Tagraxofusp, a CD123-targeted therapy, for chronic myelomonocytic leukemia: final results of a phase 1/2 study

Chronic myelomonocytic leukemia (CMML) is an aggressive hematologic neoplasm characterized by an expansion of CD123⁺ monocytes and plasmacytoid dendritic cells (pDCs). pDC bone marrow clusters in CMML have been associated with higher rates of acute myeloid leukemia transformation. We evaluated tagraxofusp, a CD123-targeted therapy, in a phase 1/2 trial for patients with CMML. There were no dose-limiting toxicities. At the recommended phase 2 dose of 12 μg/kg per day, 37 patients were treated: 15 were treatment naïve; 22 had relapsed/refractory disease (median number of previous therapies, 1 [range, 1-7]). Common nonhematologic treatment-emergent adverse events (AEs) included fatigue (49%), hypoalbuminemia (46%), nausea, hypokalemia, and decreased appetite (44% each). Capillary leak syndrome occurred in 9 patients (23%; grade 3-4, 13%), whereas tumor lysis syndrome was seen in 13%. Hematologic grade 3/4 treatment-related AEs included thrombocytopenia (28%), anemia (13%), leukocytosis (15%), and neutropenia (13%). No complete or partial responses were observed. One patient each in the treatment-naïve and relapsed/refractory groups achieved complete cytogenetic remission with marrow response. Stable disease and clinical benefit were achieved by 40% and 27% of treatment-naïve patients and by 59% and 23% of relapsed/refractory patients, respectively. After a median follow-up of 43.7 months, overall survival was 11.2 months in treatment-naïve and 15.6 months in relapsed/refractory patients. Exploratory analysis showed stable CD123⁺ blast frequency, mutational variant allele frequencies, and monocyte subsets with treatment. Tagraxofusp demonstrated a manageable safety profile with limited clinical efficacy in CMML. This trial was registered at www.ClinicalTrials.gov as #NCT02268253.