Phase II Study Evaluating the Efficacy and Safety of the Combination of Tagraxofusp and Venetoclax in Treatment-naive Blastic Plasmacytoid Dendritic Cell Neoplasm Patients

Inclusion criteria

• 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
• Age >18 years
• Ability to understand the protocol and to sign an informed consent
• Possibility of follow-up
• ECOG < 3
• Adequate renal function as demonstrated by a calculated creatinine clearance ≥ 60 mL/min by the Cockcroft-Gault formula.
• Adequate cardiac function defined by LVEF >/= 50% by MUGA or ECHO and no clinically significant abnormalities on a 12-lead ECG
• Albumin level≥3,2g/dL
• 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
• Men, and women of childbearing potential must be using a highly effective method of contraception
• Negative urine/blood pregnancy test within 1 week prior to the initiation of treatment (if applicable)
• Patient covered by any social security system

Exclusion criteria

• Participation to another clinical trial with any investigative drug within 30 days prior to study enrolment.
• Previous treatment with venetoclax or tagraxofusp
• Treatment of BPDCN with any prior chemotherapy or investigational agents, except hydroxyurea for less than 14 days at the time of inclusion
• Concomitant immunosuppressive therapy -except for low-dose prednisone (≤10 mg/day)
• Known allergy or sensitivity to tagraxofusp, venetoclax, and any of its components or excipients.
• Pregnant or breastfeeding woman
• 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
• Evidence of uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal)
• 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.
• 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.
• Malabsorption syndrome or other conditions that preclude enteral route of administration
• Patient with hereditary fructose intolerance