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Introduction: Unique among hematologic malignancies, blastic plasmacytoid dendritic cell neoplasm (BPDCN) affects multiple compartments including bone marrow, hematologic, lymphatic, dermatologic, and central nervous systems (CNS). Treating BPDCN is challenging, historically, as patients display refractoriness to chemotherapy and absence of long-term remissions in many cases not treated with hematopoietic stem cell transplantation. Discovering the prevalent overexpression of surface receptor CD123 (IL3-Rα) on BPDCN cells led to development of tagraxofusp, a novel anti-CD123 agent for patients with BPDCN., Areas Covered: Herein, the authors discuss the preclinical development and phase I/II clinical studies, which led to the approval of tagraxofusp. They discuss the current treatment landscape of BPDCN with tagraxofusp alone or combined with chemotherapy and highlight several ongoing clinical trials involving combinations of tagraxofusp with novel targeted therapeutics for BPDCN., Expert Opinion: Tagraxofusp has significantly improved the treatment landscape for patients with newly diagnosed BPDCN and has led to investigative efforts and augmentation of various strategies of targeting CD123, such as antibody-drug conjugates and anti-CD123 chimeric antigen receptor T-cells. However, relapsed/refractory disease and CNS-involvement of BPDCN remain therapeutic challenges. The authors recommend that healthcare providers consider multiple-agent clinical trial approaches and adequate CNS-prophylaxis for all patients with BPDCN.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy arising from the aberrant transformation of plasmacytoid dendritic cells (pDCs) and involving skin, bone marrow, lymph nodes, and central nervous system. Characteristically unique from other myeloid neoplasms, BPDCN cells express CD4, CD56, and CD123 as well as TCL-1 and TCF4 in almost all cases. Historically, this malignancy has exhibited a poor prognosis, with median survival of less than 2 years. Traditional treatment approaches have involved conventional cytotoxic chemotherapy followed by hematopoietic stem cell transplantation; however, patients frequently relapse with chemotherapy-resistant disease. We have recently entered a modern era of therapy with targeting of CD123, with first-in-class agent tagraxofusp, a CD123- targeted agent approved by the US Food and Drug Administration for therapy of patients with BPDCN ages 2 and older. Relapsed and refractory BPDCN remains an elusive therapeutic challenge, but better understanding of the underlying pathophysiology has led to the development of other CD123-targeted agents and combination therapy, as well as agents targeting beyond CD123. Specifically, the use of venetoclax in targeting BCL2 has been promising in BPDCN treatment. This review will focus on the underlying diagnostic markers of BPDCN which have led to novel targeted treatment strategies, as well as future directions in therapy we can expect in coming years., Competing Interests: Disclosure NP: Consulting/honorarium:AbbVie; Celgene; Stemline; Incyte; Novartis; MustangBio; Roche Diagnostics, LFB, Sanofi, ImmunoGen; Research funding/clinical trials support: Stemline; Novartis; AbbVie; Samus; Cellectis; Plexxikon; Daiichi-Sankyo; Affymetrix; Grants/funding: Affymetrix, SagerStrong Foundation. The remaining authors have stated that they have no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)