RARE DISEASE
Nodal marginal zone B-cell lymphoma
Nodal marginal zone B-cell lymphoma
Nodal marginal zone B-cell lymphoma
Synonyms: NMZL
Synonyms: NMZL
Synonyms: NMZL
Drug discovery
12
drugs
With orphan designations
Overview
Nodal Marginal Zone B-cell Lymphoma (NMZL) is a rare indolent B-cell non-Hodgkin lymphoma characterized by lymph node involvement, often with bone marrow infiltration. It accounts for 1–2% of NHL cases and typically presents with painless lymphadenopathy. NMZL is managed through watchful waiting in asymptomatic cases, while advanced disease utilizes chemo-immunotherapy (e.g., rituximab + bendamustine) or radiotherapy for localized stages [1][3][7][9].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
222 drug discovery papers about Nodal marginal zone B-cell lymphoma, with 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
222 drug discovery papers about Nodal marginal zone B-cell lymphoma, with 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-02-16 | Lisocabtagene maraleucel in patients with relapsed or refractory marginal zone lymphoma (TRANSCEND FL): primary analysis results from the global, multicohort, single-arm, phase 2 study.
Effective treatments with deep and durable responses for relapsed or refractory marginal zone lymphoma (MZL) are lacking. The objective of the primary analysis from the MZL cohort of TRANSCEND FL was to evaluate the efficacy and safety of the CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel. In this phase 2, single-arm, multicohort study, patients from 30 sites in the USA, Canada, Europe, and Japan with relapsed or refractory MZL who had at least two previous lines of systemic therapy were eligible to receive lisocabtagene maraleucel (100 × 106 CAR+ T cells). Bridging therapy was allowed. The primary endpoint was overall response rate per independent review committee by CT by use of Lugano 2014 criteria (null hypothesis ≤50%). This study is registered with ClinicalTrials.gov, NCT04245839, and is ongoing. Of 77 leukapheresed patients recruited between November 11, 2020, and August 24, 2023, 67 received lisocabtagene maraleucel and 66 were efficacy evaluable. MZL subtypes included nodal (n=32 [48%]), splenic (n=18 [27%]), and extranodal-mucosa-associated lymphoid tissue (n=17 [25%]). Median (IQR) previous lines of systemic therapy was 3 (2-4). Median on-study follow-up was 24·1 months. The primary endpoint was met, with an overall response rate of 95% (n=63; 95% CI, 87·3-99·1; one-sided p<0·0001). All patients experienced a treatment-related adverse event. Grade 3 cytokine release syndrome or neurological events occurred in three (4%) patients each (no grade 4-5 events). 11 (16%) patients had grade ≥3 infections: six (9%) patients during the 90-day treatment-emergent period and seven (10%) during the post-treatment-emergent period. In patients with relapsed or refractory MZL, lisocabtagene maraleucel showed high rates of durable responses. The safety profile was manageable, with no new safety signals. These results support lisocabtagene maraleucel as a new treatment option for patients with relapsed or refractory MZL. Celgene, a Bristol-Myers Squibb Company.
2025-11-03 | Analysis of the cost-effectiveness without compromising clinical outcomes in outpatient CD19-directed CAR-T therapy in non-Hodgkin lymphoma patients at a community-based medical center
Abstract Context: Since FDA approval in 2017, CAR-T therapies have transformed treatment for hematologic malignancies; however, most CAR-T infusions occur in inpatient academic centers, limiting access for over 41% of eligible patients. Expanding delivery to community outpatient settings may improve access and reduce costs by minimizing hospital stays. Current data on outpatient administration remain scarce. Objectives: To retrospectively evaluate the feasibility and cost-effectiveness of outpatient CD19-directed CAR-T therapy for non-Hodgkin lymphoma in a community setting. While safety and efficacy are well-established, this analysis aimed to demonstrate that outpatient administration offers comparable outcomes with significant cost savings and reduced financial burden. Secondary objectives included assessment of toxicity, response, and survival in patients receiving axicabtagene ciloleucel (axi-cel), brexucabtagene autoleucel (brexu-cel), lisocabtagene maraleucel (liso-cel), or tisagenlecleucel (tisa-cel). Design: Retrospective cohort study of outpatient CAR-T therapy between 2019-2024. Patients were monitored for hospitalization, toxicity, and treatment outcomes. Observers were not blinded. Setting: Oncology Hematology Care, a community-based, independent practice in Cincinnati, Ohio. Patients: 54 patients: 8 follicular, 40 diffuse large B-cell, 5 mantle cell, and 1 nodal marginal zone lymphoma. CAR-T products included axi-cel (n=23), brexu-cel (n=5), liso-cel (n=10), and tisa-cel (n=16). One patients received prophylactic dexamethasone in 2024. Median age was 67 (range 33–86); 34 male, 20 female. At treatment, 48.1% had stage III and 51.9% stage IV disease. Interventions: All patients received lymphodepletion followed by CAR-T cell infusion on day 0, with daily outpatient monitoring for 28 days. In 2024, one patient received prophylactic dexamethasone prior to infusion. Chart review was captured demographics, baseline characteristics, incidence and severity of toxicity, number of days hospitalized, treatment response, and survival outcomes. Main outcomes measures: Primary endpoints were the rate of hospitalization within 30 days following CAR-T administration and the associated length of stay. Secondary endpoints included the incidences of CRS and ICANS, as well as key efficacy measures such as objective response rate (ORR), progression-free survival (PFS), overall survival (OS). Results: Median hospital stay was 6 days compared to 15 days in ZUMA-1. CRS occurred in 57.5% (0 grade 3 or 4); ICANS in 34.0% (2 grade 3, 4 grade 4). No treatment-related deaths. ORR was 77.78%. Median PFS: 10.6 months; OS: 16.5 months. Conclusions: Based on CMS data and the ZUMA-1 trial, the median inpatient stay for CAR-T therapy is approximately 15 days, with Medicare reimbursing an average of $498,700 per admission. This includes the high cost of the CAR-T product and the intensive inpatient care needed to manage toxicities like CRS and ICANS. In contrast, a typical 7-day inpatient hospital stay costs Medicare only $13,000 to $18,000. Over the past five years, our center has demonstrated a cost savings of around $78,000 to $108,000 per patient with just a 6-day inpatient stay without compromising safety or efficacy. In fact, CAR-T stays are 2.5 times longer and are nearly 30 to 40 times more expensive. Outpatient CAR-T administration has therefore emerged as a viable, cost-effective alternative that maintains clinical outcomes while significantly reducing financial burden for patients and the healthcare system. These promising results underscore the need for larger prospective studies to confirm long-term benefits.
2025-03-30 | [Update on marginal zone lymphoma classification, diagnosis and treatment in 2024].
Marginal zone lymphoma (MZL) is the third most frequent lymphoma in Western countries with an increasing incidence with age. There are different histologic subtypes: Splenic MZL (SMZL), Nodal MZL (NZML), Extranodal MZL (EMZL) or MALT lymphoma and more recently, a novel entity called splenic diffuse red pulp small B-cell lymphoma. The accurate diagnosis relies on morphologic, phenotypic, cytogenetic and molecular features in order to rule out other indolent non-Hodgkin lymphomas. First line treatment depends on MZL subtypes: depending on localized or disseminated disease, MALT lymphoma are managed with radiotherapy on immunochemotherapy. SMZL, when requiring therapy, are treated with splenectomy ore more frequently monotherapy Rituximab or immunochemotherapy depending on age, comorbidities and tumor burden. Management of NMZL is often similar to Follicular lymphoma treatment. Treatment of refractory or relapsed MZL takes into account the time between the diagnosis and the progression, the nature and outcomes of previous therapies and the general condition of the patient. Conventional treatments may be a suitable option but novel therapies are more frequently used. In this review, we focus on the role of Bruton Tyrosine Kinases (where only Zanubrutinib has marketing authorization in France), PI3Kinases, Syk and BCL-2 inhibitors as well as on the results of immunomodulatory drugs and more recently the use of bispecific antibodies and T-cell chimeric antigen receptor (CAR-T cell).
2025-03-09 | SOHO State of the Art Updates and Next Questions: Treatment Options for Marginal Zone Lymphoma.
Current classifications identify 3 primary types of marginal zone lymphoma (MZL): extra nodal, splenic, and nodal MZL. MZLs typically have excellent long-term outcomes and often do not require immediate treatment. For asymptomatic patients, active surveillance (watch-and-wait) is the standard approach. However, exceptions exist. Asymptomatic patients with Helicobacter pylori-positive gastric MZL should receive antibiotic eradication therapy upon diagnosis. Similarly, asymptomatic patients infected with hepatitis C virus (HCV) should receive antiviral therapy. Surgical resection is generally not indicated. Involved-site radiotherapy (ISRT) is recommended for localized disease (20-24Gy, depending on the anatomical site). While higher doses are often needed for curative intent, very low-dose ISRT (2×2 Gy) can achieve long-term control and provide effective palliation with minimal toxicity when a definitive cure is not the goal. Symptomatic patients with advanced-stage disease may benefit from systemic rituximab-based treatment. Rituximab monotherapy is suitable for patients who cannot tolerate chemotherapy or prioritize a low-toxicity initial approach. The combination of rituximab with bendamustine or chlorambucil can result in longer response duration and progression-free survival, but not in improved overall survival, and may be preferred for severely symptomatic patients with advanced disease. More intensive doxorubicin-containing regimens, which are more toxic, should be reserved for patients with histological transformation, aggressive presentations, or bulky masses. Although data from clinical trials are limited, several new therapies have shown encouraging results, including bispecific antibodies, chimeric antigen receptor (CAR)-T cell therapy, and small molecules. Treatment choices depend on the MZL subtype, stage, age, comorbidities, and therapeutic goals.
2024-08-21 | A Rare Case of Refractory Nodal Marginal Zone Lymphoma in a Child, Successfully Cured by Allogeneic Stem Cell Transplant: A Case Report.
Nodal marginal zone lymphoma (NMZL) is a rare form of non-Hodgkin lymphoma (NHL), accounting for around 2% of all NHL in pediatrics and adults. It is considered the least common subtype of marginal zone lymphoma, which is rarely seen in pediatrics and is usually viewed as a mild disease. In adults, its presentation varies from mild to aggressive disease with multiple lymph node enlargement and systemic symptoms. Here, we report an interesting case of a 31-month-old boy who developed refractory EBV-positive NMZL with extensive disease. The tumor did not respond well to conventional chemotherapy and Rituximab. Therefore, we manage the disease with second-line chemotherapy, including bortezomib, followed by an allogeneic hematopoietic stem cell transplant (HSCT) with an excellent outcome. Very few cases have been reported for aggressive NMZL children. The tumor was refractory to first line chemotherapy. However, the successful outcome was achieved by allogeneic stem cell transplant with myeloablative conditioning chemotherapy. The significance of this particular case is that this is the first reported case from pediatrics for refractory NMZL, which responded well to allogeneic stem cell transplant.
small molecules
2026-09-03 | BRAF V600E-mutated marginal zone lymphoma may exhibit features that partially overlap with hairy cell leukemia.
To establish the occurrence of BRAF mutation in marginal zone lymphomas (MZLs) and study its impact on clinical presentation, pathologic features, and disease classification. Conventional histology, immunohistochemistry, flow cytometry, and molecular methods were used. We identified 2 BRAF‑mutated MZL cases: a nodal MZL (NMZL) with BRAF V600E and partial morphologic/immunophenotypic overlap with hairy cell leukemia (HCL) and an extranodal MZL with a non-V600E BRAF mutation co‑occurring with TET2, KRAS, and TP53 variants. The NMZL case showed strong CD25 and CD123 expression and patchy cyclin D1 expression; together with the presence of a BRAF V600E mutation, these features overlapped with HCL. However, the absence of annexin A1 and CD103 expression, along with the remaining morphologic features in the lymph node, supported accurate classification as NMZL. These 2 cases expand the mutational spectrum of MZL and illustrate important diagnostic pitfalls. These observations underscore that BRAF V600E, while highly specific and clinically useful for HCL in the context of a B‑cell lymphoproliferative process involving blood and marrow, is not entirely pathognomonic and must be interpreted alongside morphology and a full immunophenotypic panel. Integrating BRAF testing into the workup of challenging small B‑cell lymphomas may refine diagnosis and reveal rare, potentially targetable MAPK pathway lesions.
2026-09-01 | Trends in Survival of Marginal Zone Lymphoma by Treatment Era in the United States
ABSTRACT Marginal zone lymphoma (MZL) comprises three biologically and clinically distinct subtypes. Prior population-based studies have demonstrated improving survival trends for extranodal (EMZL) and nodal (NMZL) subtypes, but not for splenic MZL (SMZL); however, these analyses largely predate the use of novel targeted therapies. Using the SEER-17 database, we identified 40,438 adults diagnosed with MZL between 2000 and 2023. Patients were stratified by diagnosis era: 2000–2008 (rituximab era), 2009–2016 (bendamustine era), and 2017–2023 (novel therapies era). Three-year age-standardized relative survival (RS) was estimated using the Pohar-Perme method. Cumulative incidence of MZL-specific death and death from other causes were estimated using Gray's method, and adjusted subdistribution hazard ratios (SHR) were obtained from Fine-Gray models. Three-year RS improved across eras for all subtypes: EMZL (91.9% to 93.8% to 94.9%), NMZL (85.4% to 89.1% to 90.7%), and SMZL (87.1% to 89.9% to 90.5%). The 5-year cumulative incidence of MZL-specific death for the overall cohort decreased from 12.1% (2000–2008) to 9.2% (2009–2016) and 8.4% (2017–2023, P <0.001), while death from other causes remained stable across eras (P=0.308). In adjusted models, patients diagnosed in 2017–2023 had approximately half the risk of MZL-specific death compared to 2000–2008 (SHR=0.52, 95%CI=0.48–0.57), with consistent improvements across all subtypes (interaction P=0.319). MZL-specific survival has improved steadily across all three subtypes from 2000 to 2023, including SMZL where prior analyses had shown no improvement. The gains were not attributable to a single therapeutic introduction, suggesting a cumulative benefit of evolving management strategies.
2025-11-03 | Genetic analysis and clinical correlations in marginal zone lymphoma
Abstract Background: Marginal zone lymphoma (MZL) is a heterogeneous group of indolent B-cell malignancies with distinct molecular landscapes across its subtypes (extranodal/MALT, splenic, nodal, and disseminate). Genetic characteristics of MZL and its clinical relevance were not well defined. This study aims to explore subtype-specific genetic signatures and their clinical correlations in a retro-prospective MZL cohort Methods: We retrospectively analyzed MZL patients who underwent targeted Next-Generation Sequencing(NGS) panel for lymphoproliferative disorders at our institution and examining their mutational profiles and correlations with clinical characteristics and outcomes. Results:From December 2017 and August 2024, 136 MZL patients with NGS testing results underwent systemic treatment in our center. The median age was 63 years (range 30–92) and the male-to-female ratio was 1.1. This cohort comprised 52(38.2%) MALT/EMZL, 7(5.2%) NMZL, 65 (47.8%)SMZL and 12(8.8%) dissMZL patients, respectively. The most frequently detected mutations were MYD88L265P(13.2%),TP53 (12.5%), CXCR4 (6.6%), DNMT3A (6.6%), EP300 (6.6%), TET2 (5.9%),TNFAIP3 (5.1%)，in descending order of frequency. No associations were found between mutations and clinical features such as Ann Arbor stage or MZL-IPI. However, patients with large B cell transformation showed higher frequencies of EP300 (22.2% vs. 4.3%, p=0.019) and EZH2 (11.1% vs. 0.1%, p=0.017) mutations. TNFAIP3 mutations varied significantly across subtypes: 0% (MALT/EMZL), 14.3% (NMZL), 9.2% (SMZL), and 0% (dissMZL) (p=0.045). With median follow-up of 65.3months(range 2.2-262), the 5-year PFS and OS rates were 46.1% (95% CI 36.8–57.5) and 85.2% (78.5–92.4), respectively. Progression of disease within 24 months was observed in 27.4% of patients. TP53 mutations adversely impacted OS (HR 2.85, 95% CI 1.17–6.95; p=0.014) but not PFS. No other mutations predicted survival. Conclusion: This study delineates the distinct mutational landscape of MZL, revealing subtype-specific patterns (TNFAIP3 variation) and transformation-associated alterations (EP300/EZH2). The adverse impact of TP53 mutations on OS underscores its prognostic value, while the 27.4% POD24 rate highlights unmet needs in high-risk subsets. These findings advocate for integrating molecular profiling (particularly TP53, EP300, and TNFAIP3) with clinical indices like MZL-IPI to refine risk stratification and guide targeted therapy development in MZL.
2025-04-22 | Impact of Age on Biology, Presentation and Outcomes in Marginal Zone Lymphoma: Results From a Multicenter Cohort Study.
Given the paucity of age-specific data about biology, presentation, and treatment outcomes in adults with MZL, we sought to evaluate differences between younger (≤ 70 years) and older (> 70 years) patients with MZL in a large retrospective cohort treated in the contemporary era (2010 onwards). The primary objective was progression-free survival (PFS), while secondary objectives included the evaluation of overall survival (OS) and the cumulative incidence of transformation between the 2 groups. A total of 598 patients were included in the analysis and among these 32% were > 70 years of age. There were no age-based differences in the prevalence of NMZL, SMZL, and EMZL. Older patients had a higher incidence of adverse prognostic features at diagnosis such as worse performance status, advanced stage disease, and bone marrow involvement, yet were more likely to be treated with single-agent rituximab than chemoimmunotherapy. Age > 70 years was associated with inferior PFS and OS after controlling for clinically relevant risk factors and accounting for differences in first-line treatment. Receipt of rituximab monotherapy was associated with significantly inferior PFS overall, however, the type of first-line therapy did not impact OS in any group. Our data suggests that despite the development of new drugs for MZL, age remains an independent predictor of inferior outcomes. Investigation of targeted therapy combinations in the first-line setting may yield the required balance of efficacy and toxicity in older adults with MZL.
2024-09-25 | Transformation in marginal zone lymphoma: results from a prospective cohort and a meta-analysis of the literature.
Marginal zone lymphoma (MZL) includes extranodal MZL (EMZL), splenic MZL (SMZL), and nodal MZL (NMZL) subtypes. Histologic transformation (HT) to large B-cell lymphomas is well documented but with a large variability in published cumulative incidence rates. We report results from the Molecular Epidemiology Resource (MER) cohort on the cumulative incidence of HT (with death as competing risk) and the associated risk factors and outcomes. We also conducted a meta-analysis of available studies on the cumulative incidence of HT. From 2002 to 2015, 529 patients with MZL were enrolled in the MER study (69% EMZL, 16% SMZL, and 15% NMZL). The 10-year overall survival (OS) from diagnosis was 66%. HT occurred in 21 patients with a 5-year and 10-year cumulative incidence of 2.7% (95% confidence interval [CI], 0.02-0.05) and 3.6% (95% CI, 0.02-0.06), respectively. HT was associated with an increased risk for death (subdistribution hazard ratio [HR], 3.95; 95% CI, 2.06-7.55). Predictors of HT were ≥2 extranodal sites and mucosa-associated lymphoid tissue International Prognostic Index score ≥2. The OS was 79% at 5 years and 55% at 10 years after HT. In the meta-analysis of 12 studies (6161 patients), the 5- and 10-year cumulative incidence of HT across all subtypes were 5% (95% CI, 0.05-0.06) and 8% (95% CI, 0.07-0.09), respectively. These rates were lower in EMZL (3% and 5%) than in SMZL (7% and 13%) and NMZL (9% and 13%). Although HT is relatively uncommon in the first decade after MZL diagnosis, it is associated with an inferior outcome and needs new approaches for prevention and management.
antibodies
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.
2026-01-06 | Clonal Hematopoiesis and Lymphoma-Associated Mutations in Hematopoietic Progenitors in B-Cell Non-Hodgkin Lymphoma.
The contribution of clonal hematopoiesis (CH) and disease-initiating precursors in B-cell non-Hodgkin lymphomas (B-NHLs) remains underexplored. Such precursors may drive clonal evolution, contributing to disease progression and relapse. Here, we systematically profiled genetic precursor lesions in 43 B-NHL patients using complementary whole exome, targeted, and single-cell sequencing approaches. CH-associated mutations with a variant allele frequency of ≥1% were detected in the peripheral blood of 55% of patients, with significantly higher frequencies in indolent compared to aggressive B-NHL (p=0.03). Quantification of allele burden in flow-sorted cell populations revealed a B-cell-skewed expansion of CH clones - contrasting the myeloid differentiation bias reported in individuals without hematologic malignancies. Gene-specific expansion patterns were evident among the most frequent CH lesions, with DNMT3A-mutant clones exhibiting impaired hematopoietic differentiation and TET2-mutant clones showing multi-lineage propagation. Notably, identical CH clones were detected in 41% of corresponding lymphomas, displaying distinct clonal dynamics: tumor-promoting CH (expansion in B-NHL; 10/16 clones; mainly TP53) and tumor-infiltrating CH (no expansion; mainly DNMT3A). Moreover, we identified lymphoma-associated mutations in flow-sorted hematopoietic progenitors from patients with indolent but not aggressive B-NHL and observed a stepwise accumulation of mutations along the lymphoid differentiation path. Single-cell genotyping confirmed the presence of mutated progenitors in 3 follicular, 2 mantle cell and 2 marginal zone lymphoma patients, providing direct evidence of a pre-neoplastic state in disease pathogenesis. Our findings offer novel insight into the cellular origin of nodal B-NHLs and highlight a previously underappreciated role for early clonal events involving the stem/progenitor cell compartment.
2025-11-03 | A phase II investigator-initiated frontline trial of evorpacept (ALX148), lenalidomide and rituximab for high tumor burden indolent b-cell non-Hodgkin lymphoma
Abstract Introduction . We have recently completed a phase I trial of evorpacept (formerly known as ALX148), a novel high-affinity signal regulatory protein (SIRP)a fusion protein that blocks cluster of differentiation (CD)47, in combination with lenalidomide and rituximab (R2) in patients with relapsed refractory indolent B-cell non-Hodgkin lymphoma (iNHL). The combination was safe, no dose limiting toxicity was observed at a dose of 60 mg/Kg on day (D) 1 of a 28-day cycle, and more than 80% of patients experienced a complete response (CR). We present here a phase 2 study investigating the efficacy of this regimen in patients with previously untreated and high tumor burden iNHL. Methods. This single arm phase II study (NCT05025800) was conducted between January and November 2025 (data cut-off 07/2025). Adult patients with previously untreated and advanced stage iNHL, who met indication for treatment according to The Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria were included. Evorpacept was administered intravenously (IV), in a 28-day cycle, for 6 cycles, at the recommended phase 2 dose of 60 mg/Kg on D1; rituximab IV was given weekly during cycle 1, and on D1 during cycles 2-6; lenalidomide was given orally on D1-21 during cycles 1-6. Toxicity was evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 5. The primary endpoint was best CR rate per Lugano 2014 criteria. Results. Twenty-four patients were included in the study, and all were evaluable for safety and efficacy. Median age was 64 (33-76) and 13 (54%) were male; 14 (58%) had follicular lymphoma, including 5 patients with grade 3A, and 10 (42%) had marginal zone lymphoma (MZL), including 4 with extra-nodal, 4 with nodal, and 2 with splenic subtype; median largest lymph node size was 3.6 cm (range, 1.5-7.5 cm), median maximum standardized uptake volume was 7.1 (range, 3-32), and all patients had intermediate-high Follicular Lymphoma International Prognostic Index (FLIPI). Median number of cycles was 6 (range, 3-6), and all patients had completed treatment at time of data cut-off. The most common (> 1 patient) grade 3-4 adverse events included: neutropenia (29%), all resolved with growth factor, infections (12.5%), alanine transferase (ALT) increase (12.5%), aspartate transferase (AST) increase (12.5%), and infusion related reaction (8%). Ten (42%) patients required a dose reduction in lenalidomide, mainly due to infections, but none in evorpacept; 2 (8%) patients discontinued lenalidomide and 1 (4%) evorpacept, due to AST/ALT elevation. Twenty-two (92%) patients achieved CR, 2 (8%) partial response, and overall response rate was 100%. After a median follow-up of 10 months (95% confidence interval, 9-12 months), 2 patients have progressed (1 with likely baseline transformed MZL), with a 1-year progression-free survival rate of 87%. At most recent follow-up no patients have died, and 1-year overall survival rate was 100%. Conclusions. The addition of evorpacept to R2 is a safe and effective frontline non-chemotherapy regimen for iNHL patients, resulting in high CR rates. While longer follow-up matures, serial blood samples are being evaluated for circulating tumor DNA by phased variant enrichment and detection sequencing (PhasED-seq) to determine the minimal residual disease eradication rate with this novel regimen.
2025-09-30 | The biology of marginal zone lymphoma subtypes: challenge and relevance of classification.
Marginal zone lymphomas (MZLs) are a heterogeneous group of low-grade B-cell neoplasms classified into different entities by the current lymphoma classifications. They share some features, but differ significantly in clinical presentation, associated inflammatory conditions, anatomic sites of involvement, and molecular alterations. Etiopathogenesis is strongly linked to chronic antigenic stimulation and specific infections or autoimmune disorders for extranodal disease. Genetic hallmarks include constitutive NF-κB activation and common trisomies 3 and 18, alongside subtype-specific lesions such as translocations in extranodal MZL, recurrent KLF2/NOTCH2 mutations in both nodal and splenic MZL, and deletions involving chromosome 7q, predominantly observed in splenic MZL. Diagnosis can be challenging due to overlapping features with other lymphomas such as follicular and lymphoplasmacytic lymphomas; integrating morphology, immunophenotype, and molecular data is essential. Transformation to aggressive diffuse large B-cell lymphoma occurs in 3% to 15% of cases and is associated with the accumulation of genetic lesions, particularly in cell cycle, NF-κB, and epigenetic regulators, with subtype-specific drivers including TNFAIP3, TP53, and CDKN2A/B alterations. The tumor microenvironment plays a critical but understudied role, influenced by chronic antigen stimulation and involving complex interactions with immune cells that can promote immune suppression and influence therapeutic response. Understanding the heterogeneity of MZLs across their classification, genetic landscapes, and interaction with the microenvironment is crucial for accurate diagnosis, prognosis, and the development of effective targeted therapies.
2025-09-23 | A multi-omics analysis of transformed nodal marginal zone lymphoma
Background The mechanisms underlying transformation of nodal marginal zone lymphoma (NMZL) into diffuse large B-cell lymphoma (DLBCL) remain unclear. Patients and methods We applied a multi-omics approach to analyze genomic and transcriptomic changes in 17 NMZL and 15 transformed NMZL (tNMZL), using whole genome sequencing, targeted sequencing, and gene expression profiling. Results We included 15 nodal DLBCL cases as controls. The median fraction of genome altered was significantly higher in tNMZL compared with NMZL [0.23 (range 0.14-0.67), versus 0.11 (range 3.1 × 10 −4 -0.34), P < 0.01]. The median number of mutations was not different, with 3 (range 0-10) in NMZL, compared with 6.5 (range 2-16) ( P = 0.10) in tNMZL. In contrast, the median number of pathogenic mutations in nodal DLBCL (8.5, range 5-17) was significantly higher compared with NMZL ( P < 0.01) and tNMZL ( P = 0.04). The most frequently mutated genes in tNMZL included B2M (30%) and MEF2B (30%). Protein expression of BCL6 , a downstream target of MEF2B , was observed more frequently in tNMZL (73%), compared with NMZL (6%) ( P < 0.01). Overall, six genes were differentially expressed between NMZL and tNMZL. Conclusion In conclusion, our study indicates that transformation of NMZL is characterized by a slight increase in genomic complexity and a gain of BCL6 expression.
cell therapies
2026-02-16 | Lisocabtagene maraleucel in patients with relapsed or refractory marginal zone lymphoma (TRANSCEND FL): primary analysis results from the global, multicohort, single-arm, phase 2 study.
Effective treatments with deep and durable responses for relapsed or refractory marginal zone lymphoma (MZL) are lacking. The objective of the primary analysis from the MZL cohort of TRANSCEND FL was to evaluate the efficacy and safety of the CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel. In this phase 2, single-arm, multicohort study, patients from 30 sites in the USA, Canada, Europe, and Japan with relapsed or refractory MZL who had at least two previous lines of systemic therapy were eligible to receive lisocabtagene maraleucel (100 × 106 CAR+ T cells). Bridging therapy was allowed. The primary endpoint was overall response rate per independent review committee by CT by use of Lugano 2014 criteria (null hypothesis ≤50%). This study is registered with ClinicalTrials.gov, NCT04245839, and is ongoing. Of 77 leukapheresed patients recruited between November 11, 2020, and August 24, 2023, 67 received lisocabtagene maraleucel and 66 were efficacy evaluable. MZL subtypes included nodal (n=32 [48%]), splenic (n=18 [27%]), and extranodal-mucosa-associated lymphoid tissue (n=17 [25%]). Median (IQR) previous lines of systemic therapy was 3 (2-4). Median on-study follow-up was 24·1 months. The primary endpoint was met, with an overall response rate of 95% (n=63; 95% CI, 87·3-99·1; one-sided p<0·0001). All patients experienced a treatment-related adverse event. Grade 3 cytokine release syndrome or neurological events occurred in three (4%) patients each (no grade 4-5 events). 11 (16%) patients had grade ≥3 infections: six (9%) patients during the 90-day treatment-emergent period and seven (10%) during the post-treatment-emergent period. In patients with relapsed or refractory MZL, lisocabtagene maraleucel showed high rates of durable responses. The safety profile was manageable, with no new safety signals. These results support lisocabtagene maraleucel as a new treatment option for patients with relapsed or refractory MZL. Celgene, a Bristol-Myers Squibb Company.
2025-11-03 | Analysis of the cost-effectiveness without compromising clinical outcomes in outpatient CD19-directed CAR-T therapy in non-Hodgkin lymphoma patients at a community-based medical center
Abstract Context: Since FDA approval in 2017, CAR-T therapies have transformed treatment for hematologic malignancies; however, most CAR-T infusions occur in inpatient academic centers, limiting access for over 41% of eligible patients. Expanding delivery to community outpatient settings may improve access and reduce costs by minimizing hospital stays. Current data on outpatient administration remain scarce. Objectives: To retrospectively evaluate the feasibility and cost-effectiveness of outpatient CD19-directed CAR-T therapy for non-Hodgkin lymphoma in a community setting. While safety and efficacy are well-established, this analysis aimed to demonstrate that outpatient administration offers comparable outcomes with significant cost savings and reduced financial burden. Secondary objectives included assessment of toxicity, response, and survival in patients receiving axicabtagene ciloleucel (axi-cel), brexucabtagene autoleucel (brexu-cel), lisocabtagene maraleucel (liso-cel), or tisagenlecleucel (tisa-cel). Design: Retrospective cohort study of outpatient CAR-T therapy between 2019-2024. Patients were monitored for hospitalization, toxicity, and treatment outcomes. Observers were not blinded. Setting: Oncology Hematology Care, a community-based, independent practice in Cincinnati, Ohio. Patients: 54 patients: 8 follicular, 40 diffuse large B-cell, 5 mantle cell, and 1 nodal marginal zone lymphoma. CAR-T products included axi-cel (n=23), brexu-cel (n=5), liso-cel (n=10), and tisa-cel (n=16). One patients received prophylactic dexamethasone in 2024. Median age was 67 (range 33–86); 34 male, 20 female. At treatment, 48.1% had stage III and 51.9% stage IV disease. Interventions: All patients received lymphodepletion followed by CAR-T cell infusion on day 0, with daily outpatient monitoring for 28 days. In 2024, one patient received prophylactic dexamethasone prior to infusion. Chart review was captured demographics, baseline characteristics, incidence and severity of toxicity, number of days hospitalized, treatment response, and survival outcomes. Main outcomes measures: Primary endpoints were the rate of hospitalization within 30 days following CAR-T administration and the associated length of stay. Secondary endpoints included the incidences of CRS and ICANS, as well as key efficacy measures such as objective response rate (ORR), progression-free survival (PFS), overall survival (OS). Results: Median hospital stay was 6 days compared to 15 days in ZUMA-1. CRS occurred in 57.5% (0 grade 3 or 4); ICANS in 34.0% (2 grade 3, 4 grade 4). No treatment-related deaths. ORR was 77.78%. Median PFS: 10.6 months; OS: 16.5 months. Conclusions: Based on CMS data and the ZUMA-1 trial, the median inpatient stay for CAR-T therapy is approximately 15 days, with Medicare reimbursing an average of $498,700 per admission. This includes the high cost of the CAR-T product and the intensive inpatient care needed to manage toxicities like CRS and ICANS. In contrast, a typical 7-day inpatient hospital stay costs Medicare only $13,000 to $18,000. Over the past five years, our center has demonstrated a cost savings of around $78,000 to $108,000 per patient with just a 6-day inpatient stay without compromising safety or efficacy. In fact, CAR-T stays are 2.5 times longer and are nearly 30 to 40 times more expensive. Outpatient CAR-T administration has therefore emerged as a viable, cost-effective alternative that maintains clinical outcomes while significantly reducing financial burden for patients and the healthcare system. These promising results underscore the need for larger prospective studies to confirm long-term benefits.
2025-03-30 | [Update on marginal zone lymphoma classification, diagnosis and treatment in 2024].
Marginal zone lymphoma (MZL) is the third most frequent lymphoma in Western countries with an increasing incidence with age. There are different histologic subtypes: Splenic MZL (SMZL), Nodal MZL (NZML), Extranodal MZL (EMZL) or MALT lymphoma and more recently, a novel entity called splenic diffuse red pulp small B-cell lymphoma. The accurate diagnosis relies on morphologic, phenotypic, cytogenetic and molecular features in order to rule out other indolent non-Hodgkin lymphomas. First line treatment depends on MZL subtypes: depending on localized or disseminated disease, MALT lymphoma are managed with radiotherapy on immunochemotherapy. SMZL, when requiring therapy, are treated with splenectomy ore more frequently monotherapy Rituximab or immunochemotherapy depending on age, comorbidities and tumor burden. Management of NMZL is often similar to Follicular lymphoma treatment. Treatment of refractory or relapsed MZL takes into account the time between the diagnosis and the progression, the nature and outcomes of previous therapies and the general condition of the patient. Conventional treatments may be a suitable option but novel therapies are more frequently used. In this review, we focus on the role of Bruton Tyrosine Kinases (where only Zanubrutinib has marketing authorization in France), PI3Kinases, Syk and BCL-2 inhibitors as well as on the results of immunomodulatory drugs and more recently the use of bispecific antibodies and T-cell chimeric antigen receptor (CAR-T cell).
2025-03-09 | SOHO State of the Art Updates and Next Questions: Treatment Options for Marginal Zone Lymphoma.
Current classifications identify 3 primary types of marginal zone lymphoma (MZL): extra nodal, splenic, and nodal MZL. MZLs typically have excellent long-term outcomes and often do not require immediate treatment. For asymptomatic patients, active surveillance (watch-and-wait) is the standard approach. However, exceptions exist. Asymptomatic patients with Helicobacter pylori-positive gastric MZL should receive antibiotic eradication therapy upon diagnosis. Similarly, asymptomatic patients infected with hepatitis C virus (HCV) should receive antiviral therapy. Surgical resection is generally not indicated. Involved-site radiotherapy (ISRT) is recommended for localized disease (20-24Gy, depending on the anatomical site). While higher doses are often needed for curative intent, very low-dose ISRT (2×2 Gy) can achieve long-term control and provide effective palliation with minimal toxicity when a definitive cure is not the goal. Symptomatic patients with advanced-stage disease may benefit from systemic rituximab-based treatment. Rituximab monotherapy is suitable for patients who cannot tolerate chemotherapy or prioritize a low-toxicity initial approach. The combination of rituximab with bendamustine or chlorambucil can result in longer response duration and progression-free survival, but not in improved overall survival, and may be preferred for severely symptomatic patients with advanced disease. More intensive doxorubicin-containing regimens, which are more toxic, should be reserved for patients with histological transformation, aggressive presentations, or bulky masses. Although data from clinical trials are limited, several new therapies have shown encouraging results, including bispecific antibodies, chimeric antigen receptor (CAR)-T cell therapy, and small molecules. Treatment choices depend on the MZL subtype, stage, age, comorbidities, and therapeutic goals.
2024-08-21 | A Rare Case of Refractory Nodal Marginal Zone Lymphoma in a Child, Successfully Cured by Allogeneic Stem Cell Transplant: A Case Report.
Nodal marginal zone lymphoma (NMZL) is a rare form of non-Hodgkin lymphoma (NHL), accounting for around 2% of all NHL in pediatrics and adults. It is considered the least common subtype of marginal zone lymphoma, which is rarely seen in pediatrics and is usually viewed as a mild disease. In adults, its presentation varies from mild to aggressive disease with multiple lymph node enlargement and systemic symptoms. Here, we report an interesting case of a 31-month-old boy who developed refractory EBV-positive NMZL with extensive disease. The tumor did not respond well to conventional chemotherapy and Rituximab. Therefore, we manage the disease with second-line chemotherapy, including bortezomib, followed by an allogeneic hematopoietic stem cell transplant (HSCT) with an excellent outcome. Very few cases have been reported for aggressive NMZL children. The tumor was refractory to first line chemotherapy. However, the successful outcome was achieved by allogeneic stem cell transplant with myeloablative conditioning chemotherapy. The significance of this particular case is that this is the first reported case from pediatrics for refractory NMZL, which responded well to allogeneic stem cell transplant.
small molecules
2026-09-03 | BRAF V600E-mutated marginal zone lymphoma may exhibit features that partially overlap with hairy cell leukemia.
To establish the occurrence of BRAF mutation in marginal zone lymphomas (MZLs) and study its impact on clinical presentation, pathologic features, and disease classification. Conventional histology, immunohistochemistry, flow cytometry, and molecular methods were used. We identified 2 BRAF‑mutated MZL cases: a nodal MZL (NMZL) with BRAF V600E and partial morphologic/immunophenotypic overlap with hairy cell leukemia (HCL) and an extranodal MZL with a non-V600E BRAF mutation co‑occurring with TET2, KRAS, and TP53 variants. The NMZL case showed strong CD25 and CD123 expression and patchy cyclin D1 expression; together with the presence of a BRAF V600E mutation, these features overlapped with HCL. However, the absence of annexin A1 and CD103 expression, along with the remaining morphologic features in the lymph node, supported accurate classification as NMZL. These 2 cases expand the mutational spectrum of MZL and illustrate important diagnostic pitfalls. These observations underscore that BRAF V600E, while highly specific and clinically useful for HCL in the context of a B‑cell lymphoproliferative process involving blood and marrow, is not entirely pathognomonic and must be interpreted alongside morphology and a full immunophenotypic panel. Integrating BRAF testing into the workup of challenging small B‑cell lymphomas may refine diagnosis and reveal rare, potentially targetable MAPK pathway lesions.
2026-09-01 | Trends in Survival of Marginal Zone Lymphoma by Treatment Era in the United States
ABSTRACT Marginal zone lymphoma (MZL) comprises three biologically and clinically distinct subtypes. Prior population-based studies have demonstrated improving survival trends for extranodal (EMZL) and nodal (NMZL) subtypes, but not for splenic MZL (SMZL); however, these analyses largely predate the use of novel targeted therapies. Using the SEER-17 database, we identified 40,438 adults diagnosed with MZL between 2000 and 2023. Patients were stratified by diagnosis era: 2000–2008 (rituximab era), 2009–2016 (bendamustine era), and 2017–2023 (novel therapies era). Three-year age-standardized relative survival (RS) was estimated using the Pohar-Perme method. Cumulative incidence of MZL-specific death and death from other causes were estimated using Gray's method, and adjusted subdistribution hazard ratios (SHR) were obtained from Fine-Gray models. Three-year RS improved across eras for all subtypes: EMZL (91.9% to 93.8% to 94.9%), NMZL (85.4% to 89.1% to 90.7%), and SMZL (87.1% to 89.9% to 90.5%). The 5-year cumulative incidence of MZL-specific death for the overall cohort decreased from 12.1% (2000–2008) to 9.2% (2009–2016) and 8.4% (2017–2023, P <0.001), while death from other causes remained stable across eras (P=0.308). In adjusted models, patients diagnosed in 2017–2023 had approximately half the risk of MZL-specific death compared to 2000–2008 (SHR=0.52, 95%CI=0.48–0.57), with consistent improvements across all subtypes (interaction P=0.319). MZL-specific survival has improved steadily across all three subtypes from 2000 to 2023, including SMZL where prior analyses had shown no improvement. The gains were not attributable to a single therapeutic introduction, suggesting a cumulative benefit of evolving management strategies.
2025-11-03 | Genetic analysis and clinical correlations in marginal zone lymphoma
Abstract Background: Marginal zone lymphoma (MZL) is a heterogeneous group of indolent B-cell malignancies with distinct molecular landscapes across its subtypes (extranodal/MALT, splenic, nodal, and disseminate). Genetic characteristics of MZL and its clinical relevance were not well defined. This study aims to explore subtype-specific genetic signatures and their clinical correlations in a retro-prospective MZL cohort Methods: We retrospectively analyzed MZL patients who underwent targeted Next-Generation Sequencing(NGS) panel for lymphoproliferative disorders at our institution and examining their mutational profiles and correlations with clinical characteristics and outcomes. Results:From December 2017 and August 2024, 136 MZL patients with NGS testing results underwent systemic treatment in our center. The median age was 63 years (range 30–92) and the male-to-female ratio was 1.1. This cohort comprised 52(38.2%) MALT/EMZL, 7(5.2%) NMZL, 65 (47.8%)SMZL and 12(8.8%) dissMZL patients, respectively. The most frequently detected mutations were MYD88L265P(13.2%),TP53 (12.5%), CXCR4 (6.6%), DNMT3A (6.6%), EP300 (6.6%), TET2 (5.9%),TNFAIP3 (5.1%)，in descending order of frequency. No associations were found between mutations and clinical features such as Ann Arbor stage or MZL-IPI. However, patients with large B cell transformation showed higher frequencies of EP300 (22.2% vs. 4.3%, p=0.019) and EZH2 (11.1% vs. 0.1%, p=0.017) mutations. TNFAIP3 mutations varied significantly across subtypes: 0% (MALT/EMZL), 14.3% (NMZL), 9.2% (SMZL), and 0% (dissMZL) (p=0.045). With median follow-up of 65.3months(range 2.2-262), the 5-year PFS and OS rates were 46.1% (95% CI 36.8–57.5) and 85.2% (78.5–92.4), respectively. Progression of disease within 24 months was observed in 27.4% of patients. TP53 mutations adversely impacted OS (HR 2.85, 95% CI 1.17–6.95; p=0.014) but not PFS. No other mutations predicted survival. Conclusion: This study delineates the distinct mutational landscape of MZL, revealing subtype-specific patterns (TNFAIP3 variation) and transformation-associated alterations (EP300/EZH2). The adverse impact of TP53 mutations on OS underscores its prognostic value, while the 27.4% POD24 rate highlights unmet needs in high-risk subsets. These findings advocate for integrating molecular profiling (particularly TP53, EP300, and TNFAIP3) with clinical indices like MZL-IPI to refine risk stratification and guide targeted therapy development in MZL.
2025-04-22 | Impact of Age on Biology, Presentation and Outcomes in Marginal Zone Lymphoma: Results From a Multicenter Cohort Study.
Given the paucity of age-specific data about biology, presentation, and treatment outcomes in adults with MZL, we sought to evaluate differences between younger (≤ 70 years) and older (> 70 years) patients with MZL in a large retrospective cohort treated in the contemporary era (2010 onwards). The primary objective was progression-free survival (PFS), while secondary objectives included the evaluation of overall survival (OS) and the cumulative incidence of transformation between the 2 groups. A total of 598 patients were included in the analysis and among these 32% were > 70 years of age. There were no age-based differences in the prevalence of NMZL, SMZL, and EMZL. Older patients had a higher incidence of adverse prognostic features at diagnosis such as worse performance status, advanced stage disease, and bone marrow involvement, yet were more likely to be treated with single-agent rituximab than chemoimmunotherapy. Age > 70 years was associated with inferior PFS and OS after controlling for clinically relevant risk factors and accounting for differences in first-line treatment. Receipt of rituximab monotherapy was associated with significantly inferior PFS overall, however, the type of first-line therapy did not impact OS in any group. Our data suggests that despite the development of new drugs for MZL, age remains an independent predictor of inferior outcomes. Investigation of targeted therapy combinations in the first-line setting may yield the required balance of efficacy and toxicity in older adults with MZL.
2024-09-25 | Transformation in marginal zone lymphoma: results from a prospective cohort and a meta-analysis of the literature.
Marginal zone lymphoma (MZL) includes extranodal MZL (EMZL), splenic MZL (SMZL), and nodal MZL (NMZL) subtypes. Histologic transformation (HT) to large B-cell lymphomas is well documented but with a large variability in published cumulative incidence rates. We report results from the Molecular Epidemiology Resource (MER) cohort on the cumulative incidence of HT (with death as competing risk) and the associated risk factors and outcomes. We also conducted a meta-analysis of available studies on the cumulative incidence of HT. From 2002 to 2015, 529 patients with MZL were enrolled in the MER study (69% EMZL, 16% SMZL, and 15% NMZL). The 10-year overall survival (OS) from diagnosis was 66%. HT occurred in 21 patients with a 5-year and 10-year cumulative incidence of 2.7% (95% confidence interval [CI], 0.02-0.05) and 3.6% (95% CI, 0.02-0.06), respectively. HT was associated with an increased risk for death (subdistribution hazard ratio [HR], 3.95; 95% CI, 2.06-7.55). Predictors of HT were ≥2 extranodal sites and mucosa-associated lymphoid tissue International Prognostic Index score ≥2. The OS was 79% at 5 years and 55% at 10 years after HT. In the meta-analysis of 12 studies (6161 patients), the 5- and 10-year cumulative incidence of HT across all subtypes were 5% (95% CI, 0.05-0.06) and 8% (95% CI, 0.07-0.09), respectively. These rates were lower in EMZL (3% and 5%) than in SMZL (7% and 13%) and NMZL (9% and 13%). Although HT is relatively uncommon in the first decade after MZL diagnosis, it is associated with an inferior outcome and needs new approaches for prevention and management.
antibodies
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.
2026-01-06 | Clonal Hematopoiesis and Lymphoma-Associated Mutations in Hematopoietic Progenitors in B-Cell Non-Hodgkin Lymphoma.
The contribution of clonal hematopoiesis (CH) and disease-initiating precursors in B-cell non-Hodgkin lymphomas (B-NHLs) remains underexplored. Such precursors may drive clonal evolution, contributing to disease progression and relapse. Here, we systematically profiled genetic precursor lesions in 43 B-NHL patients using complementary whole exome, targeted, and single-cell sequencing approaches. CH-associated mutations with a variant allele frequency of ≥1% were detected in the peripheral blood of 55% of patients, with significantly higher frequencies in indolent compared to aggressive B-NHL (p=0.03). Quantification of allele burden in flow-sorted cell populations revealed a B-cell-skewed expansion of CH clones - contrasting the myeloid differentiation bias reported in individuals without hematologic malignancies. Gene-specific expansion patterns were evident among the most frequent CH lesions, with DNMT3A-mutant clones exhibiting impaired hematopoietic differentiation and TET2-mutant clones showing multi-lineage propagation. Notably, identical CH clones were detected in 41% of corresponding lymphomas, displaying distinct clonal dynamics: tumor-promoting CH (expansion in B-NHL; 10/16 clones; mainly TP53) and tumor-infiltrating CH (no expansion; mainly DNMT3A). Moreover, we identified lymphoma-associated mutations in flow-sorted hematopoietic progenitors from patients with indolent but not aggressive B-NHL and observed a stepwise accumulation of mutations along the lymphoid differentiation path. Single-cell genotyping confirmed the presence of mutated progenitors in 3 follicular, 2 mantle cell and 2 marginal zone lymphoma patients, providing direct evidence of a pre-neoplastic state in disease pathogenesis. Our findings offer novel insight into the cellular origin of nodal B-NHLs and highlight a previously underappreciated role for early clonal events involving the stem/progenitor cell compartment.
2025-11-03 | A phase II investigator-initiated frontline trial of evorpacept (ALX148), lenalidomide and rituximab for high tumor burden indolent b-cell non-Hodgkin lymphoma
Abstract Introduction . We have recently completed a phase I trial of evorpacept (formerly known as ALX148), a novel high-affinity signal regulatory protein (SIRP)a fusion protein that blocks cluster of differentiation (CD)47, in combination with lenalidomide and rituximab (R2) in patients with relapsed refractory indolent B-cell non-Hodgkin lymphoma (iNHL). The combination was safe, no dose limiting toxicity was observed at a dose of 60 mg/Kg on day (D) 1 of a 28-day cycle, and more than 80% of patients experienced a complete response (CR). We present here a phase 2 study investigating the efficacy of this regimen in patients with previously untreated and high tumor burden iNHL. Methods. This single arm phase II study (NCT05025800) was conducted between January and November 2025 (data cut-off 07/2025). Adult patients with previously untreated and advanced stage iNHL, who met indication for treatment according to The Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria were included. Evorpacept was administered intravenously (IV), in a 28-day cycle, for 6 cycles, at the recommended phase 2 dose of 60 mg/Kg on D1; rituximab IV was given weekly during cycle 1, and on D1 during cycles 2-6; lenalidomide was given orally on D1-21 during cycles 1-6. Toxicity was evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 5. The primary endpoint was best CR rate per Lugano 2014 criteria. Results. Twenty-four patients were included in the study, and all were evaluable for safety and efficacy. Median age was 64 (33-76) and 13 (54%) were male; 14 (58%) had follicular lymphoma, including 5 patients with grade 3A, and 10 (42%) had marginal zone lymphoma (MZL), including 4 with extra-nodal, 4 with nodal, and 2 with splenic subtype; median largest lymph node size was 3.6 cm (range, 1.5-7.5 cm), median maximum standardized uptake volume was 7.1 (range, 3-32), and all patients had intermediate-high Follicular Lymphoma International Prognostic Index (FLIPI). Median number of cycles was 6 (range, 3-6), and all patients had completed treatment at time of data cut-off. The most common (> 1 patient) grade 3-4 adverse events included: neutropenia (29%), all resolved with growth factor, infections (12.5%), alanine transferase (ALT) increase (12.5%), aspartate transferase (AST) increase (12.5%), and infusion related reaction (8%). Ten (42%) patients required a dose reduction in lenalidomide, mainly due to infections, but none in evorpacept; 2 (8%) patients discontinued lenalidomide and 1 (4%) evorpacept, due to AST/ALT elevation. Twenty-two (92%) patients achieved CR, 2 (8%) partial response, and overall response rate was 100%. After a median follow-up of 10 months (95% confidence interval, 9-12 months), 2 patients have progressed (1 with likely baseline transformed MZL), with a 1-year progression-free survival rate of 87%. At most recent follow-up no patients have died, and 1-year overall survival rate was 100%. Conclusions. The addition of evorpacept to R2 is a safe and effective frontline non-chemotherapy regimen for iNHL patients, resulting in high CR rates. While longer follow-up matures, serial blood samples are being evaluated for circulating tumor DNA by phased variant enrichment and detection sequencing (PhasED-seq) to determine the minimal residual disease eradication rate with this novel regimen.
2025-09-30 | The biology of marginal zone lymphoma subtypes: challenge and relevance of classification.
Marginal zone lymphomas (MZLs) are a heterogeneous group of low-grade B-cell neoplasms classified into different entities by the current lymphoma classifications. They share some features, but differ significantly in clinical presentation, associated inflammatory conditions, anatomic sites of involvement, and molecular alterations. Etiopathogenesis is strongly linked to chronic antigenic stimulation and specific infections or autoimmune disorders for extranodal disease. Genetic hallmarks include constitutive NF-κB activation and common trisomies 3 and 18, alongside subtype-specific lesions such as translocations in extranodal MZL, recurrent KLF2/NOTCH2 mutations in both nodal and splenic MZL, and deletions involving chromosome 7q, predominantly observed in splenic MZL. Diagnosis can be challenging due to overlapping features with other lymphomas such as follicular and lymphoplasmacytic lymphomas; integrating morphology, immunophenotype, and molecular data is essential. Transformation to aggressive diffuse large B-cell lymphoma occurs in 3% to 15% of cases and is associated with the accumulation of genetic lesions, particularly in cell cycle, NF-κB, and epigenetic regulators, with subtype-specific drivers including TNFAIP3, TP53, and CDKN2A/B alterations. The tumor microenvironment plays a critical but understudied role, influenced by chronic antigen stimulation and involving complex interactions with immune cells that can promote immune suppression and influence therapeutic response. Understanding the heterogeneity of MZLs across their classification, genetic landscapes, and interaction with the microenvironment is crucial for accurate diagnosis, prognosis, and the development of effective targeted therapies.
2025-09-23 | A multi-omics analysis of transformed nodal marginal zone lymphoma
Background The mechanisms underlying transformation of nodal marginal zone lymphoma (NMZL) into diffuse large B-cell lymphoma (DLBCL) remain unclear. Patients and methods We applied a multi-omics approach to analyze genomic and transcriptomic changes in 17 NMZL and 15 transformed NMZL (tNMZL), using whole genome sequencing, targeted sequencing, and gene expression profiling. Results We included 15 nodal DLBCL cases as controls. The median fraction of genome altered was significantly higher in tNMZL compared with NMZL [0.23 (range 0.14-0.67), versus 0.11 (range 3.1 × 10 −4 -0.34), P < 0.01]. The median number of mutations was not different, with 3 (range 0-10) in NMZL, compared with 6.5 (range 2-16) ( P = 0.10) in tNMZL. In contrast, the median number of pathogenic mutations in nodal DLBCL (8.5, range 5-17) was significantly higher compared with NMZL ( P < 0.01) and tNMZL ( P = 0.04). The most frequently mutated genes in tNMZL included B2M (30%) and MEF2B (30%). Protein expression of BCL6 , a downstream target of MEF2B , was observed more frequently in tNMZL (73%), compared with NMZL (6%) ( P < 0.01). Overall, six genes were differentially expressed between NMZL and tNMZL. Conclusion In conclusion, our study indicates that transformation of NMZL is characterized by a slight increase in genomic complexity and a gain of BCL6 expression.
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Drug Discovery Landscape
12 orphan drug designations for Nodal marginal zone B-cell lymphoma, including 5 approved therapies.
12 orphan drug designations for Nodal marginal zone B-cell lymphoma, including 5 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
odronextamab | antibodies | FDA | Regeneron Pharmaceuticals, Inc. | |
tafasitamab-cxix | antibodies | FDA | Incyte Corporation | |
lisocabtagene maraleucel [Breyanzi] | cell therapies | FDA | Approved | Juno Therapeutics, Inc., a Bristol-Myers Squibb Company |
zanubrutinib [Brukinsa] | small molecules | FDA | Approved | BeOne Medicines USA, Inc. |
axicabtagene ciloleucel | cell therapies | FDA | Kite Pharma, Inc. | |
parsaclisib | small molecules | FDA | Incyte Corporation | |
umbralisib [Ukoniq] | small molecules | FDA | Approved | TG Therapeutics, Inc. |
copanlisib | small molecules | FDA | Bayer HealthCare Pharmaceuticals, Inc. | |
lenalidomide [Revlimid] | small molecules | FDA | Approved | Celgene Corporation |
ibrutinib [Imbruvica] | small molecules | FDA | Approved | Pharmacyclics, LLC |
idelalisib | small molecules | FDA | Gilead Sciences, Inc. | |
ublituximab | antibodies | FDA | TG Therapeutics, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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