Tagraxofusp Shows Safety but Minimal Efficacy in CMML

A phase 1/2 study (NCT02268253)¹ revealed that tagraxofusp, a CD123-targeted therapy, demonstrated a manageable safety profile but limited clinical efficacy in patients with chronic myelomonocytic leukemia (CMML).²

Complete response (CR) and partial response were not observed in either patient group. One patient in each group achieved complete cytogenetic remission with marrow response. Stable disease (SD) proved to be the best response for 6 patients who were treatment-naive (40%) and 13 patients in the relapsed/refractory group (59%). SD lasted longer than 8 weeks in 40% of patients who were treatment-naive and 32% of patients in the relapsed/refractory group. Clinical benefit, as defined by the 2015 MDS/MPN criteria, was achieved by 27% of patients who were treatment-naive and 23% of patients in the relapsed/refractory group.

No dose-limiting toxicities were observed at any dose level, and no new safety signals were identified. A total of 39 patients received tagraxofusp at the recommended phase 2 dose of 12 kg per day.

Common treatment-emergent adverse events included fatigue (49%), hypoalbuminemia (46%), nausea (44%), hypokalemia (44%), and decreased appetite (44%). Capillary leak syndrome occurred in 9 patients (23%) and was resolved or managed with supportive care, tumor lysis syndrome occurred in 5 patients (13%), and acute kidney injury occurred in 10 patients (26%).

The nonrandomized, multicenter, open-label trial evaluated tagraxofusp monotherapy in patients with CMML or myelofibrosis in 3 stages. The trial examined patients that were both treatment-naive and those who had relapsed/refractory CMML.

In evaluable patients with myeloproliferative CMML, tagraxofusp monotherapy resulted in total symptom score reduction in both evaluable patients and a spleen response in 1 of 4 patients with splenomegaly at baseline. There was an absolute monocyte count reduction observed in 73% of patients who were treatment-naive, and 27% achieved normalization. The median overall survival (OS) for the total population of patients was 15.3 months. The median OS for patients who were treatment-naive was 11.2 months and was 15.6 months for patients in the relapsed/refractory group.

The study suggests that the median OS for patients in the relapsed/refractory group may have been longer partially due to inclusion criteria, which stated that patients in the treatment-naive group were selected based on molecular features associated with a poor prognosis.

Other patient inclusion criteria included a life expectancy of > 6 months, having an ECOG performance status of 0 to 2, and having adequate baseline organ function, including cardiac, renal, and hepatic functions.¹

Patient exclusion criteria included having persistent clinically significant toxicities grade ≥2 from previous therapies, having received treatment with any disease-related therapy within 14 days of the study entry, having received an allogeneic stem cell transplant within 3 months of the study entry, and having been previously treated with tagraxofusp or having a known hypersensitivity to any components of the drug.¹ 

“Studies are underway to evaluate various combination regimens, and preliminary evidence suggests improved clinical response with novel regimens (44%–55% CR, and 51% marrow response in trials of lenzilumab + azacitidine and venetoclax [Venclexta] + decitabine + cedazuridine),” stated the authors of the study.² “It is also possible that combination therapies targeting both pDCs [plasmacytoid dendritic cells] and IDO [indoleamine 2,3-dioxygenase] could be synergistic in altering CMML disease biology by halting critical DC–T-cell interactions. Tagraxofusp may represent a rational backbone on which to develop combination regimens, and the combination of tagraxofusp with the HMA [hypomethylating agents] decitabine is currently under investigation in a phase 1/2 trial in patients with CMML.”

The phase 1/2 (NCT05038592)³ trial mentioned above is examining the safety, tolerability, and maximum tolerable dose of tagraxofusp in combination with decitabine.

REFERENCES:

1.Tagraxofusp (SL-401) in Participants With Chronis Myelomonocytic Leukemia (CMML) and Myelofibrosis (MF). ClinicalTrials.gov. Updated January 6, 2025. Accessed October 15, 2025. https://www.clinicaltrials.gov/study/NCT02268253 

2.Patnaik MM, Ali H, Wang ES, et al. Tagraxofusp, a CD123-targeted therapy, for chronic myelomonocytic leukemia: final results of a phase 1/2 study. Blood Neoplasia. 2025;2(4):100115. doi:10.1016/j.bneo.2025.100115

3.Phase I/​II Study of Tagraxofusp in Combination With Decitabine for Patients With Myelomonocytic/​Myeloproliferative Neoplasm and High Risk Myelodysplastic Syndromes. ClinicalTrials.gov. Updated July 29, 2025. Accessed October 15, 2025. https://www.clinicaltrials.gov/study/NCT05038592