Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and clinically challenging hematologic malignancy with dismal outcomes. With a median age of ∼70 years, the majority of patients with BPDCN have experienced historically suboptimal responses with intensive chemotherapy regimens. The major scientific breakthrough in this field was the recognition of overexpression of a surface receptor, CD123/interleukin 3 (IL-3) receptor α, in all patients. Importantly, a novel therapeutic agent consisting of a truncated diphtheria toxin (DT) payload fused to recombinant human IL-3 was being developed, one that targeted CD123, initially known as DT-IL-3 (later known as SL401; tagraxofusp; tagraxofusp-erzs [Elzonris]). The identification of this agent, and subsequent clinical trials specifically dedicated to patients with BPDCN (including a pilot study, followed by a larger phase 1/2 multicenter study [90% overall response rate [ORR] in frontline and 67% ORR in relapsed/refractory setting]), in part led to approval of tagraxofusp-erzs on 21 December 2018. Tagraxofusp-erzs was the first agent approved for BPDCN (for patients ages 2 years and older), and importantly, established this drug as the first CD123-targeted agent ever approved. The most notable toxicity of tagraxofusp-erzs is occurrence of the capillary leak syndrome, which occurs frequently at all grades, and has also been observed to be life-threatening, appropriately leading to a US Food and Drug Administration "black box" warning in the package insert. The preclinical and clinical aspects of drug development of tagraxofusp-erzs as monotherapy leading to drug approval are reviewed herein, with discussion of future directions of this novel agent, including consideration for rational combinations in BPDCN and beyond.
© 2020 by The American Society of Hematology.