Zynlonta (loncastuximab tesirine-lpyl) / Overland ADCT BioPharma, Mitsubishi Tanabe, SOBI - LARVOL DELTA

Relapsed/Refractory Indolent Lymphoma: Options Beyond Immunotherapy (SOHO 2025) - "Third-line immunotherapy-based strategies are now approved for the treatment of patients with multiple relapses, including the chimeric antigen receptor T-cell (CAR-T) constructs axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel, as well as bispecific antibodies like the anti-CD20 × CD3 agents mosunetuzumab and epcoritamab...Obinutuzumab was chosen as the companion of zanubrutinib due to the high proportion of rituximab-refractory patients enrolled in the study and was administered in both arms up to 20 infusions...Loncastuximab with Rituximab In a population of 39 advanced-stage FL patients, including 20 cases of disease relapse within 24 months since frontline treatment (POD24), the combination of the two drugs in an outpatient fixed-duration regimen produced a complete response rate of 67% after 12 weeks on-therapy, which rose to 77% within 21 weeks...Compared with existing agents targeting Ikaros/Aiolos, such as lenalidomide, avadomide, and..."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CRBN • IKZF1

Next Questions: Mantle Cell Lymphoma (SOHO 2025) - "Glofitamab is being evaluated in a phase 3 randomized clinical trial (GLOBRYTE) in patients with MCL who have relapsed following BTKi therapy, 7 which may prove to be an excellent option in this population...The combination of mosunetuzumab with the ADC polatuzumab vedotin (M-Pola) was evaluated in a phase 1b/2 study, with an ORR of 75% (15/20) and CRR of 70% (14/20)...The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is present in MCL, and the ADC zilovertamab vedotin recognizes ROR1 and delivers the anti-microtubule cytotoxin monomethyl auristatin E. In a phase 1 study that included patients with MCL, the ORR was 47% (7/15). 12 Loncastuximab tesirine is an ADC containing a CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin...Novel immunomodulatory agents (ie, golcadomide) are being evaluated in both FL and DLBCL and currently demonstrate favorable outcome — especially in combination with rituximab. 16, 17..."

B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Oncology • Waldenstrom Macroglobulinemia • CD20 • CRBN • ROR1

CAR-T Cell Therapy in B-Cell Lymphoma (ICBMT 2025) - P3 | "In light of these data, large trials in the second-line setting were conducted in transplant-eligible patients who were refractory or relapsed within 12 months of first-line treatment, randomizing between CAR T-cell therapy (axi-cel in ZUMA-7, liso-cel in TRANSFORM and tisa-cel in BELINDA) versus standard-of-care (SOC) with immunochemotherapy (ICT) and an autologous stem cell transplant consolidation5-7...Based on these results, an ongoing randomized study (ZUMA-23, NCT05605899) is evaluating upfront CAR-T vs ICT (R-CHOP or DA-EPOCH-R) in LBCL patients with IPI 4 or 5 at diagnosis...Three main issues should be taken into account when planning treatment for a potential CART candidate: 1) Confirming an adequate washout of prior systemic treatment at time of leukapheresis, including at least 2 weeks in case of chemotherapy and 6-12 months for bendamustine 15,47; 2) CD20/CD3-targeted BsAbs seem safe prior to leukapheresis, if a sufficient time interval is maintained 48,..."

CAR T-Cell Therapy • IO biomarker • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Infectious Disease • Large B Cell Lymphoma • Lymphoma • Mediastinal B Cell Lymphoma • Non-Hodgkin’s Lymphoma • Primary Mediastinal Large B-Cell Lymphoma • T Cell Histiocyte Rich Large B Cell Lymphoma • BCL2 • BCL6

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for B-Cell Lymphomas, Version 3.2025. (NCCN)

NCCN guideline • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • High-grade B-cell lymphoma • Mantle Cell Lymphoma • Primary Mediastinal Large B-Cell Lymphoma

Treatment of diffuse large B-cell lymphoma progressing or relapsing after chimeric antigen receptor T-cell therapy. (PubMed, Transplant Cell Ther) - "The results from this SR/MA aimed at providing the totality of evidence pertaining to the efficacy (or lack thereof) of various available therapies considered in relapsed and/or refractory DLBCL after CAR T-cell therapy shows that treatment choice is a complex process that must consider the patient's performance status and disease-related characteristics, whether localized or systemic, and history of prior therapies, among others."

Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation

Bispecific Antibodies and Antibody-Drug Conjugates in Relapsed/Refractory Aggressive Non-Hodgkin Lymphoma, Focusing on Diffuse Large B-Cell Lymphoma. (PubMed, Cancers (Basel)) - "Bispecific antibodies, including epcoritamab and glofitamab, third-line therapies for diffuse large B-cell lymphoma, are recombinant immunoglobulins engineered to recognize two distinct antigens or epitopes simultaneously...In the context of new therapies, antibody-drug conjugates, such as loncastuximab tesirine, are therapies composed of monoclonal antibodies linked to cytotoxic agents, in which the antibody selectively binds to tumor-associated antigens, delivering the cytotoxic payload directly to cancer cells while minimizing off-target effects...Ongoing clinical trials are investigating other molecules like odronextamab and the use of bispecific antibodies in combination regimens and earlier lines of therapy. The aim of this review is to explore actual therapies in relapsed/refractory diffuse large B-cell lymphoma, focusing on bispecific antibodies and antibody-drug conjugates."

Journal • Review • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

The Optimal Management of Waldenström Macroglobulinemia (SOHO 2025) - "Standard treatment options include alkylating agents (eg, bend-amustine or cyclophosphamide) or proteasome inhibitors (eg, bortezomib, carfilzomib, or ixazomib) in combination with anti-CD20 monoclonal antibody rituximab, covalent Bruton tyrosine kinase (BKT) inhibitors (eg ibrutinib, acalabrutinib, or zanubrutinib), BCL2 antagonists (eg, venetoclax), and non-covalent BTK inhibitors (eg, pirtobrutinib) 13–23...The combination of bendamustine and rituximab showed superior progression-free survival (PFS) to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in a study by the STiL group 13...The all-oral, non-chemo, fixed-duration combination of pirtobrutinib and venetoclax has shown promise in early relapse 29.Inlate relapse, multiple agents are under active development, including second-generation BCL2 antagonists (eg, sonrotoclax), BTK degraders (eg, BGB-16673 30, NX-5948), conjugated radioisotopes (eg, iopofosine I-131 31), antibody-drug conjugates..."

IO biomarker • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Indolent Lymphoma • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Waldenstrom Macroglobulinemia • B2M • BCL2 • CXCR4 • MYD88 • TP53

Holding and Bridging Therapy Selection in Relapsed/Refractory Aggressive B-Cell Lymphoma (SOHO 2025) - P3 | "This treatment approach was first available in the third- or later-line (3L+) setting, based on the results from single-arm trials — namely ZUMA-1 (axicabtagene ciloleucel [axi-cel]), JULIET (tisagenlecleucel [tisa-cel]), and TRANSCEND-NHL-001 (lisocabtagene maracelucel [liso-cel])...It is part of an approved regimen for R/R LBCL in second- or later-line treatments — namely the rituximab-bendamustine-polatuzumab (RBP) combination...23,24 Both loncastuximab and tafasitamab are approved for R/R LBCL patients, 25,26 and they share the same target as CAR T cells...Response to BT has a significant prognostic impact on the efficacy and toxicity of CAR T-cell therapy. Ongoing trials with radiotherapy and novel agents will shed light on their role in this setting."

IO biomarker • B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Indolent Lymphoma • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6 • CD4

Targeted Therapies and Immunotherapies for Diffuse Large B-Cell Lymphoma. (PubMed, Cancers (Basel)) - "Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL) [...]."

Journal • Review • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Sequencing Anti-CD19 Therapies in Diffuse Large B-Cell Lymphoma: From Mechanistic Insights to Clinical Strategies. (PubMed, Int J Mol Sci) - "We examine mechanisms of resistance such as antigen loss, epitope masking, and T-cell exhaustion, as well as the implications of tumor microenvironmental immunosuppression. Future efforts should prioritize the integration of real-time diagnostics, such as flow cytometry, immunohistochemistry, and transcriptomic profiling, and AI-assisted predictive models to optimize therapeutic sequencing and expand access to personalized immunotherapy."

Journal • Review • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Cutaneous toxicities to antibody-drug conjugate loncastuximab tesirine: A multicenter retrospective analysis (EADV 2025) - No abstract available

Retrospective data • Oncology

Updated Safety Run-In Results From LOTIS-5: A Phase 3, Randomized Trial of Loncastuximab Tesirine With Rituximab Versus Immunochemotherapy in Patients With R/R DLBCL/HGBL (SOHO 2025) - P3 | "Fixed duration Lonca-R showed no new safety signals and demonstrated encouraging antitumor activity, with signs of durable response in four patients who maintained CR for >28 months after EOT. Lonca-R resulted in lower median Cmax than monotherapy in C1. CD19 staining was not predictive of efficacy."

Clinical • P3 data • Diffuse Large B Cell Lymphoma • Oncology • CD19

Efficacy and Safety of Loncastuximab Tesirine Monotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: A Systematic Review and Meta-Analysis (SOHO 2025) - "This meta-analysis supports the efficacy of loncastuximab tesirine monotherapy in heavily pretreated R/R DLBCL, with an ORR of ∼46% and manageable toxicity. These findings reinforce its role as a valuable treatment option in patients with limited alternatives and highlight the need for further randomized studies to optimize patient selection and sequencing strategies."

Monotherapy • Retrospective data • Review • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Management of Adverse Reactions to Loncastuximab in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma. (PubMed, Hematol Oncol) - "The survey results align with findings from prior clinical trials and support the manageability of Lonca-associated AEs in a wide variety of settings. The included algorithm provides guidance for managing AEs, such as edema, myelosuppression, and cutaneous reactions."

Journal • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Fatigue • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Announced strategic restructuring and prioritization plan, discontinuing early development efforts for the remaining preclinical programs in solid tumors and focusing on ZYNLONTA. (Financial Times) - "As research and development efforts and related programs are closed out, the Company plans to shut down its UK facility and reduce the global workforce across functions by approximately 30%, which is expected to be substantially completed by September 30, 2025...Net product revenues were $18.1 million for the second quarter ended June 30, 2025, and $35.5 million for the first six months of 2025 as compared to $17.0 million and $34.9 million for the same periods in 2024."

Commercial • Pipeline update • Diffuse Large B Cell Lymphoma • Indolent Lymphoma • Solid Tumor

Initial Results From LOTIS-7: A Phase 1b Study of Loncastuximab Tesirine Plus Glofitamab in Patients With Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) (SOHO 2025) - P1 | "Lonca-Glofit in R/R B-NHL showed a manageable/consistent safety profile and encouraging efficacy in heavily pretreated aggressive lymphoma patients. Results suggest Lonca complements Glofit's mechanism and provides additive efficacy. Funding: ADC Therapeutics SA and Sobi; medical writing: Citrus Health Group."

Clinical • P1 data • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20 • CD4 • CD8 • IL6

Efficacy and Safety of Loncastuximab Tesirine in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Meta-Analysis of Prospective Monotherapy Trials (SOHO 2025) - "Loncastuximab tesirine demonstrates significant clinical activity and a manageable safety profile in heavily pretreated, highly refractory DLBCL. These findings support its use in heavily pretreated, CD19-positive populations, warranting further exploration in combination therapies or earlier treatment lines."

Monotherapy • Retrospective data • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Loncastuximab Tesirine and Venetoclax for Relapsed/ Refractory Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: Paolo Caimi, MD | Trial completion date: Dec 2025 ➔ Jun 2026 | Trial primary completion date: Jun 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Deep Learning-Based Body Composition Analysis for Outcome Prediction in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Insights From the LOTIS-2 Trial. (PubMed, JCO Clin Cancer Inform) - P2 | "The pretreatment SM*/VF* body composition index shows promise as a biomarker for patients with rel/ref DLBCL undergoing treatment with loncastuximab tesirine. The proposed deep learning-based approach for body composition analysis demonstrated comparable performance to the manual process, presenting a more cost-effective alternative to conventional methods."

Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Follicular Lymphoma: Current Therapeutic Landscape and Future Prospects (ICML 2025) - P3 | "The ability of maintenance rituximab, obinutuzumab induction, or bendamustine-based induction to lower early progression rates without affecting OS or HT rate [10, 12, 18] suggests that not all POD24 cases are equal, with a subset remaining resistant to current treatments...Since 2021, three CAR-T constructs—axicabtagene-ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel)—and three CD3 × CD20 BsAbs—mosunetuzumab, epcoritamab, and odronextamab—have gained regulatory approval in Europe and/or US as options for third line and later...Loncastuximab tesirine (CD19-directed ADC) shows promising activity in 2L+ R/R FL (CR 67%, manageable toxicity in a small Phase 2 cohort) [40]. Adding tafasitamab, an anti-CD19 antibody, to R2 in R/R FL patients improved PFS by 57% in the inMIND trial after a median follow-up of 14 months [41]...However, the ROSEWOOD trial showed obinutuzumab-zanubrutinib was superior to Obinutuzumab alone..."

IO biomarker • B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • EZH2 • IGH

A Study of MT-2111 in Patients With Relapsed/Refractory DLBCL (clinicaltrials.gov) - P1/2 | N=46 | Active, not recruiting | Sponsor: Mitsubishi Tanabe Pharma Corporation | Recruiting ➔ Active, not recruiting

Enrollment closed • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6

T-Cell Redirecting Strategies in Large B-Cell Lymphoma and Follicular Lymphoma (ICML 2025) - "The randomized STARGLO trial compared the combination of glofitamab with gemcitabine and oxaliplatin (GemOx) versus rituximab-GemOx, meeting its primary endpoint of OS in favor of the experimental arm (HR 0.62 [95% CI 0.43–0.88])...Other treatment options to consider in this R/R patient population are tafasitamab/lenalidomide [107], loncastuximab tesirine [108] and rituximab-bendamustine-polatuzumab [109], amongst others...Three CAR-T constructs are available based on Phase 2, single-arm trials, namely ZUMA-5 (axi-cel), ELARA (tisa-cel), and TRANSCEND-FL (liso-cel)...Mosunetuzumab, epcoritamab and odronextamab received regulatory approval (U.S...She started treatment with a bispecific antibody, aiming to carry out her first imaging assessment after three cycles. Permission to Reproduce Material From Other Sources The author has nothing to report."

IO biomarker • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Large B Cell Lymphoma • Lymphoma • Mediastinal B Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Mediastinal Large B-Cell Lymphoma • T Cell Histiocyte Rich Large B Cell Lymphoma • T Cell Non-Hodgkin Lymphoma • CD19

Loncastuximab Tesirine and Rituximab as Bridging Therapy Prior to Standard-of-care CD19 CAR T-cell Therapy in Patients With Large B-cell Lymphoma (clinicaltrials.gov) - P2 | N=29 | Recruiting | Sponsor: University of Utah | Not yet recruiting ➔ Recruiting

Enrollment open • IO biomarker • B Cell Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

“Based on the review of the data on safety and efficacy, the benefit-risk balance of Zynlonta (loncastuximab tesirine) in the approved indication(s) remains unchanged” (European Medicines Agency) - Pharmacovigilance Risk Assessment Committee (PRAC) Minutes of meeting on 5 – 8 May 2025: “Nevertheless, the product information should be updated to add sepsis as a warning and as an undesirable effect with a frequency ‘common’. Therefore, the current terms of the marketing authorization(s) should be varied”

PRAC • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma: drug profile and expert opinion on the prevention and management of adverse events. (PubMed, Leuk Lymphoma) - "While loncastuximab has an overall manageable safety profile, it may cause drug-specific adverse events (AEs) different from other R/R DLBCL treatments. After summarizing the profile of loncastuximab, here we discuss PBD-specific AEs such as phototoxicity & cutaneous reactions, edema & effusions, and liver enzyme elevation; and use available clinical trial data, real-world evidence and clinical scenarios to provide expert opinion and practical advice on how to prevent and manage these non-hematological, PBD-specific AEs."

Adverse events • Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma