Loncastuximab Tesirine – Uses, Dosage, Side Effects, Interaction

Relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL) is a therapeutic challenge for patients who have undergone prior systemic therapies with limited success.^[rx] Prognosis is poor and more effective therapies are needed to treat relapsed/refractory cases and improve survival. On April 23, 2021, the Food and Drug Administration granted accelerated approval for the antibody-drug conjugate, loncastuximab tesirine-lpyl, also known as Zynlonta. This therapy was developed by ADC Therapeutics and its accelerated approval for relapsed or refractory B-cell lymphoma is based on promising results from the LOTIS-2 clinical trial.^[rx,rx]

Mechanism of action

Human CD19 antigen is a membrane glycoprotein in the immunoglobulin superfamily expressed in the various stages of B-cell development; it is detected in most malignancies of B-cell origin. Additionally, CD19 has rapid internalization kinetics and does not shed into the general circulation, rendering it a useful therapeutic target for antibody-drug conjugates (ADCs) in the treatment of B-cell malignancies.^[rx]

Loncastuximab tesirine is an antibody-drug conjugate designed to target human CD19. It is a humanized monoclonal antibody and conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin by a protease enzyme cleavable valine-alanine linker.^[rx] The monoclonal IgG1 kappa antibody component binds to CD19, a transmembrane protein located on B-cell surfaces. The small molecule component, SG3199, functions as a PBD dimer and alkylating agent. Following binding to CD19, loncastuximab tesirine becomes internalized into the cell and subsequently proteolytic cleavage releases the SG3199 component. SG3199 binds to the DNA minor groove, forming cytotoxic DNA interstrand crosslinks, leading to B-cell cell death.^[rx]

Loncastuximab tesirine exhibits antitumour activity against malignant B-cells, treating lymphomas. Higher exposure in Cycle 1 of therapy in clinical trials was associated with an increased incidence of Grade ≥2 adverse reactions, including liver function test abnormalities, skin and nail reactions, and liver function test abnormalities.^[rx]

Indications

• Loncastuximab tesirine is indicated for the treatment of adults with relapsed or refractory large B-cell lymphoma who have undergone two or more prior lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma. The above indication is approved under accelerated FDA approval following the results of clinical studies. Continued approval is dependent upon the results of confirmatory clinical trials.^[rx]
• Refractory Large B-cell Lymphoma
• Relapsed Diffuse Large B-cell Lymphoma (DLBCL)
• Loncastuximab tesirine is indicated for the treatment of adults with relapsed or refractory large B-cell lymphoma and high-grade B-cell lymphoma.
• For the treatment of adult patients with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma

Use in Cancer

Loncastuximab tesirine-lpyl is approved to treat:

• B-cell non-Hodgkin lymphoma (NHL), including the following types:
  • Diffuse large B-cell lymphoma (DLBCL).
  • DLBCL in patients who had low-grade lymphoma.
  • High-grade B-cell lymphoma.

  It is used in adults whose cancer has relapsed (come back) or has not gotten better after at least two types of systemic therapy.

Loncastuximab tesirine-lpyl is approved under FDA’s Accelerated Approval Program. As a condition of approval, confirmatory trial(s) must show that it provides a clinical benefit in these patients.

Loncastuximab tesirine-lpyl is also being studied in the treatment of other types of cancer.

Contraindications

• a bad infection
• anemia
• decreased blood platelets
• low levels of a type of white blood cell called neutrophils
• pregnancy
• a patient who is producing milk and breastfeeding
• Child-Pugh class A liver impairment

Dosage

Strengths: lpyl 10 mg

Lymphoma

• 0.15 mg/kg IV over 30 minutes on Day 1 of each cycle (every 3 weeks) for 2 cycles, then 0.075 mg/kg IV over 30 minutes every 3 weeks for subsequent cycles
• Premedicate with dexamethasone 4 mg orally or IV 2 times a day for 3 days beginning the day before this drug.
• If dexamethasone administration does not begin the day before this drug, dexamethasone should begin at least 2 hours prior to administration of this drug.

Dose Adjustments

DOSE DELAYS OR MODIFICATIONS: HEMATOLOGIC ADVERSE REACTIONS:

• Neutropenia (absolute neutrophil count less than 1 x 10(9)/L): Withhold this drug until neutrophil counts return to 1 x 10(9)/L or higher.
• Thrombocytopenia (platelet count less than 50,000/mcL): Withhold this drug until platelet count returns to 50,000/mcL or higher.

NONHEMATOLOGIC ADVERSE REACTIONS:
Edema or Effusion:

• Grade 2 or higher: Withhold this drug until the toxicity resolves to Grade 1 or less.

Other Adverse Reactions:

• Grade 3 or higher: Withhold this drug until the toxicity resolved to Grade 1 or less.
• If dosing is delayed by more than 3 weeks due to toxicity related to this drug, reduce subsequent doses by 50%; if toxicity reoccurs following dose reduction, consider discontinuation.

NOTE: If toxicity requires dose reduction following the second dose of 0.15 mg/kg (Cycle 2), the patient should receive the dose of 0.075 mg/kg for Cycle 3.

Reconstitution/preparation techniques:

• Reconstitute and further dilute this drug prior to infusion.
• Use appropriate aseptic technique.
• The manufacturer product information should be consulted.

Side Effects

The Most Common

• unusual tiredness or weakness
• nausea
• diarrhea
• stomach pain
• constipation
• decreased appetite
• muscle or joint pain
• darkening of skin
• rash
• itching
• blistering or peeling skin
• swelling of the hands, feet, ankles, or lower leg
• weight gain
• swelling of the stomach area
• shortness of breath
• difficulty breathing
• chest pain
• fever, chills, headache, sore throat, ongoing cough and congestion, or other signs of infection
• warm, red, painful or swollen skin following a cut or scrape
• unusual bleeding or bruising

More common

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• body aches or pain
• chills
• cough
• ear congestion
• fever
• headache
• increased sensitivity of the skin to sunlight
• itching, skin rash
• loss of voice
• lower back or side pain
• muscle or bone pain
• pain or tenderness around the eyes and cheekbones
• painful or difficult urination
• pale skin
• pinpoint red spots on the skin
• redness or other discoloration of the skin
• severe sunburn
• sore throat
• stuffy or runny nose
• swelling of the hands, ankles, feet, or lower legs
• swelling or puffiness of the face
• tightness in the chest
• trouble breathing
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness

Rare

• Anxiety
• blistering, crusting, irritation, itching, or reddening of the skin
• blue or pale skin
• chest pain, possibly moving to the left arm, neck, or shoulder
• confusion
• cracked, dry, scaly skin
• darkening of the skin
• dizziness
• dry cough
• fainting
• fast heartbeat
• general feeling of discomfort or illness
• lightheadedness
• rapid, shallow breathing
• sneezing
• thickening of bronchial secretions
• Back pain
• constipation
• decreased appetite
• diarrhea
• difficulty in moving
• joint pain
• lack or loss of strength
• muscle aches, cramps, or stiffness
• nausea
• stomach pain
• swollen joints
• unusual drowsiness, dullness, or feeling of sluggishness
• vomiting

Drug Interactions

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

Based on its mechanism of action, ZYNLONTA can cause embryo-fetal harm when administered to a pregnant woman, because it contains a genotoxic compound (SG3199) and affects actively dividing cells [see Clinical Pharmacology (12.1) and Nonclinical Toxicology
(13.1)]. There are no available data on the use of ZYNLONTA in pregnant women to evaluate for drug-associated risk. No animal reproduction studies were conducted with ZYNLONTA. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other
adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Lactation

There is no data on the presence of loncastuximab tesirine-lpyl or SG3199 in human milk, the effects on the breastfed child, or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with ZYNLONTA and for 3 months after the last dose.