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Currently, a significant percentage of patients with DLBCL are refractory or relapse after a first line of immunochemotherapy. Second relapses after autologous stem cell transplantation or chimeric antigen receptor T-cell therapies present few treatment options and do not yield good results. New molecules have entered the immunotherapy arsenal. Loncastuximab tesirine comprises a humanized anti-CD19 monoclonal conjugated antibody, which consists of an anti-CD19 antibody and cytotoxic alkylating agent, SG3199. Several studies have proven its efficacy in the treatment of refractory cases of DLBCL with a good safety profile, with the main adverse effects being neutropenia, thrombopenia, and liver enzyme involvement. In this review, we explain the mechanism of action of this molecule, the clinical data that have led to its acceptance by the FDA, and the new therapeutic options that are proposed in association with this drug. [ABSTRACT FROM AUTHOR]

Summary: Antibody-drug conjugates (ADCs) are a new class of monoclonal antibodies with the characteritic to specifically target tumor cells and to deliver a cytotoxic drug directly to the target cell thereby minimising side effects and improving the therapeutic index. In recent years, many new ADCs have been approved and are established therapeutic tools in lymphoma treatment. [ABSTRACT FROM AUTHOR]

Abstract CD19‐targeting treatments have shown promise in relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL). Loncastuximab tesirine (loncastuximab tesirine‐lpyl [Lonca]) is a CD19‐targeting antibody‐drug conjugate indicated for R/R DLBCL after at least two systemic treatments. CD19 expression was evaluated in patients receiving Lonca in the LOTIS‐2 clinical trial with available tissue samples obtained after last systemic therapy/before Lonca treatment. Lonca cytotoxicity was evaluated in a panel of six lymphoma cell lines with various CD19 expression levels. Quantitative systems pharmacology (QSP) modelling was used to predict Lonca responses. Lonca responses were seen in patients across all CD19 expression levels, including patients with low/no detectable CD19 expression and H‐scores at baseline. Similarly, Lonca induced cytotoxicity in cell lines with different levels of CD19 expression, including one with very low expression. QSP modelling predicted that CD19 expression by immunohistochemistry alone does not predict Lonca response, whereas inclusion of CD19 surface density improved response prediction. Virtual patients responded to Lonca with estimated CD19 as low as 1000 molecules/cell of CD19, normally below the immunohistochemistry detection level. We found Lonca is an effective treatment for R/R DLBCL regardless of CD19 expression by immunohistochemistry. These results provide the basis for future studies addressing CD19‐targeted agent sequencing.

OBJECTIVE: Tafasitamab, loncastuximab, tesirine, polatuzumab, and selinexor have been proposed for the treatment of relapsed/refractory B-cell lymphomas. We studied the patterns of overall survival (OS) for these four agents. PATIENTS AND METHODS: We reconstructed patient-level data from the published Kaplan-Meier OS graphs. For this purpose, we used an artificial intelligence technique (the Shiny method). Reconstructed survival curves were then subjected to standard statistics to perform between-treatment comparisons, and hazard ratios (HRs) and 95% confidence intervals (CI) were estimated. RESULTS: Using tafasitamab plus lenalidomide as a common comparator, our analysis of OS yielded the following results: a) Polatuzumab vedotin vs. tafasitamab + lenalidomide: HR=1.60 (95%CI, 0.94-2.74, p=0.0831); b) Selinexor vs. tafasitamab + lenalidomide: HR=2.28 (95%CI, 1.54-3.38, p<0.001); c) Loncastuximab tesirine vs. tafasitamab + lenalidomide: HR=2.35 (95%CI, 1.55-3.56, p<0.001). All three values favored tafasitamab + lenalidomide. CONCLUSIONS: These comparative OS results represent the original findings. Although these comparisons were indirect, our analysis offered a useful synthesis of the outcomes reported thus far for these four treatments. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of Non-Hodgkin's lymphoma in the United States, with approximately 40% of first-line DLBCL chemoimmunotherapy attempts failing. The FDA approved a new type of antibody–drug conjugate (ADC), Zynlonta (loncastuximab tesirine), once called ADCT-402, on April 23, 2021, for relapsed or refractory (R/R) DLBCL. Loncastuximab tesirine comprises a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin. Purpose: The purpose of this article is to review the pharmacological properties of loncastuximab tesirine and evaluate its efficacy and safety in the treatment of R/R DLBCL. Methods: In PubMed, Web of Science and CNKI, I searched for relevant literature as of November 2021 through some keywords. Obtained loncastuximab tesirine essential drug and related clinical trial information on https://www.adctherapeutics.com/ and clinicaltrials.gov. Results: Once it binds with cells expressing CD19, loncastuximab tesirine is internalized by the cell and then releases SG3199, which irreversibly binds to the DNA, thereby disrupting the basic DNA metabolism process and ultimately leading to cell death. The results of the main non-comparative clinical trials LOTIS-1, LOTIS-2 and LOTIS-3 were encouraging. In LOTIS-1, the overall response rate (ORR) of R/R DLBCL patients treated with loncastuximab tesirine was 42.3%, and loncastuximab tesirine had excellent stability and acceptable safety profile. The recommended dosage of loncastuximab tesirine is 0.15 mg/kg every three weeks for two cycles, 0.075 mg/kg every three weeks for each subsequent cycle. The pivotal LOTIS-2 showed that loncastuximab tesirine had substantial single-agent antitumour activity in patients with R/R DLBCL: the ORR and complete response rate were 48.3% and 24.1%, respectively, and produced a durable response with acceptable safety and tolerability. The results of the LOTIS-3 phase 1 portion indicated that loncastuximab tesirine 60 µg/kg plus ibrutinib 560 mg had encouraging antitumour activity in R/R DLBCL, with an ORR of 56.7%. Haematological adverse events such as anaemia and neutropenia, non-haematological events such as fatigue and nausea, and biochemical events such as γ-glutamyl transferase increase, and blood alkaline phosphatase increases were common after administration of loncastuximab tesirine. Conclusions: Loncastuximab tesirine is a CD19-targeted ADC that addresses the unmet needs of R/R DLBCL patients who have been heavily pretreated, comprising high-risk populations. [ABSTRACT FROM AUTHOR]

Objective: This article summarizes the background, clinical trials, and place in therapy for the first two anti-CD19 monoclonal antibodies that have been recently FDA approved for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Summary: Treatment options are limited for patients that have relapsed after or are ineligible for autologous stem cell transplant (ASCT) or chimeric antigen receptor (CAR) T-cell therapy. Recent novel therapy approvals have started to change management strategies and outcomes for these patients. Two examples of recent FDA approvals are tafasitamab and loncastuximab tesirine, which represent the first anti-CD19 targeting monoclonal antibodies for patients with R/R DLBCL. Tafasitamab was granted accelerated approval in combination with lenalidomide for adult patients with R/R DLBCL after one or more lines of therapy based on the phase 2, L-MIND trial. Loncastuximab tesirine was granted accelerated approval for adult patients with R/R DLBCL after two or more lines of therapy based on the phase 2, LOTIS-2 trial. The place in therapy and sequencing of these agents can present a challenge to prescribers especially in regards to patients being evaluated for CD19 targeting CAR T-cell therapy. Conclusion: Tafasitamab and loncastuximab tesirine are options for use in patients with R/R DLBCL and are welcome additions to the limited therapy options for these patients. Further data is needed to elucidate sequencing and the impact these agents may have on CAR T-cell therapy. Ongoing clinical trials are studying these agents in the upfront setting in combination with other chemoimmunotherapy agents which may further expand treatment options for patients with B-cell lymphomas. [ABSTRACT FROM AUTHOR]

Three new drugs are presented: dostarlimab, loncastuximab tesirine, and aducanumab. Product information, clinical trials, and recommendations are provided. Dostarlimab (Jemperli®) is FDA-indicated for the treatment of adult patients with mismatch repair deficient (dMMR - an abnormality that affects DNA repair) recurrent or advanced endometrial cancer (EC). Loncastuximab tesirine (Zynlonta®) is FDA-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, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma. Aducanumab (Aduhelm®) is FDAindicated for the treatment of Alzheimer’s disease. It is an amyloid beta-directed antibody developed by Biogen of Cambridge, Massachusetts. This indication was approved on June 7, 2021, under the accelerated approval based on the reduction in amyloid beta plaques in patients treated with the drug. [ABSTRACT FROM AUTHOR]

Relapsed or refractory diffuse large B cell lymphoma (DLBCL) has a poor prognosis. Several novel therapies have gained regulatory approval for treatment of DLBCL, however there is still a need for additional therapies to be added to the armamentarium. Loncastuximab tesirine-lpyl (ADC Therapeutics), an anti-CD19 antibody-drug conjugate (ADC), was recently approved for the treatment of relapsed, refractory diffuse large B-cell lymphoma (DLBCL). We review the design and pharmacologic characteristics of loncastuximab tesirine-lpyl, emphasizing on the significance of CD19 as an effective target as well as pyrrolobenzodiazepine (PBD) as an effective payload. We review the key findings of the phase 1 LOTIS-1 and Phase 2 LOTIS-2 trials of loncastuximab in DLBCL, including efficacy and toxicity profile. Key findings in the early-phase trial support the efficacy of Loncastuximab in DLBCL, including in high-risk subgroups. The side effects have been tolerable even in elderly patients (≥75 years). Several ongoing clinical trials are currently evaluating the safety and efficacy of loncastuximab tesirine in a variety of NHL subtypes, as well as the study of combination strategies. [ABSTRACT FROM AUTHOR]

CD19 is nearly ubiquitously expressed on B-lymphocytes and in B-cell malignancies. Although CD19-directed CAR T cells have greatly improved outcomes in B-cell malignancies, there are significant limitations with this therapy. CD19 can also be effectively targeted by other drug classes, such as monoclonal antibodies, antibody-drug conjugates, and bispecific T cell engagers or antibodies. However, the optimal patient selection and sequencing of these novel therapies has not yet been established. In this review, we discuss the utilization of CD19 as a target for the treatment of DLBCL, focusing on tafasitamab, loncastuximab tesirine, and blinatumomab. We provide a comprehensive review of the pivotal clinical trials, discussing the strength and limitations of the data for each agent. We explore the emerging evidence that CD19 expression is retained following exposure to these agents and that patients can be successfully re-challenged with anti-CD19 therapies of a different drug class upon disease relapse post-CAR T cells. Finally, we discuss how these drugs potentially fit into the most current treatment paradigm for DLBCL. [ABSTRACT FROM AUTHOR]

In the past 5 years, 3 chimeric antigen receptor (CAR) T-cell therapies, 2 antibody-drug conjugates (ADCs), 1 CD19-directed monoclonal antibody, and 1 exportin-1 inhibitor have been approved by the Food and Drug Administration for patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). The noncellular therapies received accelerated approval based on the overall response rate in clinical trials that differ in multiple aspects of the patient populations enrolled, including age, performance status, prior lines of therapy, and inclusion of patients with primary refractory DLBCL, transformed lymphoma, or high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6. ADCs approved for DLBCL differ in target antigen, antibody structure, linker, and cytotoxin, which results in a different safety and efficacy profile. Here, we comprehensively review the current knowledge of recently approved and emerging strategies for the management of R/R DLBCL with a focus on ADCs. • Replacing vincristine with polatuzumab vedotin in R-CHOP improved PFS in newly diagnosed DLBCL • CAR-T cell therapy improved EFS relative to ASCT in patients with early relapse or refractory DLBCL • Loncastuximab tesirine was recently approved for R/R DLBCL, including high-grade B-cell lymphoma • Emerging ADCs with novel targets include STRO-001, Trph-222, VLS-101, and naratuximab emtansine [ABSTRACT FROM AUTHOR]