signals, CLS and CRS can be observed in older patients.”

Nine of the 10 patients were evaluable for response. Thirty-three percent of evaluable patients had response to therapy, including one complete response. Median follow-up was 8.3 months. Median event-free survival was 2.1 months with a median overall survival of 5.9 months.

One patient remains in the study. The researchers are enrolling additional patients aged younger than 75 to confirm the long-term efficacy and safety of this treatment regimen.

Uyanik reported no conflicts of interest.

REFERENCE:

Uyanik MS, Garcia-Manero G, Maiti A, et al. Results of a phase I/II study of tagraxofusp in combination with decitabine for patients with myelodysplastic/myeloproliferative neoplasms and higher risk myelodysplastic syndromes. Abstract #1842. Presented at the American Society of Hematology Annual Meeting; December 7-10, 2024; San Diego, California.