Loncastuximab tesirine-lpyl is a CD19-directed antibody and alkylating drug conjugate indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma) following 2 or more lines of systemic therapy. Severe myelosuppression and infection have been reported with loncastuximab tesirine therapy; monitor complete blood counts and for signs and symptoms of infection.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH (Draft) 2020 List: Table 1
-Approved by FDA after NIOSH 2016 list published. The manufacturer recommends this drug be handled as a hazardous drug.
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Administer dexamethasone (unless contraindicated) for 3 days starting the day prior to the infusion; if not started the day before, give dexamethasone at least 2 hours prior to the loncastuximab tesirine infusion.
-In patients with a body mass index of 35 kg/m2 or greater, use adjusted body weight (ABW) for the dose calculation: ABW (in kg) = 35 kg/m2 X (height in meters)2.
Reconstitution:
-Calculate the dose (mg) and the number of vials required.
-Reconstitute each 10-mg vial with 2.2 mL of Sterile Water for injection for a final vial concentration of 5 mg/mL.
-Direct the stream of Sterile Water for injection toward the wall of the vial and not directly at the cake or powder.
-Gently swirl the vial to aid in dissolution; do not shake.
-The vial solution should be clear to slightly opalescent, colorless to slightly yellow, and free of visible particulates.
-Storage following reconstitution: Store the vial for up to 4 hours refrigerated (2 to 8 degrees C; 36 to 46 degrees F) or at room temperature (20 to 25 degrees C; 68 to 77 degrees F); do not freeze or expose to direct sunlight.
Dilution:
-Using a sterile syringe, withdraw the calculated dose/volume from the reconstituted vial and add to a 50 mL infusion bag of 5% Dextrose injection; loncastuximab tesirine is compatible with polyvinylchloride, polyolefin, and PAB (copolymer of ethylene and propylene) infusion bags.
-Discard any unused portion left in the vial.
-Gently mix by slowly inverting the infusion bag; do not shake.
-Storage following dilution: Store up to 24 hours refrigerated or up to 8 hours at room temperature; do not freeze.
Intravenous (IV) infusion:
-Administer as an IV infusion over 30 minutes using a dedicated infusion line containing a sterile, non-pyrogenic, low-protein binding in-line or add-on 0.2-or 0.22-micron filter and catheter.
-Monitor the infusion site for extravasation during the infusion; observe for subcutaneous infiltration.
-Do not mix or administer with other drugs.
Fatigue occurred in 38% (grade 3, 1%) of patients with relapsed or refractory large B-cell lymphoma who received loncastuximab tesirine (n = 145) in a clinical trial. The term fatigue included asthenia and lethargy.
Nausea (23%), diarrhea (17%; grade 3, 2%), abdominal pain (14%; grade 3 or 4, 3%), decreased appetite/anorexia (15%), vomiting (13%), and constipation (12%) occurred in patients with relapsed or refractory large B-cell lymphoma who received loncastuximab tesirine (n = 145) in a clinical trial.
Musculoskeletal pain occurred in 23% (grade 3, 1%) of patients with relapsed or refractory large B-cell lymphoma who received loncastuximab tesirine (n = 145) in a clinical trial. The term musculoskeletal pain included musculoskeletal chest pain, back pain, limb discomfort, extremity pain, myalgia, and neck pain.
In a pooled analysis of 2 trials (n = 215), grade 3 edema (3%) including peripheral edema and ascites, grade 3 pleural effusion (3%), and grade 3 or 4 pericardial effusion (1%) were reported in patients who received loncastuximab tesirine. Monitor patients for signs or symptoms of new or worsening effusions or edema; consider diagnostic imaging in patients who develop symptoms of effusion. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop grade 2 or higher effusion or edema; provide medical treatment as appropriate. Edema (28%; grade 3, 3%), pleural effusion (10%; grade 3, 2%), and pericardial effusion (3%) occurred in patients with relapsed or refractory large B-cell lymphoma who received loncastuximab tesirine (n = 145) in a clinical trial. The term edema included face edema/swelling, peripheral edema/swelling, ascites, and fluid overload.
In a pooled analysis of 2 trials (n = 215), grade 3 or 4 neutropenia (32%), thrombocytopenia (20%), and anemia (12%) were reported in patients who received loncastuximab tesirine; febrile neutropenia occurred in 3% of patients. Monitor complete blood counts during loncastuximab tesirine therapy. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop hematologic toxicity. Prophylactic use of granulocyte colony-stimulating factors may be considered. Thrombocytopenia (58%; grade 3 or 4, 17%), neutropenia (52%; grade 3 or 4, 30%), and anemia (51%; grade 3, 10%) that worsened from baseline and febrile neutropenia (3%) occurred in patients with relapsed or refractory large B-cell lymphoma who received loncastuximab tesirine (n = 145) in a clinical trial.
In a pooled analysis of 2 trials (n = 215), grade 3 or higher infection including opportunistic infection was reported in 10% of patients who received loncastuximab tesirine; fatal infections occurred in 2% of patients. Monitor patients for signs and symptoms of new or worsening infection. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop a grade 3 or 4 infection. Upper respiratory tract infection (10%; grade 3, less than 1%), pneumonia (5%) including lung infection, and sepsis (2%) including septic shock occurred in patients with relapsed or refractory large B-cell lymphoma who received loncastuximab tesirine (n = 145) in a clinical trial; fatal infection was reported in 1% of patients. The term upper respiratory infection included upper respiratory congestion, nasopharyngitis, rhinitis, rhinovirus infection, and sinusitis.
In a pooled analysis of 2 trials (n = 215), cutaneous reactions including rash (e.g., exfoliative and maculopapular rash), photosensitivity reaction, and erythema were reported in 4% of patients who received loncastuximab tesirine. Advise patient to avoid or minimize sunlight (UV) exposure (e.g., exposure through glass and artificial UV light) and to wear protective clothing or sunscreen during treatment with loncastuximab tesirine. Monitor patients for new or worsening cutaneous reactions, including photosensitivity reactions; consider a dermatology consult if a reaction occurs. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop a grade 3 or 4 cutaneous reaction. Rash (30%; grade 3, 2%), pruritus (12%), photosensitivity reaction (10%; grade 3, 2%), skin hyperpigmentation (4%), and dermatitis (3%) occurred in patients with relapsed or refractory large B-cell lymphoma who received loncastuximab tesirine (n = 145) in a clinical trial. The term rash included erythematous rash, maculopapular rash, pruritic rash, pustular rash, erythema, dermatitis, acneiform rash/dermatitis, bullous rash/dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia (hand and foot syndrome). Telangiectasia, blister, and vesicular rash were reported in postmarketing surveillance.
Elevated hepatic enzymes including increased AST (41%; grade 3, less than 1%) and ALT (34%; grade 3 or 4, 3%) levels, increased gamma-glutamyl transferase level (57%; grade 3 or 4, 21%), and hypoalbuminemia (37%; grade 3, less than 1%) occurred in patients with relapsed or refractory large B-cell lymphoma who received loncastuximab tesirine (n = 145) in a clinical trial. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop grade 3 or 4 hepatotoxicity.
Hyperglycemia occurred in 48% (grade 3 or 4, 8%) of patients with relapsed or refractory large B-cell lymphoma who received loncastuximab tesirine (n = 145) in a clinical trial.
Dyspnea (13%; grade 3, 1%), pneumonitis (3%), and pleuritis (3%) occurred in patients with relapsed or refractory large B-cell lymphoma who received loncastuximab tesirine (n = 145) in a clinical trial.
Pericarditis occurred in 3% of patients with relapsed or refractory large B-cell lymphoma who received loncastuximab tesirine (n = 145) in a clinical trial.
Infusion/injection site reaction, specifically extravasation, occurred in less than 1% of patients with relapsed or refractory large B-cell lymphoma who received loncastuximab tesirine (n = 145) in a clinical trial. Monitor the infusion site for extravasation during the loncastuximab tesirine infusion; observe for subcutaneous infiltration.
Effusions (pericardial effusion and pleural effusion) and edema have been reported with loncastuximab tesirine therapy. Monitor patients for signs or symptoms of new or worsening effusions or edema; consider diagnostic imaging in patients who develop symptoms of effusion (e.g., dyspnea, chest pain, and ascites). Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop grade 2 or higher effusion or edema; manage medically as appropriate.
Myelosuppression (e.g., anemia, neutropenia, and thrombocytopenia) has been reported with loncastuximab tesirine therapy. Monitor complete blood counts during loncastuximab tesirine therapy. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop hematologic toxicity. Prophylactic use of granulocyte colony-stimulating factors may be considered.
Infection (e.g., pneumonia, sepsis, and opportunistic infections) has been reported with loncastuximab tesirine therapy; some cases were fatal. Monitor patients for signs and symptoms of new or worsening infection. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop a grade 3 or 4 infection.
Cutaneous reactions including serious rash and photosensitivity have been reported with loncastuximab tesirine therapy. Advise patient to avoid or minimize sunlight (UV) exposure (e.g., exposure through glass and artificial UV light) and to wear protective clothing or sunscreen during treatment with loncastuximab tesirine. Monitor patients for new or worsening cutaneous reactions, including photosensitivity reactions; consider a dermatology consult if a reaction occurs. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop a grade 3 or 4 cutaneous reaction.
No initial loncastuximab tesirine dosage adjustment is recommended in patients with mild hepatic impairment (total bilirubin level at or below the ULN and AST level greater the ULN OR total bilirubin level greater than 1 to 1.5 times the ULN and any AST level). However, patients with baseline hepatic disease may be at increased risk for developing adverse reactions with loncastuximab tesirine. Loncastuximab tesirine therapy has not been evaluated in patients with moderate or severe impairment (total bilirubin level greater than 1.5 times the ULN and any AST level). Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop grade 3 or 4 hepatotoxicity.
Based on its mechanism of action, loncastuximab tesirine may cause fetal harm if administered during pregnancy. The small molecule component, SG3199, is an alkylating agent that is genotoxic and toxic to rapidly dividing cells. Loncastuximab tesirine has not been evaluated in animal studies. Females of reproductive potential should be advised to avoid becoming pregnant while receiving loncastuximab. Pregnant women who require this medicine should be apprised of the potential hazard to the fetus.
Counsel patients about the reproductive risk and contraception requirements during loncastuximab tesirine treatment. Pregnancy testing should be performed prior to starting loncastuximab tesirine in female patients of reproductive potential. These patients should use effective contraception and avoid pregnancy during therapy and for 10 months after the last loncastuximab tesirine dose. Additionally, male patients with a female partner of reproductive potential should use effective contraception during therapy and for 7 months after the last loncastuximab tesirine dose due to the risk of male-mediated teratogenicity. Based on animal studies, loncastuximab tesirine may cause infertility in males.
No information is available regarding the presence of loncastuximab tesirine or SG3199 (alkylating agent component) in human milk, the effects on the breastfed child, or the effects on milk production. Due to the potential for serious adverse reactions in the nursing child, breast-feeding is not recommended during therapy or for 3 months after the last loncastuximab tesirine dose.
For the treatment of Non-Hodgkin's lymphoma (NHL):
-for the treatment of relapsed or refractory large B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma) following 2 or more lines of systemic therapy:
Intravenous dosage:
Adults: 0.15 mg/kg IV on day 1 every 3 weeks for 2 cycles, then 0.075 mg/kg IV on day 1 every 3 weeks until disease progression. In patients with a body mass index of 35 kg/m2 or greater, use adjusted body weight (ABW) for the dose calculation: ABW (in kg) = 35 kg/m2 X (height in meters)2. Starting the day prior to the infusion, administer dexamethasone 4 mg orally or IV twice daily for 3 days; if not started the day before, give dexamethasone at least 2 hours prior to the loncastuximab tesirine infusion. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop toxicity. The overall response rate (evaluated by an independent review committee) was 48.3% (complete response, 24.8%) in patients with relapsed or refractory large B-cell lymphoma who received a median of 3 (range, 1 to 26) treatment cycles of loncastuximab tesirine in a multinational, single-arm, phase 2 (LOTIS-2) trial (n = 145). At a median follow-up time of 7.8 (range, 0.3 to 42.6) months, the median time to response was 41 (range, 35 to 247) days and the median duration of response was 13.4 months. The median progression-free survival and overall survival times were 4.9 and 9.5 months, respectively. In this trial, patients (median age, 66 years; range, 23 to 94 years; DLBCL not otherwise specified, 88%) had received a median of 3 (range, 2 to 7) prior therapies and 17% of patients had received a prior stem-cell transplant.
Therapeutic Drug Monitoring:
Dosage Guidelines for Treatment-Related Toxicity:
NOTE: Reduce subsequent doses by 50% if dosing is delayed by more than 3 weeks due to toxicity. If toxicity recurs, consider discontinuing therapy. If a dose reduction is required following the second dose of 0.15 mg/kg (cycle 2), give loncastuximab tesirine 0.075 mg/kg for cycle 3.
Hematologic Toxicity
Neutropenia (absolute neutrophil count (ANC) less than 1,000 cells/microliter (microL)): Hold loncastuximab tesirine therapy until the ANC is 1,000 cells/microL or higher.
Thrombocytopenia (platelet count less than 50,000 cells/microL): Hold loncastuximab tesirine therapy until the platelet count is 50,000 cells/microL or higher.
Non-Hematologic Toxicity
Grade 2 or higher edema or effusion: Hold loncastuximab tesirine therapy until the toxicity resolves to grade 1 or less.
Other grade 3 or 4 toxicity: Hold loncastuximab tesirine therapy until the toxicity resolves to grade 1 or less.
Maximum Dosage Limits:
-Adults
0.15 mg/kg IV every 3 weeks; use adjusted body weight for patients with body mass index (BMI) of 35 kg/m2 or more.
-Geriatric
0.15 mg/kg IV every 3 weeks; use adjusted body weight for patients with BMI of 35 kg/m2 or more.
-Adolescents
Safety and efficacy not established.
-Children
Safety and efficacy not established.
-Infants
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
Mild hepatic impairment (total bilirubin level at or below the ULN and AST level greater the ULN OR total bilirubin level greater than 1 to 1.5 times the ULN and any AST level): No loncastuximab tesirine dosage adjustment is necessary.
Moderate or severe hepatic impairment (total bilirubin level greater than 1.5 times the ULN and any AST level): Specific guidelines for dosage adjustments are not available; it appears that no dosage adjustments are needed.
Treatment-Related Toxicity
Grade 3 or 4 hepatotoxicity: Hold loncastuximab tesirine therapy until the toxicity resolves to grade 1 or less. Reduce subsequent doses by 50% if dosing is delayed by more than 3 weeks due to toxicity. If toxicity recurs, consider discontinuing therapy. If a dose reduction is required following the second dose of 0.15 mg/kg (cycle 2), give loncastuximab tesirine 0.075 mg/kg for cycle 3.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Loncastuximab tesirine is a CD19-directed antibody-drug conjugate (ADC), consisting of 3 components including the humanized IgG1-kappa monoclonal antibody specific for human CD19; the small molecule pyrrolobenzodiazepine dimer cytotoxic alkylating agent, SG3199; and a protease-cleavable valine-alanine linker. The component of SG3199 attached to the linker is known as SG3249 or tesirine. The anticancer activity of loncastuximab tesirine is due to the binding of the ADC to CD19 expressing B-cells followed by the internalization of the ADC-CD19 complex and the subsequent release of SG3199 via proteolytic cleavage. SG3199 binds to the DNA minor groove and causes DNA interstrand crosslinks resulting in cell death. Loncastuximab tesirine has demonstrated anticancer activity in animal models of lymphoma.
Loncastuximab tesirine is administered intravenously. It is a CD19-directed antibody-drug conjugate (ADC) consisting of 3 components including a humanized IgG1 monoclonal antibody specific for human CD19; a small molecule cytotoxic alkylating agent, SG3199; and a protease-cleavable linker that covalently attaches SG3199 to the loncastuximab antibody. Loncastuximab tesirine has a mean volume of distribution of 7.11 L (coefficient of variation (CV), 26.6%), a steady-state mean clearance of 0.275 L/day (CV, 38.2%), and a steady-state mean half-life of 20.8 +/- 7.06 days. Loncastuximab tesirine is metabolized into small peptides via catabolic pathways. Although the major excretion pathway has not been evaluated in humans, SG3199 appears to be minimally excreted in the kidneys.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4/5, P-gp
In vitro, SG3199 is a substrate of CYP3A4/5 and P-glycoprotein (P-gp). At clinically relevant unconjugated concentrations, SG3199 does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, P-gp, breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, OCT2, multi-antimicrobial extrusion protein (MATE)1, MATE2-K, or bile salt export pump (BSEP) in vitro.
-Route-Specific Pharmacokinetics
Intravenous Route
When loncastuximab tesirine was administered at the recommended IV dosage, steady-state Cmax levels were 28.2% lower than Cmax levels following the first dose. The loncastuximab tesirine steady-state mean Cmax and AUC(tau) values were 1,776 nanograms/mL (coefficient of variation (CV), 32.1%) and 16,882 nanograms/mL X day (CV, 38.2%), respectively. The time to reach steady state was 210 days.
-Special Populations
Hepatic Impairment
Although mild hepatic impairment (total bilirubin level at or below the ULN and AST level greater than the ULN OR total bilirubin level greater than 1 to 1.5 times the ULN and any AST level) may increase the exposure of unconjugated SG3199, this degree of impairment had no clinically significant impact on the pharmacokinetic (PK) parameters of loncastuximab tesirine. It is not known if moderate (total bilirubin level greater than 1.5 to 3 times the ULN and any AST level) or severe (total bilirubin level greater than 3 times the ULN and any AST level) hepatic impairment affects the PK parameters of loncastuximab tesirine.
Renal Impairment
Mild to moderate renal impairment (creatinine clearance (CrCl) of 30 to less than 90 mL/min) had no clinically significant impact on the pharmacokinetic (PK) parameters of loncastuximab tesirine. It is not known if severe renal impairment (CrCl of 15 to 29 mL/min) or end-stage renal disease with or without dialysis affects the PK parameters of loncastuximab tesirine.
Geriatric
Age (range, 20 to 94 years) had no clinically significant impact on the pharmacokinetic parameters of loncastuximab tesirine.
Gender Differences
Gender had no clinically significant impact on the pharmacokinetic parameters of loncastuximab tesirine.
Ethnic Differences
Race (Black and White patients) had no clinically significant impact on the pharmacokinetic parameters of loncastuximab tesirine.
Obesity
Weight (range, 42.1 to 160.5 kg) had no clinically significant impact on the pharmacokinetic parameters of loncastuximab tesirine.
Other
Performance status
Eastern Cooperative Oncology Group (ECOG) status (0 to 2) had no clinically significant impact on the pharmacokinetic parameters of loncastuximab tesirine.