Loncastuximab tesirine, a CD19-directed antibody-drug conjugate consisting of a humanized monoclonal immunoglobulin G1 (IgG1) kappa antibody linked to a cytotoxic alkylating agent (SG3199), is an antineoplastic agent.1
Loncastuximab tesirine-lpyl is used for the treatment of relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma, previously treated with at least 2 systemic therapy lines.1 The accelerated approval of loncastuximab tesirine for this indication is based on overall response rate.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit of loncastuximab tesirine in confirmatory studies.1 The drug has been designated an orphan drug by FDA for the treatment of this cancer.2
This indication is primarily based on the results of a multicenter, open-label, phase 2 study (LOTIS-2), which was conducted in 145 adults with refractory or relapsed DLBCL previously treated with at least 2 prior systemic therapies.1, 3 Patients enrolled in the study received loncastuximab tesirine-lpyl 0.15 mg/kg by IV infusion over 30 minutes once every 3 weeks for the first 2 cycles followed by 0.075 mg/kg by IV infusion every 3 weeks.1, 3 Loncastuximab tesirine was administered for up to 1 year or until one of the following events occurred: unacceptable toxicity, relapse or progression of disease, major protocol deviation, pregnancy, death, or withdrawal from study.3 The primary efficacy end point was overall response rate as assessed by an independent review committee.1, 3
In this study, the median age of patients was 66 years (range: 56-71 years); 59% of patients were male, 90% were White, 3% were Black, 2% were Asian, 88% had DLBCL not otherwise specified, 8% had high-grade B-cell lymphoma, and 94% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.1, 3 Patients enrolled in the study received a median of 3 prior therapies (range: 2-7).1, 3
At a median follow-up duration of 7.3 months (range: 0.3-20.2 months), the overall response rate was 48.3%; complete response was achieved in 24.1% of patients.1, 3 The median time to response was 1.3 months (range: 1.1-8.1 months) and the median duration of response was 10.3 months.1, 3 Median progression-free survival, relapse-free survival, and overall survival were 4.9, 13.4, and 9.9 months, respectively.3
In an updated analysis of LOTIS-2 (median follow-up: 7.8 months [range: 0.3 to 42.6 months]), the overall response rate was 48.3%, with a complete response achieved in 24.8% of patients.7 In the all-treated population, the median overall and progression-free survival were 9.5 and 4.9 months, respectively.7 Among patients with a complete response, the median overall and progression-free survival were not reached; however, 24-month overall and progression-free survival rates were 68.2% and 72.5%, respectively.7
Follicular lymphoma, an indolent subtype of B-cell non-Hodkin lymphoma (NHL), comprises approximately 20% of all NHLs.10001 The majority of patients with follicular lymphoma are ≥50 years of age and present with extensive disease upon diagnosis; median survival ranges from 8 to 15 years, even with advanced disease.10001 Watchful waiting remains standard care for follicular lymphoma initially and for patients with slow asymptomatic relapsing disease.10001 Per the National Cancer Institute (NCI), there are numerous therapeutic options, administered in varying sequences, when therapy is required.10001 For those with advanced disease, first-line therapy is composed of a chemotherapy backbone or lenalidomide in combination with an anti-CD20 antibody.10002 In patients with relapsed or refractory follicular lymphoma, no standard-of-care treatment currently exists.10002
A single-arm, investigator-initiated, phase 2 trial evaluated the use of loncastuximab tesirine plus rituximab in patients with relapsed or refractory follicular lymphoma†.10002 This ongoing study was performed at the Sylvester Comprehensive Cancer Center in Miami, FL and enrolled adults (≥18 years of age) with histologically confirmed follicular lymphoma (grade 1, 2, or 3A) and relapsed or refractory disease treated prior with ≥1 lines of systemic therapy.10002 Eligible patients also had an ECOG performance status of 0 to 2, life expectancy of >6 weeks, and appropriate organ function.10002 A total of 39 patients were enrolled.10002 Loncastuximab tesirine 0.15 mg/kg IV over 30 minutes was administered once every 3 weeks on Day 1 of a 21-day cycle for the initial 2 cycles, followed by 0.075 mg/kg for subsequent cycles.10002 Rituximab 375 mg/m2 IV was administered on Day 1 of Cycle 1 for four weekly doses during induction (Cycles 1-4), followed by a single dose every 8 weeks during maintenance (Cycles 5 to 7).10002 During the induction and first maintenance phases (cycles 1 to 5; 21 weeks), a total of 7 doses of loncastuximab tesirine and 5 doses of rituximab were administered.10002 The use of subcutaneous rituximab 1400 mg/hyaluronidase 23,400 units was permissible at any stage.10002 If a patient experienced a complete response at week 21 (the beginning of the second maintenance phase), loncastuximab tesirine was discontinued and two more rituximab doses were administered every 8 weeks.10002 If a partial response was observed at week 21, patients continued loncastuximab tesirine every 21 days and rituximab every 8 weeks for 18 additional weeks.10002 Upon the end of study treatment, patients were followed for 2 years to obtain disease progression and survival data.10002 Patients who experienced stable disease or disease progression on imaging at week 12 or 21 were dismissed from study treatment.10002 The primary study endpoint was complete response via [18F]FDG-PET-CT at week 12 as assessed by Lugano 2014 criteria.10002 Key secondary endpoints included overall response rate at week 12, safety and tolerability of the combination, and progression-free survival and overall survival at 2 years.10002
At baseline, the median age of patients was 68 years (range: 58 to 77 years), 54% were male, and the majority were white (95%).10002 Enrolled patients had an ECOG performance status of 0 (74%) or 1 (26%) and most experienced grade 1-2 disease (72%).10002 Refractory disease was present in 51% of patients; 49% had relapse.10002 The number of prior lines of therapy was 1 in 26 patients, 2 in 2 patients, and 3 to 6 in 11 patients.10002
The overall response rate at week 12 was 97% (38 of 39 patients).10002 A complete response rate of 67% (n=26) was observed at week 12, with 23 of these 26 patients maintaining a complete response at week 21.10002 Of note, 4 of 12 patients with a partial response at week 12 improved to a complete response at week 21.10002 This translated to an overall best complete response rate across weeks 12 and 21 of 77%.10002 The median time to overall response was 2.7 months.10002 Post hoc, responses were observed across all high risk subgroups.10002
At the time of data cutoff for this analysis, the median follow-up was 18.2 months.10002 The median duration of a complete or partial response as a “best response” was 16.2 and 6 months, respectively.10002 Progression-free and overall survival at 12 months were similar: 94.6% and 94.1%, respectively (median progression-free survival and overall survival not yet reached).10002 Three events were recorded up to the data cutoff.10002 These included 2 patients with disease progression (biopsy-proven transformation to diffuse large B-cell lymphoma with subsequent death) and a single patient with relapsed follicular lymphoma under observation due to asymptomatic and localized disease.10002
The most common treatment-emergent adverse events (TEAEs) in the safety set included hyperglycemia (44%), increased alkaline phosphatase (41%), and neutropenia, fatigue, and increased AST and ALT (38% each).10002 The most common grade 3 or worse TEAE was lymphopenia (21%).10002 Permanent discontinuation of loncastuximab tesirine due to a TEAE occurred in a single patient.10002 Dose reduction of loncastuximab tesirine was necessary in 4 patients due to grade 2 generalized edema, grade 3 dyspnea, grade 3 skin infection, and grade 3 γ-glutamyltransferase elevation.10002 Four serious TEAEs were considered to be related to the study drugs (grade 3 febrile neutropenia, grade 3 dyspnea, grade 3 generalized edema, grade 3 skin infection).10002 No fatal TEAEs were recorded.10002
Based on current evidence, loncastuximab tesirine, in combination with rituximab, as a third-line and subsequent treatment in follicular lymphoma, has Level 2 (moderate strength/quality) evidence supporting its use.10002 This combination results in clinically meaningful activity in relapsed or refractory disease with a manageable safety profile.10002 However, it is important to note that this limited sample size study is still enrolling patients, is occurring at a single center only, and enrolled patients lack racial diversity.10002 In addition, many patients were administered loncastuximab tesirine with rituximab as a second-line option in the study.10002
Dispensing and Administration Precautions
Loncastuximab tesirine-lpyl is administered by IV infusion over 30 minutes.1 Loncastuximab tesirine-lpyl should be administered through a sterile, non-pyrogenic, low-protein binding 0.2- or 0.22-µm inline or add-on filter and catheter.1
Prior to administration, loncastuximab tesirine-lpyl lyophilized powder for injection must be reconstituted and diluted.1 Strict aseptic technique must be observed in preparing and administering loncastuximab tesirine-lpyl solutions since the powder for injection contains no preservative.1 Loncastuximab tesirine-lpyl should not be admixed with or administered as an infusion with any other drug.1
Store unopened vials of loncastuximab tesirine-lpyl lyophilized powder for injection at 2-8°C in the original packaging to protect from light.1
Based on the indicated dosage of loncastuximab tesirine-lpyl, the appropriate number of vials of the drug should be reconstituted.1
Each vial labeled as containing 10 mg of loncastuximab tesirine-lpyl is reconstituted by adding 2.2 mL of sterile water for injection to provide a solution containing 5 mg/mL.1 Direct the diluent toward the wall of the vial and not directly at the loncastuximab cake or powder.1 Gently swirl the vial and inspect visually for particulate matter and discoloration prior to dilution and administration.1 Do not shake the resulting solution.1 The solution should be clear to slightly opalescent, colorless or have a slight yellow color, and free of visible particulates.1
Discard partially used vials.1
Immediately dilute reconstituted solutions of the drug; if not diluted immediately, store the reconstituted solution at 2-8°C or 20-25°C for up to 4 hours.1 Discard the reconstituted vial if it has been more than 4 hours.1 Reconstituted solutions of the drug should be protected from direct sunlight and should not be frozen.1
To prepare the final diluted loncastuximab tesirine-lpyl solution for infusion, inject the required amount of reconstituted solution into an infusion bag containing 50 mL of 5% dextrose injection.1 Loncastuximab tesirine-lpyl is compatible with infusion bags containing polyvinylchloride (PVC), polyolefin (PO), and PAB® (copolymer of ethylene and propylene).1 Mix the final diluted solution for infusion by gentle inversion; do not shake.1
Infuse the diluted solution immediately or store refrigerated (2-8°C) for up to 24 hours or at room temperature (20-25°C) for up to 8 hours following dilution.1
Loncastuximab tesirine-lpyl should be administered by IV infusion over 30 minutes.1
Dosage of loncastuximab tesirine-lpyl should be based on actual body weight; however, in patients with a body mass index of ≥35 kg/m2, the dose should be based on adjusted body weight using the following formula:
Adjusted body weight (in kg) = 35 kg/m2 × (height in meters)2.1
For the treatment of relapsed or refractory large B-cell lymphomas, the recommended adult dosage of loncastuximab tesirine-lpyl is 0.15 mg/kg by IV infusion over 30 minutes on day 1 of cycles 1 and 2, followed by 0.075 mg/kg by IV infusion on day 1 of each subsequent cycle.1 Treatment cycles are repeated every 21 days.1
Dosage Modification for Toxicity
Temporary interruption of therapy, dosage reduction, or permanent discontinuance of loncastuximab tesirine may be necessary in patients experiencing certain adverse effects.1
If administration of loncastuximab tesirine therapy is delayed by more than 3 weeks due to toxicity, reduce subsequent doses by 50%.1 However, if dosage reduction is necessary after cycles 1 and 2 of loncastuximab tesirine 0.15 mg/kg, the recommended 0.075 mg/kg dosage should be used for cycle 3 onward.1
Consider discontinuing loncastuximab tesirine therapy if toxicity recurs following dosage reduction.1
In patients with an absolute neutrophil count (ANC) less than 1000/mm3 or a platelet count less than 50,000/mm3, withhold therapy with loncastuximab tesirine until the ANC and platelet count recover to at least 1000/mm3 or 50,000/mm3, respectively.1
If grade 2 or greater edema or effusion occurs, withhold therapy with loncastuximab tesirine until the toxicity resolves to grade 1 or less.1
If grade 3 or greater nonhematologic adverse effects occur; withhold therapy with loncastuximab tesirine until edema or effusion resolves to grade 1 or less.1
When loncastuximab tesirine is used in combination with rituximab as a third-line and subsequent treatment in follicular lymphoma†, the usual dosage of loncastuximab tesirine is 0.15 mg/kg IV over 30 minutes once every 3 weeks on Day 1 of a 21-day cycle for the initial 2 cycles, followed by 0.075 mg/kg for subsequent cycles.10002 Rituximab 375 mg/m2 IV was administered on Day 1 of Cycle 1 for 4 once weekly doses during the induction phase (Cycles 1-4), followed by a single dose every 8 weeks during the 9-week maintenance cycles (Cycles 5-7), for a total of 7 doses of loncastuximab tesirine and 5 doses of rituximab during the initial 21 weeks (induction and first maintenance phase).10002 In the second maintenance phase, patients with a complete response were administered 2 more rituximab doses every 8 weeks while those with a partial response continued loncastuximab tesirine every 21 days and rituximab every 8 weeks for 18 more weeks, for a total of 13 doses of loncastuximab tesirine and 7 doses of rituximab.10002
For patients with mild hepatic impairment (total bilirubin not exceeding the ULN and AST above the ULN, or total bilirubin 1 to 1.5 times the ULN with any AST concentration), no dosage adjustment is recommended.1
Loncastuximab tesirine has not been studied in patients with moderate to severe hepatic impairment (total bilirubin greater than 1.5 times the ULN and any AST concentration).1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Serious edema and effusion have been reported among patients treated with loncastuximab tesirine.1 Grade 3 edema (most commonly ascites or peripheral edema) and grade 3 pleural effusion were each reported in 3% of patients in clinical trials; grade 3 or 4 pericardial effusion was reported in 1% of patients in clinical trials.1
If grade 2 or higher edema or effusion occurs, initiate medical management as appropriate and withhold loncastuximab tesirine therapy until the toxicity resolves.1 Diagnostic imaging may be necessary in patients with symptoms of pleural or pericardial effusion (e.g., chest pain, new or worsening shortness of breath, abdominal swelling, bloating).1
Serious or severe anemia, neutropenia, and thrombocytopenia have been reported in patients treated with loncastuximab tesirine.1 Grade 3 or 4 anemia, neutropenia, and thrombocytopenia were reported in 12, 32, and 20%, respectively, of patients treated with loncastuximab tesirine in clinical trials.1 Grade 4 neutropenia and thrombocytopenia were reported in 21% and 7% of patients, respectively.1 Febrile neutropenia was reported in 3% of patients.1
Monitor CBC during therapy with loncastuximab tesirine.1 Temporary interruption, dosage reduction, or permanent discontinuance of loncastuximab tesirine may be necessary depending on the severity of the hematologic toxicity.1 Consider prophylaxis with granulocyte colony-stimulating factor (G-CSF) as appropriate.1
Fatal and serious infections have been reported in patients treated with loncastuximab tesirine.1 Grade 3 or greater infections have been reported in 10% of patients receiving the drug in clinical trials.1 The most frequently reported infections were sepsis and pneumonia.1 Two percent of reported serious infections have been fatal.1
Patients receiving loncastuximab tesirine should be monitored for the development of signs and symptoms of infection during therapy.1 If grade 3 or 4 infection develops, withhold loncastuximab tesirine therapy until the infection resolves.1
Severe (grade 3) cutaneous reactions, including erythema, photosensitivity, and rash (including maculopapular and exfoliative rash), have been reported in 4% of patients treated with loncastuximab tesirine.1
Patients treated with loncastuximab tesirine should be monitored for new or worsening cutaneous reactions, including photosensitivity reactions.1 If severe (grade 3) cutaneous reactions develop, withhold loncastuximab tesirine therapy until symptoms resolve.1 If cutaneous reactions or rash develop, consider dermatologic consultation.1 Advise patients to minimize or avoid exposure to direct natural or artificial sunlight (including exposure through glass windows).1 The manufacturer recommends protecting skin from exposure to sunlight by wearing sun-protective clothing or using sunscreen.1
Fetal/Neonatal Morbidity and Mortality
Loncastuximab tesirine may cause fetal harm if administered to pregnant women.1 There are no adequate and well-controlled studies to date in pregnant women.1 Based on the mechanism of action of the alkylating agent SG3199, embryotoxic and teratogenic effects may occur.1
Pregnancy status should be verified prior to initiation of loncastuximab tesirine, and females of reproductive potential should use an effective method of contraception during therapy and for 10 months after the last dose.1 In addition, males who are partners of such females should use an effective method of contraception during therapy and for 7 months after the last dose.1
As with all therapeutic proteins, there is a potential for immunogenicity.1 In the LOTIS-2 study, anti-loncastuximab tesirine antibodies were detected in none of the 134 patients receiving loncastuximab tesirine.1 The potential effect of anti-drug antibodies to loncastuximab tesirine on pharmacokinetics, efficacy, or safety is unknown.1
Loncastuximab tesirine may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1
Pregnancy status should be verified in females of reproductive potential prior to initiation of loncastuximab tesirine therapy.1
It is not known whether loncastuximab tesirine is distributed into milk in humans.1 Because of the potential for serious adverse reactions from loncastuximab tesirine in breast-fed infants, women should be advised not to breast-feed during therapy and for 3 months after the last dose.1
Females and Males of Reproductive Potential
Verify pregnancy status of females of reproductive potential prior to initiation of loncastuximab tesirine therapy.1 Advise females of reproductive potential and males who are partners of such females to use an effective method of contraception during treatment with loncastuximab tesirine and for 10 or 7 months, respectively, after the last dose.1
Loncastuximab tesirine may impair fertility among males.1
Safety and effectiveness of loncastuximab tesirine have not been established in pediatric patients.1
In clinical studies, 55% of 145 patients with DLBCL were 65 years of age or older and 14% were 75 years of age or older.1 No differences in safety or efficacy were observed between geriatric patients and younger adults.1
The pharmacokinetics of loncastuximab tesirine are not significantly altered by mild hepatic impairment (total bilirubin not exceeding the ULN and AST above the ULN or total bilirubin greater than 1 to 1.5 times the ULN with any AST concentration), although mild hepatic impairment may increase exposure to unconjugated SG3199.1
Loncastuximab tesirine has not been studied in patients with moderate or severe hepatic impairment (total bilirubin greater than 1.5 to 3 times the ULN and any AST concentration or total bilirubin greater than 3 times the ULN with any AST concentration, respectively).1
The pharmacokinetics of loncastuximab tesirine are not significantly altered by mild or moderate renal impairment (creatinine clearance of 30 to less than 90 mL/min using the Cockcroft-Gault equation).1 Loncastuximab tesirine has not been studied in patients with severe renal impairment (creatinine clearance of 15 to 29 mL/min) or in those with end-stage renal disease (with or without dialysis).1
Most common (≥20%) adverse reactions, including laboratory abnormalities, in patients receiving loncastuximab tesirine include thrombocytopenia, increased gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, elevated concentrations of aminotransferase, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.1
In vitro studies have shown that the small molecule cytotoxic component of loncastuximab tesirine, SG3199, is metabolized by cytochrome P450 (CYP) isoenzymes 3A4 and 3A5.1
In vitro studies indicate that SG3199 is a substrate of P-glycoprotein (P-gp).1 SG3199 is not a substrate of breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, or organic cation transporter (OCT) 1.1
In vitro, SG3199 does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5, P-gp, BCRP, OATP1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, OCT2, OCT1, multi-antimicrobial extrusion protein (MATE) 1, MATE2-K, or bile salt export pump (BSEP).1
Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, is an antineoplastic agent.1 The anti-CD19 antibody, a humanized IgG1 kappa antibody, is conjugated with SG3199, a small molecule pyrrolobenzodiazepine (PBD) dimer and cytotoxic alkylating agent.1, 5 A dipeptide valine-alanine bond covalently links SG3199 to the antibody component.6 The antibody portion of loncastuximab tesirine binds specifically to antigen CD19, an immunoglobulin glycoprotein that is highly expressed on malignant B cells.4, 6 Following binding of the antibody portion of loncastuximab tesirine to antigen CD19, the resultant complex is internalized by the cell.5 Once internalized, activation of lysosomes causes cleavage of the covalent linker, thus releasing SG3199, which cross-links with cellular DNA and causes cell death without distorting DNA structure,4, 5 resulting in cell cycle arrest and apoptosis.6
Exposure to loncastuximab tesirine and the anti-CD19 antibody increase with increasing dose.1 Steady state concentrations are achieved in 210 days.1 The mean half-life at steady state is 20.8 days.1 The monoclonal antibody component of the drug is metabolized by catabolism into small peptides; the cytotoxic component, SG3199, is metabolized by CYP3A4 and CYP3A5. The mode of excretion for SG3199 has not been studied in humans, but in animals, is mainly through the feces5 ; it is not expected to undergo substantial renal excretion.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion only | 10 mg | Zynlonta® | ADC Therapeutics America Inc. |
1. ADC Therapeutics America, Inc. Zynlonta® (loncastuximab tesirine) for injection prescribing information. Murray Hill, NJ; 2022 Oct.
2. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. [Web]
3. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. [Web]
4. Kahl BS, Hamadani M, Radford J, et al. A phase I study of ADCT-402 (loncastuximab tesirine), a novel pyrrolobenzodiazepine-based antibody-drug conjugate, in relapsed/ refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2019;25(23):6986-6994. [Web]
5. Goparaju K, Caimi PF. Loncastuximab tesirine for treatment of relapsed or refractory diffuse large B cell lymphoma. Expert Opin Biol Ther. 2021;1-9. [Web]
6. Hartley JA. Antibody-Drug Conjugates (ADCs) delivering pyrrolobenzodiazepine (PBD) dimers for cancer therapy. Expert Opin Biol Ther. 2021;21(7):931-943. [Web]
7. Caimi PF, Ai WZ, Alderuccio JP, et al. Loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma: long-term efficacy and safety from the phase II LOTIS-2 study. Haematologica. 2024;109:1184-93.
10001. National Cancer Institute. Indolent B-cell non-Hodgkin lymphoma (PDQ®) - Health Professional Version. Updated May 14, 2025. [Web]
10002. Alderuccio JP, Alencar AJ, Schatz JH, et al. Loncastuximab tesirine with rituximab in patients with relapsed or refractory follicular lymphoma: a single-centre, single-arm, phase 2 trial. Lancet Haematol. 2025;12:e23-34.