Venetoclax, SL-401, and Chemotherapy for the Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm

PRIMARY OBJECTIVE: I. To evaluate progression-free survival (PFS) at 12 months of venetoclax (VEN) in combination with chemotherapy and SL-401 (tagraxofusp \[TAG\]) in patients with newly diagnosed blastic plasmacytoid dendritic cell neoplasm (BPDCN). SECONDARY OBJECTIVES: I. To determine the safety of the SL-401 in combination with VEN and in combination with chemotherapy in patients with newly diagnosed BPDCN by toxicity and futility monitoring. II. To determine the efficacy by measurement of progression free survival (PFS), overall response rate (ORR): complete response (CR) and complete response with incomplete marrow recovery (CRi), clinical complete response (CRc) and remission duration of SL-401 in combination with chemotherapy and VEN in patients with newly diagnosed BPDCN. III. To determine the rate of stem cell translant (SCT) within the first 8 cycles (understanding that some patients won't get SCT) in patients with newly diagnosed BPDCN. EXPLORATORY OBJECTIVES: I. To examine expression and function of BCL-2 family proteins and its modulation by VEN in BPDCN blasts. II. To determine the rate of minimal residual disease (MRD) negativity in patients achieving CR/CRi/CRc and its correlation with disease-free survival (DFS) and overall survival (OS). III. To determine CD123 levels pre- and post-therapy. IV. To determine molecular mutations pre-and post- therapy as part of 81-gene panel by next-generation sequencing. OUTLINE: INDUCTION: CYCLE 1: Patients receive tagraxofusp-erzs (SL-401) intravenously (IV) once daily (QD) over 15 minutes on days 1-5. CYCLES 2, 4, 6, and 8: Patients receive tagraxofusp-erzs IV QD over 15 minutes on days 1-5, and venetoclax orally (PO) QD on days 1-14 of cycle 2, and days 1-7 of cycles 4, 6, and 8. CYCLES 3 and 7: Patients receive venetoclax PO QD on days 1-7. Patients whose age \< 60 receive hyper-CVAD and age \>= 60 receive mini-hyper-CVD. Patients may receive rituximab IV over 90 minutes on days 1 and 8, methotrexate intrathecally (IT) on day 2, and/or cytarabine IT on day 8. Patients also receive venetoclax PO QD on days 1-7. HYPER-CVAD (AGE \< 60): Patients receive cyclophosphamide IV over 3 hours every 12 hours (Q12H) on days 1-3, vincristine IV over 15 minutes on days 1 and 8, dexamethasone orally (PO) or IV over 30 minutes on days 1-4 and 11-14, and doxorubicin IV over 24 hours on day 4. MINI-HYPER-CVD (AGE \>= 60): Patients receive cyclophosphamide IV over 3 hour Q12H on days 1-3, vincristine IV over 15 minutes on days 1 and 8, dexamethasone PO or IV over 30 minutes on days 1-4 and 11-14. CYCLE 5: Patients receive venetoclax PO QD on days 1-7. Patients who age \< 60 receive MTX/AraC and age \>= 60 receive mini-MTX/AraC. Patients may receive rituximab IV over 4-6 hours on days 1 and 8, cytarabine IT on day 5, and/or methotrexate IT on day 8. MTX/ARAC (AGE \< 60): Patients receive methotrexate IV over 24 hours on day 1, and cytarabine IV over 3 hours Q12H on days 2 and 3. MINI-MTX/ARAC (AGE \>= 60): Patients receive methotrexate IV over 24 hours on day 1, methylprednisolone IV over 2 hours Q12H on days 1-3, and cytarabine IV over 3 hours Q12H on days 2 and 3. ALL CYCLES: Treatment repeats every 28 days for 8 cycles in the absence of disease progression and unacceptable toxicity. MAINTENANCE: Patients receive venetoclax PO QD on days 1-7, POMP chemotherapy during cycles 1-5, 7-11, and 13-17, and SL-401 IV QD on days 1-5 of cycles 6, 12, and 18. Treatment repeats every 28 days for 24 cycles in the absence of disease progression or unacceptable toxicity. POMP: Patients receive mercaptopurine PO three time daily (TID) on days 1-28, vincristine IV over 15 minutes on day 1, prednisone PO QD on days 1-5, and methotrexate PO once weekly. After completion of study treatment, patients are followed up at 30 days, and then every 3 months thereafter.