Blastic Plasmacytoid Dendritic Cell Neoplasm Treated with Approved CD123-Targeted Therapy Tagraxofusp: The First European Real-World Evidence Prospective Registry of First-Line Adult Patients

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive hematologic malignancy derived from plasmacytoid dendritic cells (pDC) that overexpress CD123, the interleukin-3 (IL-3) receptor alpha. Patients with BPDCN have a poor prognosis, with median overall survival (OS) of 8-14 months. Tagraxofusp (TAG; Elzonris®), a first-in-class CD123-targeted therapy comprising human IL-3 fused to a truncated diphtheria toxin payload, is currently the only approved first-line (1L) treatment for adult patients with BPDCN. TAG demonstrated clinically relevant efficacy as well as a manageable safety profile in the 0114 pivotal trial conducted in the United States (US), with an overall response rate of 75% and complete response (CR)/CRc (CR with residual skin abnormality not indicative of active disease) rate of 57% in 1L patients. Herein, we describe the first European (EU) real-world evidence prospective registry in patients with BPDCN who received TAG, with a focus on the effectiveness and safety of receiving TAG in a real-world setting. Enrolled patients will meet the updated diagnostic classification profile recently outlined by the World Health Organization (WHO) 2022 guidance. Currently, no published treatment outcomes data exist from prospective interventional clinical trials of 1L or relapsed/refractory (R/R) BPDCN outside the US. Data collected here will increase understanding of clinical outcomes in TAG-treated patients. The registry was designed to meet the requirements outlined in the marketing authorization of the EU Commission for further evaluation of safety and efficacy in patients with 1L or R/R BPDCN.

Methods: This is a single-arm, postauthorization, noninterventional study (EudraCT: 2021-001684-24) in patients ≥18 years with a confirmed diagnosis of BPDCN (immunophenotypic analysis positive for CD123, CD4, and CD56, plus 1 additional pDC marker [TCF4, TCL1, CD303, or CD304], or a combination of 3 pDC markers, according to WHO 2022 classification). Patients will receive TAG under real-world routine clinical practice conditions: 12 mcg/kg/day intravenously (IV) on days 1-5 of a 21-day cycle (which corresponds to the approved dosage). The study will enroll a minimum 80 patients from 40-50 sites across EU, who are to be treated or who have recently (within 3 months) started treatment with TAG over an ~4-year period. Patients with R/R BPDCN will comprise an exploratory cohort.

Primary objectives of the study are rates of CR after 3 months (± 1 month) of TAG and the incidence and severity of capillary leak syndrome (CLS). Secondary objectives are rates of patients bridged to stem cell transplant (SCT), OS, progression-free survival (PFS), best overall response (BOR), and duration of response (DOR). Secondary safety assessments are incidence and severity of adverse events of special interest: hepatic-, renal-, and cardiac-related events, and choroid plexitis events. TAG dose interruptions, number of TAG doses/cycles administered, and rates of IV albumin supplementation for diagnosed, or symptoms of, CLS will also be assessed.

Data collection is anticipated quarterly, as well as at screening, enrollment, early discontinuation, and/or study end. A list of the assessments taken at each time point are shown in the Figure. Safety data collection will end 18 months after the last enrolled patient's first visit (LPFV). Interim analyses will be performed annually, with an effectiveness interim analysis scheduled for 12 months post-LPFV. Demographic, safety, and efficacy data will be summarized descriptively. The Kaplan-Meier method will be used to summarize PFS, OS, and DOR. The Clopper-Pearson exact method will determine the rates of patients bridged to SCT and BOR. Subgroup analyses for effectiveness and safety may also be performed on the basis of gender, age, or baseline Eastern Cooperative Oncology Group performance status. Enrollment is due to start in Q3-Q4 2022.

Taking the registry as the basis, upon study finalization a complementary comparative analysis of effectiveness and safety from the TAG registry with a retrospective clinical cohort will be undertaken using appropriate methodology.

Platzbecker:Takeda: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Silence Therapeutics: Honoraria; Jazz: Honoraria; Abbvie: Honoraria; BMS/Celgene: Honoraria; Geron: Honoraria. Angelucci:Celgene: Honoraria, Other: Data monitoring committee; Bluebird Bio: Consultancy; Gilead: Consultancy; Roche: Consultancy; Glaxo: Consultancy; Vertex: Honoraria, Other: Data monitoring committee; Sanofi: Speakers Bureau; Vifopr: Honoraria, Other: Data monitoring committee; Menarini/Stemline: Consultancy; Novartis: Honoraria. Montesinos:Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Menarini/Stemline: Consultancy, Research Funding; Otsuka: Consultancy; Kura Oncology: Consultancy; Incyte: Consultancy; Ryvu: Consultancy; Nerviano: Consultancy; Beigene: Consultancy. Lemoli:AbbVie: Consultancy; Janssen: Consultancy; Stemline Therapeutics: Consultancy; Jazz: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Celgene: Research Funding; Servier: Consultancy. Spyridonidis:Stemline/Menarini: Consultancy. Mughal:Informa: Other: financial benefit and/or patents; Stemline Therapeutics: Current Employment, Current holder of stock options in a privately-held company; Oxford University Press: Other: financial benefit and/or patents. Paley:Stemline Therapeutics: Current Employment. Riggi:Menarini/Stemline Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Mohty:Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Novartis: Honoraria; Adaptive Biotechnologies: Honoraria; Oncopeptides: Honoraria; Pfizer,: Honoraria; GSK: Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria.