Review of computer-assisted diagnosis model to classify follicular lymphoma histology.

The field of image processing is experiencing significant advancements to support professionals in analyzing histological images obtained from biopsies. The primary objective is to enhance the process of diagnosis and prognostic evaluations. Various forms of cancer can be diagnosed by employing different segmentation techniques followed by postprocessing approaches that can identify distinct neoplastic areas. Using computer approaches facilitates a more objective and efficient study of experts. The progressive advancement of histological image analysis holds significant importance in modern medicine. This paper provides an overview of the current advances in segmentation and classification approaches for images of follicular lymphoma. This research analyzes the primary image processing techniques utilized in the various stages of preprocessing, segmentation of the region of interest, classification, and postprocessing as described in the existing literature. The study also examines the strengths and weaknesses associated with these approaches. Additionally, this study encompasses an examination of validation procedures and an exploration of prospective future research roads in the segmentation of neoplasias.

Prolonged water-only fasting in the management of low-grade follicular lymphoma: a case series.

BACKGROUND: Follicular lymphoma typically follows an indolent and relapsing course often requiring several treatment cycles to achieve remission. Some patients opt to use complementary and alternative therapies particularly when observation is a treatment option. CASE PRESENTATION: Here we present a case series of three patients, a 50-year-old, White, Hispanic female, 56-year-old, White, non-Hispanic male, and 49-year-old, White, non-Hispanic male, who elected to undergo one or more prolonged water-only fasting and refeeding interventions to manage low to intermediate grade follicular lymphoma. Fasting was well tolerated in each patient. Each patient also experienced a reduction in the size and avidity of hypermetabolic lymph nodes as independently determined by their respective oncologists. CONCLUSION: The reported cases demonstrate positive outcomes in low-grade follicular lymphoma coinciding with prolonged water-only fasting and exclusively whole-plant-food dietary interventions. These findings highlight the potential of such interventions and warrant further exploration through preliminary observational research.

Long-Term Remission with Novel Combined Immune-Targeted Treatment for Histiocytic Sarcoma Accompanied by Follicular Lymphoma: Case Report and Literature Review.

Histiocytic sarcoma (HS) is an extremely rare but aggressive hematopoietic malignancy, and the prognosis has been reported to be rather unfavorable with a median overall survival of merely 6 months. We presented a 58-year-old female patient complaining of abdominal pain and fever, who was admitted to our institution in September 2021. Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) scan showed enlargement of generalized multiple lymph nodes. Subsequently, laparoscopic retroperitoneal lesion biopsy and bone marrow aspiration were performed. The pathological findings indicated the diagnosis of HS concurrent with follicular lymphoma. The immunohistochemistry (IHC) staining of the tumor lesion revealed a high expression of CD38 and PD-L1 proteins. Furthermore, KRAS gene mutation was identified by means of next-generation sequencing. The patient exhibited poor treatment response to both first- and second-line cytotoxic chemotherapies. Therefore, she underwent six cycles of Daratumumab (anti-CD38 monoclonal antibody), Pazopanib (multi-target receptor tyrosine kinases inhibitor) combined with third-line chemotherapy, followed by involved-site radiotherapy and maintenance therapy with the PD-1 inhibitor Tislelizumab. Long-term partial remission was finally achieved after multi-modality treatment. Duration of remission and overall survival reached 22 and 32 months, respectively. Our case indicated that immuno-targeted treatment coupled with chemotherapy and radiotherapy might constitute a potential therapeutic option for HS.

Symptomatic Follicular Lymphoma: Complete Remission After Chemoimmunotherapy with Bendamustine-Rituximab.

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in Western countries after diffuse large B-cell lymphoma. Most patients with FL present with asymptomatic disease. Survival rates have been rising over time mainly due to advancing therapeutic strategiesA-51-year-old male with a history of well-controlled diabetes mellitus treated with insulin presented to the policlinic of hematology-medical oncology with worsening right inguinal lymphadenopathy for >3 months. He had no complaints of prolonged fever, night sweat, or weight loss. Initial physical examination revealed a healthy male with bulky right inguinal lymphadenopathy. The patient was then referred to a surgeon, and excisional biopsy of the enlarged right inguinal lymph nodes was performed. Therefore, stage II bulky symptomatic low-grade FL was established. We administered chemoimmunotherapy with rituximab and bendamustine every 3 weeks for six cycles. The patient tolerated the treatment well and completed six cycles of chemoimmunotherapy, and the follow-up FDG PET/CT showed complete remission of the disease.The patient achieved complete remission after series of chemoimmunotherapy with Bendamustine-Rituximab. Future assessment is still required for this patient to ensure the remission status of the lymphoma.

A study of criteria for grading follicular lymphoma using a cell type classifier from pathology images based on complementary-label learning.

We propose a criterion for grading follicular lymphoma that is consistent with the intuitive evaluation, which is conducted by experienced pathologists. A criterion for grading follicular lymphoma is defined by the World Health Organization (WHO) based on the number of centroblasts and centrocytes within the field of view. However, the WHO criterion is not often used in clinical practice because it is impractical for pathologists to visually identify the cell type of each cell and count the number of centroblasts and centrocytes. Hence, based on the widespread use of digital pathology, we make it practical to identify and count the cell type by using image processing and then construct a criterion for grading based on the number of cells. Here, the problem is that labeling the cell type is not easy even for experienced pathologists. To alleviate this problem, we build a new dataset for cell type classification, which contains the pathologists' confusion records during labeling, and we construct the cell type classifier using complementary-label learning from this dataset. Then we propose a criterion based on the composition ratio of cell types that is consistent with the pathologists' grading. Our experiments demonstrate that the classifier can accurately identify cell types and the proposed criterion is more consistent with the pathologists' grading than the current WHO criterion.

Frequent CDKN2B/P15 and DAPK1 methylation in duodenal follicular lymphoma is related to duodenal reactive lymphoid hyperplasia.

Duodenal type follicular lymphoma (DFL), a rare entity of follicular lymphoma (FL), is clinically indolent and is characterized by a low histological grade compared with nodal follicular lymphoma (NFL). Our previous reports revealed that DFL shares characteristics of both NFL and mucosa-associated lymphoid tissue (MALT) lymphoma in terms of clinical and biological aspects, suggesting its pathogenesis may involve antigenic stimulation. In contrast to NFL, the genomic methylation status of DFL is still challenging. Here, we determined the methylation profiles of DNAs from patients with DFL (n = 12), NFL (n = 10), duodenal reactive lymphoid hyperplasia (D-RLH) (n = 7), nodal reactive lymphoid hyperplasia (N-RLH) (n = 5), and duodenal samples from normal subjects (NDU) (n = 5) using methylation specific PCR of targets previously identified in MALT lymphoma (CDKN2B/P15, CDKN2A/P16, CDKN2C/P18, MGMT, hMLH-1, TP73, DAPK, HCAD). DAPK1 was frequently methylated in DFL (9/12; 75%), NFL (9/10; 90%), and D-RLH (5/7; 71%). CDKN2B/P15 sequences were methylated in six DFL samples and in only one NFL sample. Immunohistochemical analysis showed that p15 expression inversely correlated with methylation status. Genes encoding other cyclin-dependent kinase inhibitors (CDKN2A/P16, CDKN2C/P18) were not methylated in DFL samples. Methylation of the genes of interest was not detected in DNAs from D-RLH, except for DAPK1, and the difference in the extent of methylation between NDU and D-RLH was statistically significant (P = 0.013). Our results suggest that D-RLH serves as a reservoir for the development of DFL and that methylation of CDKN2B/P15 plays an important role in this process.

[The Reduction of CD4+ T Lymphocytes after the Treatment of Follicular Lymphoma with the Bendamustine Containing Regimen May Predict the Occurrence of Infection and Efficacy].

OBJECTIVE: To investigate the effectiveness, safety, and related prognostic factors of the treatment of follicular lymphoma (FL) with a regimen containing Bendamustine. METHODS: The clinical data of 129 FL patients who were treated with Bendamustine containing regimen were collected from January 1,2020 to October 30,2022 in the Hematology Department of Lianyungang Second People's Hospital and Jiangsu Provincial People's Hospital. The patients were divided into three groups: Bendamustine plus Rituximab (BR), Bendamustine plus Obinutuzumab (GB), Rituximab + Cyclophosphamide + Epirubicin / Doxorubicin + Vindesine + Prednisone (R-CHOP). The efficacy, safety and related prognostic factors of the treatment of FL with a regimen based on Bendamustine were retrospectively analyzed. RESULTS: The ORR was 98% for the BR group, 94% for the GB group, and 72.3% for the R-CHOP group, while the CR rate was 61.2%,70% and 40.4%, respectively. The ORR and CR rates of the R-CHOP group were statistically different from those of the BR group and GB group (P < 0.05). The 3-year PFS rate of the BR group, GB group, and R-CHOP group was 89.6%, 90.9%, 48.9%, respectively. There was a statistically significant difference in 3-year PFS between the R-CHOP group, BR group, and GB group (P < 0.05), while there was no statistically significant difference in 3-year OS（P ＞0.05）. Hematological adverse reactions were mainly bone marrow suppression. Lymphocytes and CD4+T lymphocytes decreased to the lowest level about 6 months after treatment, and the incidence of lymphopenia in BR group and GB group was higher than that in R-CHOP group, with a statistical difference (P < 0.05). The higher incidence of non-Hematological adverse reactions were pulmonary infection, EB virus infection, hepatitis B virus reactivation, and gastrointestinal reactions without statistical difference in 3 groups (P >0.05), and were all controllable. The Receiver operating characteristic of CD4+T lymphocyte count showed that AUC of BR group was 0.802, and the critical value was 258/uL; AUC of GB group was 0.754 with a critical value of 322/uL. CONCLUSION: The treatment of FL with the Bendamustine containing regimen has good efficacy and controllable adverse reactions, but lymphocytopenia was significant after treatment, and the curative efficacy in combination with various CD20 monoclonal antibodies was different. The lowest CD4+T lymphocyte count can be used as a predictive factor for the occurrence of infection and efficacy of the Bendamustine containing regimen for FL.

Cost-effectiveness of treating relapsed or refractory 3L+ follicular lymphoma with axicabtagene ciloleucel vs mosunetuzumab in the United States.

Introduction: Novel therapies for 3L+ relapsed/refractory (r/r) follicular lymphoma (FL) have been approved recently by the US Food and Drug Administration including anti-CD19 CAR-T therapies such as axicabtagene ciloleucel (axi-cel) and CD20 × CD3 T-cell-engaging bispecific monoclonal antibodies such as mosunetuzumab (mosun). The objective of this study was to assess the cost-effectiveness of axi-cel compared to mosun in 3L+ r/r FL patients from a US third-party payer perspective. Methods: A three-state (progression-free, progressed disease, and death) partitioned-survival model was used to compare two treatments over a lifetime horizon in a hypothetical cohort of US adults (age ≥18) receiving 3L+ treatment for r/r FL. ZUMA-5 and GO29781 trial data were used to inform progression-free survival (PFS) and overall survival (OS). Mosun survival was modeled via hazard ratios (HRs) applied to axi-cel survival curves. The PFS HR value was estimated via a matching-adjusted indirect comparison (MAIC) based on mosun pseudo-individual patient data and adjusted axi-cel data to account for trial populations differences. One-way sensitivity analysis (OWSA) and probabilistic sensitivity analyses (PSA) were conducted. Scenario analyses included: 1) the mosun HRs were applied to the weighted (adjusted) ZUMA-5 24-month data to most exactly reflect the MAIC, 2) mosun HR values were applied to axi-cel 48-month follow-up data, and 3) recent axi-cel health state utility values in diffuse large B-cell lymphoma patients. Results: The analysis estimated increases of 1.82 LY and 1.89 QALY for axi-cel compared to mosun. PFS for axi-cel patients was 6.42 LY vs. 1.60 LY for mosun. Increase of $257,113 in the progression-free state was driven by one-time axi-cel treatment costs. Total incremental costs for axi-cel were $204,377, resulting in an ICER of $108,307/QALY gained. The OWSA led to ICERs ranging from $240,255 to $75,624, with all but two parameters falling below $150,000/QALY. In the PSA, axi-cel had an 64% probability of being cost-effective across 5,000 iterations using a $150,000 willingness-to-pay threshold. Scenarios one and two resulted in ICERs of $105,353 and $102,695, respectively. Discussion: This study finds that axi-cel is cost-effective compared to mosun at the commonly cited $150,000/QALY US willingness-to-pay threshold, with robust results across a range of sensitivity analyses accounting for parameter uncertainty.

Integrated single cell analysis reveals co-evolution of malignant B cells and tumor micro-environment in transformed follicular lymphoma.

Histological transformation of follicular lymphoma (FL) to aggressive forms is associated with poor outcome. Phenotypic consequences of this evolution and its impact on the tumor microenvironment (TME) remain unknown. We perform single-cell whole genome sequencing (scWGS) and transcriptome sequencing (scWTS) of 11 paired pre/post-transformation patient samples and scWTS of additional samples from patients without transformation. Our analysis reveals evolutionary dynamics of transformation at single-cell resolution, highlighting a shifting TME landscape, with an emerging immune-cell exhaustion signature, co-evolving with the shifting malignant B phenotype in a regulatory ecosystem. Integration of scWGS and scWTS identifies malignant cell pathways upregulated during clonal tumor evolution. Using multi-color immunofluorescence, we transfer these findings to a TME-based transformation biomarker, subsequently validated in two independent pretreatment cohorts. Taken together, our results provide a comprehensive view of the combined genomic and phenotypic evolution of malignant cells during transformation and shifting crosstalk between malignant cells and the TME.

Transformation of t(14;18)-negative follicular lymphoma to plasmablastic lymphoma: a case report with analysis of genetic evolution.

BACKGROUND: Follicular lymphoma (FL) is characterized by t(14;18)(q32;q21) involving the IGH and BCL2 genes. However, 10-15% of FLs lack the BCL2 rearrangement. These BCL2-rearrangement-negative FLs are clinically, pathologically, and genetically heterogeneous. The biological behavior and histological transformation of such FLs are not adequately characterized. Here, we report the first case of t(14;18)-negative FL that rapidly progressed to plasmablastic lymphoma (PBL). CASE PRESENTATION: A previously healthy 51-year-old man presented with leg swelling. Computed tomography (CT) showed enlarged lymph nodes (LNs) throughout the body, including both inguinal areas. Needle biopsy of an inguinal LN suggested low-grade B-cell non-Hodgkin lymphoma. Excisional biopsy of a neck LN showed proliferation of centrocytic and centroblastic cells with follicular and diffuse growth patterns. Immunohistochemical analysis showed that the cells were positive for CD20, BCL6, CD10, and CD23. BCL2 staining was negative in the follicles and weak to moderately positive in the interfollicular areas. BCL2 fluorescence in situ hybridization result was negative. Targeted next-generation sequencing (NGS) revealed mutations in the TNFRSF14, CREBBP, STAT6, BCL6, CD79B, CD79A, and KLHL6 genes, without evidence of BCL2 or BCL6 rearrangement. The pathologic and genetic features were consistent with t(14;18)-negative FL. Two months after one cycle of bendamustine and rituximab chemotherapy, the patient developed left flank pain. Positron emission tomography/CT showed new development of a large hypermetabolic mass in the retroperitoneum. Needle biopsy of the retroperitoneal mass demonstrated diffuse proliferation of large plasmablastic cells, which were negative for the B-cell markers, BCL2, BCL6, and CD10; they were positive for MUM-1, CD138, CD38, and C-MYC. The pathologic findings were consistent with PBL. The clonal relationship between the initial FL and subsequent PBL was analyzed via targeted NGS. The tumors shared the same CREBBP, STAT6, BCL6, and CD79B mutations, strongly suggesting that the PBL had transformed from a FL clone. The PBL also harbored BRAF V600E mutation and IGH::MYC fusion in addition to IGH::IRF4 fusion. CONCLUSIONS: We propose that transformation or divergent clonal evolution of FL into PBL can occur when relevant genetic mutations are present. This study broadens the spectrum of histological transformation of t(14;18)-negative FL and emphasizes its biological and clinical heterogeneity.

Moving T-Cell Therapies into the Standard of Care for Patients with Relapsed or Refractory Follicular Lymphoma: A Review.

Patients with follicular lymphoma, an indolent form of non-Hodgkin lymphoma, typically experience multiple relapses over their disease course. Periods of remission become progressively shorter with worse clinical outcomes after each subsequent line of therapy. Currently, no clear standard of care/preferred treatment approach exists for patients with relapsed or refractory follicular lymphoma. As novel agents continue to emerge for treatment in the third-line setting, guidance is needed for selecting the most appropriate therapy for each patient. Several classes of targeted therapeutic agents, including monoclonal antibodies, phosphoinositide 3-kinase inhibitors, enhancer of zeste homolog 2 inhibitors, chimeric antigen receptor (CAR) T-cell therapies, and bispecific antibodies, have been approved by regulatory authorities based on clinical benefit in patients with relapsed or refractory follicular lymphoma. Additionally, antibody-drug conjugates and other immunocellular therapies are being evaluated in this setting. Effective integration of CAR-T cell therapy into the treatment paradigm after two or more prior therapies requires appropriate patient selection based on transformation status following a rebiopsy; a risk evaluation based on age, fitness, and remission length; and eligibility for CAR-T cell therapy. Consideration of important logistical factors (e.g., proximity to the treatment center and caregiver support during key periods of CAR-T cell therapy) is also critical. Overall, an individualized treatment plan that considers patient-related factors (e.g., age, disease status, tumor burden, comorbidities) and prior treatment types is recommended for patients with relapsed or refractory follicular lymphoma. Future analyses of real-world data and a better understanding of mechanisms of relapse are needed to further refine patient selection and identify optimal sequencing of therapies in this setting.

Local radiotherapy and measurable residual disease-driven immunotherapy in patients with early-stage follicular lymphoma (FIL MIRO): final results of a prospective, multicentre, phase 2 trial.

BACKGROUND: The mainstay of treatment for early-stage follicular lymphoma is local radiotherapy, with a possible role for anti-CD20 monoclonal antibody (mAb). We aimed to evaluate the effect of these treatments using a measurable residual disease (MRD)-driven approach. METHODS: This prospective, multicentre, phase 2 trial was conducted at 27 centres of the Fondazione Italiana Linfomi (FIL) in Italy. Eligible participants were adults (≥18 years) with newly diagnosed, histologically confirmed follicular lymphoma (stage I or II; grade I-IIIa). Patients were initially treated with 24 Gy involved-field radiotherapy over 12 days; those who were MRD-positive after radiotherapy or during follow-up received eight intravenous doses (1000 mg per dose; one dose per week) of the anti-CD20 mAb ofatumumab. The primary endpoint was the proportion of patients who were MRD-positive after involved-field radiotherapy and became MRD-negative after ofatumumab treatment. Patients were included in the primary endpoint analysis population if they were positive for BCL2::IGH rearrangement at enrolment in peripheral blood or bone marrow samples. MRD positivity was defined as the persistence of BCL2::IGH rearrangement in peripheral blood or bone marrow, assessed centrally by laboratories of the FIL MRD Network. The trial was registered with EudraCT, 2012-001676-11. FINDINGS: Between May 2, 2015, and June 1, 2018, we enrolled 110 participants, of whom 106 (96%) were eligible and received involved-field radiotherapy. Of these, 105 (99%) were White, one (1%) was Black, 50 (47%) were male, and 56 (53%) were female. Of 105 participants in whom BCL2::IGH status was evaluable, 32 (30%) had a detectable BCL2::IGH rearrangement at baseline. After radiotherapy, 12 (40%) of 30 patients reached MRD-negative status, which was long-lasting (at least 36 or 42 months) in three (25%). In those who were MRD-positive after radiotherapy, ofatumumab induced MRD-negativity in 23 (92%; 95% CI 74-99) of 25 evaluable patients. After a median follow-up of 46·1 months (IQR 42·8-50·8), 14 (61%) of these 23 patients remain in complete response and are MRD-negative. The most common grade 3-4 adverse events were infusion-related reactions, observed in four patients. INTERPRETATION: Local radiotherapy is frequently not associated with the eradication of follicular lymphoma. An MRD-driven, anti-CD20 monoclonal antibody consolidation enables molecular remission to be reached in almost all patients and is associated with a reduced incidence of relapse over time. A clinical advantage of an MRD-driven consolidation is therefore suggested. FUNDING: AIRC Foundation for Cancer Research in Italy, Novartis International, and GlaxoSmithKline.

Long-term Remissions Following CD20-Directed Chimeric Antigen Receptor-Adoptive T-cell Therapy.

Chimeric antigen receptor (CAR) T-cell therapy produces high response rates in refractory B-cell non-Hodgkin lymphoma, but long-term data are minimal to date. In this study, we present long-term follow-up of a pilot trial testing a CD20-targeting third-generation CAR in patients with relapsed B-cell lymphomas following cyclophosphamide-only lymphodepletion. Two of the three patients in the trial, with mantle cell lymphoma and follicular lymphoma, had remissions lasting more than 7 years, though they ultimately relapsed. The absence of B-cell aplasia in both patients suggested a lack of functional CAR T-cell persistence, leading to the hypothesis that endogenous immune responses were responsible for these long-term remissions. Correlative immunologic analyses supported this hypothesis, with evidence of new humoral and cellular antitumor immune responses proximal to clinical response time points. Collectively, our results suggest that CAR T-cell therapy may facilitate epitope spreading and endogenous immune response formation in lymphomas. Significance: Two of three patients treated with CD20-targeted CAR T-cell therapy had long-term remissions, with evidence of endogenous antitumor immune response formation. Further investigation is warranted to develop conditions that promote epitope spreading in lymphomas.

Translational insights into the genetics and immunobiology of relapsed/refractory follicular lymphoma.

Although follicular lymphoma (FL) is traditionally classified as an indolent subtype of B cell non-Hodgkin lymphoma, clinical trajectories are often diverse based on unique disease biology, and many patients will eventually experience relapse of their disease. Furthermore, progression of disease within 24 months is associated with increased mortality rates for FL. In the last five years, we have witnessed an upsurge in the commercial availability of targeted therapies for relapsed/refractory (R/R) FL, including chimeric antigen receptor-T (CAR-T) products, bispecific T cell engagers (BiTEs), epigenetic modifier therapies, and next-generation Bruton tyrosine kinase (BTK) inhibitors. Furthermore, clinical trial options have increased tremendously and now include combinatorial strategies that exert synergy against malignant germinal center B cells. Here, we provide a 2024 update of novel therapeutic agents whose development has been informed by recent advances in the genetics and immunobiology of R/R FL. Specifically, we emphasize high-value targeted therapeutics, including anti-CD3 x anti-CD20 BiTEs and adoptive T cell therapies. We discuss prospects on selection and sequencing of BiTEs and CAR-T therapies for patients with R/R FL. We underscore the principles of FL pathobiology that are paving way for future drug discovery and shed insight into therapeutic targeting within nodal basins based on our increasing understanding of the FL microenvironment. Finally, we summarize how a greater knowledge of FL immunobiology can inform risk stratification and therapy selection on a personalized basis for R/R FL in 2025.

Rapid response in relapsed follicular lymphoma to novel anti-CD19 CAR-T therapy with pseudo-progression and cytomegalovirus infection: A case report.

CD19-directed chimeric antigen receptor (CAR) T cell therapy has been shown to achieve a considerably durable response in patients with refractory or relapsed B cell non-Hodgkin lymphomas. Most of these CARs were generated by lentivirus. With the exception of Yescarta and Tecartus, few patients with relapsed-/refractory- lymphoma have been treated clinically with a CARs using retroviral vector (RV). Here, we reported a relapsed/refractory grade 2 follicular lymphoma patient with multiple chemotherapy failures, and was treated with a novel CD19 CAR-T cell manufactured from a RV. After tumor burden was reduced with Obinutuzumab and Duvelisib, the patient was infused novel CD19 CAR-T cells at a dose of 3 × 106 cells/ kg. Then he experienced a rapid response and achieved almost complete remission by day 26. Only grade 2 CRS, bilateral submaxillary lymph node enlargement and cytomegalovirus (CMV) infection occurred without neurotoxicity, and the patient's condition improved after a series of symptomatic treatments. In addition, CAR copy number peaked at 532,350 copies/µg on day 15 and continued to expand for 5 months. This may be the first case report of RV preparation of novel CD19 CAR-T cells for direct treatment of recurrent follicular lymphoma. We will observe its long-term efficacy and conduct trials in more patients in the future.

Bispecific antibodies targeting CD20xCD3 in immunotherapy for adult B-cell lymphoma: insights from the 65th American Society of Hematology 2023 annual meeting.

INTRODUCTION: At the 65th American Society of Hematology (ASH) 2023 Annual Meeting, the latest advancements in CD20×CD3 BsAbs for B-cell lymphoma (BCL) were highlighted, particularly in relapsed/refractory (R/R) follicular lymphoma (FL) and R/R diffuse large B-cell lymphoma (DLBCL). AREAS COVERED: This summary highlights some of the major studies on CD20×CD3 BsAbs for BCL. EXPERT OPINION/COMMENTARY: CD20×CD3 is the most widely studied BsAb, with promising results in patients with R/R DLBCL and R/R FL ≥ two prior lines of systemic therapy. Trials with the first line of B-cell lymphoma also revealed promising results. Hopefully, BsAb monotherapy or BsAb-containing regimens may become the standard therapy in patients with FL and DLBCL.

Follicular lymphoma with Epstein-Barr virus-associated transformation: A case report and review of the literature.

Follicular lymphoma (FL) is a common type of B-cell lymphoma, accounting for about 20% of all lymphomas. Although FL is primarily characterized by an indolent clinical course, histological transformation (HT) remains one of the significant challenges in managing patients with FL. Here, we present a case of FL with partial large-cell transformation due to Epstein-Barr Virus (EBV) arising in a 50-year-old Japanese woman with no known immunodeficiency. Immunohistochemical studies revealed that medium-sized FL cells expressed CD20, CD10, BCL2, and BCL6, whereas large cells were positive for CD20, and MUM1. In situ hybridization (ISH) revealed large cells to be positive for EBV-encoded small RNA (EBER) and further immunohistochemical investigation demonstrated EBER+ cells to express latent membrane protein 1 (LMP1). The Ki-67 index was about 30% in FL cells, and over 70% in large cells. Fluorescence in situ hybridization for BCL2 combined with EBER-ISH identified BCL2 rearrangement in both EBV-infected large cells and EBV-uninfected FL cells, suggesting these two components were clonally related. These findings indicate that EBV contributes to the transformation of FL. As far as the authors could find, only four previous cases of FL development to EBV-positive aggressive lymphoma have been reported. Further studies are needed to clarify the role of EBV in the HT of FL.

Polatuzumab vedotin, venetoclax, and an anti-CD20 monoclonal antibody in relapsed/refractory B-cell non-Hodgkin lymphoma.

The Phase 2 portion of this study evaluated safety and efficacy of polatuzumab vedotin 1.8 mg/kg and venetoclax 800 mg, plus fixed-dose obinutuzumab 1000 mg or rituximab 375 mg/m2 in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), respectively. Patients with complete response (CR) or partial response (PR)/stable disease (FL) or CR/PR (DLBCL) at end of induction (EOI; six 21-day cycles) received post-induction therapy with venetoclax and obinutuzumab or rituximab, respectively. Primary endpoint was CR rate at EOI. Safety-evaluable populations included 74 patients (FL cohort; median age 64 years; progression of disease within 24 months on first-line treatment, 25.7%; FL International Prognostic Index 3-5, 54.1%; ≥2 previous therapies, 74.3%) and 57 patients (DLBCL cohort; median age 65 years; International Prognostic Index 3-5, 54.4%; ≥2 previous therapies, 77.2%). The most common non-hematologic adverse events (mostly Grades 1-2) in the FL and DLBCL cohorts were diarrhea (55.4% and 47.4%, respectively) and nausea (47.3% and 36.8%); neutropenia was the most common Grades 3-4 toxicity (39.2% and 52.6%). Efficacy-evaluable populations included patients treated at the recommended Phase 2 dose (FL, n = 49; DLBCL, n = 48). CR rates at EOI were 59.2% (FL) and 31.3% (DLBCL); median progression-free survival was 22.8 months (95% confidence interval [CI], 14.5-not evaluable) and 4.6 months (95% CI, 3.6-8.1), respectively. Polatuzumab vedotin plus venetoclax and obinutuzumab/rituximab had acceptable safety in patients with R/R FL or DLBCL, with promising response rates in R/R FL, including high-risk patients.