Clinical Activity and Tolerability of SL-401 (Tagraxofusp): Recombinant Diphtheria Toxin and Interleukin-3 in Hematologic Malignancies

Abstract

Overcoming the leukemia stem cell resistance to intensive chemotherapy has been an area of extensive research over the last two decades. Advances and greater understanding of the molecular biology of leukemia stem cells are in rapid progress. Targeted therapies are currently being used in clinical practice with reasonable response rates, but a cure is being achieved in only a small percentage of patients, most likely due to tumor mutational heterogeneity. A genetically engineered diphtheria toxin fused with interleukin-3 (SL-401 or tagraxofusp) has shown robust activity in blastic plasmacytoid dendritic cell neoplasm and promising response rates in different myeloid malignancies, including eradication of minimal residual disease. Multiple clinical trials are being conducted using this drug and the preliminary results are encouraging. This article reviews the clinical trials for SL-401, its mechanism of action, clinical activity, and the adverse event profile.

Bispecific human IL2‐CCR4 immunotoxin targets human cutaneous T‐cell lymphoma

“…This might be the reason that FDA approved Ontak® for multiple‐course administration (9 or 18 µg·kg −1 ·day −1 by intravenous infusion over 30–60 min for five consecutive days every 21 days for eight cycles). In December 2018, DT‐based human IL‐3 fusion toxin ELZONRIS™ (tagraxofusp‐erzs; SL‐401; Stemline Therapeutics, Inc., New York, NY, USA) was approved by FDA at 12 µg·kg −1 , intravenously over 15 min once daily on days 1–5 of a 21‐day cycle for multiple consecutive cycles for the treatment of blastic plasmacytoid dendritic cell neoplasm in adult and pediatric patients 2 years and older, in both treatment‐naïve and previously treated populations (Alkharabsheh and Frankel, 2019). We speculate that the CCR4 IT and the bispecific IT could also be administered for multiple‐course treatment of CTCL, as the same truncated diphtheria toxin DT390 was used.…”

KD025, an anti‑adipocyte differentiation drug, enhances the efficacy of conventional chemotherapeutic drugs in ABCG2‑overexpressing leukemia cells

“…In addition, ABCG2 has been widely recognized as a promising therapeutic target for eradication of LSCs, since ABCG2 is highly enriched in LSCs and serves a crucial role in the differentiation, proliferation and self-renewal of LSCs (37). Although intensive methods and drugs have been designed to inhibit ABCG2, unfortunately, even with the most advanced treatments to date, the reversal of ABCG2-mediated MDR remains unsatisfactory and the relapse risk of patients with leukemia remains high in the first two years (38). Furthermore, as of yet, appropriate inhibitors of ABCG2 are lacking, since these agents are not very potent or are toxic, and their ability to inhibit ABCG2 has not been verified in patients (4).…”

Bispecific Targeting of EGFR and Urokinase Receptor (uPAR) Using Ligand-Targeted Toxins in Solid Tumors

“…Studies showed that Ontak was efficacious against T cell lymphomas expressing human IL2 receptor CD25 [ 8 ]. Tagraxofusp (Elzonris) is a more recent example of a truncated DT immunotoxin fused with human interleukin 3 (IL-3) which received FDA approval for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in 2018 [ 9 ]. Moxetumomab pasudotox (Moxe) is an anti-CD22 immunotoxin that uses truncated Pseudomonas exotoxin as a toxin.…”