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Odronextamab, a CD20×CD3 bispecific antibody that engages cytotoxic T cells to destroy malignant B cells, has demonstrated encouraging activity across multiple subtypes of relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. This phase II study (ELM-2; NCT03888105) evaluated odronextamab in patients with R/R follicular lymphoma after two or more lines of systemic therapy. Patients received intravenous odronextamab in 21-day cycles, with step-up dosing in cycle 1 to help mitigate the risk of cytokine release syndrome, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate by independent central review. Among 128 patients evaluated, 95% completed cycle 1, and 85% completed four or more cycles. At 20.1 months' efficacy follow-up, objective response rate was 80.0% and complete response rate was 73.4%. Median duration of complete response was 25.1 months. Median progression-free survival was 20.7 months, and median overall survival was not reached. Discontinuation of odronextamab due to adverse events occurred in 16% of patients. The most common treatment-emergent adverse events were cytokine release syndrome [56%; grade ≥3 1.7% (1/60) with 0.7/4/20 mg step-up], neutropenia (39%), and pyrexia (38%). Odronextamab achieved high complete response rates with generally manageable safety in patients with heavily pretreated R/R follicular lymphoma. • Outcomes for patients with follicular lymphoma (FL) worsen with each relapse, representing a clear medical unmet need. • Odronextamab achieved high rates of deep response with durability in R/R FL, with 73% of patients attaining complete response. • Grade ≥3 cytokine release syndrome was seen in one patient with the optimized step-up regimen, and safety was generally manageable with odronextamab treatment. [ABSTRACT FROM AUTHOR]

ABSTRACT The treatment landscape for relapsed/refractory follicular lymphoma (RR‐FL) is marked by a pivotal debate between chimeric antigen receptor T‐cell (CAR‐T) therapy and bispecific antibodies (BsAbs). While both CAR‐T therapy and BsAbs target similar immunobiology and molecular markers, their efficacy comparisons are hindered by the lack of direct clinical trial comparisons. Key trials, such as the ZUMA‐5 study, underscore axicabtagene ciloleucel (axi‐cel)'s efficacy in treating RR‐FL, achieving a 79% complete response rate with a median duration of response exceeding 3 years. Similarly, lisocabtagene maraleucel (liso‐cel) in the TRANSCEND FL study reports a 94% complete response rate, emphasizing robust outcomes in heavily pretreated patients. Among BsAbs, mosunetuzumab showed promise in the GO29781 trial, with a 62% overall response rate in heavily pretreated RR‐FL patients. Thus, CAR‐T therapy offers potential curative benefits with a single infusion. However, its efficacy is tempered by significant adverse events such as cytokine release syndrome (CRS), neurotoxicity, and cytopenias, requiring specialized management and patient monitoring. In contrast, BsAbs provide a more tolerable treatment option counterbalancing by lower response rates and frequent dosing requirements. Personalized treatment strategies are crucial because of these distinct efficacy and safety profiles. When considering cost‐effectiveness, both therapies need to be evaluated in the context of their clinical outcomes and quality of life improvements. Cost‐effectiveness considerations are essential; while CAR‐T therapies incur higher initial costs, their potential for long‐term remission may mitigate expenses associated with repeated treatments or hospitalizations. Future research into resistance mechanisms and optimal therapeutic sequencing will further refine RR‐FL management strategies. [ABSTRACT FROM AUTHOR]

Background: Beta-2 microglobulin (b2M) is acknowledged as a prognostic biomarker for B-cell malignancies. However, insights into the impact of b2M on B-cell malignancy risk, and vice versa, are limited. Methods: We conducted a genome-wide meta-analysis (GWMA), bidirectional two-sample Mendelian randomization (TSMR) analysis, and pathway enrichment analysis to explore the causal relationship between b2M and B-cell malignancies and the underlying biological processes. Results: The GWMA identified 55 lead SNPs across five genomic regions (three novel: WDR72, UMOD, and NLRC5) associated with b2M. In the UKB, genetically predicted b2M showed a positive association with diffuse large B-cell lymphoma (DLBCL; odds ratio [OR]: 1.742 per standard deviation increase in b2M; 95% confidence interval [CI]: 1.215--2.498; P = 3.00 x 10-3; FDR = 7.50 x 10-3) and Hodgkin lymphoma (HL; OR: 2.270; 95% CI: 1.525--3.380; P = 5.15 x 10-5; FDR =2.58 x 10-4). However, no associations were found with follicular lymphoma (FL), chronic lymphoid leukemia (CLL), or multiple myeloma (MM). Reverse TSMR analysis revealed no association between genetically predicted B-cell malignancies and b2M. In FinnGen, b2M was found to be associated with an increased risk of DLBCL (OR: 2.098; 95% CI: 1.358-3.242; P = 8.28 x 10-4; FDR = 4.14 x 10-3), HL (OR: 1.581; 95% CI: 1.167-2.142; P = 3.13 x 10-3; FDR = 5.22 x 10-3), and FL (OR: 2.113; 95% CI: 1.292-3.455; P = 2.90 x 10-3; FDR = 5.22 x 10-3). However, no association was found with CLL or MM. Reverse TSMR analysis indicated that genetically predicted DLBCL, FL, and MM may perturb b2M levels. Pathway enrichment analysis suggested that the innate immune system represents a convergent biological process underlying b2M, DLBCL, and HL. Conclusions: Our findings suggested that elevated levels of b2M were associated with an increased risk of DLBCL and HL, which is potentially linked to dysfunction of the innate immune system. [ABSTRACT FROM AUTHOR]

The document discusses the occurrence of indolent relapse after initial aggressive B-cell lymphoma treatment, focusing on the transformation of lymphoma types and the clinical outcomes of patients. It highlights the rarity of indolent relapse following initial aggressive lymphoma and the challenges in managing such cases. The study found that patients with indolent relapse had favorable outcomes, with a 10-year overall survival rate of 60%, and suggests the inclusion of these patients in clinical trials for relapsed/refractory indolent lymphomas. [Extracted from the article]

Follicular lymphoma (FL) is the most prevalent indolent B-cell lymphoma entity, often characterized by the t(14;18) BCL2-IGH translocation. The malignancy represents a clinically and biologically highly heterogeneous disease. Most patients have favorable prognoses; however, despite therapeutic advancements, the disease remains incurable, with recurrent relapses or early disease progression. Moreover, transformation to an aggressive histology, most often diffuse large-B-cell lymphoma, remains a critical event in the disease course, which is associated with poor outcomes. Understanding the individual patient's risk of transformation remains challenging, which has motivated much research on novel biomarkers within the past four decades. This review systematically assessed the research on molecular biomarkers in FL transformation and outcome. Following the PRISMA guidelines for systemic reviews, the PubMed database was searched for English articles published from January 1984 through September 2024, yielding 6769 results. The identified publications were carefully screened and reviewed, of which 283 original papers met the inclusion criteria. The included studies focused on investigating molecular biomarkers as predictors of transformation or as prognostic markers of time-related endpoints (survival, progression, etc.). The effects of each biomarker were categorized based on their impact on prognosis or risk of transformation as none, favorable, or inferior. The biomarkers included genetic abnormalities, gene expression, microRNAs, markers of B cells/FL tumor cells, markers of the tumor microenvironment, and soluble biomarkers. This comprehensive review provides an overview of the research conducted in the past four decades, underscoring the persistent challenge in risk anticipation of FL patients. [ABSTRACT FROM AUTHOR]

Most follicular lymphomas (FLs) demonstrate an indolent clinical course with favorable outcomes; however, a fraction of patients experiences progression of disease within 24 months (POD24) and has adverse outcomes. This study aimed to determine the predictive risk factors for POD24 in patients with FL, and the characteristics of the microenvironment in FL with POD24. By multivariate analysis, we revealed that increased Ki-67 expression was associated with POD24 events in patients with FL (hazard ratio [HR]: 6.29, 95% confidence interval [CI]: 1.96–20.22, p = 0.0020). Additionally, patients with FL with POD24 demonstrated immune cell reduction by immunohistochemistry analysis. Our results help better understand the therapeutic strategies for FL with POD24. [ABSTRACT FROM AUTHOR]

The letter to the editor in Leukemia & Lymphoma discusses the link between a high Ki67 index and shorter progression-free survival in patients with Follicular Lymphoma undergoing frontline immunochemotherapy. The study underscores the significance of Ki67 as a prognostic factor for evaluating the proliferative activity of lymphoma cells. Research conducted at two tertiary care medical centers revealed that an IF Ki67 index ≥ 30% was associated with an elevated risk of disease progression, emphasizing the necessity for further investigations to identify predictive baseline characteristics in Follicular Lymphoma. The study examined the correlation between FLIPI/Ki67 (FKi) score and progression-free survival (PFS) in FL patients receiving frontline immunochemotherapy, with the FKi score predicting an increased risk of progression and being linked to PFS. Despite limitations like a retrospective analysis and a small sample size, the study suggests the potential value of integrating Ki67 into prognostic indices for FL, calling for additional research to validate these findings and explore the incorporation of FLIPI and Ki67 in contemporary FL treatment protocols. [Extracted from the article]

Summary Grade 3B follicular lymphoma (G3BFL) is a rare lymphoma thought to sit on a continuum between low‐grade FL and diffuse large B‐cell lymphoma (DLBCL). The prognostic impact of quantitative positron emission tomography (PET) metrics such as total metabolic tumour volume (TMTV), total lesion glycolysis (TLG), and maximum standard uptake value (SUVmax) have been extensively analysed in FL and DLBCL, but G3BFL data are lacking. Here, we describe PET outcomes and radiomic characteristics in 46 G3BFL cases uniformly treated with R‐CHOP (like) chemotherapy. Central semi‐automated PET TMTV, TLG, and SUVmax analyses, using MIM software, were correlated with clinical outcomes and compared with published results in low‐grade FL and DLBCL. In G3BFL, the end‐of‐treatment complete metabolic response was associated with improved progression‐free survival (PFS; p = 0.002) and overall survival (OS; p = 0.04). G3BFL median TLG (1455) and SUVmax (16.50) sit between published values for low‐grade FL (TLG: 1112, SUVmax: 11.3) and DLBCL (TLG: 3004, SUVmax: 24.35). No association between TMTV (>350 cm3) and survival was seen (PFS: p = 0.24; OS: p = 0.40). High SUVmax (>19.2) and TLG (>2760) both conferred inferior PFS but not OS (PFS: SUVmax p = 0.004; TLG p = 0.05). These data support the routine incorporation of PET radiomics at baseline and treatment response for G3BFL. [ABSTRACT FROM AUTHOR]

Background: Patients with follicular lymphoma (FL) often relapse or become refractory to treatment (R/R). While the R/R FL treatment landscape evolves, little is known about the priorities of patients and physicians. This discrete‐choice experiment (DCE) study assessed patients' and physicians' treatment preferences, and the trade‐offs they would be willing to make between efficacy, tolerability, and administration. Methods: An online survey was conducted in US‐based patients (≥18 years) with R/R FL and FL‐treating physicians. The DCE was informed by a targeted literature review, clinical data, expert oncologist input, and pilot interviews. Participants completed eight experimental choice tasks where they chose between two hypothetical treatment profiles defined by six attributes: progression‐free survival (PFS), administration/monitoring, risks of laboratory abnormalities requiring intervention, severe infections, diarrhea, and cytokine release syndrome (CRS). Relative attribute importance (RAI) and willingness to trade‐off between PFS and other attributes were estimated. Results: Two‐hundred patients (mean age 63.5 years; median three prior lines of therapy) and 151 FL‐treating physicians participated. Increasing PFS was most important for both groups, although it was relatively less important to patients than physicians (RAI 35.2% vs. 45.7%). Administration/monitoring was three times more important to patients than physicians (RAI 28.8% vs. 9.5%); patients preferred oral treatment and would be willing to tolerate a significant reduction in PFS for oral administration over weekly intravenous infusions. Avoiding CRS was less important to patients than to physicians (RAI 7.7% vs. 15.8%). Both groups would accept shorter PFS for reduced risks of side effects (especially of laboratory abnormalities for patients and of CRS for physicians). Conclusion: Although PFS was the most important attribute to patients and physicians, both would tolerate lower PFS for reduced side effects. Patients would also accept a substantial reduction in PFS for oral administration. Differences between the preferences/priorities of patients and physicians highlight the importance of shared decision‐making. [ABSTRACT FROM AUTHOR]

The article discusses the impact of total lesion glycolysis (TLG) in predicting the response of follicular lymphoma (FL) to rituximab. FL is a common type of non-Hodgkin lymphoma characterized by the (14;18) translocation. The study evaluates whether early rituximab monotherapy could delay chemotherapy in FL patients with low tumor burden. Results suggest that patients with FL should be evaluated using 18F-FDG PET scan and stratified based on TMTV and TLG thresholds to guide treatment decisions. [Extracted from the article]

Simple Summary: This research aims to identify new protein markers that can help predict the risk of disease progression in patients with follicular lymphoma (FL) at the time of diagnosis. By analyzing a large number of proteins in FL samples, the study found significant differences in protein composition among patients, which may help distinguish those at higher risk of disease progression. These findings could improve our understanding of FL biology and lead to the discovery of new biomarkers or treatment targets, potentially allowing for more personalized and effective treatment strategies for FL patients, improving their outcomes. Background: Follicular lymphoma (FL) is characterized by an indolent nature and generally favorable prognosis, yet poses a particular clinical challenge, since disease progression is observed in a notable subset of patients. Currently, it is not possible to anticipate which patients will be at risk of progression, highlighting the need for reliable predictive biomarkers that can be detected early in the disease. Methods: We applied tandem-mass-tag labelled nano-liquid chromatography tandem mass spectrometry (nLC-MS/MS) on 48 diagnostic formalin-fixed, paraffin-embedded tumor samples from patients with advanced-stage FL. Of these, 17 experienced subsequent progression (subsequently-progressing, sp-FL) while 31 did not (non-progressing, np-FL). Results: We identified 99 proteins that were significantly differentially expressed between sp-FL samples and np-FL samples (p < 0.05; log2-fold changes between 0.2 and −1.3). Based on this subset of proteins, we classified patients into high-risk and low-risk subgroups using unsupervised machine learning techniques. Pathway analyses of the identified proteins revealed aberrancies within the immune system and cellular energy metabolism. In addition, two proteins were selected for immunohistochemical evaluation, namely stimulator of interferon genes 1 (STING1) and isocitrate dehydrogenase 2 (IDH2). Notably, IDH2 retained significantly lower expression levels in sp-FL samples compared with np-FL samples (p = 0.034). Low IDH2 expression correlated with shorter progression-free survival (PFS, p = 0.020). Conclusions: This study provides evidence for some of the biological mechanisms likely to be involved in FL progression and, importantly, identifies potential predictive biomarkers for improvement of risk stratification up-front at time of FL diagnosis. [ABSTRACT FROM AUTHOR]

The concept of time toxicity in oncology refers to the presence of frequent healthcare-related interactions that can interfere with patient well-being. In this review, we examine several manifestations of time toxicity in non-Hodgkin lymphoma and multiple myeloma and discuss their impact on decision-making with patients. For example, time toxicity may influence the choice of chemoimmunotherapy versus lenalidomide-rituximab in follicular lymphoma. In myeloma, it may inform the optimal dosing schedule for proteasome inhibitors and bisphosphonates. In both malignancies, varying time toxicity profiles are a key distinction between chimeric antigen receptor T-cell therapies and bispecific antibodies. We outline the challenges with measuring time toxicity as a trial endpoint but discuss its importance as a consideration for patient care, both in standard-of-care settings and in clinical trials. Throughout the review, we highlight strategies to lower the time toxicity of therapies in lymphoma and myeloma without compromising their efficacy or patient safety. [ABSTRACT FROM AUTHOR]

Introduction: The histological transformation (HT) of follicular lymphoma (FL) is a crucial biological event. The study aimed to evaluate the incidence, clinicial characteristics, prognosis and impact of HT time on survival of FL transforming to diffuse large B‐cell lymphoma in population‐based large‐scale cohorts. Methods: A retrospective cohort study of FL with HT was performed in the Surveillance, Epidemiology, and End Results database. The Hematological Malignancy Research Network FL cohort and Aristotle study FL cohort were used to assess the external validity. Results: Among 44,127 FL cases from the Surveillance, Epidemiology, and End Results database, 1311 cases were pathology‐proven recorded to transform to diffuse large B‐cell lymphoma. The cumulative rates of HT at 5, 10, and 15 years after FL diagnosis were estimated to be 1.19%, 2.93%, and 5.01%, respectively. Significantly worse overall survival and cancer‐specific survival were exhibited in patients with HT than those without HT. Early HT (transformation of FL within 48 months after FL diagnosis [TOD48]) was an independent predictor for adverse overall survival of HT patients, regardless of treatment modalities before transformation. The adverse prognostic effect of TOD48 was validated in the Hematological Malignancy Research Network cohort and Aristotle study cohort. Older age (>75 years) and B symptoms within FL at diagnosis were the independent risk factors of TOD48. Furthermore, a novel prognostic model combining TOD48 with Follicular Lymphoma International Prognostic Index (TOD48‐FLIPI) was constructed and validated for risk stratification. Conclusion: TOD48 was a risk indicator of HT, and the novel prognostic model "TOD48‐FLIPI" for HT patients was proposed. [ABSTRACT FROM AUTHOR]

AbstractObjectiveMethodsResultsConclusions Trial registration\nPLAIN LANGUAGE SUMMARYWe report patient-reported outcomes (PROs) measuring health-related quality of life (HRQoL) from the ROSEWOOD trial (NCT03332017), which demonstrated superior efficacy and a manageable safety profile with zanubrutinib plus obinutuzumab (ZO) versus obinutuzumab (O) in patients with heavily pretreated relapsed/refractory follicular lymphoma (R/R FL).PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30 (EORTC QLQ-C30) and EQ-5D-5L questionnaires at baseline and subsequently every 12 weeks. All QLQ-C30 domains and EQ-5D-5L visual analog scale (VAS) scores were analyzed descriptively. At the key clinical timepoints (weeks 12 and 24), a mixed model for repeated measures (MMRM) analysis was used to evaluate the key PRO endpoints, including global health status, physical and role functioning, and symptoms of fatigue, pain, diarrhea, and nausea/vomiting. Clinically meaningful change was defined as a ≥ 5-point mean difference from baseline and between the ZO and O arms.Patients were randomized to ZO (n = 145) or O (n = 72). By week 48, descriptive analysis results indicated that patients in the ZO arm demonstrated improved outcomes in role functioning and fatigue and nausea/vomiting symptoms, compared with those in the O arm. Both groups experienced improvements in pain symptoms. EQ-5D-5L VAS scores showed no observable differences between treatment arms through week 48. MMRM analysis revealed that the global health status/quality of life of patients treated with ZO improved, as did fatigue, at week 12. At week 24, patients in the ZO arm experienced a clinically meaningful improvement in role functioning, pain, and fatigue.In patients with R/R FL, ZO was associated with improved PROs compared with O. These findings suggest that zanubrutinib contributed clinically meaningful benefits to patient HRQoL when added to obinutuzumab.The ROSEWOOD trial is registered on ClinicalTrials.gov (BGB-3111-212; ClinicalTrials.gov identifier: NCT03332017).Follicular lymphoma (or FL) is a common blood cancer where abnormal white blood cells form lumps in organs and glands in the body that normally help fight infection (lymph nodes). Zanubrutinib selectively blocks Bruton tyrosine kinase, which can prevent cancer cells growing and lead to their death. Obinutuzumab binds to a protein called CD20 on cancer cells, facilitating their removal using the body’s natural defense system. Previous results from the ROSEWOOD trial showed that zanubrutinib plus obinutuzumab had improved cancer-fighting effects versus obinutuzumab alone, with manageable side effects in patients whose cancer returned after treatment or when treatment had failed. This study examined how these two cancer treatments impacted the patients’ wellbeing and day-to-day functioning as reported directly by them (patient-reported outcomes). Researchers found that by week 48 of the trial, patients who received zanubrutinib plus obinutuzumab found it easier to manage daily activities (role functioning) and had fewer symptoms of feeling exhausted all the time (fatigue) and nausea/vomiting versus those who received obinutuzumab alone. Further analysis showed that the patients who received zanubrutinib plus obinutuzumab had noticeable improvements from the start of treatment in role functioning, pain, and fatigue versus patients receiving obinutuzumab alone at week 24 of the trial. In conclusion, this study showed that zanubrutinib plus obinutuzumab was associated with improved patient-reported outcomes versus obinutuzumab alone in patients with relapsed or refractory FL. [ABSTRACT FROM AUTHOR]

Summary Some ‘watch and wait’ (W&W) FL patients suffer from rapid progression in a short term. Herein, we sought to identify these patients and also develop a risk score to screen them at diagnosis. Between 2008 and 2022, a total of 411 FL patients managed by the W&W strategy from 16 cancer centres were retrospectively enrolled in this study, and their time to lymphoma treatment (TLT) and progression‐free survival (PFS) were evaluated. Thirty‐five percent of W&W FL patients experienced TLT within 24 months (TLT24) after diagnosis. Their 5‐year PFS rate was significantly lower than those without treatment at 24 months (62.3% vs. 89.5%). In multivariable analysis, five factors were identified as independent predictors of TLT24: stages III–IV, β2 microglobulin ≥3 mg/L, lymphocyte‐to‐monocyte ratio <3.8, bone marrow involvement and spleen enlargement (above umbilical line). Their AUCs for TLT24 were 0.76 (95% CI, 0.70–0.82) in the training cohort and 0.76 (95% CI, 0.67–0.85) in the validation cohort respectively. Risk groups were also associated with PFS (p < 0.001). In FL patients initially managed by W&W, TLT24 was associated with poor outcomes. This multivariable model helps screening for predicting TLT24, which may be useful to identify candidates for early interventional treatment. [ABSTRACT FROM AUTHOR]

This document is a report on the progression of disease in follicular lymphoma patients in Denmark during the rituximab era. The study analyzed real-world data from a Danish cohort of patients diagnosed between 2005 and 2020. The incidence of disease progression within 24 months was found to be 23%, and patients with this progression had worse outcomes compared to those without it. The study identified several risk factors associated with disease progression, including high FLIPI risk scores, age above 60, and advanced disease stage. The authors emphasize the importance of close monitoring and further research to improve the prognosis of high-risk patients. [Extracted from the article]

Summary Acalabrutinib is a selective, second‐generation Bruton tyrosine kinase inhibitor. In this open‐label, parallel‐group study, patients with relapsed/refractory (R/R) follicular lymphoma (FL) were randomised to either acalabrutinib monotherapy or acalabrutinib plus rituximab. An additional cohort of patients with treatment‐naive (TN) FL received only the acalabrutinib‐rituximab combination. Acalabrutinib‐rituximab was well tolerated and active in R/R and TN FL; in the TN cohort the overall response rate was 92.3% with most remissions lasting over 4 years. Acalabrutinib monotherapy was also well tolerated and active in R/R FL. These results support further study of acalabrutinib alone and in combination with rituximab in FL. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusion Epigenetics has been shown to be relevant in oncology: BMI1 overexpression has been reported in leukemias, EZH2 mutations have been found in follicular lymphoma, and USP22 seems to stabilize BMI1 protein. In this study, we measured the expression of BMI1, EZH2, and USP22 in lymph nodes from 56 diffuse large B‐cell lymphoma (DLBCL) patients.A new multiplex digital droplet PCR (ddPCR) has been set up to measure the expression of 4 genes (BMI1, EZH2, USP22, and GAPDH) in the same reaction on RNA extracted from paraffin‐embedded tissues.The specificity of ddPCR was confirmed by a 100% alignment on the BLAST platform and its repeatability demonstrated by duplicates. A strict correlation between expression of BMI1 and EZH2 and BMI1 and USP22 has been found, and high expression of these genes was correlated with extra‐nodal lymphomas. Progression‐free survival (PFS) and overall survival (OS) were conditioned by IPI, bone marrow infiltration, and the complete response achievement. High levels of BMI1 and USP22 did not condition the response to therapy, but impaired the PFS, especially for patients defined at “high risk” based on the cell of origin (no germinal center [GCB]), high BCL2 expression, and IPI 3‐5. In this subgroup, the probability of relapse/progression was twice higher than that of patients carrying low BMI1 and USP22 levels.High expression of BMI1 and of USP22 might be a poor prognostic factor in DLBCL, and might represent the target for novel inhibitors. [ABSTRACT FROM AUTHOR]

AbstractDuodenal-type follicular lymphoma (DFL) is a rare subtype classified by the 5th edition of the WHO and international consensus classifications of lymphoid neoplasms, typically presenting as localized disease with favorable outcomes. This multicenter retrospective study examines 53 Brazilian DFL patients with a median age of 58.2 years (33–85), with males comprising 50% (n = 27). According to Lugano GI tract classification, 40 patients (75%) were stage I. Median follow-up was 2.9 years (range 0.1–11). Incidental diagnosis occurred in 28 patients (52.8%) during routine endoscopy; 24 patients (45%) presented mild gastrointestinal symptoms. Treatments included watchful waiting (32 patients, 60.4%), rituximab monotherapy (15 patients, 28.3%), radiotherapy (three patients, 5.7%), and chemoimmunotherapy (three patients, 5.7%). Three patients experienced disease progression; watchful waiting showed three spontaneous remissions. No deaths occurred during follow-up. This study, the first from Latin America, demonstrates a good prognosis across treatments, highlighting Watchful waiting’s effectiveness. [ABSTRACT FROM AUTHOR]

Background Although patients with lymphoma appear particularly vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the clinical evolution of coronavirus disease 2019 (COVID-19) in a patient with lymphoid malignancies has been under-represented, especially in relation to chemo-, chemo-immunotherapy. Materials and Methods Among adult patients with lymphoma receiving treatment in a specialized lymphoma center at a 500-bed, university-affiliated hospital, we retrospectively reviewed the medical records of patients diagnosed with SARS-CoV-2 infection from January 2020 to April 2022. Results A total of 117 patients with a median age of 53 years were included. One hundred twelves (95.7%) were non-Hodgkin lymphoma. Eighty-six patients (73.5%) were on active chemotherapy and 9 were post stem cell transplant state. Sixty-one patients had more than one comorbidity and 29 had hypogammaglobulinemia. Thirty-four patients (29.1%) had never received a COVID-19 vaccine. During a median follow-up of 134 days, COVID-19 pneumonia developed in 37 patients (31.6%). Excluding three patients who died before the 30 days, 31 out of 34 patients had ongoing symptomatic COVID-19. Eleven patients (9.4%) had post COVID-19 lung condition that persisted 90 days after COVID-19 diagnosis. Overall mortality was 10.3% (12 of 117), which was higher in patients with pneumonia. In multivariate analyses, age 65 years or older, follicular lymphoma, receiving rituximab maintenance therapy, and lack of vaccination were significantly associated with the development of COVID-19 pneumonia. Conclusion Patients with lymphoma are at high risk for developing pneumonia after SARS-CoV-2 infection and suffer from prolonged symptoms. More aggressive vaccination and protective measures for patients with lymphoma who have impaired humoral response related to rituximab maintenance therapy and hypogammaglobulinemia are needed. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, advanced therapy medicinal products (ATMPs) have revolutionised medicine with the promise of new treatments for previously incurable diseases. Chimeric antigen receptor (CAR T) cell therapies, in particular, have emerged as a highly active area of research and entrepreneurship. CAR T-cells are generated by introducing into T-cells a chimeric receptor (CAR). The CAR confers the T-cells the capacity to recognise a molecule expressed by the tumour. There are at least 10 different CAR T-cells with approval by different regulatory agencies around the globe. Several clinical trials have been performed in patients with solid tumours, as well as in patients with autoimmune conditions. There are several studies showing the potential benefit of CAR T-cells for other non-malignant diseases such as asthma and even fungal infections. We offer a brief summary of some of the most relevant aspects of the use of CAR T-cells for some of these conditions. The use of chimeric antigen receptors (CAR T-cells) for the treatment of patients with malignant haematological diseases has become a well-established application for conditions such as refractory or relapsed B-cell acute lymphoblastic leukaemia (B-ALL), B-cell lymphomas (BCL), and multiple myeloma (MM). Nearly 35,000 patients have received autologous CAR T-cells for the treatment of these conditions only in the USA. Since their approval by the Food and Drug Administration (FDA) in 2017, over 1200 clinical trials have been initiated globally and there are at least 10 different CAR T-cells with approval by different regulatory agencies around the globe. In the USA, the FDA has approved six commercial CAR T-cells that are widely distributed worldwide. At the time of writing, several clinical trials have been performed in patients with solid tumours such as glioblastoma, renal and pancreatic cancer, as well as in patients with autoimmune conditions such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SS). There are also several studies showing the potential benefit of CAR T-cells for other non-malignant diseases such as asthma and even fungal infections. In this review, without pretending to cover all current areas of treatments with CAR T-cells, we offer a brief summary of some of the most relevant aspects of the use of CAR T-cells for some of these conditions. [ABSTRACT FROM AUTHOR]

Infections remain a major concern following bispecific antibody therapy but are not well described in pivotal trials. We present the first well-documented case of a classic but rare opportunistic infection, disseminated Mycobacterium avium complex, in a patient receiving bispecific antibody therapy. [ABSTRACT FROM AUTHOR]

Objective: Previous results about prognostic value of CD4+ T cells in follicular lymphoma (FL) remain controversial. Methods: Immunohistochemistry was used to examine expression of positive CD4 cells in 103 patients with FL 1‐3A. Early failure was described as failing to achieve event‐free survival (EFS) at 12 or 24 months. Results: There were 49 (47.6%) male and 54 (52.4%) females, with a median age of 54 years. Compared to patients with <20% of positive CD4 cells, patients with ≥20% of positive CD4 cells exhibited a significant lower risk of early failure (2‐year EFS rate: 56.7% vs 73.5%, p = 0.047). When patients were stratified based on positive CD4 cell combined with FLIPI, the median EFS (p = 0.002) and median OS (p = 0.007) were significantly different. Conclusions: This study demonstrated that higher expression of positive CD4 cells predicts lower risk of early failure in follicular lymphoma, and combination analysis of CD4 and FLIPI could better predict disease relapse and survival outcome. [ABSTRACT FROM AUTHOR]

Introduction: The development of secondary hypogammaglobulinemia (sHGG) because of tumor treatment and/or the primary underlying hematologic disorder holds substantial clinical significance. B-cell-derived malignancies and anti-CD20 monoclonal antibodies (mAbs) represent important risk factors for the development of sHGG. In addition, the occurrence of acute thrombocytopenia (AT) induced by anti-CD20 therapy is a known, albeit rare, phenomenon. Case Presentation: A 54-year-old patient experiencing the first relapse of classical follicular lymphoma has commenced salvage therapy following the R-DHAP protocol. After rituximab infusion, platelet count dropped from 116 × 109/L to 13 × 109/L within 24 h. Reduced immunoglobulin G levels indicated moderate HGG; thus, we immediately administered intravenous immunoglobulins (IVIg). Within 5 days after initiation of IVIg, platelet count increased and stabilized at >50 × 109/L. Conclusions: It seems possible that anti-CD20 mAbs act like or activate similar mechanisms as autoantibodies in immune thrombocytopenia (ITP). Assuming that anti-CD20 therapy-induced AT is an ITP-like condition, HGG could be considered a potential risk factor. Thus, appropriate treatment of HGG with IVIg prior to anti-CD20 mAb therapy could potentially alleviate anti-CD20 therapy-induced AT. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the reliability of the Deauville score (DS) in therapy response assessment and to define the prognostic value of the metabolic response of end of induction (EOI) [18F]FDG PET (PET) in follicular lymphoma patients. Methods: Adult patients with untreated grade 1–3a FL/ stage II‐IV enrolled in the multicentre, prospective, phase III FOLL12 trial (NCT02063685) were randomized to receive standard immunochemotherapy followed by rituximab maintenance (standard arm) versus standard immunochemotherapy followed by response-adapted post‐induction management (experimental arm). Baseline and EOI PET were mandatory for the study. All PET scans were centralized on the WIDEN® platform and classified according to DS in a blind independent central review. DS1–3 was considered negative (CMR), whereas DS4‐5 was considered positive (not CMR). The primary endpoint was PFS. The main secondary endpoint was overall survival (OS). Results: Overall, 807 follicular lymphoma patients—52% women, 89% stage III-IV disease, 40% with a high-risk FLIPI-2 score (3–5)—were enrolled in the study; 729 (90.4%) baseline and EOI PET were available for the analysis. EOI PET was positive (DS4–5) in 88/729 (12.1%) cases. Overall inter-reviewer agreement on PET pos/neg result was 0.92, while agreement on positive and negative cases was 0.77 and 0.94, respectively. The median follow-up was 69 months; 247 events were registered in the 5-yr follow-up, with a 5-yr PFS of 67% (95%CI: 63%–70%). The 5-yr PFS rate for PET neg (DS1–3) and PET pos (DS4–5) patients was 71% (95%CI: 67%–75%) and 36% (95%CI: 25%–46%), respectively, with HR 3.49 (95%CI: 2.57–4.72). Five-year PFS was worse as DS increased, with 74% (70%–78%), 58% (48%–67%; HR 1.71; p = 0.001)] and 36% (25%–46%; HR 3.88; p < 0.001) in DS1–2, DS3 and DS4–5, respectively. EOI PET maintained its prognostic value in both the standard and experimental arms. In the whole population, 5-yr OS was 94% (95%CI: 92%–96%), with 96% (95%CI: 94–97) and 82% (95%CI: 72%–89%) in EOI PET negative (DS1–3) and positive (DS4–5), respectively (HR 4.48; p < 0.001). When DS was associated with FLIPI-2, patients with DS3 or DS1–2 with high FLIPI-2 (3–5) experienced worse OS than patients with DS1–2 and low FLIPI-2 (1–2) (p = 0.003). Conclusion: This study shows that DS is a reliable prognostic tool to evaluate EOI PET in follicular lymphoma patients, with prognostic value maintained both in the standard and experimental arms, making metabolic imaging a robust tool to assess response in FL. Moreover, although preliminary, this study provides further information on DS3 patients, who are considered as CMR but show a less favourable PFS than DS1–2 patients. [ABSTRACT FROM AUTHOR]

The survival rate of non-Hodgkin lymphoma (NHL) has steadily improved. However, osteoporosis introduced by treatment is prevalent and associated with increased mortality and disability for patients with NHL. We aimed to investigate factors impacting bone mineral density (BMD) reduction and osteoporosis, and the trend of BMD after chemotherapy. Overall, 97 newly diagnosed patients with follicular lymphoma (FL) were retrospectively enrolled. CT attenuation values were measured to assess BMD levels. Although 73.2% of patients received calcium and vitamin D supplements, 44.3% showed significant BMD reduction, and baseline BMD and hemoglobin levels were the risk factors. 26.6% of patients newly developed osteoporosis post-chemotherapy where age and cumulative dose of glucocorticoid were risk factors. The results of 20 patients with consecutive follow-up showed that BMD continued to decline for 6 months post-chemotherapy and did not return to baseline values. Therefore, BMD evaluation and more positive anti-resorption treatments should be administered for high-risk patients. [ABSTRACT FROM AUTHOR]

Summary: Implementation of targeted drugs in the treatment landscape of indolent B‑cell malignancies has facilitated long-term remissions and reduced treatment-related toxicities for a substantial proportion of patients across several disease entities. Yet, adverse prognostic genetic aberrations such as TP53 dysfunctions and short-lived remissions after front-line therapy cannot be fully compensated with currently licensed novel agents thereby predisposing affected patients to inferior clinical outcomes in the long run. Moreover, acquired resistance and increasing drug intolerability typically evolving with continuous treatment remain challenges to overcome in daily clinical practice. With these unmet medical needs in mind, several clinical trials are currently investigating the efficacy and feasibility of time-limited novel drug combinations across several indolent B‑cell malignancies. This short review aims to give an update on novel clinical trial data presented at the International Conference of Malignant Lymphoma 2023. [ABSTRACT FROM AUTHOR]

Follicular lymphoma is one of the most common non-Hodgkin’s lymphomas in adults. One of the rather rare variants of follicular lymphoma is pediatric follicular lymphoma. This variant, despite the name, is diagnosed not only in children, but also among young adults. Pediatric follicular lymphoma is characterized by early (I, II) stages, the absence or weak BCL2 expression, and the predominant absence of t(14;18)(q32;q21) translocation. Treatment tactics vary widely from radical surgical tumor resection with subsequent follow-up to chemoimmunotherapy with rituximab.This article presents a clinical case of advanced pediatric follicular lymphoma (stage III) in a 5-year-old patient. Using a combined treatment approach (surgery followed by immunochemotherapy) allowed to achieve a complete metabolic response which lasts more than a year.

Recent advances in the diagnosis and understanding of follicular lymphoma (FL) pathogenesis have had a significant impact on therapeutic tactics. The life expectancy of patients has increased significantly. Currently, the 5-year overall survival of FL patients achieved 90 %, and its median is approaching 20 years. However, FL remains an incurable disease with periods of remission and relapse, requiring multiple therapy courses throughout the patient’s life.The main problem is the treatment of patients with refractory/relapsed forms, especially after 3rd line of therapy, as well as with a primarily resistant course and early (in the first 2 years) relapses. Therefore, despite the indolent FL course in most patients, there remains a need for new drugs that can ensure increased treatment efficacy with minimal toxicity and simultaneously maintain a high quality of life, mainly in the presence of primary refractoriness, early progression and in later lines of therapy. In recent years, new targeted drugs have been studied – phosphoinositide 3-kinase, enhancer of zeste homolog 2 inhibitors, as well as immunological drugs (CAR-T therapy (CAR – chimeric antigen receptor) and bispecific antibodies).The article presents the possibilities of treatment for refractory/relapsed FL as 3rd and subsequent therapy lines.

Abstract Follicular lymphoma (FL) is an indolent, germinal center B cell–derived lymphoid neoplasm, for which recent advances in treatment have substantially improved patient survival. However, FL remains an incurable and heterogeneous disease, with groups of patients experiencing early disease progression, histologic transformation, or a high risk of treatment-related toxicity. Additionally, FL is a continually relapsing disease, and response rates and disease-control intervals decrease with each subsequent line of therapy. In this review, we explore the current treatment landscape for relapsed or refractory FL and promising therapies in development, highlighting the efficacy and potential risks of each treatment. We provide a real-world perspective on the unmet needs of patients with FL. Novel therapeutic approaches in development offer a wide array of options for clinicians when treating relapsed or refractory FL. A nuanced approach is required to address the needs of individual patients, taking into consideration both the risks and benefits of each treatment option, as well as patient preferences.

Background. Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of hematological malignancies, the vast majority of which are B-cell tumors. The most common variant of NHL is diffuse large B-cell lymphoma (DLBCL), characterized by an aggressive course, which accounts for 30–40% of all NHL. The second most common is follicular lymphoma (FL), traditionally classified as an indolent variant accounting for up to 25% of all NHL. Current therapies for these lymphoproliferative disorders which includes innovative drugs in the 1st line of therapy (LT) have demonstrated high efficacy. However, some patients develop a relapse or a refractory disease. Despite recent significant progress in the development and implementation of innovative targeted drugs, in most cases, it is not possible to achieve persistent long-term remissions after disease relapse, which leaves patients with an unmet need for effective and well-tolerated treatment options. Aim. To obtain objective data on the incidence, clinical course, and effectiveness of therapy for the most common variants of NHL in real-world practice in Russia. Materials and methods. From February to March 2023, 130 hematologists and oncologists from 30 regions of Russia were surveyed to update the data on DLBCL and FL. Results. Over the past 12 months, 5,689 patients with NHL were observed, of which 56% had DLBCL; 62% of them received the 1st LT, 22% received the 2nd LT, 10% received the 3rd LT, and only a few reached later lines. Analysis of the administered treatment options in the 2nd and 3rd LTs shows that there is no standard of care for this population, and the effectiveness of the regimens used in real-world Russian practice is extremely low. FL accounted for 23% of all 5,689 patients with NHL, of which 56% were newly diagnosed and 44% received treatment for relapse. The majority of patients with FL who received ≥3 LTs had an inferior prognosis and rapid disease progression: the median time from diagnosis to the beginning of the 3rd LT was only 26.4 months. The analysis of treatment options for patients with relapsed FL indicates a lack of standard and effective therapies. Conclusion. Relapsed and refractory DLBCL and FL represent a complex clinical situation where the main goal of treatment is disease control due to the impossibility of achieving stable remissions with existing treatment options. Clinicians with great hope are looking to the emergence of new classes of drugs that will be able to improve the prognosis for this complex population.

Background. The COVID-19 pandemic, which swept the world in 2020–2021, had a significant impact on the epidemiological picture of hematological malignancies. Aim. To study the dynamics of epidemiological indicators of five chronic hemoblastoses in Moscow over a 12-year period, and also to assess the impact of the COVID-19 pandemic on these indicators. Materials and methods. A population-based study was conducted for five types of oncohematological diseases: multiple myeloma, Hodgkin's lymphoma, follicular lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia. The annual rates of morbidity, mortality, prevalence of these nosologies, overall survival, and expected overall survival were calculated. Gender and age characteristics for each disease were determined. Results and discussion. The present study showed a uniform increase in the incidence and prevalence of five hematological malignancies between 2012 and 2019. Convincing evidence of an increase in mortality and a decrease in the number of diagnosed cases in comparison with the expected figures for these hematological malignancies in 2020–2021 was presented. A greater reduction was shown for cases diagnosed at early stages compared to later ones. During the pandemic, a significant increase in mortality was recorded among patients with chronic lymphocytic leukemia and multiple myeloma, while in cohorts of patients with chronic myeloid leukemia and Hodgkin lymphoma it increased slightly. The return of morbidity, mortality and prevalence rates to the original dynamics in 2022–2023 has been demonstrated. Conclusion. This study demonstrated the features of the regional pattern of incidence, mortality, prevalence and gender-age characteristics of five hematological malignancies and provided the changes in the indicators dynamics of different hematological malignancies during the COVID-19 pandemic.

Abstract 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.

Abstract Follicular lymphoma (FL) is a clinically heterogeneous disease. The need for treatment, treatment sequencing, number of treatment lines, and its association with survival have not been described in a population‐based setting. We identified all patients diagnosed with FL in the Swedish Lymphoma register from 2007 to 2014, followed until 2020, with detailed data on progression/relapse, transformation, and 2nd and further lines of therapy. During a median follow‐up of 6.8 years, 1226 patients (69%) received 1st systemic treatment, 358 patients (20%) were managed with watch‐and‐wait (WaW) only, and 188 (10%) patients were treated with radiotherapy and did not require additional therapy during the study period. Among patients starting systemic treatment, 496 (40%), 224 (18%), and 88 (7%) received 2nd‐, 3rd‐, or 4th‐line therapy, respectively. The 10‐year cause‐specific cumulative incidence of transformation was 13%. Among patients managed with 1st line R‐single, R‐CHOP, or BR, 54%, 33%, and 29% required 2nd line, respectively. The cumulative probability of starting subsequent treatment within 2 years was 26% after 1st line and 35% after 2nd line treatment. Two‐year OS following 1st, 2nd, 3rd, and 4th line systemic treatment was 84%, 70%, 52%, and 36%, respectively, and remained similar when excluding transformations. We conclude that a substantial proportion of FL patients can be managed with WaW for a long period of time, while patients who require multiple treatment lines constitute a group with a large clinical unmet need. These results constitute valuable real‐world reference data for FL.

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma in Western countries. While FL is generally incurable, standard initial therapies are associated with high response rates and durable remissions for most patients. In addition, novel targeted agents and immunotherapies are changing the treatment algorithm for patients with relapsed or refractory disease. This review discusses the initial staging, prognosis, and treatment options for newly diagnosed and relapsed/refractory FL. Initial treatment options for FL include active surveillance, radiotherapy, rituximab monotherapy, and chemoimmunotherapy. Staging with positron emission tomography/ computed tomography and bone marrow biopsy is crucial for identifying early-stage patients. Most patients with FL will receive chemoimmunotherapy as the initial treatment with options including rituximab or obinutuzumab plus cyclophosphamide, vincristine, and prednisone; cyclophosphamide, doxorubicin, vincristine, and prednisone; bendamustine; or lenalidomide. No significant differences in overall survival have been observed in randomized studies comparing these regimens. Maintenance therapy with rituximab or obinutuzumab in responders to initial chemoimmunotherapy improves progression-free survival. For relapsed/refractory FL, treatment options include chemoimmunotherapy, lenalidomidebased regimens, tazemetostat, chimeric antigen receptor (CAR)-T cell therapy (axicabtagene ciloleucel and tisagenlecleucel), and CD3/ CD20 bispecific antibodies (BsAbs). Given the encouraging outcomes obtained with CAR-T cell therapy and BsAbs, multiple trials are testing these highly active agents in earlier lines of therapy and among highrisk patients with early relapse after frontline chemoimmunotherapy. Additional studies and follow-up are needed to understand how these novel agents may further change treatment algorithms for FL.

Introduction: Follicular Lymphoma (FL) results from the malignant transformation of germinal center (GC) B cells. FL B cells display recurrent and diverse genetic alterations, some of them favoring their direct interaction with their cell microenvironment, including follicular helper T cells (Tfh). Although FL-Tfh key role is well-documented, the impact of their regulatory counterpart, the follicular regulatory T cell (Tfr) compartment, is still sparse. Methods: The aim of this study was to characterize FL-Tfr phenotype by cytometry, gene expression profile, FL-Tfr origin by transcriptomic analysis, and functionality by in vitro assays. Results: CD4+CXCR5+CD25hiICOS+ FL-Tfr displayed a regulatory program that is close to classical regulatory T cell (Treg) program, at the transcriptomic and methylome levels. Accordingly, Tfr imprinting stigmata were found on FL-Tfh and FL-B cells, compared to their physiological counterparts. In addition, FL-Tfr co-culture with autologous FL-Tfh or cytotoxic FL-CD8+ T cells inhibited their proliferation in vitro. Finally, although FL-Tfr shared many characteristics with Treg, TCR sequencing analyses demonstrated that part of them derived from precursors shared with FL-Tfh. Discussion: Altogether, these findings uncover the role and origin of a Tfr subset in FL niche and may be useful for lymphomagenesis knowledge and therapeutic management. [ABSTRACT FROM AUTHOR]

Summary Despite the clinical and molecular heterogeneity of follicular lymphoma (FL), there remains a lack of biomarker‐directed therapeutic approaches in routine clinical practice, with the notable exception of the EZH2 inhibitor tazemetostat in EZH2‐mutant FL. Here we examined whether gene mutation status predicts response to clinical mTOR inhibitors (mTORi) in FL, by performing targeted mutational profiling of biopsies from 21 relapsed/refractory FL patients treated with mTORi everolimus or temsirolimus within clinical trials. We observed an enrichment of mutations within the catalytic histone acetyltransferase (HAT) domain of CREBBP in mTORi‐responders, and describe distinct transcriptional characteristics and co‐occurring mutations of FL harbouring these mutations; reinforcing the growing appreciation of CREBBPHAT mutation as a key biological determinant and its promise as a therapeutic biomarker in FL. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) is an indolent, germinal center B cell–derived lymphoid neoplasm, for which recent advances in treatment have substantially improved patient survival. However, FL remains an incurable and heterogeneous disease, with groups of patients experiencing early disease progression, histologic transformation, or a high risk of treatment-related toxicity. Additionally, FL is a continually relapsing disease, and response rates and disease-control intervals decrease with each subsequent line of therapy. In this review, we explore the current treatment landscape for relapsed or refractory FL and promising therapies in development, highlighting the efficacy and potential risks of each treatment. We provide a real-world perspective on the unmet needs of patients with FL. Novel therapeutic approaches in development offer a wide array of options for clinicians when treating relapsed or refractory FL. A nuanced approach is required to address the needs of individual patients, taking into consideration both the risks and benefits of each treatment option, as well as patient preferences. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) is the most common indolent type of B-cell non-Hodgkin lymphoma. Advances in treatment have improved overall survival, but early relapse or transformation to aggressive disease is associated with inferior outcome. To identify early genetic events and track tumor clonal evolution, we performed multi-omics analysis of 94 longitudinal biopsies from 44 FL patients; 22 with transformation (tFL) and 22 with relapse without transformation (nFL). Deep whole-exome sequencing confirmed recurrent mutations in genes encoding epigenetic regulators (CREBBP, KMT2D, EZH2, EP300), with similar mutational landscape in nFL and tFL patients. Calculation of genomic distances between longitudinal samples revealed complex evolutionary patterns in both subgroups. CREBBP and KMT2D mutations were identified as genetic events that occur early in the disease course, and cases with CREBBP KAT domain mutations had low risk of transformation. Gains in chromosomes 12 and 18 (TCF4), and loss in 6q were identified as early and stable copy number alterations. Identification of such early and stable genetic events may provide opportunities for early disease detection and disease monitoring. Integrative analysis revealed that tumors with EZH2 mutations exhibited reduced gene expression of numerous histone genes, including histone linker genes. This might contribute to the epigenetic dysregulation in FL. [ABSTRACT FROM AUTHOR]

Background: Haematological malignancies (blood cancers) often follow chronic trajectories that can span many months or years. Management of these diseases typically involves periods of 'Watch & Wait', whereby patients are monitored by the hospital and only treated at progression, if or when this occurs, which might be never or on multiple occasions. Such remitting-relapsing pathways are unpredictable and can cause anxiety and distress. This study aimed to generate evidence about information preferences, with a view to underpinning future patient-facing resources; potentially mitigating psycho-social difficulties and promoting effective shared decision-making. Methods: A qualitative study was conducted, set within a UK population-based cohort of patients with haematological malignancies. Sampling was purposive, based on age (initially around the median age of diagnosis) and disease subtype (chronic lymphocytic leukaemia, follicular lymphoma, marginal zone lymphoma and myeloma); and in-depth interviews took place with 35 patients (10 with relatives). Analysis drew on qualitative description and thematic content analysis and included critical reading and annotation of transcripts, identification of common and rare phenomena, generation of codes and coding of material, and theme development. Results: Patients discussed their preferences and experiences at length and rich data were generated from diagnosis onwards, across diagnostic subtypes. The overarching theme identified was 'Variations in preferences' with needs seen to differ from person to person; as well as changing over time for individuals. Five sub-themes were identified: 1) To know or not to know? 2) Needs are dynamic; 3) The polarising issue of prognosis; 4) Preferred sources; and 5) Differences in content, depth and presentation. Conclusions: Varied, dynamic information preferences indicate that resources should be developed in a way that provides maximum choice, enabling patients to select relevant material at different time-points on their trajectory. The development of blood cancer subtype-specific "real-world clinical scenarios" could improve patient experiences and inform shared decision-making. [ABSTRACT FROM AUTHOR]

This case report aims to highlight the importance of considering lymphoma as a potential differential diagnosis in patients presenting with laryngeal mass and associated cervical lymphadenopathy, particularly those with a history of chronic tonsillitis. A case of a 63-year-old male patient who underwent bilateral tonsillectomy for tumor in the left tonsil was presented. Two months after the procedure, he developed throat discomfort, dysphagia, neck swelling, and other symptoms. The patient was initially diagnosed with "tongue base mass" and chronic lymphadenitis. Partial excision of the tongue base mass was performed twice in another hospital, revealing chronic inflammation of the epithelial mucosa. Further evaluations, including electron laryngoscopy and imaging studies, were conducted to investigate the condition. A computed tomography (CT) scan showed irregular soft tissue density in the oropharyngeal region, along with multiple lymph nodes in the neck. Subsequent histopathological examination of the lingual base biopsy revealed peripheral T-cell lymphoma with a follicular T-helper cell phenotype. Immunohistochemical staining confirmed specific markers while ruling out other markers. In situ hybridization testing demonstrated positivity for Epstein-Barr virus-encoded RNA, and TCRG clonality was confirmed. The duration from symptom onset to diagnosis was 2 months. This case emphasizes the importance of considering lymphoma in patients with laryngeal mass and associated cervical lymphadenopathy, especially when a history of chronic tonsillitis is present. Accurate diagnosis and early intervention are crucial for effective management and improved patient outcomes. [ABSTRACT FROM AUTHOR]

Summary Radiotherapy is routinely used for management of limited‐stage follicular lymphoma (FL), yet half of patients ultimately relapse. We hypothesized that the presence of specific gene mutations may predict outcomes. We performed targeted sequencing of a 69‐gene panel in 117 limited‐stage FL patients treated with radiotherapy and identified recurrently mutated genes. CREBBP was most frequently mutated, and mutated CREBBP was associated with inferior progression‐free survival, though not after false discovery rate adjustment. This association failed to validate in an independent cohort. We conclude that recurrent gene mutations do not predict outcomes in this setting. Alternative biomarkers may offer better prognostic insight. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) exhibits considerable variability in biological features and clinical trajectories across patients. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and associated with a lower proliferative history than the other subtypes. The AR subtype was unique in its enrichment for IgM-expressing FL cases and was associated with advanced-stage and more than 4 nodal sites. The existence of subtypes was validated in an independent cohort of 418 samples from the GALLIUM trial. Notably, patients assigned to the TT subtype consistently experienced inferior progression-free survival when treated with immunochemotherapy. Our findings offer insight into core pathways distinctly linked with each FL cluster and are expected to be informative in the era of targeted therapies. [ABSTRACT FROM AUTHOR]

Summary: Immune responses to primary COVID‐19 vaccination were investigated in 58 patients with follicular lymphoma (FL) as part of the PETReA trial of frontline therapy (EudraCT 2016–004010‐10). COVID‐19 vaccines (BNT162b2 or ChAdOx1) were administered before, during or after cytoreductive treatment comprising rituximab (depletes B cells) and either bendamustine (depletes CD4+ T cells) or cyclophosphamide‐based chemotherapy. Blood samples obtained after vaccine doses 1 and 2 (V1, V2) were analysed for antibodies and T cells reactive to the SARS‐CoV‐2 spike protein using the Abbott Architect and interferon‐gamma ELISpot assays respectively. Compared to 149 healthy controls, patients with FL exhibited lower antibody but preserved T‐cell responses. Within the FL cohort, multivariable analysis identified low pre‐treatment serum IgA levels and V2 administration during induction or maintenance treatment as independent determinants of lower antibody and higher T‐cell responses, and bendamustine and high/intermediate FLIPI‐2 score as additional determinants of a lower antibody response. Several clinical scenarios were identified where dichotomous immune responses were estimated with >95% confidence based on combinations of predictive variables. In conclusion, the immunogenicity of COVID‐19 vaccines in FL patients is influenced by multiple disease‐ and treatment‐related factors, among which B‐cell depletion showed differential effects on antibody and T‐cell responses. [ABSTRACT FROM AUTHOR]

The results of a recent single-arm trial (ZUMA-5) of axicabtagene ciloleucel (axi-cel) for relapsed/refractory (r/r) follicular lymphoma (FL) demonstrated high rates of durable response and tolerable toxicity among treated patients. To quantify the value of axi-cel compared with standard of care (SOC) to manage r/r FL patients who have had at least 2 prior lines of systemic therapy (3L+), a cost-effectiveness model was developed from a US third-party payer perspective. A 3-state partitioned-survival cost-effectiveness model was developed with a lifetime horizon. Patient-level analyses of the 36-month ZUMA-5 (axi-cel) and SCHOLAR-5 (SOC) studies were used to extrapolate progression-free and overall survivals. After 5 years of survival, an estimated 40% of the modeled population was assumed to experience long-term remission based on literature. Results include the incremental cost-effectiveness ratio (ICER) measured as incremental cost per quality-adjusted life year (QALY) gained. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analyses were performed. All outcomes were discounted 3% per year. Axi-cel led to an increase of 4.28 life-years, 3.64 QALYs, and a total cost increase of $321 192 relative to SOC, resulting in an ICER of $88 300 per QALY. Across all parameters varied in the one-way sensitivity analysis, the ICER varied between $133 030 and $67 277. In the probabilistic sensitivity analysis, axi-cel had a 99% probability of being cost-effective across 5000 iterations using a $150 000 willingness-to-pay threshold. Given the robustness of the model results and sensitivity analyses, axi-cel is expected to be a cost-effective treatment in 3L+ r/r FL. • Relapse, recurrence, and disease burden remain common in follicular lymphoma; 19% of patients relapse within 2 years of treatment, and treatment toxicity and follow-up substantially impair quality of life. Given the high rates of relapse and recurrence in this patient population and the availability of novel treatments that confer proven clinical benefit, contextualizing the value of these novel treatments is of great importance. • The value of axicabtagene ciloleucel (axi-cel) compared with the standard of care (SOC) was assessed using a 3-state partitioned-survival cost-effectiveness model with a lifetime horizon. Patient-level analyses of the 36-month ZUMA-5 (axi-cel) and SCHOLAR-5 (SOC) studies were used to extrapolate progression-free and overall survivals. Axi-cel led to an increase of 4.28 life-years, 3.64 quality-adjusted life years (QALYs), and a total cost increase of $321 192 relative to SOC, resulting in an incremental cost-effectiveness ratio of $88 300 per QALY. • Given the incremental cost-effectiveness ratio under the commonly accepted willingness-to-pay thresholds of $100 000 to $150 000/QALY in the United States, axi-cel is expected to be a cost-effective treatment in relapsed and recurrent follicular lymphoma patients who have failed 2 prior lines of systemic therapy. [ABSTRACT FROM AUTHOR]

We describe two types of IGH::BCL2 breakpoints involving the 5′ region of BCL2 (5′ BCL2). One was ins(14;18)(q32;q21q21) observed in 2 follicular lymphoma (FL) cases, in which IGH was cleaved at 3' of IGHD and 5' of IGHJ and BCL2 was cleaved at 5' BCL2 and downstream regions, and a 281- or 201-kilobase pair fragment containing the BCL2 protein-coding sequences was invertedly inserted into IGH. In another type observed in 2 FL and 2 chronic lymphocytic leukemia (CLL) cases, breakage and reunion occurred within the switch region associated with IGHM (Sµ) and 5′ BCL2, creating IGH Sµ::5′ BCL2 fusion sequences on der(18)t(14;18)(q32;q21). The former is considered to be mediated by VDJ-recombination, while the latter by the class switch recombination process. There were no particular features in FL or CLL cases with IGH::5′ BCL2 breakpoints compared with those with t(14;18)(q32;q21)/IGH::BCL2 involving the 3′ breakpoint cluster regions. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) is the most common indolent non‐Hodgkin lymphoma subtype, accounting for 15–20% of all lymphoma diagnoses. Although typically slow‐growing and responsive to frontline therapies, advanced‐stage FL remains incurable with current treatments and typically follows a chronic relapsing/remitting course with increasingly shorter responses to subsequent lines of therapy. Outcomes are highly variable; some patients experience prolonged first remissions that may approximate a 'functional cure'. By contrast, a significant minority of patients experience disease progression shortly after frontline treatment resulting in high rates of lymphoma‐related mortality. Reflecting on the heterogeneous natural history of FL, clinical practice varies widely, particularly in controversial areas, including appropriate disease staging, selection of management strategies and duration of clinical follow‐up. This position statement presents an evidence‐based synthesis of the literature for application in Australasian practice. [ABSTRACT FROM AUTHOR]

Introduction: Follicular lymphoma (FL) is an indolent subtype of non-Hodgkin's lymphoma (NHL), characterized by a long natural course of remissions/relapses. We aimed to evaluate real-world quality of life (QoL) in patients with FL, by line of therapy (LOT), and across countries. Methods: Data were drawn from the Adelphi FL Disease Specific Programme™, a cross-sectional survey of physicians and their patients in Europe [France, Germany, Italy, Spain, the United Kingdom (UK)], and the United States (US) from June 2021 to January 2022. Patients provided demographics and patient-reported outcomes via the European Organisation for Research and Treatment of Cancer QoL questionnaire (EORTC QLQ-C30). Bivariate analysis assessed QoL versus NHL, across LOT [first line (1L), second line (2L), third line or later (3L+)] and country. Results: Patients (n = 401) had a mean [standard deviation (SD)] age of 66.0 (9.24) years, 58.1% were male, and 41.9%/22.9% were Ann Arbor stage III/IV. Patients with FL mean EORTC global health status (GHS)/QoL, nausea/vomiting, pain, dyspnea, appetite loss, and diarrhea scores were statistically significantly worse (p < 0.05) versus the NHL reference values. Mean (SD) GHS/QoL worsened from 1L [56.5 (22.21)] to 3L+ [50.4 (20.11)]. Physical and role functioning, fatigue, pain, dyspnea, and diarrhea scores also significantly worsened across later LOTs (p < 0.05). Across all functional domains, mean scores were significantly lower (p < 0.05) and almost all symptom scores (excluding diarrhea) were significantly higher (p < 0.05) for European versus US patients. Conclusions: Patients with FL at later LOTs had significantly worse scores in most QoL aspects than earlier LOTs. European patients had significantly lower functioning and higher symptom burden than in the US. These real-world findings highlight the need for novel FL therapies that alleviate patient burden, positively impacting QoL. Plain Language Summary: There is little information about the effects of follicular lymphoma and treatments on quality of life as assessed by patients. We surveyed doctors and their patients with follicular lymphoma across France, Germany, Italy, Spain, the United Kingdom, and the United States (US), and asked patients to complete a form reporting their quality of life. A total of 401 patients were included. In general, patients with follicular lymphoma treated across all lines of treatment had worse quality of life and symptoms of nausea and vomiting, pain, shortness of breath, appetite loss, and diarrhea compared to a reference group of patients with non-Hodgkin's lymphoma (NHL). Overall quality of life and physical, role, and social functioning of patients with follicular lymphoma worsened from the first to the third line of treatment. Fatigue, pain, dyspnea, and diarrhea symptom scores also worsened across the lines of therapies. European patients had worse quality of life, functioning, and symptoms compared to US patients. Better treatments are needed to improve symptoms, functions, and quality of life for patients with follicular lymphoma. [ABSTRACT FROM AUTHOR]