U.S. Food and Drug Administration (FDA)-Approved Indications

Zynlonta is indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.

Compendial Uses

Loncastuximab tesirine-lpyl is available as Zynlonta (ADC Therapeutics America) is an antibody and alkylating agent conjugate targeting CD19. Loncastuximab tesirine-lpyl binding to CD19 results in the release of SG3199 via proteolytic cleavage. Subsequently, SG3199 binds to the DNA minor groove and produces highly cytotoxic DNA interstrand crosslinks and ensuing cell death (ADC Therapeutics, 2021b).

Loncastuximab tesirine-lpyl (Zynlonta) carries the following warnings and precautions:

Per the prescribing information, the most common (≥ 20%) adverse reactions include thrombocytopenia, increased gamma-glutamyl transferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most frequent histologic subtype of non-Hodgkin lymphoma (NHL) responsible for an estimated 25 % of NHL cases worldwide. DLBCL is a heterogenous group of cancer cells consisting of large, transformed B cells with distinct nucleoli and basophilic cytoplasm, a diffuse growth pattern and a high proliferation fraction. Cancer cells in DLBCL generally express pan B cell antigens (CD19, CD20, CD22, CD79a) (Freedman and Aster, 2023). Refractory and relapsed DLBCL are characterized by disease recurrence after achieving a complete remission or disease that fails to respond adequately to treatment, respectively (UpToDate, 2021). Patients who fail first-line therapy have poor prognoses and disease worsening with each line of therapy. The chance for cure or long-term disease-free survival (DFS) decreases in this patient population (ADC Therapeutics, 2021).

On April 23, 2021, the U.S. Food and Drug Administration (FDA) approved Zynlonta (loncastuximab tesirine-lpyl) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL not otherwise specified (NOS), DLBCL arising from low-grade lymphoma and high-grade B-cell lymphoma. The FDA granted accelerated approval based on supporting data from the LOTIS-2 study (ADC Therapeutics, 2021).

The LOTIS-2 study consisted of a large phase-II, multi-national, open-label, single-arm clinical trial of 145 adult patients with relapsed or refractory DLBCL following at least 2 prior systemic regimens. Zynlonta was administered as 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles until disease progression or unacceptable toxicity. Efficacy evaluation was based on overall response rate (ORR). The trial demonstrated an ORR in 48.3 % (70/145) of patients inclusive of a complete response (CR) in 24.1 % (35/145) of patients and a partial response (PR) in 24.1 % (35/145) of patients. A median time to response was noted as 1.3 months with a median duration of response (mDOR) for the 70 responders as 10.3 months.

: Requires Precertification:

Precertification of loncastuximab tesirine-lpyl (Zynlonta) is required of all Aetna participating providers and members in applicable plan designs. For precertification of loncastuximab tesirine-lpyl (Zynlonta), call (866) 752-7021 (Commercial), or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see

Criteria for Initial Approval

Large B-cell Lymphoma

Aetna considers loncastuximab tesirine-lpyl (Zynlonta) medically necessary for treatment of relapsed, progressive, or refractory large B-cell lymphoma (e.g., DLBCL NOS, DLBCL arising from low grade lymphoma, high-grade B-cell lymphoma) when

of the following criteria are met:

Histologic Transformation of Indolent Lymphomas to Diffuse Large B-cell Lymphoma

HIV-Related B-cell Lymphomas

Aetna considers loncastuximab tesirine-lpyl (Zynlonta) medically necessary for treatment of relapsed, progressive or refractory HIV-related diffuse large B-cell lymphoma, primary effusion lymphoma, and human herpesvirus-8 (HHV8)-positive diffuse large B-cell lymphoma when all of the following criteria are met:

Aetna considers all other indications as experimental and investigational.

Continuation of Therapy

Aetna considers continuation of loncastuximab tesirine-lpyl (Zynlonta) therapy medically necessary for members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Loncastuximab tesirine-lpyl (Zynlonta) is available for injection as 10 mg of loncastuximab tesirine-lpyl as a lyophilized powder in a single-dose vial for reconstitution and further dilution for intravenous infusion.

Diffuse Large B-cell Lymphoma

Zynlonta is administered as an intravenous infusion over 30 minutes on day 1 of each cycle (every 3 weeks). The recommended dosage is as follows:

Premedication with dexamethasone 4 mg orally or intravenously is given twice daily for 3 days beginning the day before Zynlonta administration.

Source: ADC Therapeutics, 2022