Tagraxofusp, Azacitidine, and Venetoclax in Blastic Plasmacytoid Dendritic Cell Neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an orphan, aggressive hematologic malignancy characterized by high CD123 expression. Tagraxofusp (TAG), a CD123-directed toxin, is the only approved therapy. Prior studies demonstrated BPDCN dependence on BCL2, sensitivity to venetoclax (VEN), and reversal of TAG resistance with azacitidine (AZA). We conducted a phase 2 study evaluating combination therapy with TAG, AZA, and VEN in patients with BPDCN (NCT03113643). Patients with previously untreated (1L) or relapsed/refractory (R/R) BPDCN received 28-day cycles of AZA (75 mg/m² days 1-7), VEN (400 mg days 1-21), and TAG (12 µg/kg days 4-6). Eligibility followed TAG guidelines to mitigate risk of capillary leak syndrome (CLS). Twenty-seven patients were enrolled (16 1L, 11 R/R), with median age of 70 years (range 21-81). Composite complete remission (CR/CRi/CRc) rates were 88% in 1L and 64% in R/R cohorts. Median duration of response was not reached in 1L and was 7.2 months in R/R patients. CLS occurred in 15% of patients; most were grade 2. In the 1L cohort, median overall and progression-free survival were not reached; the 2-year overall survival was 65% and 2-year progression-free survival was 53%. Median overall survival in R/R patients was 8.4 months. A high proportion of patients proceeded to allogeneic stem cell transplantation in remission (63% 1L, including 10 of 11 patients age 75 or younger; and 55% R/R). TAG-AZA-VEN is highly active in both untreated and relapsed BPDCN with a predictable and manageable safety profile, supporting its use as a new therapeutic option.