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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.

What Is This Summary About?: This article provides a plain-language summary of the results of a clinical trial called the LOTIS-2 study.The LOTIS-2 study included 145 participants with an aggressive type (one that forms, grows, or spreads quickly) of non-Hodgkin lymphoma called diffuse large B-cell lymphoma (a type of blood cancer), or DLBCL for short, whose disease came back or did not respond after 2 or more previous treatments. The LOTIS-2 study was conducted from August 2018 to September 2022.Participants received loncastuximab tesirine, also referred to as Lonca, for up to 1 year, or longer if the treatment was working, and their health was monitored. The primary purpose of the LOTIS-2 study was to find out if participants' lymphoma shrank partially or completely after receiving Lonca., What Were the Results?: A total of 145 participants who were treated with Lonca lived a median (meaning the middle value in a set of numbers) of 9.5 months after starting Lonca treatment. The lymphoma shrank partially or completely in nearly half of participants and shrank completely in 1 in 4 participants. Among participants whose disease either shrank partially or completely in response to Lonca treatment, responses happened relatively quickly, with a median time to response (the time between starting treatment and when the participant's lymphoma either partially or completely shrank) of 41 days. In these participants, the lymphoma did not grow or come back for a median of 13.4 months. Researchers estimated that 83% of participants whose disease shrank completely remained disease free for at least 1 year.Nearly all participants had a side effect from Lonca treatment. The most common side effects were abnormal liver tests (increased gamma-glutamyl transferase), decreased white blood cells (neutropenia), and decreased platelets (thrombocytopenia). One in 4 participants had their treatment stopped due to side effects. The most common side effects that resulted in participants needing to stop Lonca treatment were abnormal liver tests (increased gamma-glutamyl transferase), swelling in the arms or legs (peripheral edema), swelling in an individual spot (localized edema), and fluid around the lungs (pleural effusion)., What Do the Results of the Study Mean?: These results show that Lonca is a treatment option with controllable side effects for many patients with DLBCL whose disease did not respond or came back after 2 or more previous treatments. For participants whose lymphoma completely shrank while taking Lonca, those responses to treatment occurred quickly and lasted for over a year.

What Is This Summary About?: In this article, we summarize results from a clinical study called LOTIS-2, in which researchers looked at patients with a type of blood cancer called diffuse large B-cell lymphoma, or DLBCL for short. Patients received the drug loncastuximab tesirine, or Lonca for short, which targets a marker on the surface of tumor cells called CD19.Patient information from the LOTIS-2 study, other studies of Lonca, and information from scientific publications was used to develop a quantitative systems pharmacology (QSP) model, which can predict how Lonca works in the body. The goal was to use the QSP model to see if CD19 levels can predict tumor size changes after Lonca treatment and if Lonca can still work to treat DLBCL when CD19 levels are very low. The prior LOTIS-1 and LOTIS-2 trials demonstrated an acceptable safety profile for Lonca, and therefore the current study did not evaluate safety data., What Were the Results?: Researchers used immunohistochemistry, a common technique to evaluate CD19 expression. They found that there was no association between patients who responded to Lonca treatment and levels of CD19 on their tumor cells. Some patients with low or even undetectable levels of CD19 on their tumor cells had observable decreases in tumor size after Lonca treatment., What Do the Results of the Study Mean?: While Lonca uses the CD19 target to find and destroy cancer cells, Lonca does not require a large amount of CD19 to kill tumor cells. These results mean that Lonca may be an effective treatment for patients with DLBCL, even if CD19 expression in tumors is undetectable by immunohistochemistry.

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]

Background and objectives Glofitamab, tafasitamab, loncastuximab tesirine, polatuzumab, and selinexor have been proposed for the treatment of relapsed-refractory diffuse large B-cell lymphoma (DLBCL). We studied the pattern of overall survival (OS) for these five agents. Methods We reconstructed patient-level data from the Kaplan-Meier OS graphs published in five pivotal trials. For this purpose, we used an artificial intelligence technique (the Shiny method). Reconstructed survival curves were subjected to standard statistics to perform cross-trial indirect comparisons; medians and hazard ratios (HRs) with 95% confidence interval (CI) were estimated for each treatment. Results Using glofitamab (a bispecific antibody) as a common comparator, our analysis of OS yielded the following results: a) tafasitamab plus lenalidomide, HR: 0.514 (95% CI: 0.341 to 0.776; P=0.0015); b) polatuzumab vedotin, HR: 0.822 (95% CI: 0.509 to 1.327); c) selinexor, HR: 1.170 (95% CI: 0.852 to 1.603); and d) loncastuximab tesirine, HR: 1.120 (95% CI: 0.868 to 1.659). Medians were estimated as follows: a) tafasitamab plus lenalidomide, 26.5 months (95% CI: 18.9 to NA); b) polatuzumab vedotin, 12.5 months (95% CI: 9.03 to NA); c) glofitamab, 11.7 months (95% CI: 7.96 to 18.0); d) loncastuximab tesirine, 10.2 months (95% CI: 6.97 to 11.6); and e) selinexor, 10.1 months (95% CI: 6.72 to 14.2). Conclusions These comparative results represent an original finding generated by the Shiny method. Although these comparisons are indirect, our analysis offers a useful synthesis of the outcomes of these treatments. According to these results, glofitamab, despite its improved mechanism of action, does not seem to confer any OS advantage compared with the other four treatments., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Messori et al.)

Loncastuximab tesirine-lpyl (ADC Therapeutics) is an anti-CD19 antibody-drug conjugate which consists of anti-CD19 antibody and cytotoxic alkylating agent, SG3199. Data from preclinical in vitro and animal studies demonstrated its selectivity and efficacy. The phase I LOTIS-1 study for relapsed, refractory B-cell non-Hodgkin lymphoma (NHL) demonstrated efficacy and a tolerable safety profile, with major adverse effects being neutropenia, thrombocytopenia, elevated liver enzymes, and fluid accumulation. Based on pharmacokinetics analysis in this study, a dose of 150 μg/kg every 3 weeks for cycles 1 and 2 followed by 75 μg/kg every 3 weeks until disease progression or intolerability was chosen for the phase II LOTIS-2 study. This study recruited relapsed, refractory diffuse large B-cell lymphoma and confirmed similar safety profile. Overall response rate was 48.6% (24.1% complete response), and overall survival was 9.9 months. Due to its safety and efficacy reported in the above trials, loncastuximab tesirine was recently approved by the US Food and Drug Administration for the treatment of relapsed, refractory diffuse large B-cell lymphoma. Several clinical trials are ongoing to assess its safety and efficacy in NHL in various clinical settings., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Mehdi Hamadani reports: Consultancy: Janssen R &D (2015); Incyte Corporation (2021); ADC Therapeutics (2021); Pharmacyclics (2018), Omeros (2021), Verastem (2019), TeneoBio (2019), MorphoSys (2021), Kite (2021), Genmab (2021), SeaGen (2021), and Gamida Cell (2021). Speaker’s Bureau: Sanofi Genzyme (2021), AstraZeneca (2021), and BeiGene (2021)., (© The Author(s), 2022.)

Introduction: Chimeric antigen receptor T (CAR-T) therapy has revolutionized the treatment of relapsed/refractory large B-cell lymphoma (LBCL). However, patients who are excluded or have no access to CAR-T represent a challenge for clinicians and have generally a dismal outcome. The landscape for this category of patients is constantly evolving: new agents have been approved in the last 2-3 years, alone or in combination, and novel treatment modalities are under investigation., Areas Covered: Thereafter, we reviewed the currently available therapeutic strategies: conventional chemotherapy, antibody-drug conjugate ADC (mainly polatuzumab and loncastuxumab), bispecific antibodies (CD19/CD3 and focus on novel CD20/CD3 Abs), immunomodulatory drugs (covering tafasitamab and lenalidomide, checkpoint inhibitors mainly in PMBL), small molecules (selinexor, BTK, and PI3K inhibitors), and the role of radiotherapy., Expert Opinion: Navigating this scenario will uncover new challenges, including identifying an ideal sequence for these therapies, the most effective combinations, and search for consistent predictive factors to help selecting the appropriate population of LBCL patients. At present, supporting clinical research for CAR-T ineligible patients, a new and challenging group, must remain a major focus that is complementary to advances in CAR T-cell therapy.