Tagraxofusp-Erzs – Uses, Dosage, Side Effects, Interaction

Tagraxofusp ERZS is a CD123-directed cytotoxin used to treat blastic plasmacytoid dendritic cell neoplasm. Tagraxofusp is a CD123-directed cytotoxin. It is a fusion protein composed of a human interleukin-3 (IL-3) that is genetically fused to the catalytic and translocation domains of truncated diphtheria toxin (DT) produced in Escherichia coli.^[rx,rx,rx] Tagraxofusp received its first global approval by the FDA on December 21, 2018, as the first FDA-approved treatment for blastic plasmacytoid dendritic cell neoplasm, which is a myeloid malignancy in the dendritic cell lineage.^[rx] It was also approved by the European Commission on January 7, 2021.^[rx]

Tagraxofusp is an anti-cancer medication for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp is a fusion protein consisting of interleukin 3 (IL-3) fused to diphtheria toxin. The fusion protein readily kills cultured pDC by binding to their IL-3 receptors to thereby gain entrance to the cells and then blocking these cells’ protein synthesis (due to its diphtheria toxin portion inhibiting eukaryotic elongation factor 2)

Mechanism of action

Interleukin 3 (IL-3) is a cytokine and hematopoietic growth factor that promotes the differentiation of hematopoietic cells into various myeloid cells. It mediates its biological actions by binding to the IL-3 receptor, which is made up of two subunits: the alpha (α) subunit – also known as CD123 – is the site of ligand attachment and confers receptor specificity, while the beta (β) subunit, also known as CDw131 – plays a role in signal transduction, internalization of the ligand-receptor complexes, and activation of the Ras signalling pathway.^[rx] The expression of the IL-3 receptor is prevalent in CD34⁺ hematopoietic cells as well as on granulocytes and monocyte precursors.^[rx] CD123, the subunit of the IL-3 receptor, has also been implicated in the pathophysiology of BPDCN, as transformed plasmacytoid dendritic cells that overexpress CD123 are frequently observed.^[rx,rx]

Tagraxofusp has potent antitumour activity against BPDCN cells in both in vitro and in vivo models.^[rx] It is a cytotoxin that works to cause cell death in malignant cells that express CD123, which is a subunit of the interleukin 3 (IL-3) receptor. In vitro, tagraxofusp decreased cell proliferation and increased expression of apoptotic markers in BPDCN cell lines and in blasts from patients with BPDCN.^[rx]

Indications

• Tagraxofusp is indicated for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). In the US, it is approved for use in adults and pediatric patients over 2 years old.^[rx] In Europe, it is only approved for use in adults.^[rx]
• Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Contraindication

• low amount of albumin proteins in the blood
• slow heartbeat
• liver problems
• decreased kidney function
• fever
• pregnancy
• a patient who is producing milk and breastfeeding
• chronic kidney disease stage 3A (moderate)
• chronic kidney disease stage 3B (moderate)
• chronic kidney disease stage 4 (severe)
• chronic kidney disease stage 5 (failure)
• fast heartbeat

Dosage

Strengths: 1000 mcg/mL

Malignant Disease

• 12 mcg/kg IV over 15 minutes once daily on Days 1 to 5 of a 21-day cycle until disease progression or unacceptable toxicity
• Premedicate patients with an H1-histamine antagonist (e.g., diphenhydramine), H2-histamine antagonist (e.g., ranitidine), corticosteroid (e.g., 50 mg IV methylprednisolone or equivalent) and acetaminophen approximately 60 minutes prior to each infusion.
• The dosing period may be extended for dose delays up to Day 10 of the cycle.

Pediatric Dose for Malignant Disease

2 years and older:

• 12 mcg/kg IV over 15 minutes once daily on Days 1 to 5 of a 21-day cycle until disease progression or unacceptable toxicity
• Premedicate patients with an H1-histamine antagonist (e.g., diphenhydramine), H2-histamine antagonist (e.g., ranitidine), corticosteroid (e.g., 50 mg IV methylprednisolone or equivalent) and acetaminophen approximately 60 minutes prior to each infusion.
• The dosing period may be extended for dose delays up to Day 10 of the cycle.

Dose Adjustments

RECOMMENDED DOSE MODIFICATIONS:

• SERUM ALBUMIN 3.5 g/dL or less or reduced 0.5 g/dL or greater from the value measured prior to initiation of the current cycle: See CLS Management Guidelines.
• BODY WEIGHT increases 1.5 kg or greater over pretreatment weight on prior treatment day: See CLS Management Guidelines.
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) increase to 5 times the upper limit of normal (ULN): Withhold therapy until transaminase elevations are 2.5 x ULN or less.
• SERUM CREATININE greater than 1.8 mg/dL or CrCl 60 mL/minute or less: Withhold therapy until serum creatinine resolves to 1.8 mg/dL or less or CrCl is 60 mL/min or greater.
• SYSTOLIC BLOOD PRESSURE greater than or equal to 160 mmHg OR less than or equal to 80 mmHg: Withhold therapy until systolic blood pressure is less than 160 mmHg or greater than 80 mmHg.
• HEART RATE greater than or equal to 130 bpm OR less than or equal to 40 bpm: Withhold therapy until heart rate is less than 130 bpm or greater than 40 bpm.
• BODY TEMPERATURE 38C or greater: Withhold therapy until body temperature is less than 38C.
• MILD OR MODERATE HYPERSENSITIVITY REACTIONS: Withhold therapy until resolution of any mild or moderate hypersensitivity reaction; resume therapy at the same infusion rate.
• SEVERE OR LIFE-THREATENING HYPERSENSITIVITY REACTIONS: Permanently discontinue therapy.

CLS MANAGEMENT GUIDELINES:
PRIOR TO FIRST DOSE IN CYCLE 1:

• Serum albumin less than 3.2 g/dL: Administer this drug when serum albumin is 3.2 g/dL or greater.
• Serum albumin less than 3.5 g/dL: Interrupt dosing until resolved; administer albumin at 25 g IV every 12h or more frequently as practical until serum albumin is greater than or equal to 3.5 g/dL AND not more than 0.5 g/dL lower than the value measured prior to dosing initiation of the current cycle.
• Serum albumin reduced by greater than or equal to 0.5 g/dL from the albumin value measured prior to initiation of the current cycle: Interrupt dosing until resolved; administer albumin at 25 g IV every 12h or more frequently as practical until serum albumin is greater than or equal to 3.5 g/dL AND not more than 0.5 g/dL lower than the value measured prior to dosing initiation of the current cycle.

DURING DOSING:

• A predose body weight that is increased by greater than or equal to 1.5 kg over the previous day’s predose weight: Interrupt dosing until resolved; administer albumin at 25 g IV every 12 hours or more frequently as practical and manage fluid status as indicated clinically (e.g., generally with IV fluids and vasopressors if hypotensive and with diuretics if normotensive or hypertensive), until body weight increase has resolved (i.e., the increase is no longer greater than or equal to 1.5 kg greater than the previous day’s predose weight).
• Edema, fluid overload and/or hypotension: Interrupt dosing until resolved; administer albumin at 25 g IV every 12 hours or more frequently as practical and manage fluid status as indicated clinically serum albumin is greater than or equal to 3.5 g/dL. Administer 1 mg/kg of methylprednisolone (or an equivalent) per day, until resolution of CLS sign/symptom or as indicated clinically. Aggressive management of fluid status and hypotension if present, which could include IV fluids and/or diuretics or other blood pressure management, until resolution of CLS sign/symptom or as clinically indicated.

NOTE: Administration may resume in the same cycle if all CLS signs/symptoms have resolved and the patient did not require treatment of hemodynamic instability. The administration should be held for the remainder of the cycle if CLS symptoms have not resolved or the patient required treatment for hemodynamic instability (e.g., required administration of IV fluids and/or vasopressors to treat hypotension) (even if resolved), and therapy may only resume in the next cycle if all CLS signs/symptoms have resolved, and the patient is hemodynamically stable.

Administration advice:

• Administer the first cycle of this drug in an inpatient setting. Subsequent cycles may be administered in the inpatient or outpatient setting.

Side Effects

The most common

• nausea
• vomiting
• constipation
• diarrhea
• extreme tiredness
• headache
• decreased appetite
• sore throat
• pain in back, arms, or legs
• cough
• difficulty falling asleep or staying asleep
• feeling nervous or confused
• nose bleed
• small red, brown, or purple spots on the skin
• rash, itching, difficulty breathing, mouth sores or swelling
• extreme tiredness, yellowing of skin or eyes, loss of appetite, pain in the upper right part of the stomach
• fever, chills
• fast heartbeat
• blood in urine

More common

• Black, tarry stools
• bloating or swelling of the face, arms, hands, lower legs, or feet
• bloody or cloudy urine
• blurred vision
• chills
• confusion
• cough
• decrease or increase in the amount of urine
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fast, pounding, or irregular heartbeat or pulse
• fever
• headache
• itching skin
• lower back or side pain
• nausea
• nervousness
• nosebleed
• painful or difficult urination
• pale skin
• pounding in the ears
• rapid weight gain
• slow heartbeat
• small red or purple spots on the skin
• sore throat
• stomach pain
• sweating
• tightness in the chest
• tingling of the hands or feet
• troubled breathing
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness
• unusual weight gain or loss

Rare

• fever
• headache
• itching skin
• lower back or side pain
• nausea
• nervousness
• nosebleed
• painful or difficult urination
• pale skin
• pounding in the ears
• rapid weight gain
• slow heartbeat
• small red or purple spots on the skin
• sore throat
• stomach pain
• sweating
• tightness in the chest
• tingling of the hands or feet
• troubled breathing
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness
• unusual weight gain or loss

Drug Interaction

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

Based on its mechanism of action, this drug has the potential for adverse effects on embryofetal development. Advise females of reproductive potential to use contraceptive methods during therapy and for at least 1 week after. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Verify negative pregnancy status in females of reproductive potential within 7 days prior to initiating therapy.

Lactation

Use should be avoided.
Excreted into human milk: Unknown
Excreted into animal milk: Data not available
Because of the potential for serious adverse reactions in breastfed children from this drug, breastfeeding is not recommended during therapy and for 1 week after.

References