6502 Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy with (w/) historically dismal outcomes, including median (med) overall survival (OS) of 8 – 12 months (mos) and frequent central nervous system (CNS) involvement (Martin-Martin Oncotarget 2016, Pemmaraju Blood 2021). Tagraxofusp (TAG; first CD123-targeted therapy approved for BPDCN) improves responses (Pemmaraju JCO 2022), but relapse remains common. Venetoclax (VEN) demonstrates activity in BPDCN (Montero Cancer Disc 2017), and intensified chemotherapy may improve outcomes. We report the results of a phase II investigator-initiated trial (NCT04216524) of TAG, Hyper-CVAD, and VEN in newly diagnosed (ND) or relapsed/refractory (R/R) BPDCN. Methods: Adults (≥18 years yrs) w/ ND or R/R BPDCN received: Cycle C 1: TAG days d 1-5; C2, 4, 6, 8: TAG d1 – 5 w/ VEN d2 – 14 (C2) and d1 – 7 (C4, 6, 8); C3, 7: VEN d1 – 7 w/ Hyper-CVAD or mini-hyper-CVD; C5: VEN d1 – 7 w/ high-dose methotrexate/cytarabine or mini-methotrexate/cytarabine. Cycles were 28 days for up to 8 cycles, followed by POMP, VEN, and TAG maintenance. Pts received ≥8 intrathecals. Results: Nineteen pts were enrolled (14 ND; 5 R/R). Med age was 61 yrs (range, 20 – 79); 79% male. Disease sites included 84% skin, 63% bone marrow, 16% CNS, 16% extramedullary. Co-occurring mutations were TET2 (60%), ASXL1 (33%), DNMT3A (20%), NRAS (13%), KRAS (13%). Two pts had prior/concomitant MDS. For ND, overall response rate (ORR; complete remission CR plus CR w/ incomplete count recovery CRi plus partial response PR) was 93% (13/14, all CR/CRi). Pts received a med of 2 (1 – 6) cycles w/ 2 (1 – 3) cycles to best response. The 30- and 60-day mortality was 0%. After a 55-mos med follow-up, (19.5 – NR), med OS was 15 mos w/ 24-month OS of 42%. Med EFS was 14.6 mos w/ 24-month EFS of 42%. Nine pts (65%) went to stem cell transplant (SCT) (2 died in CR, 6 remain alive in CR; of these, 3 remain alive in CR almost 5 yrs; with only 1 post-SCT relapse). In the 4 responding pts who did not go to SCT, 3 relapsed, 1 died in CR. For R/R, ORR was 100%; CR/CRi of 50%. Pts received a med of 2 (2 – 4) prior lines; 3 (60%) had prior SCT. Pts received a med of 3 (1 – 7) cycles w/ 3 (1 – 3) to best response. Two pts went to SCT (1 auto, 1 allo); 1 pt is alive on active treatment. The 30- and 60-day mortality was 0% and 20%. With f/u ranging 1.4 – 21.8 mos, med OS and EFS is 8.9 mos; 12-month OS and EFS was 30%. In responding pts, causes of death were progression n = 4; died in CR n = 5 (3 ND, 2 R/R, 1 post SCT, 1 unknown, 3 sepsis). The most common any grade adverse events (AE) were edema (n = 13) and fatigue (n = 11). There were 2 grade 5 AE (progression, respiratory failure). Two grade 3 capillary leak events were observed. Conclusions: As frontline therapy, TAG with Hyper-CVAD, and VEN shows promising safety with no early mortality or high-grade CLS, with high response rates enabling frequent SCT consolidation and no CNS relapse. Clinical trial information: NCT04216524 .
Goulart et al. (2026) studied this question.