Diffuse Large B-Cell Lymphoma (DLBCL)


Zynlonta® (loncastuximab tesirine-lpyl) is an antibody-drug conjugate (ADC) designed to direct treatment at the B-cell surface antigen CD19. It is indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL deriving from low-grade lymphoma, and high-grade B-cell lymphoma, after treatment with 2 or more regimens of systemic therapy.1 Zynlonta was developed by ADC Therapeutics, and it was approved by the US Food and Drug Administration (FDA) on April 23, 2021.2,3

Mechanism of Action

The active substance of Zynlonta is loncastuximab tesirine-lpyl, which is an antibody-drug conjugate. This conjugate is formed by the humanized monoclonal anti-CD19 antibody loncastuximab in combination with a protease-cleavable linker with SG3199 (a pyrrolobenzodiazepine DNA-alkylating agent). The combination of the linker with the SG3199 component is known as tesirine (or SG3249 drug-linker).1,3 Loncastuximab is produced using mammalian cells, while the other small molecules are manufactured through chemical synthesis.1

CD19 is a transmembrane protein located on the surface of B-cells and thus is considered a target in the treatment of B-cell non-Hodgkin lymphoma.1,4 After loncastuximab binds to CD19, the antibody-drug conjugate is rapidly internalized in the cell, releasing the SG3199 component through proteolytic cleavage.1,5 SG3199 is capable of binding to the DNA, forming cytotoxic crosslinks that lead to cell death.1,5 The systemic effects of this treatment are limited due to the short half-life associated with this component.5

Read more about DLBCL experimental therapies

Administration

Premedication with 4 mg dexamethasone should be administered twice daily for 3 days, beginning the day before treatment with Zylonta. The dexamethasone can be given orally or by intravenous injection.1 

Zynlonta should be administered by intravenous infusion on day 1 of each 3-week cycle. The infusion occurs over 30 minutes, and the recommended dose is 0.15 mg/kg every 3 weeks for 2 cycles and 0.075 mg/kg every 3 weeks for subsequent cycles.1 

Read more about DLBCL treatment

Adverse Events

The most frequent adverse events following Zynlonta use, with an incidence >20%, include thrombocytopenia, neutropenia, anemia, hypoalbuminemia, hyperglycemia, elevations in gamma-glutamyltransferase and transaminase, fatigue, nausea, edema, musculoskeletal pain, and rash.1

Warnings and Precautions

The use of this medication can promote the development of serious effusions and edema, including pleural effusion, pericardial effusion, ascites and peripheral edema. Diagnostic imaging may be considered to monitor the development of these symptoms. Blood cell counts should be monitored for severe myelosuppression, and Zynlonta may need to be withheld, reduced or discontinued. Infections and serious cutaneous reactions with photosensitivity events may develop and need treatment.1

Effective contraception is advised during treatment, as Zynlonta may cause fetal harm. Female patients should use effective contraception during treatment and for 9 months following the last Zynlonta dose. Male patients should be advised to use effective contraception during treatment and for 6 months following the last Zynlonta dose. Female patients should also be advised not to breastfeed during treatment and for 3 months following the last dose of Zynlonta.1

Get full prescribing information for Zynlonta at MPR

Safety and Efficacy in Trials

A phase 1, first-in-human clinical trial, LOTIS-1 (NCT02669017), reported that loncastuximab tesirine had an acceptable safety profile and potential anticancer activity in relapsed or refractory B-cell non-Hodgkin lymphoma.6-8 This trial also reported hematological adverse events and liver toxicities associated with the treatment that were usually reversible and manageable with dose delays.8

The approval of Zynlonta was based on the results of the LOTIS-2 clinical trial (NCT03589469).9 This was a multicenter, open-label, single-arm, phase 2 trial that included 145 difficult-to-treat adult patients with relapsed or refractory DLBCL who had received at least 2 systemic treatments before enrolling in the study.1,5 Loncastuximab tesirine was administered on day 1 of each 21-day cycle at a dose of 150 μg/kg for 2 cycles and 75 μg/kg thereafter. Treatment was administered for up to 1 year or until disease relapse, disease progression, unacceptable toxicity, or death occurred.5 

The main clinical outcome of LOTIS-2 was the overall response rate (ORR), which was reported to be 48.3% for 70 of the 145 patients. The complete response rate was 24.1%, and the median response duration considering a median follow-up of 7.3 months was 10.3 months. Serious adverse events were observed in 39% of the participants. However, loncastuximab tesirine was shown to have an acceptable safety profile and to provide anticancer activity with a durable response.2,5

A phase 1/2 clinical trial, LOTIS-3 (NCT03684694), is currently evaluating the safety and efficacy of loncastuximab tesirine in combination with ibrutinib, a kinase inhibitor.10,11 Data reported in August 2020 showed an ORR of 62.9% in 35 included participants with relapsed or refractory DLBCL or mantle cell lymphoma. A complete response was observed in 31.4% of the participants.3

Another active clinical trial on loncastuximab tesirine in patients with DLBCL is LOTIS-5 (NCT04384484), a phase 3 trial designed to evaluate the efficacy of loncastuximab tesirine when combined with rituximab (Lonca-R) and compared to standard immunochemotherapy.12 In July 2022, ADC Therapeutics also announced that the first patient was dosed in the phase 2 clinical trial LOTIS-9 (NCT05144009), which is currently recruiting for the evaluation of Lonca-R in unfit and frail participants with previously untreated DLBCL.13,14 

Read more about DLBCL prognosis

References

1. Zynlonta. Prescribing information. ADC Therapeutics; 2021. Accessed August 10, 2022.

2. FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma. US Food and Drug Administration (FDA). April 23, 2021. Accessed August 10, 2022.

3. Lee A. Loncastuximab tesirine: first approval. Drugs. 2021;81(10):1229-1233. doi:10.1007/s40265-021-01550-w

4. Makita S, Tobinai K. Antibody therapy targeting CD19 for B-cell non-Hodgkin’s lymphoma. Ann Oncol. 2018;29(5):1086-1089. doi:10.1093/annonc/mdy092

5. 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. doi:10.1016/S1470-2045(21)00139-X

6. Study of ADCT-402 in patients with relapsed or refractory B-cell lineage non Hodgkin lymphoma (B-NHL). ClinicalTrials.gov. January 29, 2016. Updated May 19, 2021. Accessed August 10, 2022.

7. 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. doi:10.1158/1078-0432.CCR-19-0711

8. Hamadani M, Radford J, Carlo-Stella C, et al. Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Blood. 2021;137(19):2634-2645. doi:10.1182/blood.2020007512

9. Study to evaluate the efficacy and safety of loncastuximab tesirine in patients with relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2). ClinicalTrials.gov. July 18, 2018. Updated June 1, 2022. Accessed August 10, 2022.

10. Safety and efficacy study of loncastuximab tesirine + ibrutinib in diffuse large B-cell or mantle cell lymphoma. ClinicalTrials.gov. September 26, 2018. Updated July 25, 2022. Accessed August 10, 2022.

11. Ibrutinib. MedlinePlus. Updated May 15, 2019. Accessed August 10, 2022.

12. Study to evaluate loncastuximab tesirine with rituximab versus immunochemotherapy in participants with relapsed or refractory diffuse large B-cell lymphoma (LOTIS 5). ClinicalTrials.gov. May 12, 2020. Updated August 5, 2022. Accessed August 10, 2022.

13. A study of loncastuximab tesirine and rituximab (Lonca-R) in previously untreated unfit/frail participants with diffuse large B-cell lymphoma (DLBCL) (LOTIS-9). ClinicalTrials.gov. December 3, 2021. Updated July 5, 2022. Accessed August 10, 2022.

14. ADC Therapeutics announces first patient dosed in phase 2 clinical trial of Zynlonta® (loncastuximab tesirine-lpyl) in combination with rituximab in first-line diffuse large B-cell lymphoma. News release. ADC Therapeutics SA; July 20, 2022.

Reviewed by Harshi Dhingra, MD, on 8/11/2022.