The goal of this clinical trial is to study the efficacy of the tagraxofusp + venetoclax combination in treatment-naive blastic plasmacytoid dendritic cell neoplasm adult patients.

The main question is to verify the response in patients after 3 cycles of tagraxofusp+venetolax and to demonstrate if the combination of tagraxofusp + venetoclax increases the rate of complete remission, assessed after 3 months of treatment.

Patients will receive a ramp-up phase of venetoclax during 3 days and at least 3 cycles of venetoclax. After, the investigators will evaluate the response, and depending on the response observed, patients may receive additional cycles of treatment for a maximum of 24 cycles, or receive an allograft or discontinue the treatment in the case of therapeutic failure.

Inclusion Criteria:

1. Patients with a confirmed BPDCN diagnosis according to WHO 2022 revised criteria and have not received previous treatment : patients with skin or lymph node lesions but no bone marrow involvement can be included

2. Age >18 years

3. Ability to understand the protocol and to sign an informed consent

4. Possibility of follow-up

5. ECOG < 3

6. Adequate renal function as demonstrated by a calculated creatinine clearance ≥ 60 mL/min by the Cockcroft-Gault formula.

7. Adequate cardiac function defined by LVEF >/= 50% by MUGA or ECHO and no clinically significant abnormalities on a 12-lead ECG

8. Albumin level≥3,2g/dL

9. Adequate liver function as demonstrated by:

   • aspartate aminotransferase (AST) ≤ 2.5 × ULN*
   • alanine aminotransferase (ALT) ≤ 2.5 × ULN*
   • bilirubin ≤ 3.0 × ULN, unless due to Gilbert's syndrome* * Unless considered due to leukemic organ involvement, in that cases values must be ≤ 10 × ULN

10. Men, and women of childbearing potential must be using a highly effective method of contraception

11. Negative urine/blood pregnancy test within 1 week prior to the initiation of treatment (if applicable)

12. Patient covered by any social security system

Exclusion Criteria:

1. Participation to another clinical trial with any investigative drug within 30 days prior to study enrolment.

2. Previous treatment with venetoclax or tagraxofusp

3. Treatment of BPDCN with any prior chemotherapy or investigational agents, except hydroxyurea for less than 14 days at the time of inclusion

4. Concomitant immunosuppressive therapy -except for low-dose prednisone (≤10 mg/day)

5. Known allergy or sensitivity to tagraxofusp, venetoclax, and any of its components or excipients.

6. Pregnant or breastfeeding woman

7. Known positivity for hepatitis B or C infection except for those subjects with an undetectable viral load or subjects with serologic evidence of prior vaccination to HBV

8. Evidence of uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal)

9. Subject has any history of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study including, but not limited to:

   • Cardiovascular disease e.g., NYHA heart failure > class 2, uncontrolled angina, history of myocardial infarction, unstable angina, or stroke within 6 months prior to study entry, uncontrolled hypertension, or clinically significant arrythmias not controlled by medication.
   • Renal, pulmonary, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia.

10. Subject with a history of other malignancies within the last three years prior to study entry, except for:

    • Adequately treated in situ carcinoma of the breast or cervix uteri
    • Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin
    • Prostate cancer without needs for specific therapy
    • Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.

11. Malabsorption syndrome or other conditions that preclude enteral route of administration

12. Patient with hereditary fructose intolerance

The individual participant data collected will be analyzed by the sponsor and therefore not shared.