Diffuse large B-cell lymphoma (DLBCL), a form of non-Hodgkin lymphoma, is the most common form of blood cancer. Lymphomas occur when cells of the immune system, known as B lymphocytes, grow and multiply uncontrollably.

DLBCL occurs mostly in adults and is an aggressive lymphoma. The disease can start in the lymph nodes or outside of the lymphatic system in the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain.[1]

One of the first signs and symptoms of the disease is a generally painless rapid swelling in the neck, armpit, abdomen, or groin. This swelling is caused by enlarged lymph nodes. Some other symptoms may include an increase in night sweats, unexplained fevers, and weight loss.[1][2]

Poor prognosis
DLBCL is associated with a generally poor prognosis. Patients with R/R disease after frontline anthracycline-based chemotherapy have a 3-year event-free survival of ∼30%.1  Even in fit patients with chemosensitive disease to salvage therapy, ∼50% will ultimately progress after autologous hematopoietic cell transplant (AHCT) and experience a median overall survival (OS) of 10 months. [3][4] Those who have disease refractory to primary or salvage chemotherapy or relapse in ≤12 months after AHCT have especially poor outcomes, with an overall response rate (ORR) of 26% to the next line of therapy and median OS of 6.3 months. 

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Treatment Options
Treatment may differ depending on the location of the tumor and the subtype of lymphoma.[1][3] For patients diagnosed with advanced DCBCL who have not yet been treated previously, a combination of chemotherapy and the monoclonal antibody rituximab (Rituxan®), a treatment combination called R-CHOP (Rituximab + Cyclophosphamide + Doxorubicin Hydrochloride (Hydroxydaunomycin) + Vincristine Sulfate (Oncovin) and Prednisone) [1][2][4].

CAR T-cell therapy
In addition to this treatment option, the FDA approved axicabtagene ciloleucel (Yescarta®; Gilead/Kite) in October 2017.  Axicabtagene ciloleucel is a powerful form of immunotherapy known as chimeric antigen receptor (CAR) T-cell therapy, a type of rapidly emerging immunotherapy approach is called adoptive cell transfer or ACT which involves collecting and using a patients’ own immune cells to treat their cancer. The treatment option has been approved by the United States for the treatment of DCBCL that is not responding to at least two treatment attempts or has returned after being treated before.[4] A stem cell transplant may also be an option if DLBCL returns or relapses.

Antibody-drug Conjugate
In 2019 the FDA approved polatuzumab vedotin (Polivy®; Genentech/Roche) for the treatment of adult patients with DLBCL to be used along with the chemotherapy drug bendamustine and rituximab (a combination known as “BR”). Polatuzumab vedotin contains a humanized monoclonal antibody (mAb) targeting B-cell antigen receptor complex-associated protein beta chain (CD79b) conjugated to the synthetic dolastatin 10 analog microtubule-disrupting monomethyl auristatin E (MMAE) through engineered cysteines (THIOMABs) by a protease-cleavable peptide linker (valine–citrulline; Maleimidocaproylvaline-citrulline-p-aminobenzoyloxycarbonyl or MC-VC-PABC).

A new treatment option
This week, the FDA approved Loncastuximab Tesirine (Zynlonta®; ADC Therapoeutics) as the first and only CD19-targeted antibody-drug conjugate (ADC) as a single-agent treatment for adult patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL).  The new treatment option addresses an unmet need across a broad population of third-line (3L)+ r/r patients, including patients with DLBCL not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma.

The FDA has been granted accelerated approval based on the overall response rate (ORR). However, continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

“There is a significant unmet need for treatment options for patients with r/r DLBCL, including those who have been heavily pretreated and have difficult-to-treat disease,” said Paolo F. Caimi, MD, University Hospitals Cleveland Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University.

“Single-agent Loncastuximab Tesirine demonstrated clinically important outcomes in the pivotal LOTIS-2 study across several disease subtypes. Notably, this included transplant eligible and ineligible patients and patients who previously received stem cell transplant or CAR-T cell therapy.”

Clinical trials
In clinical trials, Loncastuximab Tesirine demonstrated 48.3% overall response rate, 24.1% complete response rate, and durable responses in heavily pretreated patients in pivotal LOTIS-2 trial

The FDA approval was based on data from LOTIS-2, a large (n=145) Phase 2 multinational, single-arm clinical trial of Loncastuximab Tesirine for the treatment of adult patients with r/r DLBCL following two or more prior lines of systemic therapy. Results from the trial demonstrated an overall response rate (ORR) of 48.3% (70/145 patients), which included a complete response (CR) rate of 24.1% (35/145 patients) and a partial response (PR) rate of 24.1% (35/145 patients). Patients had a median time to response of 1.3 months and the median duration of response (mDoR) for the 70 responders was 10.3 months (inclusive of patients who were censored).

Adverse events
In a pooled safety population the most common adverse reactions (≥20%) were thrombocytopenia, gamma-glutamyltransferase increased, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain. In LOTIS-2 study, the most common (≥10%) grade ≥3 treatment-emergent adverse events were neutropenia (26.2%), thrombocytopenia (17.9%), gamma-glutamyltransferase increased (17.2%) and anemia (10.3%).

Dose reductions due to an adverse reaction of Loncastuximab Tesirine occurred in 8% of patients. Adverse reactions resulting in dose reduction of Loncastuximab Tesirine in ≥4% was gamma-glutamyltransferase increased.

Exciting advancement
“The FDA approval of Loncastuximab Tesirine is an exciting advancement for patients with r/r DLBCL and a transformational event for ADC Therapeutics,” noted Chris Martin, Chief Executive Officer of ADC Therapeutics.

“We extend our deepest gratitude to the patients who participated in our LOTIS-1 and LOTIS-2 clinical trials, their families, the study investigators and our employees, as their commitment made this important milestone possible,” Martin added

Availability
Loncastuximab Tesirine will be commercially available in the United States shortly. ADC Therapeutics has launched the Advancing Patient Support Program, a comprehensive patient support program offering financial assistance, ongoing education, and other resources to eligible patients.

Clinical trials
Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL) – NCT02669017
Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (LOTIS-2) – NCT03589469
Safety and Antitumor Activity Study of Loncastuximab Tesirine and Durvalumab in Diffuse Large B-Cell, Mantle Cell, or Follicular Lymphoma – NCT03685344
Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine Versus Idelalisib in Participants With Relapsed or Refractory Follicular Lymphoma (LOTIS 6) – NCT04699461

Highlights of prescribing information
Loncastuximab Tesirine (Zynlonta™; ADC Therapeutics [Prescribing Information].

References
[1] American Cancer Society. Types of B-cell Lymphoma. Online Last accessed on April 22, 2021.
[2] Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, Lefort S, Marit G, Macro M, Sebban C, Belhadj K, Bordessoule D, Fermé C, Tilly H. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 2010 Sep 23;116(12):2040-5. doi: 10.1182/blood-2010-03-276246. Epub 2010 Jun 14. PMID: 20548096; PMCID: PMC2951853.
[3] Freedman, Arnold and Friedberg, Jonathan. Patient information: Diffuse large B cell lymphoma in adults (Beyond the Basics). UpToDate. Online. Last accessed on April 22, 2021 August 15 2017; .
[4] Ghandi, S. Diffuse Large Cell Lymphoma. MedScape Reference. Online. April 21, 2021
[5] Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800-1808. Blood. 2018 Feb 1;131(5):587-588. doi: 10.1182/blood-2017-11-817775. Erratum for: Blood. 2017 Oct 19;130(16):1800-1808. PMID: 29437609; PMCID: PMC5794504.
[6] Klink AJ, Nabhan C, Lee CH, et al. J Clin Pathways. 2020;6:44-53.

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