Real-world impact of differences in the WHO and ICC classifications of non-Hodgkin lymphoma: a LEO Cohort Study analysis.

Recent introduction of two different lymphoma classifications has raised concerns about consistency in diagnosis, management, and clinical trial enrollment. Data from a large cohort reflecting real-world clinical practice suggest that differences between the classifications will impact <1% of non-Hodgkin lymphomas.

Transformation in Marginal Zone Lymphoma: Results from a Prospective Cohort and a Meta-Analysis of the Literature.

Marginal zone lymphoma (MZL) includes extranodal (EMZL), splenic (SMZL), and nodal (NMZL) subtypes. Histological 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 for the cumulative incidence of HT (with death as competing risk) and associated risk factors and outcomes. We also conduct a meta-analysis of available studies on the cumulative incidence of HT. From 2002-2015, 529 patients with MZL were enrolled in the MER (69% EMZL, 16% SMZL, 15% NMZL). Ten-year overall survival (OS) from diagnosis was 66%. HT occurred in 21 patients, with 5-year and 10-year cumulative incidence of HT 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 of death (subdistribution hazard ratio (HR)=3.95; 95%CI 2.06-7.55). Predictors of HT were ≥2 extranodal sites and MALT-IPI score ≥2. OS was 79% at 5 and 55% at 10 years after HT. Age at HT≥70 years was the only predictor of OS after HT (HR=3.57; 95%CI 1.34-9.48). In meta-analysis of 12 studies (6,161 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. Rates were lower in EMZL (3% and 5%) than in SMZL (7% and 13%) and NMZL (9% and 13%). While HT is relatively uncommon in the first decade after MZL diagnosis, it is associated with an inferior outcome and needs new approaches to prevention and management.

Relapsed mantle cell lymphoma manifesting with soft tissue tumors of the extremities: University of Miami experience and review of the literature.

Mantle cell lymphoma (MCL) is frequently diagnosed at advanced stages and is characterized by multiple extranodal sites of disease, most notably the bone marrow, peripheral blood, and gastrointestinal tract. Historically the prognosis of mantle cell lymphoma has been poor with median survival of four to five years. With new treatment regimens, however, patients have been able to achieve prolonged remissions and require special attention while being evaluated for relapse. This report describes four patients treated for stage IV mantle cell lymphoma at the University of Miami who developed soft tissue relapse presenting as non-tender large masses of the extremities, including one patient who presented without associated nodal involvement. Average time to soft tissue relapse was 99 months (range: 28-240) following initial diagnosis. Providers who care for patients with mantle cell lymphoma should be aware of soft tissue lesions as a presentation of mantle cell lymphoma that merits evaluation for disease relapse.

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

ABSTRACT: Follicular 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.

Transposon DNA sequences facilitate the tissue-specific gene transfer of circulating tumor DNA between human cells.

The exchange of genes between cells is known to play an important physiological and pathological role in many organisms. We show that circulating tumor DNA (ctDNA) facilitates cell-specific gene transfer between human cancer cells and explain part of the mechanisms behind this phenomenon. As ctDNA migrates into the nucleus, genetic information is transferred. Cell targeting and ctDNA integration require ERVL, SINE or LINE DNA sequences. Chemically manufactured AluSp and MER11C sequences replicated multiple myeloma (MM) ctDNA cell targeting and integration. Additionally, we found that ctDNA may alter the treatment response of MM and pancreatic cancer models. This study shows that retrotransposon DNA sequences promote cancer gene transfer. However, because cell-free DNA has been detected in physiological and other pathological conditions, our findings have a broader impact than just cancer. Furthermore, the discovery that transposon DNA sequences mediate tissue-specific targeting will open up a new avenue for the delivery of genes and therapies.

Defining primary refractory large B-cell lymphoma.

ABSTRACT: Patients with large B-cell lymphoma (LBCL) that fail to achieve a complete response (CR) or who relapse early after anthracycline-containing immunochemotherapy (IC) have a poor prognosis and are commonly considered to have "primary refractory disease." However, different definitions of primary refractory disease are used in the literature and clinical practice. In this study, we examined variation in the time to relapse used to define refractory status and association with survival outcomes in patients with primary refractory LBCL in a single-center prospective cohort with validation in an independent multicenter cohort. Patients with newly diagnosed LBCL were enrolled in the Molecular Epidemiological Resource cohort (MER; N = 949) or the Lymphoma Epidemiology of Outcomes cohort (LEO; N = 2755) from September 2002 to May 2021. Primary refractory LBCL was defined as no response (stable disease [SD]) or progressive disease (PD) during, or by the end of, frontline (1L) IC (primary PD; PPD); partial response at end of treatment (EOT PR); or relapse within 3 to 12 months after achieving CR at EOT to 1L IC (early relapse). In the MER cohort, patients with PPD had inferior overall survival (OS; 2-year OS rate: 15% MER, 31% LEO) when compared with other subgroups considered in defining primary refractory disease, EOT PR (2-year OS rate: 38% MER, 50% LEO) and early relapse (2-year OS rate: 44% MER, 58% LEO). Among patients receiving 1L IC with curative intent, we identified that patients with PPD are the key subgroup with poor outcomes. We propose a definition of primary refractory LBCL as SD or PD during, or by the end of, 1L treatment.

Marginal zone lymphoma international prognostic index: a unifying prognostic index for marginal zone lymphomas requiring systemic treatment.

Background: Marginal zone lymphomas (MZL), comprised of three unique but related subtypes, lack a unifying prognostic score applicable to all the patients in need for systemic chemotherapy and/or immunotherapy. Methods: Patients from the prospective NF10 study (NCT02904577) with newly diagnosed MZL and receiving frontline systemic therapy at diagnosis or after observation were used to train a prognostic model. The primary endpoint was progression-free survival (PFS) from start of treatment. The model was externally validated in a pooled analysis of two independent cohorts from the University of Iowa and Mayo Clinic Molecular Epidemiology Resource and the University of Miami. Findings: We identified 501 eligible patients. After multivariable modeling, lactate dehydrogenase (LDH) above upper normal limit, hemoglobin <12 g/dL, absolute lymphocyte count <1 × 109/L, platelets <100 × 109/L, and MZL subtype (nodal or disseminated) were independently associated with inferior PFS. The proposed MZL International Prognostic index (MZL-IPI) combined these 5 factors, and we defined low (LRG, 0 factors, 27%), intermediate (IRG, 1-2 factors, 57%) and high (HRG, 3+ factors, 16%) risk groups with 5-y PFS of 85%, 66%, and 37%, respectively (c-Harrell = 0.64). Compared to the LRG, the IRG (Hazard Ratio [HR] = 2.30, 95% CI 1.39-3.80) and HRG (HR = 5.41, 95% CI 3.12-9.38) had inferior PFS. Applying the MZL-IPI to the pooled US cohort (N = 353), 94 (27%), 192 (54%), and 67 (19%) patients were classified as LRG, IRG, and HRG, respectively, and the model was validated for PFS (log-rank test p = 0.0018; c-Harrell = 0.578, 95% CI 0.54-0.62). The MZL-IPI was also prognostic for OS in both the training and the external validation sets. Interpretation: MZL-IPI is a new prognostic score for use in all patients with MZL considered for systemic treatment. Funding: The MER was supported by P50 CA97274 and U01 CA195568.

Safety and efficacy of zandelisib plus zanubrutinib in previously treated follicular and mantle cell lymphomas.

The combination of the phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor zandelisib with the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib was hypothesized to be synergistic and prevent resistance to single-agent therapy. This phase 1 study (NCT02914938) included a dose-finding stage in patients with relapsed/refractory (R/R) B-cell malignancies (n = 20) and disease-specific expansion cohorts in follicular lymphoma (FL; n = 31) or mantle cell lymphoma (MCL; n = 19). The recommended phase 2 dose was zandelisib 60 mg on Days 1-7 plus zanubrutinib 80 mg twice daily continuously in 28-day cycle. In the total population, the most common adverse events (AEs; all grades/grade 3-4) were neutropenia (35%/24%), diarrhoea (33%/2%), thrombocytopenia (32%/8%), anaemia (27%/8%), increased creatinine (25%/0%), contusion (21%/0%), fatigue (21%/2%), nausea (21%/2%) and increased aspartate aminotransferase (24%/6%). Three patients discontinued due to AEs. The overall response rate was 87% (complete response [CR] = 33%) for FL and 74% (CR = 47%) for MCL. The median duration of response and progression-free survival (PFS) were not reached in either group. The estimated 1-year PFS was 72.3% (95% confidence interval [CI], 51.9-85.1) for FL and 56.3% (95% CI, 28.9-76.7) for MCL (median follow-up: 16.5 and 10.9 months respectively). Zandelisib plus zanubrutinib was associated with high response rates and no increased toxicity compared to either agent alone.

The Lymphoma Epidemiology of Outcomes cohort study: Design, baseline characteristics, and early outcomes.

To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18-99). Participants came from 49 US states and included 538 Black/African-Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 years, and 1513 rural residents. At study baseline, we abstracted clinical, pathology, and treatment data; banked serum/plasma (N = 5883, 76.0%) and germline DNA (N = 5465, 70.7%); constructed tissue microarrays for four major NHL subtypes (N = 1189); and collected quality of life (N = 5281, 68.3%) and epidemiologic risk factor (N = 4489, 58.0%) data. Through August 2022, there were 1492 deaths. Compared to population-based SEER data (2015-2019), LEO participants had a similar distribution of gender, AA race, Hispanic ethnicity, and NHL subtype, while LEO was underrepresented for patients who were Asian and aged 80 years and above. Observed overall survival rates for LEO at 1 and 2 years were similar to population-based SEER rates for indolent B-cell (follicular and marginal zone) and T-cell lymphomas, but were 10%-15% higher than SEER rates for aggressive B-cell subtypes (diffuse large B-cell and mantle cell). The LEO cohort is a robust and comprehensive national resource to address the role of clinical, tumor, host genetic, epidemiologic, and other biologic factors in NHL prognosis and survivorship.

Mosunetuzumab with polatuzumab vedotin in relapsed or refractory aggressive large B cell lymphoma: a phase 1b/2 trial.

Relapsed/refractory aggressive large B cell lymphoma (LBCL) remains an area of unmet need. Here we report the primary analysis of a phase 1b/2 trial of outpatient mosunetuzumab (a CD20xCD3 T-cell-engaging bispecific antibody) plus polatuzumab vedotin (an anti-CD79B antibody-drug conjugate) in relapsed/refractory LBCL. The phase 2 component is a single arm of an ongoing multi-arm trial. The primary endpoint during dose expansion was independent review committee (IRC)-assessed best overall response rate. Secondary endpoints included investigator-assessed overall response rate, complete response, duration of response, progression-free survival and overall survival. At data cutoff, 120 patients were enrolled (22 dose escalation, 98 dose expansion). The primary endpoint was met during dose expansion, with IRC-assessed best overall response rate and complete response rates of 59.2% (58/98; 95% confidence interval (CI): 48.8-69.0) and 45.9% (45/98; 95% CI: 35.8-56.3), respectively (median follow-up, 23.9 months). Median duration of complete was not reached (95% CI: 20.5-not estimable (NE)). Median progression-free survival was 11.4 months (95% CI: 6.2-18.7). Median overall survival was 23.3 months (95% CI: 14.8-NE). Across dose escalation and expansion, the most common grade 3 or higher adverse events were neutropenia (25.0%, 30/120) and fatigue (6.7%, 8/120). Any-grade cytokine release syndrome occurred in 16.7% of patients. These data demonstrate that mosunetuzumab plus polatuzumab vedotin has a favorable safety profile with highly durable responses suitable as second-line therapy in transplant-ineligible relapsed/refractory LBCL. ClinicalTrials.gov identifier: NCT03671018 .

PET/CT Biomarkers Enable Risk Stratification of Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma Enrolled in the LOTIS-2 Clinical Trial.

PURPOSE: Significant progress has occurred in developing quantitative PET/CT biomarkers in diffuse large B-cell lymphoma (DLBCL). Total metabolic tumor volume (MTV) is the most extensively studied, enabling assessment of FDG-avid tumor burden associated with outcomes. However, prior studies evaluated the outcome of cytotoxic chemotherapy or chimeric antigen receptor T-cell therapy without data on recently approved FDA agents. Therefore, we aimed to assess the prognosis of PET/CT biomarkers in patients treated with loncastuximab tesirine. EXPERIMENTAL DESIGN: We centrally reviewed screening PET/CT scans of patients with relapsed/refractory DLBCL enrolled in the LOTIS-2 (NCT03589469) study. MTV was obtained by computing individual volumes using the SUV ≥4.0 threshold. Other PET/CT metrics, clinical factors, and the International Metabolic Prognostic Index (IMPI) were evaluated. Logistic regression was used to assess the association between biomarkers and treatment response. Cox regression was used to determine the effect of biomarkers on time-to-event outcomes. We estimated biomarker prediction as continuous and binary variables defined by cutoff points. RESULTS: Across 138 patients included in this study, MTV with a cutoff point of 96 mL was the biomarker associated with the highest predictive performance in univariable and multivariable models to predict failure to achieve complete metabolic response (OR, 5.42; P = 0.002), progression-free survival (HR, 2.68; P = 0.002), and overall survival (HR, 3.09; P < 0.0001). IMPI demonstrated an appropriate performance, however, not better than MTV alone. CONCLUSIONS: Pretreatment MTV demonstrated robust risk stratification, with those patients demonstrating high MTV achieving lower responses and survival to loncastuximab tesirine in relapsed/refractory DLBCL.

A phase 2 study of the PI3Kδ inhibitor parsaclisib in relapsed and refractory marginal zone lymphoma (CITADEL-204).

ABSTRACT: Parsaclisib, a potent and highly selective PI3Kδ inhibitor, has shown clinical benefit in patients with relapsed or refractory (R/R) B-cell lymphomas. The phase 2 CITADEL-204 study (NCT03144674, EudraCT 2017-000970-12) assessed efficacy and safety of parsaclisib in Bruton tyrosine kinase (BTK) inhibitor-experienced (cohort 1) or BTK inhibitor-naive (cohort 2) patients with R/R marginal zone lymphoma (MZL). Patients aged ≥18 years with histologically confirmed R/R MZL, treated with ≥1 prior systemic therapy (including ≥1 anti-CD20 antibody) received parsaclisib 20 mg once daily for 8 weeks then 20 mg once weekly (weekly dosing group [WG]) or parsaclisib 20 mg once daily for 8 weeks then 2.5 mg once daily (daily dosing group [DG]); DG was selected for further assessment. Primary end point of the study was objective response rate (ORR). Owing to slower than expected recruitment, cohort 1 was closed with 10 patients (WG, n = 4; DG, n = 6) enrolled. Based on a planned interim analysis in cohort 2, the futility boundary was not crossed, and enrollment continued to study completion. At data cutoff (15 January 2021), 100 patients were enrolled and treated in cohort 2 (WG, n = 28; DG, n = 72). In the DG, the ORR was 58.3% (95% confidence interval [CI], 46.1-69.8), with a complete response rate of 4.2% (95% CI, 0.9-11.7); the lower bound of the ORR 95% CI exceeded the protocol-defined threshold of 40%. The median duration of response was 12.2 months (95% CI, 8.1-17.5) and progression-free survival was 16.5 months (95% CI, 11.5-20.6); median overall survival was not reached. The most common treatment-emergent adverse events (TEAEs) among all patients were diarrhea (47.0%), cough (23.0%), and rash (18.0%); the most common grade ≥3 TEAEs included diarrhea (12.0%), neutropenia, and pneumonia (9.0% each). TEAEs led to dose interruptions, reductions, and discontinuations in 56.0%, 16.0%, and 29.0% of all patients, respectively. Durable responses and an overall manageable safety profile were demonstrated in patients with R/R MZL treated with parsaclisib monotherapy.

Matching-adjusted indirect comparison from the Lymphoma Epidemiology of Outcomes Consortium for Real World Evidence (LEO CReWE) study to a clinical trial of mosunetuzumab in relapsed or refractory follicular lymphoma.

Mosunetuzumab is a novel bispecific antibody targeting epitopes on CD3 on T cells and CD20 on B cells with the goal of inducing T-cell mediated elimination of malignant B cells. A recent pivotal phase I/II clinical trial (GO29781) demonstrated that mosunetuzumab induced an overall response rate of 80%, complete response rate of 60%, and a median progression-free survival of 17.9 months in patients with relapsed/refractory (r/r) follicular lymphoma (FL) following at least two prior lines of systemic therapy, including alkylator and anti-CD20 antibody-based therapy. Historical data from cohorts receiving therapy for r/r FL can provide some context for interpretation of single-arm trials. We compared the results from the mosunetuzumab trial to outcomes from a cohort of patients with r/r FL from the LEO Consortium for Real World Evidence (LEO CReWE). We applied clinical trial eligibility criteria to the LEO CReWE cohort and utilized matching-adjusted indirect comparison weighting to balance the clinical characteristics of the LEO CReWE cohort with those from the mosunetuzumab trial. Overall response rates (73%, 95% CI:65-80%) and complete response rates (53%, 95% CI:45-61%) observed in the weighted LEO CReWE cohort were lower than those reported on the mosunetuzumab trial (ORR=80%, 95% CI:70-88%; CR=60%, 95% CI:49-70% respectively). Progression-free survival at 12 months was similar in the weighted LEO CReWE (60%, 95% CI:51-69%) and the mosunetuzumab trial (PFS 58%, 95% CI:47-68%). Sensitivity analyses examining the impact of matching variables, selection of line of therapy, and application of eligibility criteria, provide context for best practices in this setting.

Mosunetuzumab in combination with CHOP in previously untreated DLBCL: safety and efficacy results from a phase 2 study.

Up to 40% of patients with diffuse large B-cell lymphoma (DLBCL) are refractory to or relapse after first-line therapy, highlighting the need for better treatments. Mosunetuzumab is a CD20 × CD3 bispecific antibody that engages and redirects T cells to eliminate malignant B cells. In this phase 2, open-label study (NCT03677141), 40 patients (52.5% with international prognostic index ≥3) with previously untreated DLBCL initiated 6 cycles of IV mosunetuzumab with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. Mosunetuzumab was administered in cycle 1 as step-up doses to mitigate cytokine release syndrome [CRS], and a dose of 30 mg was given on day 1 of cycles 2-6. Efficacy end points included objective and complete response rates, as determined by the investigator, via positron emission tomography-computed tomography, using Lugano 2014 criteria (87.5% and 85.0%, respectively). At a median follow-up of 32.0 months, the estimated 2-year progression-free survival and event-free survival rates were 65.4% (95% confidence interval [CI], 49.5-81.4) and 60.4% (95% CI, 44.7-76.1), respectively. CRS occurred in 60.0% of patients; all events were grade 1 (45.0%) or grade 2 (15.0%) and occurred primarily in cycle 1. Mosunetuzumab-related grade ≥3 neurologic adverse events (AEs) potentially consistent with immune effector cell-associated neurotoxicity syndrome occurred in 1 patient (2.5%). Grade 5 AEs were reported in 2 patients. Neutropenia occurred in 70.0% of patients, mostly during cycle 1 and was of short duration. These findings demonstrate promising activity and a manageable safety profile for mosunetuzumab-CHOP and warrant further investigation of mosunetuzumab in first-line combination regimens for DLBCL.

Impact of cumulative dose of brentuximab vedotin on outcomes of frontline therapy for advanced-stage Hodgkin lymphoma.

In the pivotal study ECHELON-1, brentuximab vedotin (BV), doxorubicin, vinblastine, and dacarbazine (A + AVD) demonstrated superior efficacy compared with bleomycin + AVD for the treatment of advanced-stage classic Hodgkin lymphoma (cHL). However, there are minimal available data regarding the frequency of dose reductions or omission of BV during curative therapy and the potential impact on patient outcomes. In a real-world analysis, we retrospectively reviewed the characteristics and outcomes of 179 patients with stage III or IV cHL treated with frontline A + AVD from January 2010 to April 2022. Treatment consisted of up to 1.2 mg/kg of BV and standard dose AVD IV on days 1 and 15 of each 28-day cycle for up to 6 cycles. At the time of treatment, the median patient age was 37 years, and a high-risk International Prognostic Score was observed in 46% of patients. Overall, 91% of patients received 6 cycles of AVD; 55% of patients did not receive the intended cumulative dose of BV (CDB); 28% of patients received two-thirds or less than the planned CDB. At a median follow-up time of 27.4 months (95% confidence interval [CI], 24.8-29), the median progression-free survival (PFS) was not reached, and the 12-month PFS was 90.3% (95% CI, 85.9-95.0). The impact of CDB on PFS was not significant (P = .15), nor was high CDB significantly associated with increased adverse events. In real-world experience, A + AVD is a highly effective treatment for patients with advanced-stage cHL, including for patients with prominent dose reductions of BV.

Correction: The Genetic Landscape of Ocular Adnexa MALT Lymphoma Reveals Frequent Aberrations in NFAT and MEF2B Signaling Pathways.

[This corrects the article DOI: 10.1158/2767-9764.CRC-21-0022.][This corrects the article DOI: 10.1158/2767-9764.CRC-21-0022.].

Mutations associated with progression in follicular lymphoma predict inferior outcomes at diagnosis: Alliance A151303.

Follicular lymphoma (FL) is clinically heterogeneous, with select patients tolerating extended watch-and-wait, whereas others require prompt treatment, suffer progression of disease within 24 months of treatment (POD24), and/or experience aggressive histologic transformation (t-FL). Because our understanding of the relationship between genetic alterations in FL and patient outcomes remains limited, we conducted a clinicogenomic analysis of 370 patients with FL or t-FL (from Cancer and Leukemia Group B/Alliance trials 50402/50701/50803, or real-world cohorts from Washington University School of Medicine, Cleveland Clinic, or University of Miami). FL subsets by grade, stage, watch-and-wait, or POD24 status did not differ by mutation burden, whereas mutation burden was significantly higher in relapsed/refractory (rel/ref) FL and t-FL than in newly diagnosed (dx) FL. Nonetheless, mutation burden in dx FL was not associated with frontline progression-free survival (PFS). CREBBP was the only gene more commonly mutated in FL than in t-FL yet mutated CREBBP was associated with shorter frontline PFS in FL. Mutations in 20 genes were more common in rel/ref FL or t-FL than in dx FL, including 6 significantly mutated genes (SMGs): STAT6, TP53, IGLL5, B2M, SOCS1, and MYD88. We defined a mutations associated with progression (MAP) signature as ≥2 mutations in these 7 genes (6 rel/ref FL or t-FL SMGs plus CREBBP). Patients with dx FL possessing a MAP signature had shorter frontline PFS, revealing a 7-gene set offering insight into FL progression risk potentially more generalizable than the m7-Follicular Lymphoma International Prognostic Index (m7-FLIPI), which had modest prognostic value in our cohort. Future studies are warranted to validate the poor prognosis associated with a MAP signature in dx FL, potentially facilitating novel trials specifically in this high-risk subset of patients.

Enhancing prognostication and personalizing treatment of extranodal marginal zone lymphoma.

INTRODUCTION: Extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissue is an indolent lymphoma originating from marginal zone B-cells and associated with chronic inflammation. EMZL demonstrates distinct genomic alterations according to the primary extranodal site of disease but commonly affects signaling pathways including NF-ĸB, B-cell receptor, and NOTCH. Treatment with radiation therapy is commonly implemented in localized diseases, and multiple agents are available for patients with advanced-stage diseases in need of therapy. Bendamustine with rituximab is a frontline platform associated with high efficacy. AREAS COVERED: Clinical features, diagnosis, genomics, models enabling risk stratification, treatment options, and future directions. EXPERT OPINION: The lack of consistent genotyping profile in EMZL precludes the development of tissue and circulatory biomarkers for the diagnosis, risk stratification, and monitoring of minimal residual disease. Furthermore, the biological heterogeneity observed in extranodal sites associated with overall limited genomic data prevents the testing of druggable pathways aiming for a personalized treatment approach. Future clinical trials should focus on EMZL considering the unique clinical characteristics in the eligibility criteria and response assessment to better inform efficacy of novel agents and delineate sequences of therapies.

Casein Protein Block to Optimize Immunohistochemistry Detection of Surface Immunoglobulin Heavy Chain Expression in Lymphoid Cells.

We describe our recent experience of studying expression of immunoglobulin (Ig) heavy chain (IgG, IgM, and IgA) in lymphoid cells comprising a research set of formalin-fixed, paraffin-embedded human diffuse large B-cell lymphoma samples. We found that using typical clinical automated immunohistochemistry protocols and usual buffers as blocking agents, the extent of undesirable staining was extreme and impaired our ability to interpret heavy chain Ig expression by individual lymphoid cells. We were not able to optimize this with serial dilutions in antibody concentration or time of primary antibody exposure. We therefore developed an added step of casein protein block, which solved the problem. We are not aware of other such reports in clinical or human research tissue sets and believe this solution may be useful when clinical pathologists or researchers encounter similar technical issues.