Nodal Marginal Zone Lymphoma Research Articles

Evaluation of Ki-67 expression and large cell content as prognostic markers in MZL: a multicenter cohort study

Marginal zone lymphoma (MZL) can have varied presentations and pathologic features, including high Ki-67 expression ( > 20%) as well as increased numbers of large B cells (LC). However, there are limited data available demonstrating the prognostic significance of these variables in patients with MZL. In this multi-institutional retrospective cohort study of patients with MZL treated at 10 centers, we evaluated the association between the presence of Ki-67 expression and increased LCs on survival and risk of histologic transformation (HT). A total of 785 patients were included (60% with extranodal MZL, 20% with nodal MZL, and 20% with splenic MZL). Among the 440 patients with Ki-67 staining, 22% had high Ki-67 (Ki-67 >20%). The median progression-free survival (PFS) for patients with high Ki-67 was 5.4 years compared to 7.0 years for patients with low Ki-67 (HR = 1.45, 95%CI = 1.03–2.05). Ki-67 > 20% strongly correlated with high LDH level. The risk of HT was higher in patients with increased Ki-67 than those without (5-year risk, 9.8% vs 3.87%, p = 0.01). Twelve percent of patients had LC reported on biopsy with 6% having >10% LC. The presence of LC was associated with high Ki-67 (p < 0.001), but not associated with shorter PFS or overall survival (OS). The cumulative risk for HT was higher in patients with LC compared to those without LC (5-year risk, 9.4% vs 2.9%, p = 0.04). Receipt of anthracycline-based therapy did not impact PFS or OS in either group. Ki-67 staining >20% was a prognostic factor for worse survival and strongly correlated with elevated LDH. Novel therapies should be investigated for their potential ability to overcome the high-risk features in MZL. Our data reinforce the importance of obtaining biopsies at relapse or progression, particularly in patients with baseline high Ki-67 and increased LCs, given their increased risk for HT.

Utility of MEF2B Immunohistochemistry in Distinguishing Follicular Lymphoma and Marginal Zone Lymphoma in Diagnostically Challenging Cases

Abstract Introduction/Objective Distinguishing follicular lymphoma (FL) from marginal zone lymphoma (MZL) can be challenging, as the morphology and immunophenotype can overlap particularly in CD10-negative cases or those with marginal zone differentiation (MZD). MEF2B (Myocyte enhancer binding factor B) is a transcription factor that controls BCL6 expression in germinal center (GC) B-cells. Previous studies report MEF2B to have a high sensitivity and specificity for FL compared to other GC markers. We investigated the expression of MEF2B in low grade B cell lymphomas (LGBCL) to evaluate its utility in classifying diagnostically challenging cases and FL with MZD. Methods/Case Report Our archives were searched from 2005-2023 to identify excisional biopsies of LGBCL with MZD, including (FL), splenic MZL (SMZL), MZL of mucosa-associated lymphoid tissue (MALT), nodal MZL (NMZL) and difficult-to-classify (DTC) cases with a differential diagnosis of MZL and FL. MEF2B immunohistochemistry was performed retrospectively (Atlas Antibodies). Two hematopathologists assigned a pre-and post-MEF2B diagnosis to DTC cases. Results (if a Case Study enter NA) 57 cases were included: 21 FL (12 with MZD), 11 SMZL, 13 MALT, 4 NMZL, and 8 DTC cases. 19/21 FL cases (90%) were positive for MEF2B, including 11/12 (92%) cases with MZD. However, MEF2B expression was restricted to the follicles and negative in MZD areas in 7/11 cases (64%), while 4 cases showed partial weak expression in the areas of MZD. 0/11 SMZL (0%), 0/13 MALT (0%), and 0/4 (0%) NMZL were positive for MEF2B. 6/8 DTC cases (75%) were positive for MEF2B. Within DTC cases, retrospective inclusion of MEF2B results helped to render a more definitive diagnosis in 5 cases (2 negative/3 positive). Conclusion MEF2B immunohistochemistry can aid in distinguishing FL from MZL in challenging cases. However, it is often negative in areas of FL with MZD so care must be taken on interpretation in small biopsies.

Pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma: additional evidence to support they are a single disease with variation in the histologic spectrum.

Pediatric-type follicular lymphoma (PTFL) and pediatric nodal marginal zone lymphoma (PNMZL) are two rare indolent B-cell lymphomas with overlapping features. Recently, cases showing hybridizing features of PTFL and PNMZL have been reported. Herein, we retrospectively analyzed the clinicopathologic features of 59 patients, including 39 with PTFL, 5 with PNMZL, and 15 with mixed-type tumors (MTT). And next-generation sequencing analysis was performed on 3 PTFL, 2 PNMZL, and 2 MTT cases. In addition, previously published mutational data of 96 PTFLs, 25 PNMZLs, and 46 MTTs were also analyzed. There were 52 male and 7 female patients, with a median age of 17years. Most patients (96.6%) had lymph node involvement in the head and neck region and were diagnosed with stage I disease. Among the 50 patients (85%) with telephone follow-up, 44 (88%) adopted a watch-and-wait strategy after surgical resection of the lesions. Only one PTFL patient experienced a relapse 6months after diagnosis. Microscopically, not only the MTT cases showed a composite form of enlarged follicles and interfollicular lymphocytic proliferation producing a progressively transformed germinal center (PTGC) pattern, but also focal follicles with a PTGC-like pattern were observed in PTFL cases. Genetically, the most frequently mutated genes were TNFRSF14 (in 3 PTFLs and 2 MTTs), MAP2K1 (in 2 PTFLs, 1 PNMZL and 1 MTT), and IRF8 (in 2 MTTs and 1 PNMZL). Based on the similar or overlapping clinical, pathologic, and genetic features, PTFL and PNMZL are likely to represent two different histologic patterns of the same disease.

Histomorphologic spectrum of nodal marginal zone lymphoma as defined by its methylome.

Primary nodal marginal B-cell lymphoma (NMZL) is rare and histologically very variable. Its large-cell presentation is difficult to distinguish from nodal diffuse large B-cell lymphoma (nDLBCL) due to the absence of specific markers for nodal marginal zone lymphomas in general. Using a comprehensive cohort of NMZLs and a control cohort of nDLBCLs, we conducted a methylome analysis on subgroups of both. The methylomes were strikingly different between the cohorts but unexpectedly homogeneous within the NMZL cohort. This allowed us to describe the morphologic spectrum of NMZL in all its value ranges. The considerable overlap in growth pattern and cytology of NMZL with nDLBCL was explored morphometrically, leading to an operational tool for separating both by a simple measurement of cell size and nuclear size. This was integrated in a hierarchical approach, including a scoring system for the parameter growth pattern, follicular colonization, follicular dendritic network, IgD expression, and Ki-67 rate, and led to a proposal for a classifier that we present here. This methylome-based study extends the morphological spectrum of NMZL towards large cell morphology and offers a conventional way to distinguish it from nDLBCL.

7824 Orbital Lymphoma masquerading as Thyroid Eye Disease

Abstract Disclosure: S. Ganawa: None. S. Joseph: None. C. Anshuman: None. D. Luciane L: None. A. Sajid: None. C. Anne: None. S. Dhage: None. Thyroid eye disease (TED) is the most common extrathyroidal manifestation in Graves’ disease (GD). In this case report, we present a case of a 64 years old lady, who was initially diagnosed with thyroid eye disease about 9 years ago. However, she was clinically and biochemically euthyroid. She was offered an orbital decompression surgery by local ophthalmology team. Patient wasn’t keen on the surgery at this stage.Recently she experienced increased swelling of her eyes, with conjunctival redness, oedema, and diplopia bilaterally, more evident on the left side. She was initiated on intravenous methylprednisolone (IVMP) weekly, by local ophthalmology team and was referred to our specialist thyroid eye clinic for further management.On presentation to us, her clinical activity score (CAS) was 5/7, but she was euthyroid clinically and biochemically. She was continued on weekly IVMP and oral mycophenolate mofetil (MMF) was added on as per the latest EUGOGO guidelines published in 2021. Her treatment was reviewed after the anti thyroperoxidase (TPO) and anti-Thyroid Stimulating Hormone receptor (TSH) antibodies were reported as negative and her eyes worsened despite the treatment with IVMP and MMF.Her repeat MR orbit at this stage showed possible orbital lymphoma. Her immunosuppressive medications were discontinued at this stage. After further discussions at regional thyroid eye MDT and radiology MDT, an orbital biopsy was arranged for, which confirmed Extra nodal Marginal Zone lymphoma, with no high-grade component. She has been referred to the oncology unit for further assessment and management.This case highlights the importance of considering alternative differential diagnosis in certain patients with atypical features or those who are non-responders to the first line immunosuppressive therapies for thyroid eye disease. Details of this case and relevant literature will be reviewed in this report. Presentation: 6/3/2024

Real-world data for marginal zone lymphoma patients in the French REALYSA cohort: The REALMA study.

Marginal Zone Lymphoma (MZL) comprises three subtypes: extranodal MZL (EMZL), splenic MZL (SMZL) and nodal MZL (NMZL). Since clinical trials have limited representativeness, there is a need for real-world data (RWD) evidence in MZL. Real-world data in Lymphoma and survival in Adults (REALYSA) is a prospective multicentric French cohort of newly diagnosed lymphoma patients. This study consists of the first abstraction of MZL patients prospectively included in REALYSA between 12/2018 and 01/2021 with at least 1year of follow-up. It provides a landscape description of clinical characteristics, initial workup, quality of life and first-line therapy performed in routine practice. Among 207 included patients, 122 presented with EMZL, 51 with SMZL and 34 with NMZL. At baseline, median age was 67years (range 28-96), and patients reported a favorable global health status (75/100 (IQR 58,83)) - which was higher in NMZL and lower in SMZL patients (p=0.006). 18FDG-PET/CT was frequently performed at initial workup (EMZL 72%, SMZL 73%, NMZL 85%). Active surveillance was the initial management for 58 (28%) patients. The most prescribed therapies were rituximab-chlorambucil in the EMZL population (30%), rituximab monotherapy in the SMZL population (37%) and R-CHOP (24%)/bendamustine-rituximab (15%) in the NMZL population. At end of first line, overall response rate was 93% among treated patients with 75% of complete response. This French nationwide study provided for the first time prospective RWD on clinical characteristics, initial management and treatment response of MZL patients.

Transformation in marginal zone lymphoma: results from a prospective cohort and a meta-analysis of the literature

AbstractMarginal 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.

Risk of transformation by frontline management in follicular and marginal zone lymphomas: a US population–based analysis

AbstractFollicular lymphoma (FL) and marginal zone lymphoma (MZL) often have long overall survival (OS), however, high-grade transformation (HGT) to diffuse large B-cell lymphoma markedly reduces survival. The roles of upfront treatment vs observation on the incidence and outcome of HGT remain unclear. Thus, we analyzed a Surveillance, Epidemiology, and End Results database to address this question. Patients diagnosed with FL grades 1 to 2 or MZL between 2000 and 2020 were included. Fine-Gray models estimated the impact of covariates on HGT cumulative incidence and lymphoma-specific survival (LSS) and Cox regression on OS. HGT occurred in 4.2% of 23 384 patients with FL and 2.5% of 20 530 patients with MZL. The 5- and 10-year HGT cumulative incidence rates were 2.80% and 4.87% for FL, and 1.74% and 2.95% for MZL, respectively, which are notably lower than in earlier studies. The annual HGT incidence rate peaked in the first 2 years, then steadily declined over 2 decades for FL and all MZL subtypes. In FL, upfront observation vs treatment increases HGT risk (sub-distribution hazard ratio [SHR], 1.23; 95% confidence interval [CI], 1.09-1.40; P < .001) and barely affects OS (hazard ratio [HR], 0.95; 95% CI, 0.90-0.99; P = .03). Conversely, upfront observation was associated with lower HGT risk in nodal (SHR, 0.71; 95% CI, 0.53-0.94; P = .01) and extranodal (SHR, 0.64; 95% CI, 0.48-0.86; P = .003) MZL and did not affect survival in extranodal disease (HR, 0.94; 95% CI, 0.97-1.02; P = .15). HGT was associated with decrease in LSS across all histologies. Upfront treatment reduced the risk of HGT only in FL but not MZL.

The Genetic Landscape of Primary Breast Marginal Zone Lymphoma Identifies a Mutational-driven Disease With Similarities to Ocular Adnexal Lymphoma.

Extranodal marginal zone lymphomas (eMZL) can occur in any organ and site of the body. Recent research has shown that they differ from organ to organ in terms of their mutational profile. In this study, we investigated a cohort of primary breast marginal zone lymphomas (PBMZL) to get a better insight into their morphologic and molecular profile. A cohort of 15 cases (14 female and 1 male) was characterized by immunohistochemistry (IHC) for 19 markers, fluorescence in situ hybridization (FISH), and high throughput sequencing (HTS) using a lymphoma panel comprising 172 genes. In addition, PCR for the specific detection of Borrelia spp. and metagenomics whole genome sequencing were performed for infectious agent profiling. Follicular colonization was observed in most cases, while lymphoepithelial lesions, though seen in many cases, were not striking. All 15 cases were negative for CD5, CD11c, and CD21 and positive for BCL2 and pan B-cell markers. There were no cases with BCL2 , BCL10 , IRF4 , MALT1 , or MYC translocation; only 1 had a BCL6 rearrangement. HTS highlighted TNFAIP3 (n=4), KMT2D (n=2), and SPEN (n=2) as the most frequently mutated genes. There were no Borrelia spp. , and no other pathogens detected in our cohort. One patient had a clinical history of erythema chronicum migrans affecting the same breast. PBMZL is a mutation-driven disease rather than fusion-driven. It exhibits mutations in genes encoding components affecting the NF-κB pathway, chromatin modifier-encoding genes, and NOTCH pathway-related genes. Its mutational profile shares similarities with ocular adnexal and nodal MZL.

Marginal zone lymphomas: a consensus practice statement from the Australasian Lymphoma Alliance.

Marginal zone lymphomas (MZLs) are a rare, indolent group of non-Hodgkin lymphomas with different diagnostic, genetic and clinical features and therapeutic implications. The most common is extranodal MZL of mucosa-associated lymphoid tissue, followed by splenic MZL and nodal MZL. Patients with MZL generally have good outcomes with long survival rates but frequently have a relapsing/remitting course requiring several lines of therapy. The heterogeneous presentation and relapsing course present the clinician with several diagnostic and therapeutic challenges. This position statement presents evidence-based recommendations in the setting of Australia and New Zealand.

Transformation risk and associated survival outcome of marginal zone lymphoma: A nationwide study.

Histological transformation into an aggressive B-cell lymphoma indicates a poor survival outcome for patients with indolent marginal zone lymphoma (MZL), which has been less studied. Large-scale data with long-term follow-up to investigate MZL transformation is limited. Here, by reporting a US-Nationwide cohort of 30,619 MZL patients diagnosed between 2000 and 2019, we found that transformation occurred in 2.08% (N = 624) of MZL cases, with the transformation incidence of 3.1 per 1,000 person-years. Advanced Ann Arbor stage, nodal MZL (NMZL) and splenic MZL (SMZL) were associated with an elevated risk of transformation. Certain subtype-specific characteristics, such as non-gastric extra-nodal MZL (vs. gastric, HR, 1.51, 95%CI 1.13-2.04; p = 0.006), and receiving splenectomy for SMZL (HR, 2.04, 95%CI 1.28-3.26; p = 0.003), also indicated a higher risk of transformation. Besides, transformation independently increased the overall mortality risk (HR, 1.38, 95%CI 1.24-1.53, p < 0.001), especially the higher lymphoma-caused mortality risk (HR, 3.21, 95%CI 2.81-3.67, p < 0.001). Transformation was also associated with a higher percentage of lymphoma-caused deaths. The post-transformation prognostic analyses demonstrated that female gender and age ≥ 65 years independently affected patients' mortalities. These findings, based on the largest cohort to date, contribute to a better understanding of transformed MZL, and provide valuable reference points for guidelines and patient counseling.

Recognizing puzzling PD1 + infiltrates in marginal zone lymphoma by integrating clonal and mutational findings: pitfalls in both nodal and transformed splenic cases

BackgroundA marked increase in PD1-positive TFH cells in nodal MZL cases (NMZL) was reported previously and could prompt suspicion for a diagnosis of peripheral T-cell lymphoma (PTCL), especially angioimmunoblastic T-cell lymphoma (AITL).Case presentationTo demonstrate that the pitfall might exist not only in NMZL but also in transformed splenic MZL (tSMZL), two NMZL cases (70 y/o female with enlarged left cervical lymph node and 75 y/o male with generalized lymphadenopathy) and one case of tSMZL (47 y/o male with nodal and extranodal involvement) with obvious PD1-positive T-cell hyperplasia were described here. Although all their initial diagnoses were prompted to be AITL, they were comprehensively characterized by clinical features, morphologic, immunophenotypic, clonality, and targeted exosome sequencing (TES) findings. Case 1 and Case 2 were NMZL with increased PD1 + T cells in the “peripheral pattern” or “mixed peripheral and central pattern”, and Case 3 was SMZL with abundant PD1-positive T cells in the “nodular pattern” that transformed to tSMZL (DLBCL) with PD1-positive T cells distributed in the “diffuse pattern.” In addition to the monoclonal IG rearrangement and polyclonal TCR rearrangement results, TES demonstrated enriched and recurrent mutations in MZLs and failed to find aberrations described in AITL- or TFH-derived lymphomas.ConclusionsIt is important to realize that this pitfall can also occur in more diagnostically difficult tSMZL cases; the integration of histopathology with clonality and mutation studies is also highlighted.

Risk of Transformation By Frontline Management in Follicular Lymphoma and Marginal Zone Lymphoma: A US Population-Based Analysis

INTRODUCTION Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are commonly characterized by an indolent nature and favorable overall survival (OS). However, patients (pts) may experience high-grade transformation (HGT) into DLBCL, with an estimated annual risk of 1%-3% and cumulative incidence of HGT are 8% for FL and 10% for MZL at 10 and 12 years, respectively. The impact of treatment and surveillance strategies on the incidence of HGT remains uncertain, with some studies indicating reduced risk in treated pts without significant OS difference post-HGT. This study uses population-based data to assess the cumulative incidence and risk factors associated with HGT, post-HGT OS and lymphoma-specific survival (LSS) across lymphoma subtypes, with either treatment or surveillance as initial strategies. METHODS We extracted data for pts diagnosed with grades 1-2 FL, splenic MZL (SMZL), nodal MZL (NMZL), and extranodal MZL (MALT) from SEER database (period 2000-2015 with follow-up through 2018). We only included pts with histologic confirmed lymphoma as first malignancy, complete survival and treatment data, and a minimum of 3 months from FL and MZL diagnosis to HGT. Competing risk methods were used to estimate HGT cumulative incidence rates, with time to first event (HGT or death) defined from lymphoma diagnosis to date of first event; event-free pts were censored at date of last contact. Gray's test and Fine-Gray (FG) proportional subdistribution hazard modelling was employed to identify variables associated with risk of HGT. Post-HGT OS and LSS analyses utilized Cox and FG regression models, respectively. RESULTS 26827 pts met inclusion criteria. FL comprised 14229 pts (53%) while MZL types were SMZL 1182 (4.4%), NMZL 3916 (14.6 %) and MALT 7500 (28%). Treatment was given at diagnoses in 60.2%, 33.7%, 53.8% and 49.8% of pts with FL, SMZL, NMZL, MALT, respectively. 864 (3.2%) pts developed HGT to DLBCL, 553 (3.9%) in FL and 311 (2.5%) in MZL pts. After a median follow-up of 84 months (range 1-227), the 10-year cumulative incidence of HGT were for FL 4.24% (95%CI 3.88%-4.62%), SMZL 6.46% (95%CI 4.98%-8.20%), NMZL 3.28% (95%CI 2.70%-3.95%) and MALT 1.73% (95%CI 1.42%-2.09%). In FL, the 10-year cumulative incidence of HGT was 3.83% (95%CI 3.40-4.31%) in treated pts and 4.88% (95%CI 4.26%-5.54%) for those under surveillance (SHR=0.80, 95%CI 0.68-0.94; p=0.009) (Figure 1). This finding was confirmed in a multivariable analysis (p=0.001) that conversely identified female gender (p&amp;lt;0.001) and advanced stage at diagnosis (p&amp;lt;0.001) with higher risk of HGT (Figure 1). In MZL, the 10-year cumulative incidence rate of HGT in treated pts versus those managed with surveillance depicted by subtypes were as follows: SMZL 6.93% (95%CI 4.40%-10.2%) vs 6.29% (95%CI 4.53%-8.43%); NMZL 3.71% (95%CI 2.87%-4.70%) vs 2.78% (95%CI 2.03%-3.71%); MALT 2.01% (95%CI 1.54%-2.57%) vs 1.45% (95%CI 1.07%-1.93%). No significant difference between treatment versus surveillance were detected in univariable and multivariable analyses for SMZL (p=0.72 and 0.54) and NMZL (p=0.07 and 0.07), whereas surveillance pts had lower risk of HGT in MALT (p=0.02 and 0.01) (Figure 2). There were 429 (49.7%) deaths, including 337 (39%) lymphoma-specific deaths recorded in 864 pts with HGT in the entire cohort; and the median OS after HGT was 3.67 years (95%CI 2.5-6.25). Frontline therapy for FL was associated with higher risk of overall and lymphoma-specific deaths post-HGT (HR=1.32, 95%CI 1.03-1.69, p=0.02; and SHR=1.33, 95%CI 1.02-1.75, p=0.03); however, there was no significant difference in OS between frontline therapy and surveillance approach in SMZL (p=0.11), NMZL (p=0.73) and MALT (p=0.70). Interestingly, in SMZL worse LSS post-HGT was observed in those managed with frontline therapy (SHR=2.68, 95%CI 1.32-5.45, p=0.006). CONCLUSIONS Frontline treatment was associated to reduced HGT risk in FL, with advanced stage and female gender identified as risk factors for HGT. Contrarily, for SMZL, NMZL, and MALT, initial treatment neither diminished HGT risk nor improved overall survival post-HGT. Interestingly, in MALT initial treatment exhibits a higher HGT risk, likely due to selection bias, even though HGT cumulative incidence in MALT was lower compared to other subtypes. SMZL displayed a particularly high cumulative incidence of HGT and poorer LSS.

Clinicopathologic Features of CD23-Positive Nodal Marginal Zone Lymphomas

Abstract Objectives: To identify and describe the clinicopathologic features characterizing a set of patients with nodal marginal zone lymphoma (N-MZL) positive for expression of CD23 and to contrast findings against those of a cohort of patients with CD23-negative N-MZL. Methods: Cases of N-MZL diagnosed over a 20-year interval were identified from the medical record and allocated to two cohorts based on immunophenotypic expression of CD23. Clinical, morphologic, immunophenotypic and cytogenetic data were retrospectively reviewed. Results: Twenty-six cases with histological and immunophenotypic findings typical of N-MZL were identified, 12 of which expressed CD23 by flow cytometry or immunohistochemistry. In the CD23-positive N-MZL cohort, only 2/12 (17%) of patients demonstrated multicompartment lymphadenopathy and another 3/12 (25%) demonstrated bone marrow involvement, with an Ann Arbor disease stage IV. In the CD23-negative cohort, 8/14 (57%) patients presented with multicompartment lymphadenopathy and an additional 6/14 (43%) demonstrated bone marrow involvement, with an Ann Arbor disease stage IV. The average follow-up period for all patients (CD23-positive and CD23-negative cohorts) was 6.7 years (range: 1-17; IQR: 10). In the CD23-positive disease cohort, treatment and follow-up data were recorded for 10/12 (83%) patients. Three patients were followed without intervention, one of which transformed to an aggressive lymphoma. This patient was treated with a series of rituximab-based chemotherapies and remains well two years post stem cell transplant. One patient was surgically managed with adjuvant radiation and remains well with no evidence of disease. Six others were treated with various rituximab-based chemotherapy regimens. Two died secondary to sequalae related to progression of their disease. The others remain alive and well with no evidence of active disease. In the CD23-negative disease cohort, treatment and follow-up data were recorded for 13/14 (93%) patients. For seven patients in this cohort followed by observation only, five were alive and well at last follow-up. Two were deceased due to unrelated causes. For those otherwise treated, there was only a single fatality due to progression of disease. Comparing the two cohorts, those with CD23-positive disease were significantly more likely to present with a lower Ann Arbor stage (p=0.0155) and FLIPI score (p=0.0086). However, neither 5-year (p=0.6908) nor overall survival (p=0.5956) were significantly different between the two cohort medians. Conclusions: CD23 expression in our cohort of N-MZL patients correlated with greater likelihood of single versus multiple compartment lymphadenopathy, restriction of lymphadenopathy to the head and neck regions, lower Ann Arbor stage, and lower FLIPI score. The data here, while derived from a limited cohort, demonstrates that CD23 correlates with a lower-grade clinical assessment at time of disease presentation but is associated with a more rapid clinical decline given a lack of evidence for survival benefits in the long term.

Is Breast Involvement in Marginal Zone Lymphoma Associated with Worse Outcomes? a Nationwide Analysis

Background Marginal zone lymphoma (MZL) is the second most common indolent non-Hodgkin's lymphoma (NHL). It accounts for 6% of all B-cell lymphomas. Several MZL subtypes are recognized in the World Health Organization classification with the following rates :70% Extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissue (MALT lymphoma), 10% splenic MZL and 20% nodal MZL. MZL involving the breast, is a rare occurrence, it constitutes 1.7-2.2% of all extranodal NHLs and 0.04-0.5% of all malignant neoplasms of the breast (P L Cohen, 1991) and (M Vasei, 1997). Involvement of the breast by a primary lymphoma like DLBCL portends a more aggressive behavior but data is lacking in indolent lymphomas like MZL. We assume that patients with EMZL involving the breast will require earlier treatment compared with nodal MZL. In this population-based analysis we intend to examine this theory and investigate predictors of breast involvement in MZL and its outcomes. Methods We conducted a retrospective cohort analysis using de-identified data accessed from NCDB. The NCDB provided records of 17,198 patients diagnosed with nodal MZL and 1250 patients diagnosed with EMZL involving the breast between 2004 and 2016. We excluded patients without histologic or cytologic confirmation of the diagnosis. We also excluded patients who received treatment outside the reporting facility and patients missing survival data. Exploratory analysis of the patient groups was performed. Summary statistics are presented as percentages for categorical data and median with interquartile range for quantitative data. Chi square test was used to compare categorical variables and t-test was used to compare means. Multivariate regression models were used to analyze the predictors of breast involvement and survival. Results We identified 11,130 patients with nodal MZL and 769 patients with EMZL involving the breast. The median age was 68 (IQR 58-77), there were 56.5% females. Majority of the patients were non-Hispanic whites (85.9%), had a government insurance (58.5%), had comorbidity score of 0 (78.6%), belonged to a metropolitan area (86.2%), and were treated at a comprehensive community cancer centers or academic programs (79.1% combined). Black race, receiving treatment in a comprehensive community cancer center, and having insurance were associated with more breast involvement of MZL. While younger age was associated with less breast involvement. Median follow up was 9.1 years (IQR 8.8-9.5). Black race was associated with worse survival (HR 1.1, 95CI 1.0-1.3, p 0.004). Receiving treatment in a comprehensive community cancer center (HR 0.84, 95CI 0.76-0.93, p ≤ 0.01), older age (HR 0.996, 95CI 0.993-0.999, p 0.003), and living in an urban area (HR 0.92, 95CI 0.84-0.99, p 0.03) were associated with better survival. Breast involvement did not affect survival (HR 1.02, 95CI 0.93-1.12, p 0.71). The average days to start treatment in patients with EMZL involving the breast was 48 compared with 37 in nodal MZL (p ≤0.01). Conclusion Our study highlights clinical and socioeconomic predictors of breast involvement in MZL. Breast involvement in the whole cohort was not associated with worse clinical outcomes and our data does not suggest a different treatment approach for this patient population. Although, African American patients tend to have more breast involvement in MZL and it was associated with decreased survival. Our study is limited by its retrospective nature and its inherent selection bias, adjustment for baseline characteristics using univariate and multivariate analyses was used to mitigate this bias.

Prognostic Significance of Monoclonal Paraproteinemia in Marginal Zone Lymphoma

Introduction and aim:Marginal zone lymphoma (MZL) is an indolent lymphoma which can progress with frequent relapses and transform to aggressive lymphoma. Therefore, the factors that affect prognosis are important fields of interest. This study was aimed to investigate the effect of immunoglobulin (Ig) paraproteinemia on MZL prognosis and survival. Material and method: Between January 2000 and June 2022, 73 patients who applied to Dokuz Eylül University Faculty of Medicine Hospital Department of Hematology, diagnosed with MZL, and continued their follow-up in our center were assessed. Patients whose paraproteinemia was investigated by immunofixation (SIFE), serum protein electrophoresis (SPEP), or free kappa and lambda free light chain (FLC) assays were included in the study. Demographic characteristics and laboratory data were retrospectively analyzed. Results: Ig paraproteinemia was ascertained in 20 patients which 11 of 20 was IgM type. The median follow-up was 58 (3-200) months. Median overall survival (OS) and progression free survival (PFS) were not reached. Mean OS and PFS were 169±8.5 and 146±10.6 months, respectively. Serum Ig paraproteinemia was detected in 20 of 73 patients (27.3%). Most were IgM- κ (9, 45%), followed by IgG-κ (7, %35), IgM-λ (2, %10), IgA-λ (1, %5), and IgA-κ (1, %5). The presence of Ig paraproteinaemia was significantly associated with advanced age (p&amp;lt;0.001), advanced disease stage (III-IV) (p=0.023), elevated ß2 microglobulin (ß2MG) level (p=0.001), decreased hemoglobin level (p=0.002), decreased albumin level (p&amp;lt;0.001), and bone marrow involvement (p=.026). Gender, elevated lactate dehydrogenase (LDH) level, and elevated Ki-67 were not significantly associated with the presence of Ig paraproteinaemia. In our cohort Ig paraproteinemia was shown in 35%, 10% and 55% of extranodal MZL, splenic MZL and nodal MZL respectively (p=0,009) which favors nodal MZL dominance. The prognostic value of Ig paraproteinaemia and other clinical outcomes are summarized in Table 1. The OS rate at 5 and 10 years was %87.2 and %81.9, respectively. The PFS rate at 5 and 10 years was %71.5 and %68.3 respectively. Patients with Ig paraproteinaemia has shorter OS compared to patients without any paraproteinemia (73,8 mo. vs 178,8 mo. p&amp;lt;0,05). This survival disadvantage was more pronounced in patients with IgM paraproteinemias. Kaplan-Meier survival curve analysis of PFS according to the occurrence of Ig paraproteinaemia are shown in Figure 1. Conclusion: Although MZL is an indolent lymphoma type and there are many prognostic factors affecting its prognosis, it may show relapsed or refractory disease course or histological transformation. 55% of our nodal MZL cohort had Ig paraproteinemia which is higher than all reported cohorts in the literature so far. Several studies have previously shown that Ig paraproteinemia may be a potential prognostic factor for NHL and MALT lymphoma 1-3. Ren et al. showed that Ig paraproteinemia was an independent prognostic predictor for MALT lymphoma 4. Epperla et al. showed that patients diagnosed with MZL with Ig paraproteinemia had inferior survival in comparation with no-M protein group 5. In conclusion, this study provides evidence that Ig paraproteinaemia and especially of IgM type shortens PFS and OS in patients with MZL. Thus, our study is the first in literature to show survival disadvantage for MZL patients specifically with IgM paraproteinemia and deserves confirmation with further studies.

Pirtobrutinib, a Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Relapsed / Refractory Marginal Zone Lymphoma: Results from Phase 1/2 BRUIN Study

Background: Marginal zone lymphoma (MZL) is an indolent lymphoma that is typically treated with chemoimmunotherapy, but often requires sequential therapy. Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) are increasingly being used in the relapsed or refractory (R/R) setting, but options for pts with MZL after cBTKi therapy may be limited. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi has favorable once daily oral pharmacology that enables continuous BTK inhibition throughout the dosing interval, regardless of intrinsic rate of BTK turnover. Pirtobrutinib has demonstrated promising efficacy and tolerability in pts with poor-prognosis B-cell malignancies following prior therapy, including prior cBTKi. Pirtobrutinib is approved in the USA to treat R/R mantle cell lymphoma after at least two lines of systemic therapy including prior BTKi treatment. Here we report the safety and efficacy of pirtobrutinib in pts with MZL from the BRUIN study (NCT03740529). Methods: Pts with previously treated B-cell malignancies, including MZL, were eligible for pirtobrutinib monotherapy treatment in either the dose escalation or expansion portion of the multicenter, phase 1/2 BRUIN study. MZL diagnosis required local pathologic review of an adequate biopsy. Endpoints include overall response rate (ORR) assessed by investigator per Lugano 2014 criteria, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. A 05 May 2023 data cut was used. Results: Among the 36 pts with MZL, 34 (94%) received the recommended phase 2 dose of pirtobrutinib, 200mg once daily.Pts had a median age of 68 (range 22-83), a majority were female (56%, n=20), and median prior lines of systemic therapy were 3 (range 1-10). Pts had nodal (47%, n=17), splenic (36%, n=13), and extranodal (17%, n=6) MZL subtypes. Most pts had Ann Arbor stage III/IV disease (81%, n=29). Most pts were in high risk MALT-IPI group (53%, n=19), 10 (28%) were intermediate, 1 (3%) was low, and missing in 6 (17%) pts. Baseline LDH was elevated in 15 (42%) pts and hemoglobin was &amp;lt;12 g/dL in 29 (81%) pts. All 36 MZL pts were previously treated with an anti-CD20 antibody, and 31 (86%) pts had received prior chemotherapy. Of the 26 pts (72%) with MZL who received a prior cBTKi, 20 (77%) pts discontinued due to progressive disease (PD) and 6 (23%) discontinued due to toxicity/other. Median time on treatment was 9 months (range 1.1-40.8), with 15 (47.1%) pts still receiving pirtobrutinib. The ORR of the MZL cohort was 50% (95% confidence interval [CI], 32.9- 67.1), including 1 (2.8%) complete response, 17 (47.2%) partial responses ( Figure). There were 15 (41.7%) pts with stable disease. The ORR in pts with nodal, splenic, and extranodal MZL were 58.8% (95%CI, 32.9-81.6), 30.8% (95%CI, 9.1-61.4), and 66.7% (95%CI, 22.3-95.7), respectively. The ORR for MZL pts with prior cBTKi therapy was 46.2% (95%CI, 26.6-66.6). With a median follow-up time of 17.6 months, median DOR was 12.7 months (95%CI, 5.6-non-estimable [NE]). Median PFS was 16.5 months (95%CI, 7.43-22.1) with a median follow up of 15.8 months. With a median follow up of 21.5 months, the median OS was NE (95%CI, 27.6-NE) and the 24-mo OS rate was 77.5% (95%CI, 56.3-89.3). In the MZL cohort, the most frequent treatment-emergent adverse events (TEAE) of any grade regardless of attribution were diarrhea (36.1%, n=13), fatigue (33.3%, n=12), and contusion (30.6%, n=11). Grade ≥3 hemorrhage/hematoma was not observed, and any grade hypertension (5.6%, n=2) was infrequent. No atrial fibrillation/flutter was observed. The most frequent grade ≥3 TEAE was neutropenia/neutrophil count decreased (27.8%, n=10) and anemia (13.9%, n=5). Treatment-related AE led to dose reductions in 4 pts (11.1%) and pirtobrutinib discontinuation in 2 (5.6%) pts (diarrhea and platelet count decreased/neutropenia). No fatal TEAEs were observed. Conclusions: In this cohort of heavily pre-treated R/R MZL pts, pirtobrutinib showed preliminary efficacy and was well tolerated with low rates of discontinuation.Pirtobrutinib appears to be a promising therapeutic option after cBTKi treatment in R/R MZL pts.

Marsun, a Phase III, Multicenter, Open Label, Randomized, Controlled Study Investigating Mosunetuzumab-Lenalidomide Versus Investigator Choices in Patients with Relapsed or Refractory Marginal Zone Lymphoma (R/R MZL)

Background MZLs are the second most common indolent NHL (iNHL) and comprise three distinct subtypes: (i) extranodal MZL (EMZL), mostly represented by MALT lymphoma; (ii) nodal MZL (NMZL); and (iii) splenic MZL (SMZL). For patients with high tumor burden based on GELF criteria, and patients with symptoms related to disease, first-line treatments rely on immuno-chemotherapy to reach high response rates at the cost of substantial toxicities notably in elderly patients. To date, R/R MZL remain a therapeutic challenge without clear standard of care treatment between immuno-chemotherapy, targeted therapies (i.e. BTK/PI3K inhibitors or the immunomodulatory agent lenalidomide (Len)), mainly because of an underrepresentation of MZL in the “indolent NHL” trials. Mosunetuzumab is a CD20xCD3 T-cell-engaging bispecific antibody designed to redirect T-cell cytotoxic activity against B-cells with promising efficacy results as monotherapy in various B-cell NHL. Lenalidomide was approved in the USA for R/R MZL based on data from MAGNIFY (MZL=45 patients) and AUGMENT (MZL=63 patients) and previous results of a phase IB study showed that mosunetuzumab in combination with Lenalidomide has a manageable safety profile and encouraging activity in patients with R/R follicular lymphomas (Morschhauser F. et al. ASH 2021) Here we present details of a trial in progress investigating the efficacy and the safety of mosunetuzumab-lenalidomide, a chemo-free regimen, compared to investigator choice, in patients with R/R MZL in need of systemic treatment and not eligible for local therapy such as radiotherapy or surgery. Methods This is an open label, multi-center, international, randomized phase III trial to compare the efficacy of Mosunetuzumab-Lenalidomide with investigator choices exclusively in R/R MZL patients. Patients with a proven diagnosis of EMZL, SMZL or NMZL and previously treated with at least one and no more than three prior systemic treatments are eligible. Previous treatment lines must include at least one systemic line with a drug targeting CD20 (monoclonal antibody at least 2 cycles) with or without chemotherapy (CHOP, bendamustine, CVP, chlorambucil) or targeted treatment such as ibrutinib. Patients will be stratified according to MZL subtype and time to progression of disease after first-line within 2 years. Mosunetuzumab will be administered subcutaneously (21 days C1, then 28 days C2-12) and lenalidomide will be given PO 20 mg/day from Day 1 to Day 21 from cycles C2 to C6. For each patient, investigator choice must be decided before randomization between R-Len (12 cycles) and R-chemotherapy (R-Bendamustine or R-CHOP followed by a 6 months maintenance). Both arms will have the same one-year fixed duration. The primary efficacy endpoint for comparison is progression-free survival (PFS) as determined by investigator (Lugano criteria 2014). Secondary objectives include CR24 (CR at 24 months) as determined by investigator and by central review according to Lugano criteria 2014 based on PET results, overall response rate and CR other than CR24 as determined by investigator, or by central review based on PET result according to Lugano criteria 2014. 260 patients are planned to be enrolled in France, Belgium, Germany, Italy and Portugal with FPI expected in Q3 2023 and approximately 4-year accrual period. The study will comprise a first stage of 10 patients in a safety cohort with mosunetuzumab-lenalidomide followed by a stage 2 with patients randomized 1:1 to receive M-len or investigator choice (125 patients per arm). The sponsor of the trial is the Lymphoma Academic Research Organisation (LYSARC) in collaboration with GLA and FIL with the support of F.Hoffmann-La Roche Ltd.

Effectiveness and Safety of Orelabrutinib Combined with Rituximab As First-Line Treatment in Marginal Zone Lymphoma

Background: Marginal zone lymphoma (MZL) collectively is the third most common type of B-cell non-Hodgkin's lymphoma (NHL) worldwide, with an increased trend in incidence during the last two decades (Rossi D E et al., N Engl J Med. 2022). The lack of predominant first-line systemic therapy and toxicities associated with current rituximab-based therapies have inspired the exploration of more optimal treatment strategies (Becnel MR et al., Br J Haematol, 2019). Given the crucial role of bruton tyrosine kinase (BTK) in the B-cell receptor signaling pathway, BTK inhibitor has been proven to yield robust outcomes with improved tolerability in the development of NHL (Dhillon S et al., Drugs, 2021; Xu W et al., Blood, 2019; Song Y et al., Blood, 2019). Orelabrutinib is a novel BTK inhibitor with high selectivity and has been approved in China for relapsed/refractory MZL recently (Dhillon S et al., Drugs, 2021). Meanwhile, several clinical studies reported that orelabrutinib in combination with rituximab in NHL could preserve natural killer cell-mediated antibody-dependent cellular cytotoxicity induced by rituximab and enhance the clinical efficacy (Yu H et al., Mol Ther Oncolytics, 2021; Qu C et al., Blood, 2023). However, orelabrutinib plus rituximab as the first-line treatment for MZL remains largely understudied, thus, we conducted a retrospective study to evaluate its effectiveness and safety. Methods: Between July 27, 2021 and March 18, 2023, 10 patients with MZL who received orelabrutinib (150 mg, qd, po) with rituximab (375 mg/m 2, iv, day 1 of each 28-day cycle) as first-line therapy were included in this retrospective study. After 6 cycles of treatment, patients underwent orelabrutinib monotherapy (150 mg, qd, po) as maintenance for a year. Dynamic dose adjustment was performed according to the patient's clinical status. Effectiveness was assessed by positron emission tomography/computed tomography-based 2014 Lugano criteria. The primary endpoint was the overall response rate (ORR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: Ten patients (6 males; median age 63.5 years, range 45-76) were included in this study, 4 with extranodal MZL of mucosa-associated lymphoid tissue (40.0%), 2 with nodal MZL (20.0%), 1 with splenic MZL (10.0%), and 3 with unknown subtype (30%). Among a total of 10 patients, 3 (30%) achieved complete response (CR) and 6 (60%) attained partial response (PR) as their best response for an ORR of 90% ( Figure 1). After a median follow-up of 13.0 months (range 7.8-24.7), the median PFS was not reached and a 6-month PFS rate was 100% ( Table 1). OS could not be assessed due to there were no deaths occurred. As of the cut-off date (May 6, 2023), 8 patients received orelabrutinib maintenance treatment and the median duration of maintenance treatment was 9.6 months (range 3.0-17.8). The ORR was 75% (6/8) during maintenance treatment, while 1 patient had stable disease (SD) and 1 developed progressive disease (PD). In addition, abnormal hematology due to disease gradually recovered with the therapy within 4 months. No serious adverse events were observed. The off-target related AEs such as atrial fibrillation, diarrhea, and major hemorrhage were not reported. Conclusion: This retrospective data suggests that orelabrutinib with rituximab has an encouraging anti-tumor activity in MZL, with a favorable safety profile. These results provide a potential first-line treatment strategy in MZL. Further verification in prospective clinical trials of clinical outcomes of orelabrutinib in first-line MZL is warranted in the future.

Impact of Maintenance Rituximab Following First-Line Systemic Therapy on Outcomes in Patients with Marginal Zone Lymphoma: Real-World Evidence from 10 US Centers

Introduction First-line treatment options for patients (pts) with marginal zone lymphoma (MZL) include rituximab monotherapy (R) and immunochemotherapy (IC), such as bendamustine with rituximab (BR) or RCHOP/RCVP. The efficacy of maintenance rituximab (M-R) has been studied in splenic (SMZL) and nodal (NMZL) MZL, showing a benefit in progression-free survival (PFS) when M-R is administered after BR (Rummel et al., ASCO 2018). However, the role of M-R in pts with extranodal MZL (EMZL) of the mucosa-associated lymphatic tissue (MALT), or those receiving R or RCHOP/RCVP, remains uncertain. In this study, we analyzed the outcomes of pts with MZL who received M-R after their first-line systemic therapy (R or IC) using data from a large multi-institutional retrospective cohort. Methods Adult pts with MZL (SMZL, NMZL, or EMZL) who were treated at 10 US medical centers from 2010 onwards were included. Pts who had received first-line treatment with either R or IC and achieved a partial (PR) or complete (CR) response to the initial therapy were divided into groups based on whether they subsequently received M-R or not. To avoid immortal-time bias, we required a minimum follow-up of 6 months from diagnosis. Outcomes included PFS, overall survival (OS) and cumulative incidence of histologic transformation (HT). Because of non-proportional hazards, Wilcoxon test was used to compare survival curves, and Cox models (augmented by multiple imputation to account for missing data) were bounded by 6 years of follow up. Multivariable models adjusted for prognostic factors including age, sex, performance status, stage, baseline hemoglobin, albumin, LDH, type of IC and CR/PR status at the end of therapy. Results The study included 427 pts with a median age of 63 years. Of these pts, 53% were women, and 49% had EMZL, 27% had NMZL, and 23% had SMZL. The first-line therapies received were R (54%), BR (36%), RCHOP (7%), or RCVP (3%). A CR was achieved by 70% (n=298) of pts after the initial therapy. Overall, 33% (n=140) received M-R with a median of 8 cycles. Among pts who initially had PR, 39% converted to a CR during M-R therapy. The median follow-up period was 5 years. Factors associated with a higher likelihood of receiving M-R included achieving a PR instead of a CR after the first-line therapy (41% vs 29% receiving M-R, respectively; p=0.02) and having the SMZL subtype (p=0.03, Fig 1A). Pts treated with RCHOP were less likely to receive M-R compared to those receiving other regimens (p=0.049). There was also evidence of hospital-level preference to either prescribe M-R or not. We analyzed survival outcomes separately for pts who received first-line IC or R monotherapy, stratified further by MZL subtype and the type of IC regimen. Among pts who received IC (n=197), M-R was associated with longer PFS (median of 9.0 vs. 6.8 years, p=0.008, Fig 1B). However, the statistical significance was lost in the multivariable model (adjusted HR=0.52, 95%CI=0.25-1.10). When evaluated by MZL subtype, pts with EMZL had a significantly longer PFS with M-R (p=0.01), while those with NMZL and SMZL did not (p=0.41 and 0.10, respectively). When examining the type of first-line IC, pts receiving RCHOP/RCVP had a prolonged PFS with M-R (p=0.03), whereas the difference was not statistically significant after BR (p=0.12). There was no difference in OS overall (p=0.09; adjusted HR=0.55, 95%CI=0.12-2.60) or in any subgroup. Among pts who received first-line R, there were no statistically significant differences in PFS (p=0.70; adjusted HR=0.99, 95%CI=0.59-1.66) or OS (p=0.17) based on the receipt of M-R, either in the entire cohort or any subset. A total of 14 transformation events occurred during the study, including 3 in the M-R group. The cumulative incidence of HT did not significantly differ between the two groups (sub-HR=0.76, 95%CI=0.21-2.82, p=0.68). Discussion In this large retrospective cohort study, the use of M-R in MZL was primarily influenced by local preferences, the quality of response after initial treatment, and the type of IC regimen. Receipt of M-R was associated with a longer PFS for pts receiving first-line IC, especially for those with EMZL and those receiving RCHOP/RCVP. These findings suggest a PFS advantage of M-R in EMZL, which is a novel observation. However, this advantage was not observed in terms of OS or the rate of HT. M-R after initial R did not show any significant differences in outcomes for MZL.