RARE DISEASE
Marginal zone lymphoma
Marginal zone lymphoma
Marginal zone lymphoma
Drug discovery
15
drugs
With orphan designations
Overview
Marginal zone lymphoma (MZL) is a rare, indolent B-cell non-Hodgkin lymphoma arising from marginal zone B cells, comprising three subtypes: extranodal (MALT lymphoma), nodal, and splenic. It is often linked to chronic antigen stimulation (e.g., H. pylori infections, autoimmune disorders) and exhibits heterogeneous clinical behavior. Diagnosis requires integrating histopathology, molecular testing (e.g., MALT1 translocations), and staging. Treatment ranges from anti-infective therapies for localized disease to immunochemotherapy for advanced stages, with prognosis varying by subtype and risk stratification [1][5][12].
Population
Burden
Survival: 5-year relative survival ranges from 76.5% (nodal) to 93.8% (MALT) [4][7].
Prognostic challenges: Early progression (POD24) and histologic transformation to aggressive lymphoma correlate with poorer outcomes [1][12].
Economic impact: High treatment costs for relapsed/refractory cases, with immunochemotherapy and hospitalizations driving expenses [14][19].
Therapies
Localized disease: H. pylori eradication for gastric MALT; involved-site radiation (24–30 Gy) for non-responsive/extranodal cases [3][5][13].
Advanced disease: Rituximab-based regimens (e.g., bendamustine-rituximab), lenalidomide-rituximab (R2), or splenectomy/splenic radiation for splenic MZL [8][13][17].
Asymptomatic cases: Active surveillance until progression or symptom onset [6][12].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
1,315 drug discovery papers about Marginal zone lymphoma, with 2 first-in-class and 15 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,315 drug discovery papers about Marginal zone lymphoma, with 2 first-in-class and 15 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-02 | NLRC5-Deficient Macrophages Promote a Tumor-Permissive Phenotype via AXL- and MERTK-Mediated Efferocytosis.
The innate immune protein NLRC5 plays a key role in cancer immune surveillance. Reduced NLRC5 expression is associated with a poor prognosis for many types of cancers. Previously, we showed that mice with a myeloid-specific deletion of Nlrc5 (Nlrc5mø-KO) develop gastric lymphoid lesions to Helicobacter infection resembling early-stage marginal zone lymphoma. We hypothesized that NLRC5 deficiency may promote a tumor-permissive microenvironment mediated by tumor-associated macrophages (TAMs). Consistent with this hypothesis, splenic macrophages from Helicobacter-infected Nlrc5mø-KO mice had upregulated expression of genes encoding the TAM receptor tyrosine kinases, Axl and Mertk. The levels of AXL and MERTK gene expression and MERTK phosphorylation were increased in NLRC5-/- THP-1 macrophages when compared with WT cells. In response to Helicobacter stimulation, Nlrc5-/- macrophages had significantly elevated anti-inflammatory responses (IL-10, TGF-β, Socs1, Socs3) compared with WT cells. Importantly, Nlrc5-/-macrophages showed enhanced efferocytosis and reduced antigen presentation to CD8+ T cells. Pretreatment of macrophages with AXL and MERTK inhibitors (R428, UNC2025) resulted in reduced efferocytosis and phosphorylation of downstream signaling molecules, STAT3 and ERK1/2. We propose that defective NLRC5 signaling in macrophages leads to tumor-permissive responses, thereby promoting the development of gastric lymphoid neogenesis to Helicobacter infection.
2026-07-17 | Extranodal Marginal Zone Lymphoma of the Breast in a Patient with Chronic Hepatitis C Infection: A Case Report
Primary breast lymphomas account for less than 1% of all non-Hodgkin lymphomas and 0.04–0.5% of all malignant breast neoplasms. We report a case of breast extranodal marginal zone lymphoma (EMZL) in a 60-year-old woman with chronic hepatitis C virus (HCV) infection. After comprehensive evaluation excluded other known etiologies, chronic HCV infection emerged as the most plausible contributing factor. Epidemiologic and biological evidence supports an association between HCV and B-cell non-Hodgkin lymphomas, particularly marginal zone lymphomas. Our case adds to the limited literature suggesting that HCV should be considered as a potential etiological factor in breast EMZL. We discuss the emerging role of direct-acting antiviral (DAA) therapy in HCV-associated indolent lymphomas and its implications for management.
2026-06-02 | Obinutuzumab plus bendamustine as first-line therapy for indolent B-cell lymphomas: a prospective multicenter open-label study.
This study evaluated the efficacy and safety of obinutuzumab plus bendamustine (GB) as first-line treatment for indolent B-cell lymphomas. In this prospective, multicenter, single-arm trial (NCT06415708), adults with newly diagnosed indolent B-cell lymphomas-including follicular lymphoma (FL), marginal zone lymphoma (MZL), Waldenström macroglobulinemia (WM), hairy cell leukemia variant (HCL-v), and unclassified B-cell lymphoproliferative disorder (BCLPD-U)-received six induction cycles of GB followed by 2 years of obinutuzumab maintenance in responders (⩾ partial response). The primary endpoint was overall response rate (ORR), whereas secondary endpoints included complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Among 220 enrolled patients (149 with FL and 71 with non-FL), 210 completed ⩾ 3 treatment cycles. At a median follow-up of 13.1 months, ORRs in the different patient subgroups were 96.6% (FL), 100% (MZL, HCL-v), 92.9% (WM), and 88.9% (BCLPD-U). The median DOR was 16.7 months in the FL group and was not reached in the non-FL group. PFS and OS were not reached in any subgroup. The FL and non-FL groups had comparable ORRs (P = 0.435); however, the FL group showed a higher CRR (92.4% vs. 78.5%; P = 0.004) and shorter PFS (P = 0.020). Treatment-emergent adverse events occurred in 42 patients and were more frequent in the non-FL group than in the FL group (26.8% vs. 15.4%; P = 0.046), particularly infections (18.3% vs. 6.0%; P = 0.005). Overall, the GB regimen demonstrated high response rates and manageable safety in Chinese patients with indolent B-cell lymphoma.
2026-05-25 | Extranodal marginal zone lymphoma presenting as a paraspinal mass and pleural effusion.
MALT-lymphomas are a subtype of non-Hodgkin lymphomas that typically present in the gastro-intestinal tract (50% of cases), the salivary glands and lung. Pleural involvement, however, is exceedingly rare with only a few cases described in the literature to date. Here we present a case of pleural MALT-lymphoma in a 71-year-old woman presenting with progressive dyspnea since 5-6 months without cough or sputum. The CT scan showed paravertebral bilateral pleural thickening (right > left), with associated right sided pleural effusion. Positron emission tomography (PET) scan revealed FDG-uptake limited to the thickened areas of the pleura. Pleural fluid analysis was consistent with a pleural exudate with marked predominance of lymphocytes on flow cytometry (93% lymphocytes) with negative aerobic, anaerobic and mycobacterial cultures. A thoracoscopic biopsy of the right pleural mass revealed massive invasion of the pleura by a mucosa-associated lymphoid tissue lymphoma. The final diagnosis was a stage IV MALT-lymphoma for which systemic therapy with rituximab-bendamustine was administered. Follow-up FDG-PET-CT scan after 4 chemotherapy cycles confirmed complete radiological remission. The case is particularly remarkable because there was no known pre-existing pleural inflammation, which is typically a hallmark of MALT lymphoma in extranodal sites. Immunohistochemical characterization of pleural fluid lymphocyte subtypes might have provided a clue to the diagnosis. In pleural exudates with lymphocytic predominance this diagnostic step should not be overlooked.
2026-05-11 | Chemotherapy in a dog with neutropenia and marginal zone lymphoma.
A 12-year-old Beagle dog with generalized lymphadenopathy and persistent neutropenia was diagnosed with advanced marginal zone lymphoma based on cytology, histopathology, and polymerase chain reaction for antigen receptor rearrangement analysis. Bone marrow examination revealed hypocellularity predominantly affecting the myeloid lineage, while normal morphology and maturation were preserved across hematopoietic lineages, with no evidence of myelophthisis or fibrosis. Chemotherapy was initiated using a modified and dose-reduced multi-agent protocol, followed by L-asparaginase and nimustine; full-dose chemotherapy was also subsequently tolerated without serious adverse events. Two complete remissions were achieved during the treatment course. Normalization of the neutrophil count during tumor progression was presumed to reflect increased neutrophil demand associated with disease progression, indicating that compensatory hematopoietic capacity was preserved. This case illustrates that, in dogs with persistent neutropenia and myeloid hypoplasia, chemotherapy may be considered when bone marrow evaluation confirms preserved hematopoietic maturation and careful monitoring is performed.
cell therapies
2026-08-05 | A 13-Year Review of Non-Diffuse Large B Cell Lymphomas of the Central Nervous System at a Tertiary Hospital: A Case Series Study.
Non-diffuse large B-cell lymphomas (non-DLBCL) of the central nervous system (CNS) are rare and diagnostically challenging. This study aims to characterize the clinical, radiological, and pathological features of non-DLBCL CNS lymphomas diagnosed at a tertiary care center over 13 years, highlighting diagnostic pitfalls. A retrospective review was conducted of non-DLBCL CNS lymphoma cases diagnosed at Sunnybrook Health Sciences Centre, Toronto, from 2010 to 2022. Clinical, demographic, and radiological data were extracted from medical records. Imaging was reviewed by a neuroradiologist, and histopathological slides and molecular data were re-evaluated by a pathology team. Additional tests were performed to update classifications per the 5th edition of the WHO Classification of Haematolymphoid Tumors. Seventeen cases were identified (11 males, 6 females; age 38-76), compared to 72 DLBCL cases during the same period. Nine cases were extra-axial and eight intra-axial. Eight were primary and nine secondary CNS lymphomas. B-cell lymphomas (n = 13) included extra-nodal marginal zone lymphoma (n = 6), follicular lymphoma, mantle cell lymphoma, CLL, intravascular large B-cell lymphoma (n = 2), EBV+ LBCL, and polymorphic PTLD. T-cell lymphomas (n = 4) included PTCL, NOS (n = 2), ALK-negative ALCL, and secondary mycosis fungoides. Imaging revealed four major patterns, and symptoms were largely due to mass effect. This case series emphasizes the considerable heterogeneity of non-DLBCL CNS lymphomas and the diagnostic challenges they present. It highlights key features that can aid recognition and improve diagnostic accuracy for these rare CNS entities. Trial Registration: SUN-5771.
2026-05-27 | Integrated multi-omic profiling reveals two distinct splenic marginal zone lymphoma subgroups with prognostic relevance.
Splenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy with notable genetic, epigenetic, and clinical heterogeneity. This study utilized coding and non-coding sequencing (n=74), including whole-genome sequencing (WGS) on 24 paired tumour-normal samples, targeted sequencing (n=55) and DNA methylation in 126 cases to characterize the disease. From WGS, we identified recurrent, predominantly clonal, coding mutations in KLF2 (50%), KMT2D (25%) and NOTCH2 (25%), alongside rare mutations in FLNC (8%), novel mutations in FAM135B (17%) and non-coding mutational hotspots in BCL6, PAX5 and BACH2, linked to aberrant somatic hypermutation. At least one non-coding hotspot was detected in 69% of cases. Copy-number aberrations (CNAs) were present in 73% of cases, including del(7q) (27%), gain(3q) (17%) and trisomy 12 (13%). DNA methylation profiling revealed two epigenetic subgroups: SMZL-HR (high-risk, n=67) and SMZL-LR (low-risk, n=59). SMZL-HR was associated with adverse features such as female sex, IGHV1-2*04 usage, KLF2 mutations, del(7q), shorter telomeres, and elevated epiCMIT scores. Transcriptomic analysis highlighted enhanced cell proliferation in SMZL-HR, with enrichment of E2F and G2M checkpoint pathways and epigenetic regulation via EZH2. SMZL-HR patients had significantly shorter time to first treatment (TTFT) (HR: 1.9, p=.003) and reduced overall survival (HR: 2.5, p=.039): 85% of SMZL-HR patients required treatment and showed a higher frequency of transformation (p=.007) and mortality (p<.001). Multivariate analysis confirmed SMZL-HR as an independent predictor of shorter TTFT (HR: 2.4, p=.001). These findings demonstrate the role of DNA methylation and molecular profiling in SMZL risk stratification.
2026-05-08 | [Clinical and genetic characteristics of patients with mucosa-associated lymphoid tissue lymphoma transformed into diffuse large B-cell lymphoma].
To analyze the clinical and genetic characteristics of patients with mucosa-associated lymphoid tissue (MALT) lymphoma transformed into diffuse large B-cell lymphoma (DLBCL). A retrospective analysis was performed on patients diagnosed with MALT lymphoma at Henan Provincial People's Hospital from January 2016 to December 2025. According to whether DLBCL transformation occurred, the patients were divided into the transformed group (MALT lymphoma patients who developed DLBCL transformation) and the non-transformed group. The patients were followed up until December 30, 2025, and the clinical and genetic characteristics were compared between the two groups. A total of 175 patients were included, including 13 patients in the transformation group, 4 males and 9 females, aged (58±18) years; and 162 pattients in the non-transformed group, 73 males and 89 females, aged (57±12) years.The incidence of B symptoms in the transformed group [46.2% (6/13) vs 16.7% (27/162), P=0.018], the proportion with a MALT-international prognostic index (IPI) score≥2 point [69.2% (9/13) vs 17.3% (28/162), P<0.001], and lactate dehydrogenase (LDH) levels [227 (194, 262) vs 173 (146, 196) U/L, P<0.001] were all higher than those in the non-transformed group. The mutation rate of gene in the transformed group [84.6% (11/13) vs 45.7% (74/162), P=0.007] and the mutation rate of ≥2 genes [69.2% (9/13) vs 17.3% (28/162), P<0.001] were both higher than those in the non-transformed group. The mutation rates of the NOTCH1 gene [23.1% (3/13) vs 3.7% (6/162), P=0.021], the SOCS1 gene [15.4% (2/13) vs 0, P=0.005], and the KRAS gene [15.4% (2/13) vs 0, P=0.005] were all higher in the transformed group than those in the non-transformed group. Patients with MALT lymphoma who transformed to DLBCL are often accompanied by B symptoms, a higher MALT-IPI score, elevated LDH and multiple gene mutations, and the mutation frequencies of NOTCH1, SOCS1, and KRAS are higher.
2026-04-10 | Hematolymphoid neoplasms involving the breast: A single institution clinicopathologic study of 59 patients.
Breast hematopoietic neoplasms (BHN) are rare and may either primarily (PBHN) or secondarily (SBHN) involve breast tissue. The widespread use of needle biopsy for diagnosis of breast lesions necessitates knowledge of their presentation, radiologic aspects, histomorphology, and outcomes for seeking appropriate hematopathology consultation. Herein, we present our clinical experience as an academic institution and referral center of BHN in the past 20 years. We identified 59 patients diagnosed at the University of Chicago Medical Center between 2002-2021. Demographic, pathologic, radiologic, therapy, relapse data, and vital status were abstracted. Data were examined using univariable statistics with event-free and overall survival (EFS, OS) as primary outcomes examined with the lymphoma subgroup using Cox PH regression adjusted for age. The cases included 27 (46%) PBHN and 32 (54%) SBHN in a cohort comprising 93% females, mostly white (56%). The mean age at diagnosis was 58.8 years. Lymphomas were the most frequent BHN (86.4% of all cases). Patients with primary breast lymphomas (PBL) were significantly older than those with secondary breast lymphomas (SBL) (61.2 vs. 49.8 yrs, p<0.02). The most frequent lymphomas were extranodal marginal zone lymphoma (MZL) (32.2%) and diffuse large B-cell lymphoma/high grade B-cell lymphoma, not otherwise specified (DLBCL/HGBCL, NOS) (33.9%). Over half of MZLs and DLBCLs were primary in the breast. Within B-cell lymphomas, 20 (37%) were high grade with inferior 10-yr overall survival (OS) (age-adjusted HR 5.47, 95% CI 1.38, 21.64) compared to low-grade without any impact on event free survival (EFS). This is one of the largest cohorts so far describing BHN. DLBCL and MZL remain the most common lymphomas involving this site. Most patients were diagnosed via core needle biopsy (CNB) and did not have a prior BHN. Radiographically, the presentation may closely mimic breast carcinoma. FDG PET is a mainstay in the diagnosis and management of BHN.
2026-04-01 | Primary cutaneous marginal zone lymphoma presenting as a violaceous forearm plaque
A woman in her late 80s with a history significant for chronic obstructive pulmonary disease (COPD), type 2 diabetes mellitus, hypertension, hypercholesterolaemia, heart failure with reduced ejection fraction, atrial fibrillation on coumadin and prior stroke presented with a painless, firm,
proteins
2026-05-01 | C32-21 Unmasking the Swell: Recurrent Acquired Angioedema as a Manifestation of Marginal Zone Lymphoma
Abstract Introduction Acquired angioedema (AAE) due to C1-esterase inhibitor (C1-INH) deficiency is a rare, potentially fatal disorder caused by increased bradykinin activity leading to vascular permeability and submucosal edema. Unlike hereditary angioedema, AAE typically presents later in life, lacks a family history, and is frequently associated with underlying B-cell lymphoproliferative disorders or autoimmune diseases. Among these, splenic marginal zone lymphoma (MZL) is disproportionately represented, highlighting a paraneoplastic link between complement consumption and tumor activity. Because bradykinin-mediated angioedema does not respond to epinephrine, corticosteroids, or antihistamines, recognition and disease-specific management are crucial to avoid airway compromise. Case Description A 65-year-old woman with newly diagnosed splenic MZL presented with her third episode of sudden tongue swelling now accompanied by progressive dysarthria, drooling, and respiratory distress. In the emergency department, she was administered 1g intravenous (IV) Tranexamic acid, 20 mg IV Famotidine, 50 mg IV Diphenhydramine, and 125 mg IV Methylprednisolone without improvement. Worsening edema necessitated emergent endotracheal intubation for impending airway obstruction.In the intensive care unit, she was treated with intravenous corticosteroids, diphenhydramine, famotidine, and received two units of fresh frozen plasma. Complement studies revealed a low C1q level (<2 mg/dL), and markedly reduced C1 esterase inhibitor assay ( 7%), confirming acquired C1-INH deficiency. C4 level was also depressed, and autoimmune serologies were negative. Following stabilization, she self-extubated without rebound swelling and was discharged with hematology follow-up for ongoing lymphoma-directed therapy and referral to Allergy-Immunology. Discussion This case underscores a rare but clinically significant manifestation of AAE in the setting of splenic MZL. Adult-onset, recurrent, non-pruritic angioedema unresponsive to conventional histaminergic therapies should prompt evaluation for bradykinin-mediated etiologies. Diagnostic confirmation relies on complement testing, specifically, low C1q and C1-INH levels with normal C1-INH gene sequence, distinguishing AAE from hereditary forms. Acute management centers on airway protection and targeted therapy such as plasma-derived or recombinant C1-INH, icatibant (a bradykinin B2-receptor antagonist), or ecallantide (a kallikrein inhibitor), when available. FFP remains a pragmatic option in resource-limited settings. Long-term control depends on treating the underlying lymphoproliferative disorder, which can normalize complement levels and prevent recurrence.Heightened clinical awareness of AAE in patients with unexplained angioedema and concurrent B-cell malignancies can prevent morbidity and mortality through timely diagnosis and multidisciplinary management. This abstract is funded by: none
2025-09-17 | Antimicrobial Peptides Induce Cell Death in Marginal Zone Lymphoma Models Resistant to Targeted Therapies
Abstract Marginal zone lymphoma (MZL) is an indolent yet incurable B-cell malignancy in which targeted agents such as BTK and PI3K inhibitors frequently fail due to resistance or toxicity. Antimicrobial peptides (AMPs), evolutionarily conserved effectors of innate immunity, possess selective cytotoxicity against malignant cells by exploiting tumor-specific membrane alterations. We evaluated the antitumor activity of seven natural AMPs, including Antarctic fish-derived trematocines and chionodracine variants, and amphibian temporins, against MZL cell lines (VL51, Karpas1718) and derivatives resistant to BTK, PI3Kδ, or PI3Kα/δ inhibitors. Among them, W-trematocine and temporin L demonstrated potent dose-dependent cytotoxicity with IC 50 values of 5.7-10 μM, maintaining full activity in all resistant models. Other peptides showed moderate activity, while chionodracine-1 was inactive. Notably, W-trematocine displayed minimal toxicity toward non-malignant cells in prior studies, underscoring its selectivity. AMP-mediated killing, driven by membrane disruption and non-apoptotic death pathways, bypassed conventional resistance mechanisms, suggesting therapeutic potential in relapsed/refractory disease. These findings highlight natural AMPs as promising candidates for development in drug-resistant MZL, warranting further optimization and preclinical validation.
2025-07-14 | Effects of a Cancer-Associated Mutation and Multiple Serine Phosphorylation on Poly(ADP-Ribose) Polymerase 2.
Poly [ADP-ribose] polymerase 2 (PARP2) plays a crucial role in DNA repair. A common single-nucleotide polymorphism (SNP) in the PARP2 gene, rs3093921, has been associated with pancreatic cancer and marginal zone lymphoma (MZL). This SNP results in a missense mutation, D235G, in the PARP2 protein. PARP2 is also reported to undergo post-translational modifications (PTMs), particularly phosphorylation at serine residues 226, 232, and 353. The C-terminal region of PARP2 includes the Trp-Gly-Arg (WGR) and ADP-ribosyl transferase (ART) domains, and the helical subdomain (HD). The latter two, spanning residues 220 to 583, comprise the catalytic region of PARP2. The DNA-induced enzymatic activation of PARP2 is regulated by local destabilization of the HD domain. We used molecular dynamics (MD) simulations to investigate the impact of these three PTMs on both the wild-type (WT) and the mutant (D235G) forms of PARP2. Our simulations suggest that, while neither the cancer-associated mutation nor PTMs on their own significantly alter the overall flexibility of residues within the HD domain, they cause notably greater deviations in the backbone structure of the HD domain compared to the WT. In addition, PTMs in the context of the mutation show reduced interactions between the mutation site and other protein regions, likely due to structural stabilization induced by the PTMs. Importantly, PTMs mitigate the structural disruption caused by the mutation, helping the mutant protein retain a WT-like conformation. Additionally, the HD domain contributes to maintaining PARP2 in its inactive state through its connection with the ART domain. However, the D235G mutation weakens this connection. While PTMs alone do not have a significant impact on this connection, the simultaneous presence of both the mutation and PTMs partially alleviates the disruptive effect of the mutation and leads to partial restoration of the connection between the HD and ART domains.
2025-04-21 | Abstract 612: Antimicrobial peptides with antitumor activity against marginal zone lymphoma cell lines resistant to BTK, PI3K, and BCL2 inhibitors
Abstract Background: Antimicrobial peptides (AMPs) are a class of small proteins produced by all living organisms, from prokaryotes to humans. In higher eukaryotes, AMPs contribute to the host's innate immunity, promptly responding against any pathogen. Due to their mechanism of action, represented mainly by their ability to bind and perturb microbial membranes, AMPs are being explored as novel agents against multidrug-resistant bacteria and anti-cancer agents. Natural peptides could be used as a scaffold to design new AMPs with improved effectiveness, stability, and selectivity. Marginal zone lymphoma (MZL) is an indolent yet incurable B-cell lymphoid tumor. Here, we assessed the antitumor activity of seven AMPs in MZL models with acquired resistance to FDA-approved BTK, PI3K, and BCL2 inhibitors. Methods: Established human cell lines derived from MZL (VL51, Karpas1718) and derivatives with secondary resistance to targeted agents obtained by long drug exposure (n.=3 from VL51, n.=1 from Karpas1718 (Arribas et al, Haematologica 2022; Mol Cancer Ther 2024; ENA 2019; ENA 2020) were exposed to increasing concentrations of AMPs or DMSO, as control. Anti-proliferative activity was assessed by MTT assay after 72 hours of exposure. Results: MZL cell lines were exposed to AMPs originating from Antarctic fishes (Chionodraco hamatus, Trematomus bernacchii; trematocines, n.=2; chionodracines, n.=1) and amphibians (temporins, n.=4;). Anti-proliferative activity was observed in parental MZL with two synthetic AMPs: a Trematomus bernacchii - derived trematocine mutant (Della Pelle et al, Antibiotics 2020), with IC50 values of 7.5 μM in VL51 and 10 μM in Karpas1718 and the Rana temporaria - derived Temporin L (Simmaco et al, Eur J Biochem 1996) with IC50 of 8 μM in VL51 and 15 μM in Karpas1718. Notably, the antiproliferative activity was maintained in all the derivative MZL cell lines with resistance to BTK, PI3K, and BCL2 inhibitors. At higher concentrations, also the other trematocine (Karpas1718 models) and all the temporins (VL51 and Karpas1718 models) had anti-proliferative activity (IC50 values 25-50 μM). Conclusions: AMPs derived from Antarctic fishes and amphibians have in vitro anti-tumor activity in cell lines derived from MZL, including models with acquired resistance to BTK, PI3K, and BCL2 inhibitors. AMPs and their synthetic derivatives can provide novel anti-lymphoma agents with mechanisms of action deeply different from currently used drugs. Citation Format: Filippo Spriano, Alberto J. Arribas, Fangwen Zhang, Maria Luisa Mangoni, Francesco Buonocore, Francesco Bertoni. Antimicrobial peptides with antitumor activity against marginal zone lymphoma cell lines resistant to BTK, PI3K, and BCL2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 612.
2024-06-01 | Phase 1/2 of EO2463 immunotherapy as monotherapy and in combination with lenalidomide and/or rituximab in indolent NHL (EONHL1-20/SIDNEY).
7058 Background: Follicular and marginal zone B cell lymphoma (FL; MZL) demonstrate an indolent course with heterogeneous outcomes anda potential for spontaneous remissions indicating immune system intervention. Therapeutic immunization is therefore an attractive approach but new antigens that evoke a strong immune response are needed. EO2463 expands pre-existing memory CD8+ T cells recognizing non-self protein sequences from gut bacteria which cross-react with B cell antigens and can kill HLA-A2 restricted cells (T2) loaded with target peptides. EO2463 includes 4 HLA-A2 synthetically produced epitopes which exhibit molecular mimicry with the B cell markers CD20, CD22, CD37, and CD268 (BAFF-receptor), as well as a the CD4 helper-epitope UCP2 derived from hTERT. EO2463 is being used to drive anti-tumor activity against B cell malignancies. Methods: Patients (pts) with FL and MZL, stage 1-3A, and HLA-A2, are eligible. In the safety lead-in pts with relapsed/refractory (R/R) disease were given EO2463 SC q2 weeks (w) x 4, then q4w, for a max of 12 months; at w7 lenalidomide (20 mg/day for 21/28 days up to 12 cycles) is added (EL), and if no complete remission (CR) at w19, rituximab (375 mg/m 2 IV, q1w x 4, then q4w x 4) is also added (ER 2 ). Doses evaluated: 150 μg and 300μg/peptide. Results: 3 pts received 150 μg/peptide and 6 pts 300 μg/peptide (EO2463 1 pat, EL 2 pts, ER 2 6 pts): 2 MZL, 7 FL pts with median 2 lines (range 1-4) of prior systemic therapy. No related grade ≥3 adverse events were seen with EO2463 monotherapy. Most common related events were grade 1 to 2 local administration site reactions in 5/9 pts. Adverse events during combination treatment were as expected for R 2 . PET-CT on w6 after EO2463 monotherapy suggested clinical activity in 4/9 pts (1 PR, 1 pt size reduction 15%, 1 pt 20% reduced tracer uptake, 1 pt 5/6 target lesions reduced metabolic activity). Overall objective responses (OR) were seen in 6/9 pts (67%; 1 st OR on EO2463 1 pat, EL 4 pts, ER 2 1 pat), with CR in 5/9 (56%) pts; median time to response was 18w (range 8-43w), response ongoing in 5 pts, range 24-76w. Expansion of specific CD8+ T cells against mimic peptides and targeted B cell antigens were detected in all responding pts, incl. 2 pts with no measurable B cells at baseline (prior anti-CD20). Expansion of specific T cells was detected at w5 in 5/6 pts and was maintained as long as currently tested (up to w94, 43w after last EO2463 dose). No decline in expansions were seen after start rituximab. Conclusions: EO2463 (300 μg/peptide) monotherapy, EL, and ER 2 are well tolerated, with encouraging clinical activity with EO2463 monotherapy and with subsequent CR in 5/9 pts on combo. Rapid and durable expansion of specific CD8+ T cells was seen in all responding pts, consistent with the preclinical hypothesis. Additional cohorts investigate EO2463 alone or in combination in newly diagnosed or R/R pts. Results will be reported at the meeting. Clinical trial information: NCT04669171 .
antibodies
2026-06-29 | CEACAM1 expression by immunohistochemistry in B-cell lymphomas and plasma cell myeloma.
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with limited curative treatment options. Carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) has recently been implicated in B-cell receptor signaling in MCL. We evaluated CEACAM1 expression by immunohistochemistry across MCL and other mature B-cell neoplasms, including small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM). We retrospectively analyzed 164 lymphoma cases, 35 MM cases, and 2 plasmacytomas. CEACAM1 expression was assessed on tissue microarrays by immunohistochemistry and scored using a prespecified dichotomous cutoff. In DLBCL, CEACAM1 status was correlated with cell-of-origin classification and targeted mutational data. CEACAM1 was expressed in 27 of 30 MCL cases (90%), higher than in the other lymphoma subtypes combined (35%; P < .0001). Expression was also seen in SLL (20/30, 67%), MM (23/35, 66%), MZL (8/22, 36%), and DLBCL (19/82, 23%). In DLBCL, expression was more frequent in germinal center B-cell subtype than activated B-cell subtype cases (30% vs 13%; P = .023). Within sequenced DLBCL cases, CEACAM1 expression was associated with BCL2 and TNFRSF14 mutations. In MM, CEACAM1 expression was not significantly associated with recurrent cytogenetic abnormalities, although a nonsignificant trend toward higher expression in t(11;14) cases (75% vs 53%, Fisher exact P = .28). CEACAM1 is frequently expressed in MCL and in subsets of other mature B-cell neoplasms and MM. These findings support further investigation of CEACAM1 as a biologically relevant marker and potential therapeutic target in selected lymphoid malignancies.
2026-05-13 | Beyond Hypersplenism: Splenic Marginal Zone Lymphoma in an Older Adult with Hemoglobin E/Beta-Thalassemia.
With improvements in blood safety and availability, along with broad access to safe and effective iron chelation, outcomes for patients with thalassemia have greatly improved over recent decades. Previously a predominantly pediatric condition, thalassemia is now increasingly encountered in an aging population. We describe an adult man with HbE/β-thalassemia whose course was complicated by progressive splenomegaly and cytopenias, initially attributed to his underlying thalassemia. Further evaluation, however, revealed splenic marginal zone lymphoma. After the initiation of anti-B-cell therapy, he experienced rapid clinical improvement and was able to avoid surgical splenectomy. This case highlights how complications ascribed to thalassemia can overlap with other diagnoses that may become more prevalent with age, and demonstrates the importance of maintaining a broad differential when symptoms progress despite appropriate thalassemia-directed management.
2026-05-11 | Acquired bone marrow aplasia and long-lasting complete remission with Loncastuximab Tesirine in a patient with transformed marginal zone lymphoma: a case report.
Marginal zone lymphomas (MZL) are indolent lymphomas that may undergo transformation into aggressive lymphomas, most frequently diffuse large B-cell lymphoma (DLBCL). Loncastuximab tesirine (LONCA) is an antibody-drug conjugate used in the treatment of relapsed/refractory large B-cell lymphomas. Here we present the clinical case of a patient with nodal transformed DLBCL and concomitant bone marrow involvement by indolent lymphoma successfully treated with LONCA. However the therapy was discontinued after six cycles as the patient developed treatment-related bone marrow aplasia. This case raises concerns about prolonged hematologic toxicity of LONCA, particularly in patients with pre-existing marrow involvement while highlights the potential of this drug to induce deep and durable response, even after limited exposure.
2026-04-09 | Treatment and outcomes of pulmonary mucosa-associated lymphoid tissue lymphoma: A multicenter analysis of 186 patients.
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) with pulmonary involvement is a rare, indolent lymphoma with no standard treatment approaches. To clarify patient characteristics, treatment, and prognosis of pulmonary MALT lymphoma in the modern era, a multi-institutional observational study of patients diagnosed between 2013 and 2022 was conducted. A modified Ann Arbor system was used for the analysis. Among 186 eligible patients, 131 (70%) had stage IE/IIE disease, whereas 55 (30%) had stage IV disease. No patient had stage III disease. With a median follow-up of 57 months, the 4-year overall survival (OS) rates for the stage IE, IIE, and IV groups were 96%, 92%, and 90%, respectively. The stage IIE and IV groups had similar progression-free survival (PFS) that was significantly worse than that of the stage IE group (p < .001). In stage IE/IIE patients, no differences were found in OS (p = .89) or PFS (p = .90) among the first-line treatment groups. In stage IV patients, the stomach was the most common synchronous extranodal site of involvement (36%). There were no differences in OS among the first-line treatment groups (p = .64). The OS of patients with MALT lymphoma with pulmonary involvement was favorable regardless of first-line treatment modality, including watchful waiting. The short PFS in the stage IIE and IV groups indicates that these groups are candidates for therapeutic development.
2026-03-27 | High Soluble Tumor Necrosis Factor Receptor 2 in Serum Is Associated With Inferior Overall Survival Across Major Lymphoma Subtypes.
Soluble tumor necrosis factor receptor 2 (sTNFR2) is a member of the TNF superfamily whose normal bodily distribution is largely limited to low level expression on lymphoid cells. It has emerged as an important inducible receptor that activates a signaling pathway for cancer growth. We evaluated sTNFR2 as a prognostic biomarker for overall survival (OS) in newly diagnosed lymphoma using a prospective cohort study with banked pretreatment serum samples. sTNFR2 was higher in 1513 lymphoma patients compared to 499 age and sex matched controls (p < 0.0001). Using Kaplan-Meier curves and Cox proportional hazards models to estimate hazard ratios [HR] (high vs. low tertile), higher levels of sTNFR2 at diagnosis were associated with inferior OS across all seven major lymphoma subtypes: Hodgkin lymphoma (p < 0.0001; HR = 12.6), diffuse large B-cell lymphoma (p < 0.0001; HR = 2.6), follicular lymphoma (p = 0.00017; HR = 2.5), mantle cell lymphoma (p < 0.0001; HR = 4.2), small lymphocytic lymphoma (p = 0.012; HR = 2.4), marginal zone lymphoma (p = 0.0012; HR = 3.1), and T-cell lymphoma (p < 0.0001; HR = 3.1). Using CITE-seq profiling of tumor microenvironment tissue, we sought to identify cellular source(s) of circulating sTNFR2. In tumor tissue from follicular lymphoma, high TNFR2-expressing cells were found to be T-regulatory (Treg) cells, suggestive of a Treg-driven cancer. In tissue from a case of marginal zone lymphoma, high TNFR2 expression was found on CD4+ and CD8+ T cells, B cells, and monocytes but also directly on tumor cells. We conclude sTNRF2 is a strong prognostic biomarker of OS across major lymphoma subtypes and may be useful to guide therapeutic choices, including targeted therapies against immunosuppressive TNFR2-expressing Tregs.
small molecules
2026-08-02 | NLRC5-Deficient Macrophages Promote a Tumor-Permissive Phenotype via AXL- and MERTK-Mediated Efferocytosis.
The innate immune protein NLRC5 plays a key role in cancer immune surveillance. Reduced NLRC5 expression is associated with a poor prognosis for many types of cancers. Previously, we showed that mice with a myeloid-specific deletion of Nlrc5 (Nlrc5mø-KO) develop gastric lymphoid lesions to Helicobacter infection resembling early-stage marginal zone lymphoma. We hypothesized that NLRC5 deficiency may promote a tumor-permissive microenvironment mediated by tumor-associated macrophages (TAMs). Consistent with this hypothesis, splenic macrophages from Helicobacter-infected Nlrc5mø-KO mice had upregulated expression of genes encoding the TAM receptor tyrosine kinases, Axl and Mertk. The levels of AXL and MERTK gene expression and MERTK phosphorylation were increased in NLRC5-/- THP-1 macrophages when compared with WT cells. In response to Helicobacter stimulation, Nlrc5-/- macrophages had significantly elevated anti-inflammatory responses (IL-10, TGF-β, Socs1, Socs3) compared with WT cells. Importantly, Nlrc5-/-macrophages showed enhanced efferocytosis and reduced antigen presentation to CD8+ T cells. Pretreatment of macrophages with AXL and MERTK inhibitors (R428, UNC2025) resulted in reduced efferocytosis and phosphorylation of downstream signaling molecules, STAT3 and ERK1/2. We propose that defective NLRC5 signaling in macrophages leads to tumor-permissive responses, thereby promoting the development of gastric lymphoid neogenesis to Helicobacter infection.
2026-07-17 | Extranodal Marginal Zone Lymphoma of the Breast in a Patient with Chronic Hepatitis C Infection: A Case Report
Primary breast lymphomas account for less than 1% of all non-Hodgkin lymphomas and 0.04–0.5% of all malignant breast neoplasms. We report a case of breast extranodal marginal zone lymphoma (EMZL) in a 60-year-old woman with chronic hepatitis C virus (HCV) infection. After comprehensive evaluation excluded other known etiologies, chronic HCV infection emerged as the most plausible contributing factor. Epidemiologic and biological evidence supports an association between HCV and B-cell non-Hodgkin lymphomas, particularly marginal zone lymphomas. Our case adds to the limited literature suggesting that HCV should be considered as a potential etiological factor in breast EMZL. We discuss the emerging role of direct-acting antiviral (DAA) therapy in HCV-associated indolent lymphomas and its implications for management.
2026-06-02 | Obinutuzumab plus bendamustine as first-line therapy for indolent B-cell lymphomas: a prospective multicenter open-label study.
This study evaluated the efficacy and safety of obinutuzumab plus bendamustine (GB) as first-line treatment for indolent B-cell lymphomas. In this prospective, multicenter, single-arm trial (NCT06415708), adults with newly diagnosed indolent B-cell lymphomas-including follicular lymphoma (FL), marginal zone lymphoma (MZL), Waldenström macroglobulinemia (WM), hairy cell leukemia variant (HCL-v), and unclassified B-cell lymphoproliferative disorder (BCLPD-U)-received six induction cycles of GB followed by 2 years of obinutuzumab maintenance in responders (⩾ partial response). The primary endpoint was overall response rate (ORR), whereas secondary endpoints included complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Among 220 enrolled patients (149 with FL and 71 with non-FL), 210 completed ⩾ 3 treatment cycles. At a median follow-up of 13.1 months, ORRs in the different patient subgroups were 96.6% (FL), 100% (MZL, HCL-v), 92.9% (WM), and 88.9% (BCLPD-U). The median DOR was 16.7 months in the FL group and was not reached in the non-FL group. PFS and OS were not reached in any subgroup. The FL and non-FL groups had comparable ORRs (P = 0.435); however, the FL group showed a higher CRR (92.4% vs. 78.5%; P = 0.004) and shorter PFS (P = 0.020). Treatment-emergent adverse events occurred in 42 patients and were more frequent in the non-FL group than in the FL group (26.8% vs. 15.4%; P = 0.046), particularly infections (18.3% vs. 6.0%; P = 0.005). Overall, the GB regimen demonstrated high response rates and manageable safety in Chinese patients with indolent B-cell lymphoma.
2026-05-25 | Extranodal marginal zone lymphoma presenting as a paraspinal mass and pleural effusion.
MALT-lymphomas are a subtype of non-Hodgkin lymphomas that typically present in the gastro-intestinal tract (50% of cases), the salivary glands and lung. Pleural involvement, however, is exceedingly rare with only a few cases described in the literature to date. Here we present a case of pleural MALT-lymphoma in a 71-year-old woman presenting with progressive dyspnea since 5-6 months without cough or sputum. The CT scan showed paravertebral bilateral pleural thickening (right > left), with associated right sided pleural effusion. Positron emission tomography (PET) scan revealed FDG-uptake limited to the thickened areas of the pleura. Pleural fluid analysis was consistent with a pleural exudate with marked predominance of lymphocytes on flow cytometry (93% lymphocytes) with negative aerobic, anaerobic and mycobacterial cultures. A thoracoscopic biopsy of the right pleural mass revealed massive invasion of the pleura by a mucosa-associated lymphoid tissue lymphoma. The final diagnosis was a stage IV MALT-lymphoma for which systemic therapy with rituximab-bendamustine was administered. Follow-up FDG-PET-CT scan after 4 chemotherapy cycles confirmed complete radiological remission. The case is particularly remarkable because there was no known pre-existing pleural inflammation, which is typically a hallmark of MALT lymphoma in extranodal sites. Immunohistochemical characterization of pleural fluid lymphocyte subtypes might have provided a clue to the diagnosis. In pleural exudates with lymphocytic predominance this diagnostic step should not be overlooked.
2026-05-11 | Chemotherapy in a dog with neutropenia and marginal zone lymphoma.
A 12-year-old Beagle dog with generalized lymphadenopathy and persistent neutropenia was diagnosed with advanced marginal zone lymphoma based on cytology, histopathology, and polymerase chain reaction for antigen receptor rearrangement analysis. Bone marrow examination revealed hypocellularity predominantly affecting the myeloid lineage, while normal morphology and maturation were preserved across hematopoietic lineages, with no evidence of myelophthisis or fibrosis. Chemotherapy was initiated using a modified and dose-reduced multi-agent protocol, followed by L-asparaginase and nimustine; full-dose chemotherapy was also subsequently tolerated without serious adverse events. Two complete remissions were achieved during the treatment course. Normalization of the neutrophil count during tumor progression was presumed to reflect increased neutrophil demand associated with disease progression, indicating that compensatory hematopoietic capacity was preserved. This case illustrates that, in dogs with persistent neutropenia and myeloid hypoplasia, chemotherapy may be considered when bone marrow evaluation confirms preserved hematopoietic maturation and careful monitoring is performed.
cell therapies
2026-08-05 | A 13-Year Review of Non-Diffuse Large B Cell Lymphomas of the Central Nervous System at a Tertiary Hospital: A Case Series Study.
Non-diffuse large B-cell lymphomas (non-DLBCL) of the central nervous system (CNS) are rare and diagnostically challenging. This study aims to characterize the clinical, radiological, and pathological features of non-DLBCL CNS lymphomas diagnosed at a tertiary care center over 13 years, highlighting diagnostic pitfalls. A retrospective review was conducted of non-DLBCL CNS lymphoma cases diagnosed at Sunnybrook Health Sciences Centre, Toronto, from 2010 to 2022. Clinical, demographic, and radiological data were extracted from medical records. Imaging was reviewed by a neuroradiologist, and histopathological slides and molecular data were re-evaluated by a pathology team. Additional tests were performed to update classifications per the 5th edition of the WHO Classification of Haematolymphoid Tumors. Seventeen cases were identified (11 males, 6 females; age 38-76), compared to 72 DLBCL cases during the same period. Nine cases were extra-axial and eight intra-axial. Eight were primary and nine secondary CNS lymphomas. B-cell lymphomas (n = 13) included extra-nodal marginal zone lymphoma (n = 6), follicular lymphoma, mantle cell lymphoma, CLL, intravascular large B-cell lymphoma (n = 2), EBV+ LBCL, and polymorphic PTLD. T-cell lymphomas (n = 4) included PTCL, NOS (n = 2), ALK-negative ALCL, and secondary mycosis fungoides. Imaging revealed four major patterns, and symptoms were largely due to mass effect. This case series emphasizes the considerable heterogeneity of non-DLBCL CNS lymphomas and the diagnostic challenges they present. It highlights key features that can aid recognition and improve diagnostic accuracy for these rare CNS entities. Trial Registration: SUN-5771.
2026-05-27 | Integrated multi-omic profiling reveals two distinct splenic marginal zone lymphoma subgroups with prognostic relevance.
Splenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy with notable genetic, epigenetic, and clinical heterogeneity. This study utilized coding and non-coding sequencing (n=74), including whole-genome sequencing (WGS) on 24 paired tumour-normal samples, targeted sequencing (n=55) and DNA methylation in 126 cases to characterize the disease. From WGS, we identified recurrent, predominantly clonal, coding mutations in KLF2 (50%), KMT2D (25%) and NOTCH2 (25%), alongside rare mutations in FLNC (8%), novel mutations in FAM135B (17%) and non-coding mutational hotspots in BCL6, PAX5 and BACH2, linked to aberrant somatic hypermutation. At least one non-coding hotspot was detected in 69% of cases. Copy-number aberrations (CNAs) were present in 73% of cases, including del(7q) (27%), gain(3q) (17%) and trisomy 12 (13%). DNA methylation profiling revealed two epigenetic subgroups: SMZL-HR (high-risk, n=67) and SMZL-LR (low-risk, n=59). SMZL-HR was associated with adverse features such as female sex, IGHV1-2*04 usage, KLF2 mutations, del(7q), shorter telomeres, and elevated epiCMIT scores. Transcriptomic analysis highlighted enhanced cell proliferation in SMZL-HR, with enrichment of E2F and G2M checkpoint pathways and epigenetic regulation via EZH2. SMZL-HR patients had significantly shorter time to first treatment (TTFT) (HR: 1.9, p=.003) and reduced overall survival (HR: 2.5, p=.039): 85% of SMZL-HR patients required treatment and showed a higher frequency of transformation (p=.007) and mortality (p<.001). Multivariate analysis confirmed SMZL-HR as an independent predictor of shorter TTFT (HR: 2.4, p=.001). These findings demonstrate the role of DNA methylation and molecular profiling in SMZL risk stratification.
2026-05-08 | [Clinical and genetic characteristics of patients with mucosa-associated lymphoid tissue lymphoma transformed into diffuse large B-cell lymphoma].
To analyze the clinical and genetic characteristics of patients with mucosa-associated lymphoid tissue (MALT) lymphoma transformed into diffuse large B-cell lymphoma (DLBCL). A retrospective analysis was performed on patients diagnosed with MALT lymphoma at Henan Provincial People's Hospital from January 2016 to December 2025. According to whether DLBCL transformation occurred, the patients were divided into the transformed group (MALT lymphoma patients who developed DLBCL transformation) and the non-transformed group. The patients were followed up until December 30, 2025, and the clinical and genetic characteristics were compared between the two groups. A total of 175 patients were included, including 13 patients in the transformation group, 4 males and 9 females, aged (58±18) years; and 162 pattients in the non-transformed group, 73 males and 89 females, aged (57±12) years.The incidence of B symptoms in the transformed group [46.2% (6/13) vs 16.7% (27/162), P=0.018], the proportion with a MALT-international prognostic index (IPI) score≥2 point [69.2% (9/13) vs 17.3% (28/162), P<0.001], and lactate dehydrogenase (LDH) levels [227 (194, 262) vs 173 (146, 196) U/L, P<0.001] were all higher than those in the non-transformed group. The mutation rate of gene in the transformed group [84.6% (11/13) vs 45.7% (74/162), P=0.007] and the mutation rate of ≥2 genes [69.2% (9/13) vs 17.3% (28/162), P<0.001] were both higher than those in the non-transformed group. The mutation rates of the NOTCH1 gene [23.1% (3/13) vs 3.7% (6/162), P=0.021], the SOCS1 gene [15.4% (2/13) vs 0, P=0.005], and the KRAS gene [15.4% (2/13) vs 0, P=0.005] were all higher in the transformed group than those in the non-transformed group. Patients with MALT lymphoma who transformed to DLBCL are often accompanied by B symptoms, a higher MALT-IPI score, elevated LDH and multiple gene mutations, and the mutation frequencies of NOTCH1, SOCS1, and KRAS are higher.
2026-04-10 | Hematolymphoid neoplasms involving the breast: A single institution clinicopathologic study of 59 patients.
Breast hematopoietic neoplasms (BHN) are rare and may either primarily (PBHN) or secondarily (SBHN) involve breast tissue. The widespread use of needle biopsy for diagnosis of breast lesions necessitates knowledge of their presentation, radiologic aspects, histomorphology, and outcomes for seeking appropriate hematopathology consultation. Herein, we present our clinical experience as an academic institution and referral center of BHN in the past 20 years. We identified 59 patients diagnosed at the University of Chicago Medical Center between 2002-2021. Demographic, pathologic, radiologic, therapy, relapse data, and vital status were abstracted. Data were examined using univariable statistics with event-free and overall survival (EFS, OS) as primary outcomes examined with the lymphoma subgroup using Cox PH regression adjusted for age. The cases included 27 (46%) PBHN and 32 (54%) SBHN in a cohort comprising 93% females, mostly white (56%). The mean age at diagnosis was 58.8 years. Lymphomas were the most frequent BHN (86.4% of all cases). Patients with primary breast lymphomas (PBL) were significantly older than those with secondary breast lymphomas (SBL) (61.2 vs. 49.8 yrs, p<0.02). The most frequent lymphomas were extranodal marginal zone lymphoma (MZL) (32.2%) and diffuse large B-cell lymphoma/high grade B-cell lymphoma, not otherwise specified (DLBCL/HGBCL, NOS) (33.9%). Over half of MZLs and DLBCLs were primary in the breast. Within B-cell lymphomas, 20 (37%) were high grade with inferior 10-yr overall survival (OS) (age-adjusted HR 5.47, 95% CI 1.38, 21.64) compared to low-grade without any impact on event free survival (EFS). This is one of the largest cohorts so far describing BHN. DLBCL and MZL remain the most common lymphomas involving this site. Most patients were diagnosed via core needle biopsy (CNB) and did not have a prior BHN. Radiographically, the presentation may closely mimic breast carcinoma. FDG PET is a mainstay in the diagnosis and management of BHN.
2026-04-01 | Primary cutaneous marginal zone lymphoma presenting as a violaceous forearm plaque
A woman in her late 80s with a history significant for chronic obstructive pulmonary disease (COPD), type 2 diabetes mellitus, hypertension, hypercholesterolaemia, heart failure with reduced ejection fraction, atrial fibrillation on coumadin and prior stroke presented with a painless, firm,
proteins
2026-05-01 | C32-21 Unmasking the Swell: Recurrent Acquired Angioedema as a Manifestation of Marginal Zone Lymphoma
Abstract Introduction Acquired angioedema (AAE) due to C1-esterase inhibitor (C1-INH) deficiency is a rare, potentially fatal disorder caused by increased bradykinin activity leading to vascular permeability and submucosal edema. Unlike hereditary angioedema, AAE typically presents later in life, lacks a family history, and is frequently associated with underlying B-cell lymphoproliferative disorders or autoimmune diseases. Among these, splenic marginal zone lymphoma (MZL) is disproportionately represented, highlighting a paraneoplastic link between complement consumption and tumor activity. Because bradykinin-mediated angioedema does not respond to epinephrine, corticosteroids, or antihistamines, recognition and disease-specific management are crucial to avoid airway compromise. Case Description A 65-year-old woman with newly diagnosed splenic MZL presented with her third episode of sudden tongue swelling now accompanied by progressive dysarthria, drooling, and respiratory distress. In the emergency department, she was administered 1g intravenous (IV) Tranexamic acid, 20 mg IV Famotidine, 50 mg IV Diphenhydramine, and 125 mg IV Methylprednisolone without improvement. Worsening edema necessitated emergent endotracheal intubation for impending airway obstruction.In the intensive care unit, she was treated with intravenous corticosteroids, diphenhydramine, famotidine, and received two units of fresh frozen plasma. Complement studies revealed a low C1q level (<2 mg/dL), and markedly reduced C1 esterase inhibitor assay ( 7%), confirming acquired C1-INH deficiency. C4 level was also depressed, and autoimmune serologies were negative. Following stabilization, she self-extubated without rebound swelling and was discharged with hematology follow-up for ongoing lymphoma-directed therapy and referral to Allergy-Immunology. Discussion This case underscores a rare but clinically significant manifestation of AAE in the setting of splenic MZL. Adult-onset, recurrent, non-pruritic angioedema unresponsive to conventional histaminergic therapies should prompt evaluation for bradykinin-mediated etiologies. Diagnostic confirmation relies on complement testing, specifically, low C1q and C1-INH levels with normal C1-INH gene sequence, distinguishing AAE from hereditary forms. Acute management centers on airway protection and targeted therapy such as plasma-derived or recombinant C1-INH, icatibant (a bradykinin B2-receptor antagonist), or ecallantide (a kallikrein inhibitor), when available. FFP remains a pragmatic option in resource-limited settings. Long-term control depends on treating the underlying lymphoproliferative disorder, which can normalize complement levels and prevent recurrence.Heightened clinical awareness of AAE in patients with unexplained angioedema and concurrent B-cell malignancies can prevent morbidity and mortality through timely diagnosis and multidisciplinary management. This abstract is funded by: none
2025-09-17 | Antimicrobial Peptides Induce Cell Death in Marginal Zone Lymphoma Models Resistant to Targeted Therapies
Abstract Marginal zone lymphoma (MZL) is an indolent yet incurable B-cell malignancy in which targeted agents such as BTK and PI3K inhibitors frequently fail due to resistance or toxicity. Antimicrobial peptides (AMPs), evolutionarily conserved effectors of innate immunity, possess selective cytotoxicity against malignant cells by exploiting tumor-specific membrane alterations. We evaluated the antitumor activity of seven natural AMPs, including Antarctic fish-derived trematocines and chionodracine variants, and amphibian temporins, against MZL cell lines (VL51, Karpas1718) and derivatives resistant to BTK, PI3Kδ, or PI3Kα/δ inhibitors. Among them, W-trematocine and temporin L demonstrated potent dose-dependent cytotoxicity with IC 50 values of 5.7-10 μM, maintaining full activity in all resistant models. Other peptides showed moderate activity, while chionodracine-1 was inactive. Notably, W-trematocine displayed minimal toxicity toward non-malignant cells in prior studies, underscoring its selectivity. AMP-mediated killing, driven by membrane disruption and non-apoptotic death pathways, bypassed conventional resistance mechanisms, suggesting therapeutic potential in relapsed/refractory disease. These findings highlight natural AMPs as promising candidates for development in drug-resistant MZL, warranting further optimization and preclinical validation.
2025-07-14 | Effects of a Cancer-Associated Mutation and Multiple Serine Phosphorylation on Poly(ADP-Ribose) Polymerase 2.
Poly [ADP-ribose] polymerase 2 (PARP2) plays a crucial role in DNA repair. A common single-nucleotide polymorphism (SNP) in the PARP2 gene, rs3093921, has been associated with pancreatic cancer and marginal zone lymphoma (MZL). This SNP results in a missense mutation, D235G, in the PARP2 protein. PARP2 is also reported to undergo post-translational modifications (PTMs), particularly phosphorylation at serine residues 226, 232, and 353. The C-terminal region of PARP2 includes the Trp-Gly-Arg (WGR) and ADP-ribosyl transferase (ART) domains, and the helical subdomain (HD). The latter two, spanning residues 220 to 583, comprise the catalytic region of PARP2. The DNA-induced enzymatic activation of PARP2 is regulated by local destabilization of the HD domain. We used molecular dynamics (MD) simulations to investigate the impact of these three PTMs on both the wild-type (WT) and the mutant (D235G) forms of PARP2. Our simulations suggest that, while neither the cancer-associated mutation nor PTMs on their own significantly alter the overall flexibility of residues within the HD domain, they cause notably greater deviations in the backbone structure of the HD domain compared to the WT. In addition, PTMs in the context of the mutation show reduced interactions between the mutation site and other protein regions, likely due to structural stabilization induced by the PTMs. Importantly, PTMs mitigate the structural disruption caused by the mutation, helping the mutant protein retain a WT-like conformation. Additionally, the HD domain contributes to maintaining PARP2 in its inactive state through its connection with the ART domain. However, the D235G mutation weakens this connection. While PTMs alone do not have a significant impact on this connection, the simultaneous presence of both the mutation and PTMs partially alleviates the disruptive effect of the mutation and leads to partial restoration of the connection between the HD and ART domains.
2025-04-21 | Abstract 612: Antimicrobial peptides with antitumor activity against marginal zone lymphoma cell lines resistant to BTK, PI3K, and BCL2 inhibitors
Abstract Background: Antimicrobial peptides (AMPs) are a class of small proteins produced by all living organisms, from prokaryotes to humans. In higher eukaryotes, AMPs contribute to the host's innate immunity, promptly responding against any pathogen. Due to their mechanism of action, represented mainly by their ability to bind and perturb microbial membranes, AMPs are being explored as novel agents against multidrug-resistant bacteria and anti-cancer agents. Natural peptides could be used as a scaffold to design new AMPs with improved effectiveness, stability, and selectivity. Marginal zone lymphoma (MZL) is an indolent yet incurable B-cell lymphoid tumor. Here, we assessed the antitumor activity of seven AMPs in MZL models with acquired resistance to FDA-approved BTK, PI3K, and BCL2 inhibitors. Methods: Established human cell lines derived from MZL (VL51, Karpas1718) and derivatives with secondary resistance to targeted agents obtained by long drug exposure (n.=3 from VL51, n.=1 from Karpas1718 (Arribas et al, Haematologica 2022; Mol Cancer Ther 2024; ENA 2019; ENA 2020) were exposed to increasing concentrations of AMPs or DMSO, as control. Anti-proliferative activity was assessed by MTT assay after 72 hours of exposure. Results: MZL cell lines were exposed to AMPs originating from Antarctic fishes (Chionodraco hamatus, Trematomus bernacchii; trematocines, n.=2; chionodracines, n.=1) and amphibians (temporins, n.=4;). Anti-proliferative activity was observed in parental MZL with two synthetic AMPs: a Trematomus bernacchii - derived trematocine mutant (Della Pelle et al, Antibiotics 2020), with IC50 values of 7.5 μM in VL51 and 10 μM in Karpas1718 and the Rana temporaria - derived Temporin L (Simmaco et al, Eur J Biochem 1996) with IC50 of 8 μM in VL51 and 15 μM in Karpas1718. Notably, the antiproliferative activity was maintained in all the derivative MZL cell lines with resistance to BTK, PI3K, and BCL2 inhibitors. At higher concentrations, also the other trematocine (Karpas1718 models) and all the temporins (VL51 and Karpas1718 models) had anti-proliferative activity (IC50 values 25-50 μM). Conclusions: AMPs derived from Antarctic fishes and amphibians have in vitro anti-tumor activity in cell lines derived from MZL, including models with acquired resistance to BTK, PI3K, and BCL2 inhibitors. AMPs and their synthetic derivatives can provide novel anti-lymphoma agents with mechanisms of action deeply different from currently used drugs. Citation Format: Filippo Spriano, Alberto J. Arribas, Fangwen Zhang, Maria Luisa Mangoni, Francesco Buonocore, Francesco Bertoni. Antimicrobial peptides with antitumor activity against marginal zone lymphoma cell lines resistant to BTK, PI3K, and BCL2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 612.
2024-06-01 | Phase 1/2 of EO2463 immunotherapy as monotherapy and in combination with lenalidomide and/or rituximab in indolent NHL (EONHL1-20/SIDNEY).
7058 Background: Follicular and marginal zone B cell lymphoma (FL; MZL) demonstrate an indolent course with heterogeneous outcomes anda potential for spontaneous remissions indicating immune system intervention. Therapeutic immunization is therefore an attractive approach but new antigens that evoke a strong immune response are needed. EO2463 expands pre-existing memory CD8+ T cells recognizing non-self protein sequences from gut bacteria which cross-react with B cell antigens and can kill HLA-A2 restricted cells (T2) loaded with target peptides. EO2463 includes 4 HLA-A2 synthetically produced epitopes which exhibit molecular mimicry with the B cell markers CD20, CD22, CD37, and CD268 (BAFF-receptor), as well as a the CD4 helper-epitope UCP2 derived from hTERT. EO2463 is being used to drive anti-tumor activity against B cell malignancies. Methods: Patients (pts) with FL and MZL, stage 1-3A, and HLA-A2, are eligible. In the safety lead-in pts with relapsed/refractory (R/R) disease were given EO2463 SC q2 weeks (w) x 4, then q4w, for a max of 12 months; at w7 lenalidomide (20 mg/day for 21/28 days up to 12 cycles) is added (EL), and if no complete remission (CR) at w19, rituximab (375 mg/m 2 IV, q1w x 4, then q4w x 4) is also added (ER 2 ). Doses evaluated: 150 μg and 300μg/peptide. Results: 3 pts received 150 μg/peptide and 6 pts 300 μg/peptide (EO2463 1 pat, EL 2 pts, ER 2 6 pts): 2 MZL, 7 FL pts with median 2 lines (range 1-4) of prior systemic therapy. No related grade ≥3 adverse events were seen with EO2463 monotherapy. Most common related events were grade 1 to 2 local administration site reactions in 5/9 pts. Adverse events during combination treatment were as expected for R 2 . PET-CT on w6 after EO2463 monotherapy suggested clinical activity in 4/9 pts (1 PR, 1 pt size reduction 15%, 1 pt 20% reduced tracer uptake, 1 pt 5/6 target lesions reduced metabolic activity). Overall objective responses (OR) were seen in 6/9 pts (67%; 1 st OR on EO2463 1 pat, EL 4 pts, ER 2 1 pat), with CR in 5/9 (56%) pts; median time to response was 18w (range 8-43w), response ongoing in 5 pts, range 24-76w. Expansion of specific CD8+ T cells against mimic peptides and targeted B cell antigens were detected in all responding pts, incl. 2 pts with no measurable B cells at baseline (prior anti-CD20). Expansion of specific T cells was detected at w5 in 5/6 pts and was maintained as long as currently tested (up to w94, 43w after last EO2463 dose). No decline in expansions were seen after start rituximab. Conclusions: EO2463 (300 μg/peptide) monotherapy, EL, and ER 2 are well tolerated, with encouraging clinical activity with EO2463 monotherapy and with subsequent CR in 5/9 pts on combo. Rapid and durable expansion of specific CD8+ T cells was seen in all responding pts, consistent with the preclinical hypothesis. Additional cohorts investigate EO2463 alone or in combination in newly diagnosed or R/R pts. Results will be reported at the meeting. Clinical trial information: NCT04669171 .
antibodies
2026-06-29 | CEACAM1 expression by immunohistochemistry in B-cell lymphomas and plasma cell myeloma.
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with limited curative treatment options. Carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) has recently been implicated in B-cell receptor signaling in MCL. We evaluated CEACAM1 expression by immunohistochemistry across MCL and other mature B-cell neoplasms, including small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM). We retrospectively analyzed 164 lymphoma cases, 35 MM cases, and 2 plasmacytomas. CEACAM1 expression was assessed on tissue microarrays by immunohistochemistry and scored using a prespecified dichotomous cutoff. In DLBCL, CEACAM1 status was correlated with cell-of-origin classification and targeted mutational data. CEACAM1 was expressed in 27 of 30 MCL cases (90%), higher than in the other lymphoma subtypes combined (35%; P < .0001). Expression was also seen in SLL (20/30, 67%), MM (23/35, 66%), MZL (8/22, 36%), and DLBCL (19/82, 23%). In DLBCL, expression was more frequent in germinal center B-cell subtype than activated B-cell subtype cases (30% vs 13%; P = .023). Within sequenced DLBCL cases, CEACAM1 expression was associated with BCL2 and TNFRSF14 mutations. In MM, CEACAM1 expression was not significantly associated with recurrent cytogenetic abnormalities, although a nonsignificant trend toward higher expression in t(11;14) cases (75% vs 53%, Fisher exact P = .28). CEACAM1 is frequently expressed in MCL and in subsets of other mature B-cell neoplasms and MM. These findings support further investigation of CEACAM1 as a biologically relevant marker and potential therapeutic target in selected lymphoid malignancies.
2026-05-13 | Beyond Hypersplenism: Splenic Marginal Zone Lymphoma in an Older Adult with Hemoglobin E/Beta-Thalassemia.
With improvements in blood safety and availability, along with broad access to safe and effective iron chelation, outcomes for patients with thalassemia have greatly improved over recent decades. Previously a predominantly pediatric condition, thalassemia is now increasingly encountered in an aging population. We describe an adult man with HbE/β-thalassemia whose course was complicated by progressive splenomegaly and cytopenias, initially attributed to his underlying thalassemia. Further evaluation, however, revealed splenic marginal zone lymphoma. After the initiation of anti-B-cell therapy, he experienced rapid clinical improvement and was able to avoid surgical splenectomy. This case highlights how complications ascribed to thalassemia can overlap with other diagnoses that may become more prevalent with age, and demonstrates the importance of maintaining a broad differential when symptoms progress despite appropriate thalassemia-directed management.
2026-05-11 | Acquired bone marrow aplasia and long-lasting complete remission with Loncastuximab Tesirine in a patient with transformed marginal zone lymphoma: a case report.
Marginal zone lymphomas (MZL) are indolent lymphomas that may undergo transformation into aggressive lymphomas, most frequently diffuse large B-cell lymphoma (DLBCL). Loncastuximab tesirine (LONCA) is an antibody-drug conjugate used in the treatment of relapsed/refractory large B-cell lymphomas. Here we present the clinical case of a patient with nodal transformed DLBCL and concomitant bone marrow involvement by indolent lymphoma successfully treated with LONCA. However the therapy was discontinued after six cycles as the patient developed treatment-related bone marrow aplasia. This case raises concerns about prolonged hematologic toxicity of LONCA, particularly in patients with pre-existing marrow involvement while highlights the potential of this drug to induce deep and durable response, even after limited exposure.
2026-04-09 | Treatment and outcomes of pulmonary mucosa-associated lymphoid tissue lymphoma: A multicenter analysis of 186 patients.
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) with pulmonary involvement is a rare, indolent lymphoma with no standard treatment approaches. To clarify patient characteristics, treatment, and prognosis of pulmonary MALT lymphoma in the modern era, a multi-institutional observational study of patients diagnosed between 2013 and 2022 was conducted. A modified Ann Arbor system was used for the analysis. Among 186 eligible patients, 131 (70%) had stage IE/IIE disease, whereas 55 (30%) had stage IV disease. No patient had stage III disease. With a median follow-up of 57 months, the 4-year overall survival (OS) rates for the stage IE, IIE, and IV groups were 96%, 92%, and 90%, respectively. The stage IIE and IV groups had similar progression-free survival (PFS) that was significantly worse than that of the stage IE group (p < .001). In stage IE/IIE patients, no differences were found in OS (p = .89) or PFS (p = .90) among the first-line treatment groups. In stage IV patients, the stomach was the most common synchronous extranodal site of involvement (36%). There were no differences in OS among the first-line treatment groups (p = .64). The OS of patients with MALT lymphoma with pulmonary involvement was favorable regardless of first-line treatment modality, including watchful waiting. The short PFS in the stage IIE and IV groups indicates that these groups are candidates for therapeutic development.
2026-03-27 | High Soluble Tumor Necrosis Factor Receptor 2 in Serum Is Associated With Inferior Overall Survival Across Major Lymphoma Subtypes.
Soluble tumor necrosis factor receptor 2 (sTNFR2) is a member of the TNF superfamily whose normal bodily distribution is largely limited to low level expression on lymphoid cells. It has emerged as an important inducible receptor that activates a signaling pathway for cancer growth. We evaluated sTNFR2 as a prognostic biomarker for overall survival (OS) in newly diagnosed lymphoma using a prospective cohort study with banked pretreatment serum samples. sTNFR2 was higher in 1513 lymphoma patients compared to 499 age and sex matched controls (p < 0.0001). Using Kaplan-Meier curves and Cox proportional hazards models to estimate hazard ratios [HR] (high vs. low tertile), higher levels of sTNFR2 at diagnosis were associated with inferior OS across all seven major lymphoma subtypes: Hodgkin lymphoma (p < 0.0001; HR = 12.6), diffuse large B-cell lymphoma (p < 0.0001; HR = 2.6), follicular lymphoma (p = 0.00017; HR = 2.5), mantle cell lymphoma (p < 0.0001; HR = 4.2), small lymphocytic lymphoma (p = 0.012; HR = 2.4), marginal zone lymphoma (p = 0.0012; HR = 3.1), and T-cell lymphoma (p < 0.0001; HR = 3.1). Using CITE-seq profiling of tumor microenvironment tissue, we sought to identify cellular source(s) of circulating sTNFR2. In tumor tissue from follicular lymphoma, high TNFR2-expressing cells were found to be T-regulatory (Treg) cells, suggestive of a Treg-driven cancer. In tissue from a case of marginal zone lymphoma, high TNFR2 expression was found on CD4+ and CD8+ T cells, B cells, and monocytes but also directly on tumor cells. We conclude sTNRF2 is a strong prognostic biomarker of OS across major lymphoma subtypes and may be useful to guide therapeutic choices, including targeted therapies against immunosuppressive TNFR2-expressing Tregs.
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Drug Discovery Landscape
15 orphan drug designations for Marginal zone lymphoma, including 2 approved therapies.
15 orphan drug designations for Marginal zone lymphoma, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
tafasitamab-cxix | antibodies | FDA | 2024-12-03 | — | Incyte Corporation |
Gallium (68Ga) boclatixafortide | oligonucleotides | EMA | 2024-08-21 | — | Pentixapharm AG |
Zanubrutinib [Brukinsa] | small molecules | EMA | 2021-05-20 | — | Beone Medicines Ireland Limited |
Axicabtagene ciloleucel | cell therapies | EMA | 2020-06-26 | — | Kite Pharma EU B.V. |
Lutetium (177Lu) lilotomab satetraxetan | antibodies | EMA | 2020-06-04 | — | Nordic Nanovector AS |
Parsaclisib [Parsaclisib Incyte Biosciences Distribution B.V.] | small molecules | EMA | 2019-07-25 | — | Incyte Biosciences Distribution B.V. |
Copanlisib [Aliqopa] | small molecules | EMA | 2018-08-24 | — | Bayer AG |
Ibrutinib [Imbruvica] | small molecules | EMA | 2015-08-10 | — | Janssen Cilag International |
Obinutuzumab [Gazyvaro] | antibodies | EMA | 2015-06-19 | — | Roche Registration Limited |
Lenalidomide [Revlimid] | small molecules | EMA | 2015-04-24 | — | Celgene Europe B.V. |
bendamustine for 50ml admixture [Bendeka] | small molecules | FDA | 2014-07-02 | 2015-12-07 | Eagle Pharmaceuticals, Inc. |
bendamustine hydrochloride [Treanda] | small molecules | FDA | 2013-11-26 | 2008-10-31 | Cephalon, Inc. |
Idelalisib | small molecules | EMA | 2013-08-05 | — | Gilead Sciences International Limited |
Idelalisib | small molecules | EMA | 2013-08-05 | — | Gilead Sciences International Limited |
Idelalisib | small molecules | EMA | 2013-08-05 | — | Gilead Sciences International Limited |
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