Tagraxofusp, azacitidine, and venetoclax for 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 first 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. Patients with previously untreated (1L) or relapsed/refractory (R/R) BPDCN received 28-day cycles of AZA (75 mg/m2 on days 1-7), VEN (400 mg on days 1-21), and TAG (12 μg/kg on 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 (composed of: complete remission [CR], CR with incomplete count recovery, and CR clinical) 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 survival (OS) and progression-free survival (PFS) were not reached; the 2-year OS was 65% and 2-year PFS was 53%. Median OS in R/R patients was 8.4 months. A high proportion of patients proceeded to allogeneic stem cell transplantation in remission (63% in 1L, including 10/11 patients aged ≤75 years; 55% in R/R). TAG-AZA-VEN is highly active in both 1L and relapsed BPDCN with a predictable and manageable safety profile, supporting its use as a new therapeutic option. This trial was registered at www.clinicaltrials.gov as #NCT03113643.