Search Results (96)

Phosphatidylinositol-3-kinase (PI3K) inhibition has emerged as a therapeutic option against indolent lymphoma, including relapsed follicular lymphoma (FL). While inhibition of active signaling in the lymphoma cell represents the primary mode of action, PI3K inhibition also exerts immunomodulatory effects. Here we have analyzed 17 consecutive advanced treatment line FL patients treated with the delta-selective PI3K inhibitor idelalisib in a retrospective single-center observational study, with a specific focus on response and immune effects. Eleven patients achieved complete remission (CR) or partial remission (PR) with median response duration of 22 (11–88) months following a median idelalisib exposure of 15 (4–88) months. Disease response persisted in three patients for a median of 37 (21–63) months following cessation of idelalisib without another therapy being initiated. Autoimmune side effects occurred in eight of the eleven patients who responded, compared to none in six patients whose disease did not respond. In conclusion, a time-limited exposure to idelalisib may induce sustained remissions in a portion of patients with recurrent and/or refractory (r/r) FL, suggesting immunomodulatory effects of PI3K inhibition to be involved in the control of the disease. Full article

Follicular lymphoma (FL) is one of the most common types of non-Hodgkin’s lymphomas. The tumor is characterized by a wide range of clinical manifestations, ranging from indolent forms to early transformation and progression with a poor prognosis. The search for clinically significant genetic changes is essential for personalized risk assessment and treatment selection. The CREBBP gene is frequently mutated in this type of lymphoma, with changes occurring at the level of the earliest tumor precursor cells. However, the prognostic and diagnostic significance of the CREBBP gene mutation status in FL has not been fully established. In this study, we analyzed sequencing data of exons 22–30 of the CREBBP gene in 86 samples from patients with different grades of FL (1–3B), including those in the 3A–3B subgroup without the t(14;18) translocation. We also investigated the prognostic significance of CREBBP gene mutations in relation to the treatment options, namely high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT/auto-HSCT) and conventional chemotherapy programs (CCT). It was found that FL patients with a single missense mutation in the KAT domain of the CREBBP gene experienced an extremely low number of early adverse events related to lymphoma and had better long-term survival rates, regardless of treatment option. In contrast, when comparing patients with FL without a missense mutation in the KAT domain or those with multiple mutations in the CREBBP gene, overall and progression free survival were worse, and early progression and histological transformation were more common. Compared to standard therapy, patients who underwent HDCT/auto-HSCT in the FL 1–3B (14;18)-positive group without a single missense mutation in the KAT domain had better survival rates and lower rates of transformation and early progression. In addition, among patients with FL 3A–3B (14;18)-negative, we found that there were no cases of a missense mutation in the KAT domain of the CREBBP gene. This suggests that a single missense mutation in the CREBBP gene may be a feature that discriminates 14;18-positive FL with a favorable prognosis from a high-risk disease. FL 3A–3B (14;18)-negative may represent a distinct variant with different biology and underlying mechanisms of development compared to classical FL. Full article

Multispecific antibodies have redefined the immunotherapeutic landscape in hematologic malignancies. Bispecific antibodies (BsAbs), which redirect cytotoxic T cells toward malignant targets via dual antigen engagement, are now established components of treatment for diseases such as acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and multiple myeloma (MM). Clinical trials of agents like blinatumomab, glofitamab, mosunetuzumab, and teclistamab have demonstrated deep and durable responses in heavily pretreated populations. Trispecific antibodies (TsAbs), although still investigational, represent the next generation of immune redirection therapies, incorporating additional tumor antigens or co-stimulatory domains (e.g., CD28, 4-1BB) to mitigate antigen escape and enhance T-cell persistence. This review provides a comprehensive evaluation of BsAbs and TsAbs across hematologic malignancies, detailing molecular designs, mechanisms of action, therapeutic indications, resistance pathways, and toxicity profiles including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, and infections. We further discuss strategies to mitigate adverse effects and resistance, such as antigen switching, checkpoint blockade combinations, CELMoDs, and construct optimization. Notably, emerging platforms such as tetrafunctional constructs, checkpoint-integrated multispecifics, and protease-cleavable masking designs are expanding the therapeutic index of these agents. Early clinical evidence also supports the feasibility of applying multispecific antibodies to solid tumors. Finally, we highlight the transformative role of artificial intelligence (AI) and machine learning (ML) in multispecific antibody development, including antigen discovery, biomarker-driven treatment selection, toxicity prediction, and therapeutic optimization. Together, BsAbs and TsAbs illustrate the convergence of molecular precision, clinical innovation, and AI-driven personalization, establishing a new paradigm for immune-based therapy across hematologic and potentially solid tumor malignancies. Full article

Non-Hodgkin lymphomas (NHLs) encompass a diverse group of neoplasms arising from the clonal proliferation of B-cell progenitors, T-cell progenitors, mature B-cells, mature T-cells, and natural killer (NK) cells. These malignancies account for over 90% of lymphoid neoplasms. The link between the gut microbiome and neoplasms has been extensively studied in recent years. Growing evidence suggests that the gut microbiome may be involved not only in the development of the disease, but also in modulating the efficacy of implemented therapies. In this review, we summarize the current knowledge on the potential involvement of the gut microbiome in the development of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, and NK/T-cell lymphoma, including cutaneous T-cell lymphoma (CTCL). Moreover, we discuss the relationship between gut microbiome changes before and after treatment and their association with treatment outcomes, focusing on chemotherapy and CAR T-cell therapy. Full article

Background: Allogeneic hematopoietic cell transplant (alloHCT) is a curative option for relapsed/refractory B-cell lymphomas (BCLs), but its role in the evolving field of cellular therapy is increasingly unclear as recent advances in transplant procedures have improved outcomes. Methods: This retrospective, single-center study included 55 BCL patients (large B-cell lymphoma—LBCL; indolent BCL; and mantle cell lymphoma—MCL) treated with alloHCT from 2015 to 2023 at Hôpital Maisonneuve-Rosemont. Primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary endpoints included NRM and GVHD incidence. Results: A total of 55 patients were included (25 LBCLs, 16 indolent BCLs, 14 MCLs), and 76% of LBCLs were of indolent origin (Richter transformation, transformed follicular lymphoma). After a median follow-up of 6.1, 5.8 and 2.4 years for LBCLs, indolent BCLs and MCLs, their 5-year PFS and OS were 57.2% (IC 95%: 34.2–74.7) and 62.8% (IC 95%: 37.9–80.0), 81.2% (IC 95%: 52.5–93.5) and 93.8% (IC 95%: 63.2–99.1), and 39.0% (IC 95%: 14.3–63.3) and 68.1% (IC 95%: 35.4–86.8), respectively. The 5-year NRM was 16.9% (IC 95%: 8.2–28.3) with a relapse incidence of 23.4%. Overall/grade 3–4 acute GVHD occurred in 43.6% and 18.1% of patients. At 3 years, overall/moderate or severe chronic GVHD incidence was 49% and 34.5%. Conclusions: AlloHCT remains a potentially curative option and should be considered for fit patients with chemosensitive FL or LBCLs of indolent origin and a low comorbidity index. Full article

Monoclonal antibodies (mAbs) have become a cornerstone in the treatment of follicular lymphoma (FL), offering highly specific therapeutic targeting that enhances efficacy while minimizing systemic toxicity. Their mechanisms of action include antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct apoptotic signaling, effectively mediating malignant B-cell depletion. Anti-CD20 mAbs, such as rituximab and obinutuzumab, have significantly improved progression-free survival (PFS) and overall survival (OS), establishing immunochemotherapy as the standard of care for FL. However, the emergence of treatment resistance, often characterized by CD20 antigen downregulation or immune escape, has prompted the development of next-generation mAbs with enhanced effector functions. Bispecific antibodies (BsAbs), which simultaneously engage CD20-expressing tumor cells and CD3-positive cytotoxic T cells, have emerged as a novel immunotherapeutic strategy, redirecting T-cell activity to eliminate malignant B cells independently of major histocompatibility complex (MHC) antigen presentation. Additionally, antibody–drug conjugates (ADCs) offer a targeted cytotoxic approach by delivering potent chemotherapeutic payloads directly to tumor cells while limiting off-target effects. The integration of mAbs with immune checkpoint inhibitors and immunomodulatory agents is further enhancing treatment outcomes by overcoming immunosuppressive mechanisms within the tumor microenvironment. Despite these advancements, challenges remain, including optimizing the treatment sequence, mitigating immune-related toxicities—particularly cytokine release syndrome (CRS)—and identifying predictive biomarkers to guide patient selection. As the role of monoclonal antibodies continues to expand, their integration into therapeutic regimens is transforming the management of FL, paving the way for chemotherapy-free treatment approaches and long-term disease control. This review provides an updated overview of mAbs therapies for FL, emphasizing the advances brought by BsAbs and ADCs toward more tailored and effective treatments. Full article

Follicular lymphoma (FL) is a heterogeneous and incurable disease. One of the hallmark features of FL cells is the introduction of N-glycosylation (N-gly) amino acid sequence motifs into the immunoglobulin variable (IgV) region through ongoing somatic hypermutation (SHM) in the early stages of lymphoma development. These N-gly motifs, containing oligomannoses, are rarely found in healthy B cells but evidently play a crucial role in the clonal evolution and survival of FL cells in the hostile environment of germinal centers. The random nature of the ongoing SHM in FL occasionally results in the loss of productive immunoglobulin (Ig) genes or the elimination of N-gly motifs in productive genes. Such events typically lead to clonal deletion, as demonstrated by the longitudinal analysis of FL samples. However, rare N-gly-negative subclones demonstrate prolonged survival with evidence of ongoing SHM, giving rise to new N-gly-negative subclones before eventual deletion. This observation suggests the presence of specific mechanisms supporting their survival and proliferation. This perspective examines the current literature and explores whether a detailed transcriptomic and functional comparison of FL subclones characterized by different N-gly statuses, with a particular focus on N-gly-negative subclones, will lead to a comprehensive understanding of both N-gly-dependent and independent pro-survival and proliferative transcriptional signatures. Specifically, it aims to deepen our understanding of FL pathobiology and identify novel therapeutic targets for better disease management. Full article

Relapsed/refractory non-Hodgkin lymphoma (r/r/NHL) is an aggressive disease with overall poor response rates to chemo-immunotherapy and autologous stem-cell transplant, especially in patients with diffuse large B-cell lymphoma. Major improvements in this disease space have come through the incorporation of novel immune therapies, including CD19/CD20 directed CAR-T cells and bispecific antibodies. These exciting new therapies continue to change the landscape of treatment for r/r NHL and have been incorporated in earlier lines of therapy with demonstrated efficacy and patient safety. In this review, the role of these treatments in the management of relapsed/refractory NHL is discussed in detail along with future directions of research. Full article

Background/Objectives: This study aimed to determine whether interim PET/CT (iPET) scans could identify follicular lymphoma (FL) patients at high risk of relapse following first-line therapy. Methods: A total of 117 FL patients who underwent iPET scans were included, with responses interpreted using the Deauville score (DS). Progression-free survival (PFS) was evaluated over a median follow-up of 34 months. Results: Overall, 34% of patients were classified as iPET (+), with significantly worse estimated 5-year PFS compared to iPET (−) patients (34% vs. 76%, hazard ratio 4.3, p < 0.001). Multivariate analysis confirmed iPET (+) as an independent predictor of PFS. Conclusions: Interim PET results are significant predictors of PFS in FL first-line therapy and could inform response-adapted treatment strategies. Full article

Follicular lymphoma (FL) is an indolent, rarely curable B-cell malignancy with a heterogeneous clinical course. While generally treatable, FL is characterized by remissions and relapses, and its clinical presentation varies widely. Rituximab has revolutionized FL treatment, significantly improving overall survival over the past two decades. Risk assessment typically relies on histological grade, tumor burden, and the Follicular Lymphoma International Prognostic Index, which incorporates factors like age, hemoglobin level, and Ann Arbor stage. However, these indices have limitations in fully capturing the clinical variability of FL. Some patients experience indolent disease for extended periods without requiring treatment, while others present with aggressive forms resistant to standard therapies. This review examines various prognostic factors in FL, including the FLIPI, FLIPI2, PRIMA-PI, and m7-FLIPI. The FLIPI, based on five risk factors, stratifies patients into low-, intermediate-, and high-risk groups. The FLIPI2 incorporates beta2-microglobulin and the longest diameter of the largest involved node, offering improved prognostication. The PRIMA-PI, designed for patients receiving rituximab-containing regimens, uses beta2-microglobulin, bone marrow involvement, and the longest diameter of the largest involved node. The m7-FLIPI integrates mutational status with FLIPI2 parameters, further refining risk stratification. The review also discusses clinical parameters like maximum standardized uptake value on PET/CT and lymphocyte/monocyte ratio as prognostic factors. A high SUVmax and low lymphocyte/monocyte ratio identify high-risk patients. While FL remains incurable, advances in immunochemotherapy and targeted therapies have improved outcomes. This review provides a comprehensive overview of prognostic tools in FL, emphasizing the importance of risk stratification for personalized treatment strategies. Full article

Thrombosis is a critical complication in lymphomas, driven by chronic inflammation. To observe this systemic mechanism, we evaluated inflammatory cytokines, neutrophil and monocyte activation, and platelet function in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Hodgkin lymphoma (HL), with and without thrombosis using ELISA and flow cytometry according to laboratory and clinical data. Interleukin-1β was elevated across lymphomas and inversely correlated with the Khorana score for venous thromboembolism, while increased tumor necrosis factor-alpha (TNF-α) was inversely associated with the International Prognostic Index (IPI) in thrombosis-associated lymphomas. Neutrophil activation was increased in DLBCL, while elevated neutrophil extracellular traps (NETs) biomarkers were inversely consistent with thrombosis and the ThroLy score. NETs were elevated in HL. Classical monocytes were increased in all lymphoma subtypes, with intermediate and tissue factor (TF)-carrying monocytes elevated in DLBCL and HL. Platelet activation was pronounced, with platelet–monocyte aggregates and platelet-associated TF elevated in DLBCL and FL but not HL. P-selectin was increased in lymphomas with thrombosis, aligned with Khorana and ThroLy scores, and reflected clinical stage while inversely correlating with IPI in non-thrombotic lymphomas. These findings highlight distinct thromboinflammatory mechanisms across lymphoma subtypes, providing insights into biomarkers for thrombosis risk and therapeutic targets in lymphoma management. Full article

Background/Objectives: Non-Hodgkin lymphoma (NHL) represents 63% of all hematological malignancies in France, with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) being the two most frequent forms. With the improvement of therapeutics, the issue of health-related quality of life (HRQoL) is becoming increasingly crucial for these patients. The aim was to compare HRQoL of NHL survivors with that of the general French population and to identify factors associated with HRQoL in NHL survivors. Methods: We conducted a population-based study among living patients from three registries of hematological malignancies, using standardized questionnaires, including the SF-12, in September 2023. The data collected were compared to those of a normative general French cohort. Results: In total, 493 patients completed the study questionnaires, yielding a response rate of 36%. The median time since diagnosis was 8 years (IQR 6–10) These NHL survivors reported lower HRQoL compared to the general French population, except in terms of bodily pain (p < 0.01). Each one-year increase in the time since diagnosis was associated with an increase in social functioning (p = 0.009). Men had better general health (p = 0.01) and less bodily pain (p = 0.007) than women. Higher income was associated with better HRQoL (p < 0.01). Underweight or obesity were associated with poorer physical functioning (p = 0.008). The presence of comorbidities, socioeconomic deprivation, anxiety, and depression were associated with poorer HRQoL (p < 0.01). Conclusions: This study provides valuable information of HRQoL values for comparison in further follow-up studies and proposes measures that could be implemented to improve the HRQoL of NHL survivors. Full article

Background: Patients with low tumour burden follicular lymphoma (FL) are managed with an initial watchful waiting (WW) approach. The way to better predict the time-to-treatment (TTT) is still under investigation for its possible clinical impact. This study explored whether radiomic features extracted from baseline ¹⁸F-FDG PET/CT could predict TTT in FL patients on WW. Methods: Thirty-eight patients on initial WW (grade 1–3a) were retrospectively included from 2010 to 2019. Eighty-one PET/CT morphological and first-level intensity radiomic features were extracted from the total metabolic tumour burden (TMTV), the lesion having the highest SUVmax and a reference volume-of-interest placed on the healthy liver. Models using linear regression (LR) and support vector machine (SVM) were constructed to assess the feasibility of using radiomic features to predict TTT. A leave-one-out cross-validation approach was used to assess the performance. Results: For LR models, we found a root-mean-squared error of 29.4, 28.6, 26.4 and 26.8 and an R² of 0.03, 0.08, 0.21 and 0.20, respectively, incrementing the features from one to four. Accordingly, the best model included three features: the liver minimum SUV value, the liver SUV skewness and the sum of squared SUV values in the TMTV. For SVM models, accuracies of 0.79, 0.63, 0.76 and 0.68 and areas under the curve of 0.80, 0.72, 0.77 and 0.63 were found, respectively, incrementing the features from one to four. The best performing model used one feature, namely the median value of the lesion containing the SUVmax value. Conclusions: The baseline PET/CT radiomic approach has the potential to predict TTT in FL patients on WW. Integrating radiomics with clinical parameters could further aid in patient stratification. Full article

Backgroud: The introduction of highly active immunotherapies has changed the outcome of B-cell non-Hodgkin lymphomas (B-NHLs) in the last two decades. Since then, important progress has been shown using newer and more active immunotherapies, including chimeric antigen receptor T-cell therapy (CAR-T), conjugated monoclonal antibodies, and bispecific antobodies, which currently plays a significant role in the treatment of diffuse large B-cell (DLBCL), follicular (FL), and mantle cell (MCL) lymphoma. Purpose: In this review, we provide an updated overview of recently completed and ongoing BsAb trials in patients with relapsed/refractory(R/R) B-NHL and Hodgkin’s lymphoma, including single-agent results, emerging combinations, safety data, and novel constructs. Conclusions: Bispecific antibodies (BsAbs) are a novel class of “off-the-shelf” T-cell-redirecting drugs capable of targeting various cell-surface antigens. New antigen targets are currently under investigation, such as CD19 × CD3 and CD30 × CD3 or CD30 × CD16, in different settings. BsAbs are among the most promising therapeutic options for lymphoma today since they have demonstrated significant single-agent activity, along with a manageable toxicity profile, in patients with heavily pretreated B-NHL. Full article