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Goodman & Gilman's: Annual FDA Approvals


Brand Name



CD123-directed cytotoxin

FDA Indication

Blastic plasmacytoid dendritic cell neoplasm†,$


Tagraxofusp is the first therapy prospectively studied and approved for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). It was approved as a breakthrough therapy for adults and pediatric patients age ≥2 years. Tagraxofusp is a CD123-directed cytotoxin and a fusion protein. It is composed of recombinant human interleukin-3 (IL-3) fused to a truncated 388-residue diphtheria toxin (DT388) containing the DT catalytic and translocation domains.123,124 Tagraxofusp is produced by recombinant DNA technology in E. coli cells and was designed to deliver toxin to the cytosol of CD123 (IL-3 α receptor subunit)-expressing cells without triggering the CD123 signaling pathways.125,126 DT388 acts as a cytotoxin by rendering peptide elongation factor 2 (EF2) inactive through ADP-ribosylation of diphthamide (a modified histidine residue) on EF2.127 Inactivation of EF2 stops protein synthesis and causes cell death. Resistance to tagraxofusp has been associated with loss of functional diphthamide biosynthesis protein 1 (DPH1), the first enzyme in the cascade that generates EF2’s diphthamide residue.127

Tagraxofusp (SL-401) represents the first-in-class agent to target CD123+ cell lines for depletion.124 It is the second fusion protein to employ DT as a cytotoxin, preceded onto the U.S. market by denileukin diftitox,123 an IL-2-directed cytotoxin suspended from the U.S. market in 2014 due to postmarket safety signals (and based on recent FDA regulatory activity, potentially staged for a comeback).128 Based on the pharmacologic action of DT388, tagraxofusp and denileukin diftitox can both be broadly classified as protein synthesis inhibitors and, more specifically, as EF2 inhibitors. As EF2 inhibitors, tagraxofusp and denileukin diftitox share a common pharmacologic mechanism of action with moxetumomab pasudotox-tdfk†,# (Table P2-2).

The endogenous ligand for CD123 is IL-3. IL-3 is a polyfunctional hematopoietic growth factor that acts similarly to granulocyte-macrophage colony-stimulating factor (GM-CSF).126,129 IL-3 stimulates the differentiation of multipotent hematopoietic stem cells to generate progenitor cells for myeloid and lymphoid cell lines. IL-3 also stimulates the differentiation of myeloid progenitor cells to generate granulocytes, monocytes, and dendritic cells.126 IL-3 cytokine differentiation cofactors include IL-6, IL-7, erythropoietin, and GM-CSF.130 IL-3 is secreted by basophils and activated T cells to support growth and differentiation of T cells from the bone marrow in an immune response. CD123 is normally expressed on dendritic cell blasts but its expression is negligible on normal hematopoietic stem cells and mature hematopoietic cells, with the exception of basophils and esoinophils.124,126 Plasmacytoid dendritic cells (pDCs) are CD123+ immune cells characterized by co-expression of CD4 and CD56, and over-secretion of IFN-α.131 Perhaps the key feature of CD123+ malignant cell lines is the dependence on IL-3 for survival. BPDCN blast cells are ultrasensitive to tagraxofusp, with IC50 values measured in femtomolar (10–15 M) concentrations.124 Concurrent with depletion of pDCs, tagraxofusp administration is accompanied by reductions in the production of IFN-α and IL-6.131

The complex biology of endogenous IL-3 signaling through CD123 and the pharmacologic knockout of CD123+ cell lines by tagraxofusp gives rise to a safety profile for tagraxofusp that is mostly predictable.124,126 Side effects of treatment have included capillary leak syndrome (55%; 2 fatal events), hypersensitivity reactions (46%), elevations in liver enzymes (88%), anxiety, appetite decrease, chills, confusion, constipation, cough, diarrhea, dizziness, dyspnea, edema (peripheral), epistaxis, fatigue, headache, hematuria, insomnia, nausea, neutropenia (febrile), pain (back/extremity/oropharyngeal), petechiae, pruritus, pyrexia, tachycardia, vomiting, and weight increase.13 Due to prior diphtheria immunization, almost all patients will have pretreatment antidrug antibodies and approximately one-fifth of patients will start therapy with neutralizing antibodies.124 Treatment-emergent drug-neutralizing antibodies were observed in most patients during premarket trials, including anti-IL-3 antibodies (68%).13

Previously known as natural killer (NK) cell leukemia/lymphoma, BPDCN is a rare blood cancer that often presents with features of both leukemia and lymphoma.133 TET2 is thought to be the most common mutated gene in BPDCN.133 Deleterious mutations of IKZF3 and ZEB2, as well as recurrent somatic mutations of ASXL1, NPM1, and RAS family genes, also have been noted.134 Patients with BPDCN typically present with asymptomatic skin lesions that can be variable in appearance and can be associated with lymphadenopathy, splenomegaly, and cytopenias from bone marrow involvement.123 The clinical course of BPDCN is aggressive, with a rapid progression to the leukemia phase and median overall survival ranging from 9 to 20 months.123,124,134 No standardized therapeutic approach has been established for the disease, and conventional treatments have largely been borrowed from those used for AML, ALL, and lymphoma. The best hope for BPDCN patients has been allogenic HCT.123

Tagraxofusp is administered as a dose of 12 µg/kg intravenously over 15 minutes once daily on days 1–5 of a 21-day cycle. Treatment is continued until disease progression or unacceptable toxicity occurs. An algorithm for dose modification is included in the product labeling.12 Premedication with H1- and H2-antihistamines, corticosteroids, and acetaminophen is recommended. The first dose must be administered in an inpatient setting with observation for ≥24 hours and all subsequent infusions require a minimum of 4 hours of observation regardless of the setting.13 Among 13 treatment-naïve patients with BPDCN enrolled in an open-label, single-arm clinical trial (NCT02113982), seven patients (53.8%) achieved complete response (CR) or clinical complete response (CRc) within 1–4 cycles (median: 57 days).13 Among 15 patients with relapsed or refractory BPDCN, 1 patient (6.7%) achieved a CR (duration: 111 days) and another patient (6.7%) achieved a CRc (duration: 424 days). The annual cost of therapy is expected to be $400,000.135

Potential expanded uses of tagraxofusp for myelodysplastic syndromes, multiple myeloma, myelofibrosis, chronic myeloid leukemia, hairy cell leukemia, systemic sclerosis, serious autoimmune disorders characterized by overexpression of type 1 interferons (e.g., systemic lupus erythematosus and primary Sjögren’s syndrome),136 and others are under investigation.124,126,129,131 Additionally other CD123-targeted therapies in preclinical stages include a humanized anti-CD123 antibody, anti-CD123 chimeric antigen receptor T cells and cytokine-induced killer cells, anti-CD123 Fv-Pseudomonas exotoxin immunotoxins, bispecific conjugates that react with CD123 and CD16, and anti-CD123 radioimmunoconjugates.124,126

Table P2-22018 Pharmacological Similar Biologic Approvals137
Further Reading in Goodman & Gilman’s