Role of tagraxofusp in treating blastic plasmacytoid dendritic cell neoplasm (BPDCN)

ABSTRACT

Introduction: Advances and drug development in rare diseases, such as blastic plasmacytoid dendritic cell neoplasm (BPDCN), has historically been limited by small numbers of patients in the target population. In recent years, the development of tagraxofusp (SL-401) (ELZONRIS, Stemline Therapeutics) for the treatment of adult and pediatric BPDCN has been a successful story that led to US FDA approval in December 2018.

Areas covered: In this evaluation of tagraxofusp, we briefly review chemistry; pharmacokinetics and pharmacodynamics, as we focus on the clinical experience and future directions.

Expert Opinion: Tagraxofusp has been a welcome new addition and a successful initial development step in the targeted treatment of BPDCN. In phase I/II clinical trial, major responses were observed in 90% of treatment-naïve patients, with 72% of the responses observed as complete remissions. Limitations on the usage of tagraxofusp and strategies to handle those limitations were further explored in this review.

KEYWORDS:

• Tagraxofusp
• SL-401
• ELZONRIS
• BPDCN
• CD123
• blastic plasmacytoid dendritic cell neoplasm

Article highlights

• Tagraxofusp is first-in-class agent to target CD123 (interleukin 3 receptor alpha) and is the first approved treatment for BPDCN.

• The approval was based on phase I/II clinical trial data involving 47 patients with BPDCN, 32 treatment naïve (ORR 90%) and 15 relapsed/refractory (ORR 67%).

• The most common side effects noted with the use of tagraxofusp were hypoalbuminemia, transaminitis, thrombocytopenia; and, most notably, the capillary leak syndrome ‘black-box warning’.

• The most consistent predictor of capillary leak syndrome appears to be lower baseline albumin levels and/or a rapid decline in albumin during the initial treatment days.

• Downregulation of Diphthamide Biosynthesis 1 (DPH1), seems to be the primary mechanism of resistance, with an unclear role of anti-drug and neutralizing antibodies.

• Rational combinations of tagraxofusp with other effective anti-BPDCN therapies such as BH3 mimetics, hypomethylating agents, and cytotoxic chemotherapeutic agents, as well as combinations that target BPDCN resistance pathways, are anticipated.

Declaration of interest

M Konopleva: Consulting/honorarium: AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, and Kisoji. Research funding/clinical trial support AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, and Astra Zeneca. Stock options/Royalties: Reata Pharmaceutical. N Pemmaraju: Consulting/honorarium: Celgene, Stemline, Incyte Corporation, Novartis, MustangBio, Roche Diagnostics, and LFB. Research funding/clinical trials support from Stemline, Novartis, Abbvie, Samus, Cellectis, Plexxikon, Daiichi-Sankyo, Affymetrix, and SagerStrong Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This study was supported in part by the MD Anderson Cancer Centre Support Grant (CCSG) CA016672, the MD Anderson Cancer Center Leukemia SPORE CA100632, the Charif Souki Cancer Research Fund and generous philanthropic contributions to the MD Anderson Moon Shots Program.