RARE DISEASE
Indolent B-cell non-Hodgkin lymphoma
Indolent B-cell non-Hodgkin lymphoma
Indolent B-cell non-Hodgkin lymphoma
Synonyms: Indolent B-cell NHL
Synonyms: Indolent B-cell NHL
Synonyms: Indolent B-cell NHL
Drug discovery
2
drugs
With orphan designations
Overview
Indolent B-cell non-Hodgkin lymphomas (NHLs) are slow-growing malignancies comprising ~40% of NHL cases, including follicular lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma [1][6][16]. Median age at diagnosis is 68, with a 5-year survival rate of 74% [2][5]. Though often asymptomatic initially, these lymphomas are incurable and may transform into aggressive subtypes. Management spans observation (watch-and-wait) for asymptomatic cases to rituximab-based chemoimmunotherapy, targeted agents, and CAR T-cell therapy for advanced/relapsed disease [1][3][8][13].
Burden
Chronic course: Median survival ≈12–14 years, with frequent relapses [11][12].
Leading to 8th highest cancer mortality (5.0 deaths/100,000/year) [2][6].
High healthcare utilization due to lifelong monitoring, treatment-related toxicity risks, and ~20–30% risk of transformation to aggressive NHL (e.g., DLBCL) [6][15][16].
Therapies
First-line: Observation, localized radiation, or rituximab ± chemotherapy (e.g., R-CVP, R-CHOP, bendamustine-rituximab) [1][3][8].
Relapsed/refractory: BTK inhibitors (zanubrutinib), EZH2 inhibitors (tazemetostat), bispecific antibodies (mosunetuzumab), and CAR T-cell therapy [1][6][13].
Maintenance: Rituximab every 2–3 months for 2 years post-remission [1][8].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
908 drug discovery papers about Indolent B-cell non-Hodgkin lymphoma, with 3 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
908 drug discovery papers about Indolent B-cell non-Hodgkin lymphoma, with 3 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-06-08 | Antimicrobial Peptides Induce Cell Death in Marginal Zone Lymphoma Models Resistant to Targeted Therapies.
Marginal zone lymphoma (MZL) is an indolent yet incurable B-cell malignancy in which targeted agents such as BTK and PI3K inhibitors frequently fail due to resistance or toxicity. Antimicrobial peptides (AMPs), evolutionarily conserved effectors of innate immunity, possess selective cytotoxicity against malignant cells by exploiting tumor-specific membrane alterations. Peptides were synthesized and tested for their anti-proliferative activity in MZL cell lines. We evaluated the antitumor activity of seven natural AMPs, including Antarctic fish-derived trematocines and chionodracine variants, and amphibian temporins, against MZL cell lines (VL51, Karpas1718) and derivatives resistant to BTK, PI3Kδ, or PI3Kα/δ inhibitors. Among them, W-trematocine and temporin L demonstrated potent dose-dependent cytotoxicity with IC50 values of 5.7-10 µM, maintaining full activity in all resistant models. Other peptides showed moderate activity, while chionodracine-1 was inactive. Notably, W-trematocine displayed minimal toxicity toward nonmalignant cells in prior studies, underscoring its selectivity. AMP-mediated killing, driven by membrane disruption and non-apoptotic death pathways, bypassed conventional resistance mechanisms, suggesting therapeutic potential in relapsed/refractory disease. Our findings highlight natural AMPs as promising candidates for development in drug-resistant MZL, warranting further optimization and preclinical validation.
2025-11-03 | CHN1 suppresses B-cell non-Hodgkin lymphoma progression via akt/mTOR pathway
Abstract Introduction B-cell non-Hodgkin lymphoma (B-NHL) is the most prevalent NHL subtype, exhibiting high heterogeneity. Chimerin 1 (CHN1), a rac guanosine triphosphatase activating protein (racGAP), is predominantly expressed in neurons, especially in the cerebral cortex, and plays an important role in axon guidance. The previous study has estimated that CHN1 was associated with B-NHL aggressiveness, showing higher expression in indolent follicular lymphoma (FL) compared to aggressive Burkitt lymphoma (BL). In silico analysis also linked high CHN1 expression with favorable outcomes in diffuse large B-cell lymphoma (DLBCL) patients, though this prognostic value requires validation. The functional role of CHN1 in B-NHL remains unclear. Therefore, we aimed to validate the prognostic value of CHN1 in DLBCL and elucidate its biological functions and signaling pathways in B-NHL cells. Methods We retrospectively collected pathological specimens from 52 DLBCL patients. CHN1 expression was assessed by immunohistochemical (IHC) staining. Kaplan-Meier analysis evaluated the correlation between CHN1 expression levels and the prognosis of DLBCL patients. Stable CHN1-overexpressing human DLBCL cell line OCI-LY3 and human Burkitt lymphoma cell line Raji were established via lentiviral transduction. Cell proliferation was measured by direct cell counting. Migration and invasion were assessed using Transwell assays. Protein expression was analyzed by Western blotting. Transcriptome sequencing of OCI-LY3^OE^ cells, followed by GO, KEGG, and GSEA enrichment analyses, identified downstream pathways. Results IHC analysis classified DLBCL patients into CHN1-high and CHN1-low groups (cut-off value: 10% positivity). The CHN1-high group exhibited significantly higher objective response (OR: 86.2% vs. 39.1%, p=0.001) and complete response (CR: 65.5% vs. 21.7%, p=0.002) rates compared to the CHN1-low group. The disease progression (PD) rate was significantly lower in the CHN1-high group (10.3% vs. 52.2%, p=0.001). Kaplan-Meier analysis demonstrated that high CHN1 expression was significantly correlated with prolonged overall survival (OS, p=0.036) and progression-free survival (PFS, p=0.002). Successful establishment of CHN1-overexpressing RajiOE and OCI-LY3OE cells was confirmed. CHN1 overexpression significantly inhibited proliferation (p<0.001) and promoted apoptosis in both cell lines (Raji: p<0.001; OCI-LY3: p=0.002). Western blot demonstrated that CHN1 downregulated the anti-apoptotic protein BCL-2 (OCI-LY3OE: p=0.029; RajiOE: p=0.036) and upregulated the pro-apoptotic protein Bax (OCI-LY3OE: p=0.047; RajiOE: p=0.029). Furthermore, CHN1 suppressed migration (OCI-LY3: p=0.004; Raji: p=0.008) and invasion (OCI-LY3: p=0.012; Raji: p=0.007). Transcriptome sequencing of CHN1-overexpressing OCI-LY3 cells identified 867 upregulated and 1,035 downregulated genes. Enrichment analyses suggested that CHN1 involvement in cell adhesion, metabolism, vesicle formation, and cell junctions, and modulate pathways including PI3K/Akt, IL6/JAK/STAT3, and IL2/STAT5 signaling. Consistently, western blot revealed that CHN1 suppressed the phosphorylation of Akt and mTOR. Treatment with the Akt activator Sc79 partially restored Akt/mTOR phosphorylation and rescued the proliferative, migratory, and invasive capacities by CHN1 overexpression. Conclusions High CHN1 expression is a favorable prognostic marker in DLBCL, associated with higher OR/CR rates, lower PD, and prolonged OS and PFS. CHN1 suppresses B-NHL progression by inhibiting proliferation, migration, and invasion in B-NHL cells. Mechanistically, the Akt/mTOR signaling pathway may be a downstream mechanism of CHN1 in B-NHL cells.
2025-07-14 | Long-acting lipegfilgrastim and antimicrobials as vigorous primary prophylaxis in bendamustine-treated patients with indolent B cell non-Hodgkin lymphoma: a multicentric real-life experience.
Febrile neutropenia (FN) is one of the most important clinical signs of infection, especially for older patients with indolent B cell non-Hodgkin lymphomas (iBC-NHLs) receiving frontline immune-chemotherapy with bendamustine-rituximab (BR). Data on the optimal strategy for infection prophylaxis from the start of chemotherapy until 1 month after the last cycle is scanty in this setting of patients, and for this reason, we carried out a multicentric retrospective study on vigorous primary anti-infectious prophylaxis consisting of lipegfilgrastim, trimethoprim-sulfamethoxazole, and acyclovir. From January 2017 to January 2022, 200 patients met the inclusion criteria and were enrolled in the final analysis. As per the primary endpoint, during the immune-chemotherapy period, the overall incidence of FN was 6% consisting of fever of unknown origin (2%), clinically documented infections (2.5%), and microbiologically documented infections (1.5%). Chemotherapy disruption for a delay of at least 1 week related to FN that required hospitalization was recorded in 1% of patients (n = 2). Prophylaxis was well tolerated with grade 3 toxicity (bone pain) in only 10% of patients and was successfully managed with paracetamol or tramadol. Systematic, prompt, and sustained use of vigorous primary anti-infectious prophylaxis was able to reduce the rate of fever episodes, thus averting parenteral antimicrobial administrations, hospitalizations, and immune-chemotherapy disruption.
2024-02-21 | Effectiveness and safety of empegfilgrastim (Extimia®, BIOCAD) in patients with lymphoproliferative diseases receiving cytotoxic therapy: results of LEGERITY, a multicenter retrospective-and-prospective observational post-marketing study
Aim. To evaluate the effectiveness and safety of Extimia® BIOCAD (international non-proprietary name: empegfilgrastim) to reduce the incidence and duration of neutropenia, the incidence of febrile neutropenia (FN) and infections associated with FN in patients with lymphoproliferative diseases receiving myelosuppressive therapy.
Materials and methods. The paper presents the results of a multicenter retrospective-and-prospective observational post-marketing study of the safety and effectiveness of Extimia® BIOCAD (international non-proprietary name: empegfilgrastim) in patients with lymphoproliferative diseases receiving cytotoxic therapy. Initially, the study was defined as retrospective-and-prospective. However, only 2 of 671 (0.3%) patients were included retrospectively. Thus, the study is based on the evaluation of prospectively collected data. The analysis describes the characteristics and treatment of 671 patients diagnosed with lymphoma who received one or more cycles of chemotherapy in the LEGERITY study. The endpoints of interest included the incidence of grade 3–4 neutropenia, FN, and grade 3–4 infectious complications, the frequency of antibiotic therapy, and the incidence of all adverse reactions in patients who received at least one dose of the study medication.
Results. A total of 671 patients were enrolled in the study, the majority having B-cell non-Hodgkin lymphoma (428/671, 64%) and Hodgkin lymphoma (211/671, 31%). The mean age was 54 years (18–84); 35% (236/671) of patients were elderly (over 60). The number of injections of empegfilgrastim for the entire observation period was 3093 (n=671). Adverse events were reported in 57/3093 (1.8%) cases. The most common adverse events were mild to moderate ossalgia and myalgia (27/671, 4%), back pain, and arthralgia (12/671, 1.8%), which did not require drug therapy. Two patients developed serious adverse reactions – CTCAE v.5 grade 4 hypotension events. 529 (78.8%) patients received at least 4 courses of chemotherapy. FN was reported in 14 (2.6%) patients and did not require antimicrobial therapy.
Conclusion. The final analysis results confirm the high clinical efficacy and safety of the Russian original pegylated granulocyte colony-stimulating factor empegfilgrastim (Extimia®) in patients with indolent and aggressive lymphomas. The data obtained from real-world clinical practice demonstrate a favorable safety and tolerability profile of empegfilgrastim in all age groups, including the elderly population.
2023-12-01 | Analysis of vaccine responses after anti-CD20 maintenance in B-cell lymphoma in the Balearic Islands. A single reference center experience.
The use of maintenance approaches with anti-CD20 monoclonal antibodies has improved the outcomes of B-cell indolent lymphomas but may lead to significant peripheral B-cell depletion. This depletion can potentially hinder the serological response to neoantigens. Our objective was to analyze the effect of anti-CD20 maintenance therapy in a reliable model of response to neoantigens: SARS-CoV-2 vaccine responses and the incidence/severity ofCOVID-19 in a reference hospital. In our series (n=118), the rate of vaccination failures was 31%. Through ROC curve analysis, we determined a cutoff for SARS-CoV-2 vaccine serologic response at 24 months from the last anti-CD20 dose. The risk of severe COVID-19 was notably higher within the first 24months following the last anti-CD20 dose (52%) compared to after this period (just 18%) (p=0.007). In our survival analysis, neither vaccine response nor hypogammaglobulinemia significantly affected OS. While COVID-19 led to a modest mortality rate of 2.5%, this figure was comparable to the OS reported in the general immunocompetent population. However, most patients with hypogammaglobulinemia received intravenous immunoglobulin therapy and all were vaccinated. In conclusion, anti-CD20 maintenance therapy impairs serological responses to SARS-CoV-2 vaccines. We report for the first time that patients during maintenance therapy and up to 24 months after the last anti-CD20 dose are at a higher risk of vaccine failure and more severe cases of COVID-19. Nevertheless, with close monitoring, intravenous immunoglobulin supplementation or proper vaccination, the impact on survival due to the lack of serological response in this high-risk population can be mitigated, allowing for the benefits of anti-CD20 maintenance therapy, even in the presence of hypogammaglobulinemia.
cell therapies
2026-07-05 | Efficacy and safety of CD19 CAR T-cell therapy in relapsed/refractory follicular lymphoma: A systematic review and meta-analysis.
Follicular lymphoma (FL) is an indolent B-cell non-Hodgkin lymphoma characterized by frequent relapses despite initial responsiveness to chemoimmunotherapy. CD19-directed chimeric antigen receptor (CAR) T-cell therapy has shown promising efficacy in relapsed or refractory disease, though safety concerns such as cytokine release syndrome (CRS) and neurological events remain. This study aimed to evaluate the efficacy and safety of CD19 CAR T-cell therapy in relapsed or refractory FL. A comprehensive search using six databases, including PubMed, Scopus, and Embase, was performed to identify relevant studies. Data on overall response rate (ORR), complete response rate (CRR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), and adverse events, including CRS and neurological events, were extracted. Pooled estimates were calculated using the quality effects model. This review was registered in PROSPERO (CRD420251133655). Out of 2303 records initially identified, 6 studies met the inclusion criteria. The pooled efficacy analysis demonstrated an ORR of 93.5% (95% CI: 86.3-98.3%) and a CRR of 84.5% (95% CI: 72.6-93.6%). Regarding safety outcomes, the pooled estimate for CRS of any grade was 61.4% (95% CI: 45.0-76.6%). For neurological events, it was 33.6% (95% CI: 13.4-57.1%). Subgroup analyses identified prior therapy lines and CAR construct design as sources of heterogeneity. In conclusion, CD19 CAR T-cell therapy demonstrates high efficacy with a generally acceptable safety in relapsed or refractory FL, supporting its consideration for patients with limited treatment options while highlighting the need for further research on long-term outcomes.
2026-06-18 | Anti-CD19 CAR-T in transformed indolent lymphoma vs de novo large B-cell lymphoma: a meta-analysis of 5006 patients
The histological transformation (HT) of indolent non-Hodgkin lymphoma (iNHL) to aggressive lymphomas, commonly diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL), is associated with chemoresistance and poor prognosis, particularly after prior therapy.Transformed iNHL (tNHL) lacks a universally accepted standard of care.Although salvage high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is recommended by National Comprehensive Cancer Network guidelines, approximately half of the cases relapse within 3 years after ASCT.1,2 The emergence of anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the management of relapsed BCLs.However, evidence regarding its comparative effectiveness in tNHL vs de novo large B-cell lymphoma (dn-LBCL) remains controversial.[3][4][5][6] Therefore, we conducted a systematic review and meta-analysis to compare the efficacy and safety of anti-CD19 CAR-T therapy in tNHL vs dn-LBCL.We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, ClinicalTrials. gov, and conference abstracts through 30 September 2025 using terms for "CAR-T," "LBCL," and "transformed lymphoma."Eligible studies met the following criteria: (1) LBCL, including DLBCL or high-grade BCL; (2) tNHL defined as LBCL transformed from follicular lymphoma (FL) and marginal zone lymphoma, except for Richter transformation; (3) patients previously receiving ≥1 line of treatment; and (4) comparative reporting of outcomes and toxicity between tNHL and dn-LBCL receiving autologous CD19-directed CAR-T products in the main text or supplements.Studies using allogeneic CAR-Ts, dual-target constructs, or non-CD19-directed CAR-Ts were excluded.Study quality was assessed using the methodological index for nonrandomized studies scale.7 The main outcomes were complete remission (CR) rate, progression-free survival (PFS), overall survival (OS), and incidence of adverse events (AEs), including cytokine release syndrome (CRS) and neurotoxicity.PFS/OS were extracted per study definitions from CAR-T infusion, as specified by the authors of the respective studies.We extracted the best response after CAR-T infusion and during follow-up.Hazard ratios (HRs) were extracted directly from texts or reconstructed from Kaplan-Meier curves when unavailable.8 Statistical analysis was performed using Review Manager 5.4 and R Studio software.The study protocol was followed by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered in the International Prospective Register for Systematic Reviews (registration identity: CRD420251168280).After screening 2367 records, 10 articles 3-6,9-14 comprising 5006 enrolled patients were included (supplemental Figure 1A); end point-specific subsets differed by data availability.The baseline characteristics of the included studies are presented in supplemental Table 1.Sample sizes ranged from 25 to 844.In total, 1202 patients had tNHL, and 3804 patients had dn-LBCL.Bias assessment indicated moderate to good quality (supplemental Figure 1B), and the Egger publication bias test suggested no risk of publication bias (supplemental Table 2).
2026-06-17 | Outcomes of CAR T-Cell Therapy in transformed indolent Non-Hodgkin Lymphomas and de novo DLBCL: A comparative analysis from the Italian CAR T-SIE study.
Transformed indolent non-Hodgkin lymphoma (TiNHL) generally has poorer outcomes than de novo diffuse large B-cell lymphoma (dnDLBCL). Although anti-CD19 CAR T-cell therapy is standard for relapsed/refractory (R/R) large B-cell lymphoma (LBCL), its prognostic role across histologies remains unclear. We conducted a multicenter, retrospective/prospective observational study comparing R/R TiNHL and R/R dnDLBCL patients treated with commercial CAR T-cell therapy and enrolled in the Italian CART-SIE study. Among 438 patients, 107 had TiNHL (96 transformed follicular lymphoma [tFL], 11 transformed marginal zone lymphoma [tMZL]) and 331 had dnDLBCL. Baseline characteristics were comparable. TiNHL patients showed superior overall (83% vs 69%) and complete response rates (62% vs 53%) (both p < 0·01), with better 2-year progression-free survival (PFS: 44% vs 31%) and overall survival (OS: 61% vs 48%) (both p < 0·01). CAR-HEMATOTOX score predicted worse outcomes (PFS HR=2·10; OS HR=3·57). No significant differences were found between tFL and tMZL. Two-year relapse/progression incidence was lower in TiNHL (28% vs 47%, p < 0·01), with similar non-relapse mortality (11% vs 4%, p = 0·12). Safety profiles, including cytokine release syndrome and ICANS rates, were comparable. TiNHL patients receiving CAR T-cell therapy achieved better outcomes than dnDLBCL patients, with comparable safety, supporting its use as a standard treatment in TiNHL.
2026-06-03 | From CAR-T to CAAR-T: redefining targeting strategies in B-cell malignancies through idiotype-directed cellular therapy.
Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the management of selected hematologic malignancies, particularly relapsed or refractory large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma. However, currently approved CAR-T strategies largely rely on lineage-associated or differentiation antigens, such as CD19 or BCMA, and therefore do not selectively distinguish malignant B cells from their normal counterparts. This limitation contributes to on-target, off-tumor toxicity, including B-cell aplasia, hypogammaglobulinemia, infectious complications, and prolonged immune dysfunction. In addition, CAR-T therapy remains associated with cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, immune effector cell-associated hematotoxicity, manufacturing complexity, and variable efficacy across disease entities, particularly in chronic lymphocytic leukemia. Chimeric autoantibody receptor T-cell (CAAR-T) therapy represents a conceptually distinct approach in which engineered T cells are designed to recognize disease-defining immunoglobulin structures, including surface immunoglobulin or B-cell receptor idiotypes. This strategy has been most extensively explored in autoimmune diseases, where CAAR-T cells can selectively eliminate autoreactive B-cell populations while sparing the broader B-cell compartment. Its application in B-cell malignancies remains largely hypothetical, but the biological principle is attractive because many B-cell neoplasms are defined by clonotypic immunoglobulin rearrangements. In this review, we provide a disease-specific and translationally oriented assessment of idiotype-directed CAAR-T therapy in B-cell malignancies. We summarize the current evidence supporting CAAR-T biology, critically evaluate its potential in chronic lymphocytic leukemia, indolent lymphomas, multiple myeloma, and minimal residual disease, and discuss key biological, economic, manufacturing, and regulatory barriers. At present, CAAR-T should not be viewed as a near-term replacement for approved CAR-T therapies, but rather as a hypothesis-generating precision platform requiring rigorous disease-specific validation.
2026-04-16 | A Phase 2, Open-Label, Multicenter Study of the Safety and Efficacy of TAK-007 in Adult Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma
In relapsed/refractory large B-cell lymphoma (LBCL), chimeric antigen receptor (CAR)-natural killer (NK) cell therapies offer potential advantages over CAR-T-cell therapies, including off-the-shelf availability and scalable manufacturing. We performed a phase 2 study of single-dose TAK-007, a cryopreserved, cord blood-derived, off-the-shelf CD19 CAR-NK cell therapy, in 26 heavily pre-treated patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Adverse events were manageable, with limited grade 1–2 cytokine release syndrome (11.5%). Overall response rate with TAK-007 800 x106 CD19 CAR+ viable NK cells (n=14) was 60.9% (95% CI: 38.5–80.3). Median progression-free survival was 2.0 months (95% CI: 0.99–3.58) in LBCL (n=10) and 5.6 months (95% CI: 1.05–8.57) in indolent NHL (n=7) expansion cohorts. Deep molecular responses, including ctDNA-negative responses, were achieved. Not all TAK-007 products elicited clinical responses; single cell RNA-sequencing showed NK proliferating and NK-CD56dim cell enrichment in TAK-007 products eliciting/not eliciting responses, respectively, which could inform product selection. This is a single cell RNASeq dataset collected longitudinally during culturing and generation of CD19 CAR-NK cell therapies.
antibodies
2026-09-16 | Current and new approaches to the treatment landscape for adults with Waldenström macroglobulinemia.
Waldenström macroglobulinemia (WM) is an indolent B-cell lymphoma with unique clinical manifestations driven by both tumor infiltration of the bone marrow and extramedullary tissues, as well as IgM-related pathology. Recent therapeutic advances for WM have been largely driven by molecular discoveries, and current agents have significantly improved disease control and progression-free survival. However, WM remains incurable, and novel treatment strategies that balance efficacy with tolerability are needed. This review summarizes current treatment approaches, including chemoimmunotherapy and Bruton tyrosine kinase inhibitors, and discusses emerging therapeutic strategies with a focus on clinical efficacy, toxicity, and evolving treatment paradigms. We also examine the role of combination approaches and novel agents, considering their potential integration into the current treatment landscape. Despite substantial progress, key challenges remain, including the absence of definitive comparative data between various treatment strategies, the optimal sequencing of available agents, and an understanding of the impact of novel therapies on the depth of hematologic response, as well as long-term clinical and patient-reported outcomes. Future efforts should focus on biologically informed treatment selection and the development of strategies that reduce cumulative toxicities while achieving durable disease control.
2026-09-10 | Peripheral CD8⁺ T-cell clonality and NK-cell expansion mark early response to mosunetuzumab in indolent B-cell lymphoma.
Mosunetuzumab is highly effective against many B-cell lymphomas, but longitudinal immune changes induced by intermittently dosed CD20×CD3 bispecific antibodies remain incompletely characterized. We performed immune profiling of peripheral blood samples from patients receiving fixed-duration (6 months) subcutaneous mosunetuzumab for previously untreated follicular or marginal zone lymphoma on a phase 2 clinical trial (NCT04792502). Analyses included flow cytometry, cytokine profiling, and RNA-seq of isolated CD8+ T-cells with TCR repertoire inference. Early (at 3 weeks) on-treatment samples showed broad cytokine induction, CD8+ T-cell redistribution with decreased TEMRA cells and increased CD27+CD62L+ transitional effector memory-like cells, increased PD-1 and LAG-3 expression, and induction of CD8+ transcriptional programs consistent with activation, proliferation, exhaustion priming, and SREBF2-regulated cholesterol metabolism. By mid-treatment (at 3 months), activation-associated features contracted toward baseline, with no evidence of phenotypic exhaustion, though with persistent overexpression of LAG3, HAVCR2, and LAYN on RNA-seq, as well as sustained SREBF2 activation. CD8+ T-cell clonality increased at mid-treatment compared with baseline and higher clonality was associated with early clinical complete response. Mosunetuzumab also induced indirect NK-cell activation and expansion, including skewing toward CD56dimCD16bright effector state. HLA-DR upregulation on NK cells correlated with early increases in NK-activating plasma cytokines, and higher NK-cell count at mid-treatment was associated with complete response. Together, these findings define a CD8+ effector-remodeling state on mosunetuzumab therapy, characterized by clonal expansion, selective inhibitory receptor expression, sustained activation of cholesterol biosynthesis, and cytokine-linked engagement of innate immune mechanisms, providing a framework for potential strategies to support T-cell function and enhance bispecific antibody efficacy.
2026-09-08 | Follicular lymphoma and the microenvironment: potential targets and biomarkers.
Follicular lymphoma (FL) is an indolent B cell malignancy characterized by recurrent genetic alterations, yet its clinical course is highly variable and not fully explained by tumor-intrinsic features alone. Increasing evidence highlights the tumor microenvironment (TME) as a critical regulator of disease progression, therapeutic response, and immune escape. FL TME is composed of diverse cellular elements, including T cell subsets, tumor-associated macrophages, stromal cells, and follicular dendritic cells, which collectively provide survival signals and shape immune dysfunction. These interactions have led to the identification of potential therapeutic targets, such as immune checkpoint molecules, macrophage polarization pathways, and stromal-tumor signaling axes. In parallel, microenvironment-derived biomarkers, including specific immune cell compositions, spatial organization patterns, and gene expression signatures, are emerging as important predictors of prognosis and treatment outcomes. Advances in single-cell and spatial profiling technologies have further refined our understanding of TME heterogeneity, enabling the discovery of clinically relevant targets and biomarkers. Together, these insights support a more integrated model of FL biology and provide a foundation for developing microenvironment-directed therapies and precision medicine approaches.
2026-07-30 | Comparison of H1 versus combined H1/H2 antagonist premedication on incidence of rituximab infusion-related reaction: A retrospective cohort study.
IntroductionRituximab, an anti-CD20 monoclonal antibody used in B-cell malignancies, is associated with infusion-related reactions (IRRs) during the initial infusion. Standard premedication includes acetaminophen, corticosteroids, and a histamine-1 (H1) antagonist, typically diphenhydramine. Second-generation H1 antagonists offer similar efficacy with less sedation. Some institutions also incorporate histamine-2 (H2) antagonists despite limited supporting evidence. This study evaluated whether dual H1/H2 antagonist premedication reduces IRRs compared with H1-antagonist monotherapy when given with standard premedication.MethodsThis retrospective study reviewed health records of adults with a hematologic malignancy who received their first rituximab infusion at Brown University Health system between January 1, 2022 and June 30, 2025. Patients received premedication with either an H1-antagonist alone or dual H1/H2 receptor-antagonists with acetaminophen and a corticosteroid. The primary endpoint was IRR incidence during or within 24 h of infusion initiation. Secondary endpoints included IRR severity, incidence of grade 3-4 IRRs across subgroups, and time to IRR onset.ResultsAmong 299 patients (mean age 65; 55% male), 62% had aggressive lymphoma, 28% indolent lymphoma, and 10% leukemia. Baseline features included bone marrow involvement (38%), bone disease (39%), advanced-stage nodal disease (54%), B symptoms (48%), and >2 extranodal sites (28%). IRRs occurred in 38% of patients receiving dual H1/H2 antagonist premedication versus 36.5% with H1-antagonist monotherapy, with no difference in grade 3-4 IRRs. Most IRRs occurred 30 to 60 min after infusion initiation.ConclusionDual H1/H2-antagonist premedication was not associated with differences in the incidence or severity of rituximab IRRs compared with H1-antagonist monotherapy in addition to standard premedication.
2026-07-23 | Multifunctional CD38 in the pathogenesis and treatment of B-cell lymphomas.
B-cell lymphoma is a group of non-Hodgkin lymphomas with high heterogeneity. Despite advancement in therapeutics, the clinical outcomes of B-cell lymphomas need to be improved. CD38, a transmembrane multifunctional protein, is widely expressed across various B-cell lymphoma subtypes. Research indicates that CD38 plays multiple pathogenic roles in B-cell lymphomas, including regulation of proliferation, apoptosis, immune modulation, primarily through its enzymatic activity and its influence on signaling pathways in malignant lymphoma cells and immunosuppressive cells, making it a valuable therapeutic target. In recent years, CD38-targeted therapies, such as anti-CD38 antibodies and CD38-directed CAR-T cell therapies, have been explored for B-cell lymphomas. This review summarizes the knowledge on CD38 molecular functions, data of CD38 heterogeneous expression and prognostic role in B-cell lymphomas (from indolent to aggressive subtypes), anti-CD38 antibody efficacy and mechanisms of action, current understanding of the treatment resistance mechanisms, frontier advances in CD38-targeted therapies, and the challenges of novel targeted and immunotherapies in clinical applications, thereby seeking to provide a deep understanding of the role of CD38 in the pathogenesis and treatment of B-cell lymphomas. CD38-targed therapy is especially promising as a novel and optional treatment for CD20-negative lymphomas, for which standard treatment has not been established. Although the efficacy of anti-CD38 antibodies in most other B-cell lymphomas is low in previous clinical trials, in contrast to the remarkable efficacy of daratumumab in multiple myeloma, novel therapeutic strategies and combination therapies in ongoing clinical trials have the potential to overcome the counteracting actions and to improve the clinical outcomes of patients with relapsed/refractory B-cell lymphoma.
small molecules
2026-08-01 | The efficacy and safety of zanubrutinib combined with BR regimen in B-cell chronic lymphoproliferative disorder
ObjectiveTo explore the efficacy and safety of a zanubrutinib-based combination regimen as first-line treatment for patients with B-cell chronic lymphoproliferative disorder (B-CLPD). MethodsA retrospective analysis was performed on 26 patients with B-CLPD, including indolent B-cell non-Hodgkin lymphoma (B-iNHL), mantle cell lymphoma (MCL), and other unclassifiable B-CLPD, who were newly diagnosed and treated at the Department of Hematology, Zhongshan Hospital (Xiamen), Fudan University between January 2021 and January 2025. Patients were divided into two groups according to the treatment regimen: BR (bendamustine plus rituximab) and ZBR (zanubrutinib combined with BR regimen). Baseline characteristics, treatment responses, and the incidence of treatment-related adverse events (TRAE) were compared between the two groups. ResultsNo statistically significant differences in baseline characteristics were observed between the two groups. All patients completed at least four cycles of treatment. There were no significant differences between the BR and ZBR groups in partial response rate (46.2% vs 53.8%), complete response rate (53.8% vs 15.4%), overall response rate (100.0% vs 84.6%), or TRAE incidence. After the first cycle, the lymphocyte count was higher in the ZBR group than in the BR group (P＝0.002); no other statistically significant differences in other hematologic parameters were observed at any treatment cycle. ConclusionsIn patients with B-iNHL, MCL, and other unclassifiable B-CLPD, the ZBR regimen demonstrates similar safety and response rates to the BR regimen. These findings support further investigation into the clinical value of ZBR as first-line treatment regimen in a limited course for indolent lymphoid malignancies.
2026-07-07 | Bendamustine in indolent lymphoma: Letting the dust settle down.
In a large population‐based cohort of patients with indolent B‐cell lymphoma, bendamustine–rituximab was not associated with a statistically significant excess risk of secondary primary malignancies compared with cyclophosphamide‐based regimens after adjustment for confounders. These data contextualize prior safety concerns and support thoughtful optimization rather than abandonment of bendamustine‐based frontline therapies in indolent B‐cell lymphomas.
2026-07-03 | Diagnostic challenge of occult ER-positive breast carcinoma within bone marrow indolent B-cell lymphoma and response to CDK4/6 inhibitor: a case report.
Bone marrow metastasis from hormone receptor-positive breast cancer can be challenging to detect, especially in patients with concurrent hematologic malignancies, where isolated epithelial cells may be hidden by a dominant lymphoid infiltrate. This situation requires careful histopathologic and immunophenotypic evaluation to prevent misdiagnosis. We report a 74-year-old White woman with Waldenström's macroglobulinemia carrying the MYD88 L265P mutation and bone marrow infiltration by indolent B-cell non-Hodgkin lymphoma. She was evaluated for suspected skeletal disease progression due to rising tumor markers and inconclusive PET findings. Bone marrow biopsy revealed small clusters of epithelial cells positive for estrogen receptor (ER), cytokeratin AE1/AE3, and GATA3, consistent with metastatic breast carcinoma within a lymphoid background. Notably, ER positivity was the only marker indicating epithelial origin. The patient had previously received empirical aromatase inhibitor therapy after the initial detection of scattered ER-positive epithelial cells in 2018. Following disease progression in December 2024, she was treated with palbociclib and fulvestrant, while the indolent lymphoma was managed with active surveillance. At 6-month follow-up, the patient showed clinical stability, a biochemical response, and radiologic evidence of stable disease. This case emphasizes the importance of maintaining a high level of clinical and pathological suspicion when assessing bone marrow infiltration, especially in patients with a history of malignancy. The presence of isolated ER-positive epithelial cells within a lymphoid marrow environment should raise suspicion of occult breast carcinoma metastasis. Due to the rarity of this coexistence, the underlying mechanisms and optimal management strategies are still unclear. To our knowledge, this is one of the few reported cases of occult ER-positive breast carcinoma presenting solely as bone marrow involvement in a patient with indolent B-cell lymphoma, with documented response to CDK4/6 inhibitor-based therapy. This case report was prepared in accordance with the CAse REport (CARE) guidelines.
2026-03-31 | Prognostic significance of clinical risk models and genomic alterations in Waldenström macroglobulinemia before or after the BTK inhibitor era.
Waldenström macroglobulinemia (WM) is a rare indolent B-cell lymphoma with marked clinical and molecular heterogeneity. Clinical risk models, including IPSSWM, rIPSSWM, and MSSWM, were developed prior to the widespread use of Bruton tyrosine kinase inhibitors (BTKi), and their performance in the BTKi era remains uncertain. In addition, the prognostic impact of various genomic alterations is controversial. We retrospectively analyzed 453 symptomatic WM patients, including 203 who received non-BTKi therapy and 250 who received BTKi-based therapy. All three models significantly stratified prognosis in the non-BTKi cohort, with rIPSSWM showing the highest predictive accuracy, but none effectively predicted survival in BTKi-treated patients. Notably, among patients receiving first-line BTKi-based therapy, high-risk patients by any model achieved survival outcomes comparable to those of lower-risk patients, suggesting that upfront BTKi can overcome the adverse impact of high-risk clinical features. At the molecular level, MYD88 mutation was significantly associated with favorable outcomes exclusively in patients treated with first-line BTKi-based therapy, while CXCR4 and TP53 mutations predicted significantly inferior prognosis in both BTKi-based and non-BTKi cohorts. Our findings indicate that although clinical risk models remain relevant for patients receiving non-BTKi therapy, molecular features, especially MYD88, CXCR4, and TP53 mutations, provide superior prognostic insights for patients with BTKi-based regimens.
2026-03-30 | [IgG-κ lymphoplasmacytic lymphoma complicated by bilateral femoral neck fractures secondary to bone involvement].
Lymphoplasmacytic lymphoma (LPL) is a type of indolent B-cell lymphoma typically associated with IgM paraproteinemia and does not require immediate treatment until symptoms appear. However, non-IgM LPL has a higher frequency of extramedullary involvement and requires more aggressive therapy than IgM-LPL. A 51-year-old woman in treatment-free follow-up for LPL with IgG-κ paraproteinemia was referred to our hospital with a chief complaint of right coxalgia. A plain MRI scan showed multiple osteolytic bone lesions, including bilateral femoral incomplete fractures. Similar bone lesions were also detected in the right shoulder joint. Pathological examination of the bilateral femurs and the right shoulder revealed LPL lesions with amyloid deposits. MYD88 L265P gene mutations were confirmed by genetic analysis, and all lesions were considered identical. Ibrutinib plus rituximab therapy was administered, resulting in a partial response sustained to date. Bone involvement and amyloidosis are rare but critical extranodal manifestations of LPL, necessitating careful screening and follow-up even in asymptomatic patients. When these manifestations are suspected, prompt pathological and genetic evaluation is warranted, especially in non-IgM LPL cases.
other
2026-06-02 | Obinutuzumab plus bendamustine as first-line therapy for indolent B-cell lymphomas: a prospective multicenter open-label study.
This study evaluated the efficacy and safety of obinutuzumab plus bendamustine (GB) as first-line treatment for indolent B-cell lymphomas. In this prospective, multicenter, single-arm trial (NCT06415708), adults with newly diagnosed indolent B-cell lymphomas-including follicular lymphoma (FL), marginal zone lymphoma (MZL), Waldenström macroglobulinemia (WM), hairy cell leukemia variant (HCL-v), and unclassified B-cell lymphoproliferative disorder (BCLPD-U)-received six induction cycles of GB followed by 2 years of obinutuzumab maintenance in responders (⩾ partial response). The primary endpoint was overall response rate (ORR), whereas secondary endpoints included complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Among 220 enrolled patients (149 with FL and 71 with non-FL), 210 completed ⩾ 3 treatment cycles. At a median follow-up of 13.1 months, ORRs in the different patient subgroups were 96.6% (FL), 100% (MZL, HCL-v), 92.9% (WM), and 88.9% (BCLPD-U). The median DOR was 16.7 months in the FL group and was not reached in the non-FL group. PFS and OS were not reached in any subgroup. The FL and non-FL groups had comparable ORRs (P = 0.435); however, the FL group showed a higher CRR (92.4% vs. 78.5%; P = 0.004) and shorter PFS (P = 0.020). Treatment-emergent adverse events occurred in 42 patients and were more frequent in the non-FL group than in the FL group (26.8% vs. 15.4%; P = 0.046), particularly infections (18.3% vs. 6.0%; P = 0.005). Overall, the GB regimen demonstrated high response rates and manageable safety in Chinese patients with indolent B-cell lymphoma.
2026-01-08 | Non-gastric mucosa-associated lymphoid tissue lymphomas: a narrative review of pathogenesis, diagnosis, and treatment strategies.
Extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) are indolent non-Hodgkin lymphomas (NHLs) that can arise in various extranodal organs, often due to chronic inflammation. Gastric MALT lymphomas are well characterized; however, MALT lymphomas may occur in diverse sites such as the ocular adnexa, salivary glands, thyroid, lung, skin, and the small intestine. These site-specific MALT lymphomas have distinct etiologic associations, clinical presentation, and management considerations. This review provides an updated, site-specific overview to guide the diagnostic and therapeutic approach to non-gastric MALT lymphoma in adults. We reviewed peer-reviewed articles [2015-2025] on non-gastric MALT lymphomas, focusing on pathophysiology/etiology, diagnostic workup, and treatment strategies for each site. Key sources include recent reviews and guidelines from high-impact journals. Chronic antigenic stimulation is a unifying theme in MALT lymphoma genesis, either through infectious etiologies or autoimmune conditions. Ocular adnexal MALT lymphoma (OAML) is linked to Chlamydia psittaci (C. psittaci) infection in certain regions; salivary MALT lymphoma is related to Sjogren's syndrome (SS); thyroid MALT lymphoma develops in the background of Hashimoto's thyroiditis; pulmonary MALT lymphoma can be linked to chronic airway inflammation due to Achromobacter xylosoxidans (A. xylosoxidans); small intestinal MALT lymphoma can be associated with Campylobacter jejuni (C. jejuni) infection; and cutaneous MALT lymphoma can be linked to Borrelia burgdorferi (B. burgdorferi) infection. Diagnostic evaluation requires adequate tissue biopsy for histopathology and immunohistochemistry. MALT lymphomas exhibit an immunophenotype consistent with CD20+, CD79a+, IgM+ with light chain restriction, BCL2+, and negative for CD5, CD10, and cyclin D1. Staging for OAML and cutaneous lymphomas is tumor-node-metastasis (TNM)-based, while the others utilize an Ann Arbor staging system. Computed tomography (CT)/magnetic resonance imaging (MRI) and positron emission tomography (PET)/CT are used to determine the staging and spread of tumors. Treatments are not standardized but consist of therapy with radiotherapy and surgical excision for localized disease, and chemotherapy/for disseminated disease. Intestinal MALT lymphoma differs, as first-line treatment consists of antibiotics and then chemotherapy/immunotherapy. The non-gastric MALT lymphomas have an excellent prognosis as a whole; relapses are common but manageable, and disseminated disease is rare. Long-term follow-up is recommended in all cases.
2025-06-17 | The anti-CD47 antibody magrolimab with obinutuzumab and venetoclax in relapsed or refractory indolent B-cell lymphomas.
Follicular lymphoma (FL), marginal zone lymphoma (MZL), chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL) are characterized by a continuous incidence of relapse and increasing resistance to therapy. Novel immunotherapy approaches are needed. Magrolimab, a CD47-blocking antibody, disrupts CD47:SIRPα-mediated antiphagocytic signalling. When combined with a prophagocytic signal from an anti-CD20 antibody rituximab, it has shown activity in relapsed or refractory FL and MZL. In this phase 1 study, adding the BCL2-inhibitor venetoclax to magrolimab and the anti-CD20 antibody obinutuzumab resulted in complete responses in 6 of 10 (60%) evaluable patients with FL, MZL or CLL. Notably, we did not observe increased risk of infections previously reported from studies of magrolimab in acute myeloid leukaemia and higher risk myelodysplastic syndromes.
2025-06-01 | 591 | NOVEL CHEMOTHERAPY‐FREE INITIAL TREATMENT OF RITUXIMAB PLUS PEGYLATED INTERFERON Α‐2B IN UNTREATED ADVANCED INDOLENT B‐CELL LYMPHOMA: 4‐YEAR FOLLOW‐UP STUDY
G. Yan and L. Ping equally contributing author. Background: Indolent B-cell lymphomas (iBCL), accounting for 10%–15% of non-Hodgkin lymphoma (NHL) subtypes in China, exhibit clinical heterogeneity. While generally associated with favorable survival, most iBCL cases remain incurable. Rituximab monotherapy demonstrates efficacy in initial treatment, and preclinical studies suggest interferon-alpha (IFN-α) may synergistically enhance rituximab activity through immune modulation. Pegylated IFN-α2 (Peg-IFN-α2) offers improved pharmacokinetics with reduced toxicity compared to conventional IFN-α and is utilized in chronic hepatitis B (CHB) management. The phase II RIPPLE trial (NCT04246359) evaluates rituximab biosimilar combined with Peg-IFN-α2b in treatment-naïve iBCL. Methods: Newly diagnosed iBCL (follicular lymphoma [FL] grades 1–2/3a, marginal zone lymphoma [MZL], lymphoplasmacytic lymphoma [LPL], small lymphocytic lymphoma [SLL]); ECOG ≤ 2; adequate organ function; measurable disease. Patients with chronic hepatitis B co-infection (HBsAg+, HBV DNA < 3000 IU/mL, ALT < 5 × ULN) were permitted for enrollment. Induction therapy consisted of rituximab biosimilar (Henliritux; 375 mg/m2 IV day 1) plus Peg-IFN-α2b (Pegberon; 135μg SC days 1, 8) every 21 days for 6 cycles. Responders received maintenance (rituximab every 8 weeks; Peg-IFN-α2b monthly) for ≤ 2 years. CHB patients received entecavir prophylaxis. Primary endpoint: investigator-assessed ORR and CR (Lugano 2014). Secondary endpoints: TTR, DOR, PFS, OS, HBV clearance, safety (CTCAE v5.0). Results: Between September 2018 and July 2021, 57 eligible patients (median age 54 years; 56.1% female) were enrolled across six Chinese centers. 21 (36.8%) pts were symptomatic. The cohort comprised 45.6% (n = 26) FL grade 1–2, 36.8% (n = 21) MALT lymphoma, 12.3% (n = 7) FL grade 3a, 3.5% (n = 2) SLL, and 1.8% (n = 1) LPL, with 38.6% having FLIPI ≥ 3 and 10.5% being HBsAg-positive. At a median follow-up of 52.1 months (IQR 47.6–58.7), the overall response rate (ORR) was 71.9% (41/57) with 56.1% (32/57) achieving complete response (CR). Subtype-specific analyses revealed ORR/CR rates of 74.1%/48.1% in FL grade 1–2, 71.4%/71.4% in FL grade 3a, 61.9%/57.1% in MALT, 100%/50% in SLL, and 0/0 in LPL. Survival outcomes demonstrated 4-year progression-free survival (PFS) and overall survival (OS) rates of 61.6% and 93%, respectively, with medians not reached (Figure 1A,B). Treatment-emergent adverse events (TEAEs) were predominantly grade 1–2, including neutropenia (63.2%), anemia (36.5%), thrombocytopenia (29.8%), fever (28.1%), transaminase elevation (26.3%), fatigue (26.3%), and infusion reaction (21.7%, 10/46). No treatment-related deaths occurred. Conclusion: Rituximab biosimilar with Peg-IFN-α2b demonstrates durable efficacy and manageable toxicity in treatment-naïve iBCL, particularly in FL and MALT subtypes. The combination shows synergistic HBV suppression without reactivation risks. These results support further evaluation in larger randomized trials. Research funding declaration: No funding was received. Keywords: molecular targeted therapies; immunotherapy; indolent non-Hodgkin lymphoma No potential sources of conflict of interest.
2025-04-01 | A RARE DETERMINATION OF SMALL LYMPHOCYTIC LYMPHOMA ASSOCIATED WITH UNFAVORABLE EVOLUTION AND REVIEW OF THE LITERATURE.
Small lymphocytic lymphoma (SLL) is an indolent lymphoma. Hypercalcemia is rarely associated with this type of lymphoma and was reported as a Richter`s transformation sign of SLL in the literature. We report a case of a 64-year-old man, with many comorbidities, including cardiac and renal pathologies, known with hepatitis B. Small lymphocytic B lymphoma with genetic risk factors, such as TP53, 17p and unmutated IGHV was diagnosed by laterocervical node biopsy. During chemotherapy, the patient initially presented sciatic pain, leading to the suspicion of a new associated malignancy, but the lumbar MRI excluded osteolysis. A few weeks later, the patient presented with neurological symptoms and dangerous hypercalcemia and high levels of iPTH were discovered. Parathyroid determination was discovered and the second line therapy with Venetoclax- Rituximab was chosen, but unfavorable evolution was noted, with activated macrophage syndrome, disseminated intravascular coagulation and multiple organ dysfunction syndrome. The genetic risk factors and the presence of hypercalcemia are markers of negative prognosis and unfavorable evolution of the disease.
proteins
2026-06-08 | Antimicrobial Peptides Induce Cell Death in Marginal Zone Lymphoma Models Resistant to Targeted Therapies.
Marginal zone lymphoma (MZL) is an indolent yet incurable B-cell malignancy in which targeted agents such as BTK and PI3K inhibitors frequently fail due to resistance or toxicity. Antimicrobial peptides (AMPs), evolutionarily conserved effectors of innate immunity, possess selective cytotoxicity against malignant cells by exploiting tumor-specific membrane alterations. Peptides were synthesized and tested for their anti-proliferative activity in MZL cell lines. We evaluated the antitumor activity of seven natural AMPs, including Antarctic fish-derived trematocines and chionodracine variants, and amphibian temporins, against MZL cell lines (VL51, Karpas1718) and derivatives resistant to BTK, PI3Kδ, or PI3Kα/δ inhibitors. Among them, W-trematocine and temporin L demonstrated potent dose-dependent cytotoxicity with IC50 values of 5.7-10 µM, maintaining full activity in all resistant models. Other peptides showed moderate activity, while chionodracine-1 was inactive. Notably, W-trematocine displayed minimal toxicity toward nonmalignant cells in prior studies, underscoring its selectivity. AMP-mediated killing, driven by membrane disruption and non-apoptotic death pathways, bypassed conventional resistance mechanisms, suggesting therapeutic potential in relapsed/refractory disease. Our findings highlight natural AMPs as promising candidates for development in drug-resistant MZL, warranting further optimization and preclinical validation.
2025-11-03 | CHN1 suppresses B-cell non-Hodgkin lymphoma progression via akt/mTOR pathway
Abstract Introduction B-cell non-Hodgkin lymphoma (B-NHL) is the most prevalent NHL subtype, exhibiting high heterogeneity. Chimerin 1 (CHN1), a rac guanosine triphosphatase activating protein (racGAP), is predominantly expressed in neurons, especially in the cerebral cortex, and plays an important role in axon guidance. The previous study has estimated that CHN1 was associated with B-NHL aggressiveness, showing higher expression in indolent follicular lymphoma (FL) compared to aggressive Burkitt lymphoma (BL). In silico analysis also linked high CHN1 expression with favorable outcomes in diffuse large B-cell lymphoma (DLBCL) patients, though this prognostic value requires validation. The functional role of CHN1 in B-NHL remains unclear. Therefore, we aimed to validate the prognostic value of CHN1 in DLBCL and elucidate its biological functions and signaling pathways in B-NHL cells. Methods We retrospectively collected pathological specimens from 52 DLBCL patients. CHN1 expression was assessed by immunohistochemical (IHC) staining. Kaplan-Meier analysis evaluated the correlation between CHN1 expression levels and the prognosis of DLBCL patients. Stable CHN1-overexpressing human DLBCL cell line OCI-LY3 and human Burkitt lymphoma cell line Raji were established via lentiviral transduction. Cell proliferation was measured by direct cell counting. Migration and invasion were assessed using Transwell assays. Protein expression was analyzed by Western blotting. Transcriptome sequencing of OCI-LY3^OE^ cells, followed by GO, KEGG, and GSEA enrichment analyses, identified downstream pathways. Results IHC analysis classified DLBCL patients into CHN1-high and CHN1-low groups (cut-off value: 10% positivity). The CHN1-high group exhibited significantly higher objective response (OR: 86.2% vs. 39.1%, p=0.001) and complete response (CR: 65.5% vs. 21.7%, p=0.002) rates compared to the CHN1-low group. The disease progression (PD) rate was significantly lower in the CHN1-high group (10.3% vs. 52.2%, p=0.001). Kaplan-Meier analysis demonstrated that high CHN1 expression was significantly correlated with prolonged overall survival (OS, p=0.036) and progression-free survival (PFS, p=0.002). Successful establishment of CHN1-overexpressing RajiOE and OCI-LY3OE cells was confirmed. CHN1 overexpression significantly inhibited proliferation (p<0.001) and promoted apoptosis in both cell lines (Raji: p<0.001; OCI-LY3: p=0.002). Western blot demonstrated that CHN1 downregulated the anti-apoptotic protein BCL-2 (OCI-LY3OE: p=0.029; RajiOE: p=0.036) and upregulated the pro-apoptotic protein Bax (OCI-LY3OE: p=0.047; RajiOE: p=0.029). Furthermore, CHN1 suppressed migration (OCI-LY3: p=0.004; Raji: p=0.008) and invasion (OCI-LY3: p=0.012; Raji: p=0.007). Transcriptome sequencing of CHN1-overexpressing OCI-LY3 cells identified 867 upregulated and 1,035 downregulated genes. Enrichment analyses suggested that CHN1 involvement in cell adhesion, metabolism, vesicle formation, and cell junctions, and modulate pathways including PI3K/Akt, IL6/JAK/STAT3, and IL2/STAT5 signaling. Consistently, western blot revealed that CHN1 suppressed the phosphorylation of Akt and mTOR. Treatment with the Akt activator Sc79 partially restored Akt/mTOR phosphorylation and rescued the proliferative, migratory, and invasive capacities by CHN1 overexpression. Conclusions High CHN1 expression is a favorable prognostic marker in DLBCL, associated with higher OR/CR rates, lower PD, and prolonged OS and PFS. CHN1 suppresses B-NHL progression by inhibiting proliferation, migration, and invasion in B-NHL cells. Mechanistically, the Akt/mTOR signaling pathway may be a downstream mechanism of CHN1 in B-NHL cells.
2025-07-14 | Long-acting lipegfilgrastim and antimicrobials as vigorous primary prophylaxis in bendamustine-treated patients with indolent B cell non-Hodgkin lymphoma: a multicentric real-life experience.
Febrile neutropenia (FN) is one of the most important clinical signs of infection, especially for older patients with indolent B cell non-Hodgkin lymphomas (iBC-NHLs) receiving frontline immune-chemotherapy with bendamustine-rituximab (BR). Data on the optimal strategy for infection prophylaxis from the start of chemotherapy until 1 month after the last cycle is scanty in this setting of patients, and for this reason, we carried out a multicentric retrospective study on vigorous primary anti-infectious prophylaxis consisting of lipegfilgrastim, trimethoprim-sulfamethoxazole, and acyclovir. From January 2017 to January 2022, 200 patients met the inclusion criteria and were enrolled in the final analysis. As per the primary endpoint, during the immune-chemotherapy period, the overall incidence of FN was 6% consisting of fever of unknown origin (2%), clinically documented infections (2.5%), and microbiologically documented infections (1.5%). Chemotherapy disruption for a delay of at least 1 week related to FN that required hospitalization was recorded in 1% of patients (n = 2). Prophylaxis was well tolerated with grade 3 toxicity (bone pain) in only 10% of patients and was successfully managed with paracetamol or tramadol. Systematic, prompt, and sustained use of vigorous primary anti-infectious prophylaxis was able to reduce the rate of fever episodes, thus averting parenteral antimicrobial administrations, hospitalizations, and immune-chemotherapy disruption.
2024-02-21 | Effectiveness and safety of empegfilgrastim (Extimia®, BIOCAD) in patients with lymphoproliferative diseases receiving cytotoxic therapy: results of LEGERITY, a multicenter retrospective-and-prospective observational post-marketing study
Aim. To evaluate the effectiveness and safety of Extimia® BIOCAD (international non-proprietary name: empegfilgrastim) to reduce the incidence and duration of neutropenia, the incidence of febrile neutropenia (FN) and infections associated with FN in patients with lymphoproliferative diseases receiving myelosuppressive therapy.
Materials and methods. The paper presents the results of a multicenter retrospective-and-prospective observational post-marketing study of the safety and effectiveness of Extimia® BIOCAD (international non-proprietary name: empegfilgrastim) in patients with lymphoproliferative diseases receiving cytotoxic therapy. Initially, the study was defined as retrospective-and-prospective. However, only 2 of 671 (0.3%) patients were included retrospectively. Thus, the study is based on the evaluation of prospectively collected data. The analysis describes the characteristics and treatment of 671 patients diagnosed with lymphoma who received one or more cycles of chemotherapy in the LEGERITY study. The endpoints of interest included the incidence of grade 3–4 neutropenia, FN, and grade 3–4 infectious complications, the frequency of antibiotic therapy, and the incidence of all adverse reactions in patients who received at least one dose of the study medication.
Results. A total of 671 patients were enrolled in the study, the majority having B-cell non-Hodgkin lymphoma (428/671, 64%) and Hodgkin lymphoma (211/671, 31%). The mean age was 54 years (18–84); 35% (236/671) of patients were elderly (over 60). The number of injections of empegfilgrastim for the entire observation period was 3093 (n=671). Adverse events were reported in 57/3093 (1.8%) cases. The most common adverse events were mild to moderate ossalgia and myalgia (27/671, 4%), back pain, and arthralgia (12/671, 1.8%), which did not require drug therapy. Two patients developed serious adverse reactions – CTCAE v.5 grade 4 hypotension events. 529 (78.8%) patients received at least 4 courses of chemotherapy. FN was reported in 14 (2.6%) patients and did not require antimicrobial therapy.
Conclusion. The final analysis results confirm the high clinical efficacy and safety of the Russian original pegylated granulocyte colony-stimulating factor empegfilgrastim (Extimia®) in patients with indolent and aggressive lymphomas. The data obtained from real-world clinical practice demonstrate a favorable safety and tolerability profile of empegfilgrastim in all age groups, including the elderly population.
2023-12-01 | Analysis of vaccine responses after anti-CD20 maintenance in B-cell lymphoma in the Balearic Islands. A single reference center experience.
The use of maintenance approaches with anti-CD20 monoclonal antibodies has improved the outcomes of B-cell indolent lymphomas but may lead to significant peripheral B-cell depletion. This depletion can potentially hinder the serological response to neoantigens. Our objective was to analyze the effect of anti-CD20 maintenance therapy in a reliable model of response to neoantigens: SARS-CoV-2 vaccine responses and the incidence/severity ofCOVID-19 in a reference hospital. In our series (n=118), the rate of vaccination failures was 31%. Through ROC curve analysis, we determined a cutoff for SARS-CoV-2 vaccine serologic response at 24 months from the last anti-CD20 dose. The risk of severe COVID-19 was notably higher within the first 24months following the last anti-CD20 dose (52%) compared to after this period (just 18%) (p=0.007). In our survival analysis, neither vaccine response nor hypogammaglobulinemia significantly affected OS. While COVID-19 led to a modest mortality rate of 2.5%, this figure was comparable to the OS reported in the general immunocompetent population. However, most patients with hypogammaglobulinemia received intravenous immunoglobulin therapy and all were vaccinated. In conclusion, anti-CD20 maintenance therapy impairs serological responses to SARS-CoV-2 vaccines. We report for the first time that patients during maintenance therapy and up to 24 months after the last anti-CD20 dose are at a higher risk of vaccine failure and more severe cases of COVID-19. Nevertheless, with close monitoring, intravenous immunoglobulin supplementation or proper vaccination, the impact on survival due to the lack of serological response in this high-risk population can be mitigated, allowing for the benefits of anti-CD20 maintenance therapy, even in the presence of hypogammaglobulinemia.
cell therapies
2026-07-05 | Efficacy and safety of CD19 CAR T-cell therapy in relapsed/refractory follicular lymphoma: A systematic review and meta-analysis.
Follicular lymphoma (FL) is an indolent B-cell non-Hodgkin lymphoma characterized by frequent relapses despite initial responsiveness to chemoimmunotherapy. CD19-directed chimeric antigen receptor (CAR) T-cell therapy has shown promising efficacy in relapsed or refractory disease, though safety concerns such as cytokine release syndrome (CRS) and neurological events remain. This study aimed to evaluate the efficacy and safety of CD19 CAR T-cell therapy in relapsed or refractory FL. A comprehensive search using six databases, including PubMed, Scopus, and Embase, was performed to identify relevant studies. Data on overall response rate (ORR), complete response rate (CRR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), and adverse events, including CRS and neurological events, were extracted. Pooled estimates were calculated using the quality effects model. This review was registered in PROSPERO (CRD420251133655). Out of 2303 records initially identified, 6 studies met the inclusion criteria. The pooled efficacy analysis demonstrated an ORR of 93.5% (95% CI: 86.3-98.3%) and a CRR of 84.5% (95% CI: 72.6-93.6%). Regarding safety outcomes, the pooled estimate for CRS of any grade was 61.4% (95% CI: 45.0-76.6%). For neurological events, it was 33.6% (95% CI: 13.4-57.1%). Subgroup analyses identified prior therapy lines and CAR construct design as sources of heterogeneity. In conclusion, CD19 CAR T-cell therapy demonstrates high efficacy with a generally acceptable safety in relapsed or refractory FL, supporting its consideration for patients with limited treatment options while highlighting the need for further research on long-term outcomes.
2026-06-18 | Anti-CD19 CAR-T in transformed indolent lymphoma vs de novo large B-cell lymphoma: a meta-analysis of 5006 patients
The histological transformation (HT) of indolent non-Hodgkin lymphoma (iNHL) to aggressive lymphomas, commonly diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL), is associated with chemoresistance and poor prognosis, particularly after prior therapy.Transformed iNHL (tNHL) lacks a universally accepted standard of care.Although salvage high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is recommended by National Comprehensive Cancer Network guidelines, approximately half of the cases relapse within 3 years after ASCT.1,2 The emergence of anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the management of relapsed BCLs.However, evidence regarding its comparative effectiveness in tNHL vs de novo large B-cell lymphoma (dn-LBCL) remains controversial.[3][4][5][6] Therefore, we conducted a systematic review and meta-analysis to compare the efficacy and safety of anti-CD19 CAR-T therapy in tNHL vs dn-LBCL.We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, ClinicalTrials. gov, and conference abstracts through 30 September 2025 using terms for "CAR-T," "LBCL," and "transformed lymphoma."Eligible studies met the following criteria: (1) LBCL, including DLBCL or high-grade BCL; (2) tNHL defined as LBCL transformed from follicular lymphoma (FL) and marginal zone lymphoma, except for Richter transformation; (3) patients previously receiving ≥1 line of treatment; and (4) comparative reporting of outcomes and toxicity between tNHL and dn-LBCL receiving autologous CD19-directed CAR-T products in the main text or supplements.Studies using allogeneic CAR-Ts, dual-target constructs, or non-CD19-directed CAR-Ts were excluded.Study quality was assessed using the methodological index for nonrandomized studies scale.7 The main outcomes were complete remission (CR) rate, progression-free survival (PFS), overall survival (OS), and incidence of adverse events (AEs), including cytokine release syndrome (CRS) and neurotoxicity.PFS/OS were extracted per study definitions from CAR-T infusion, as specified by the authors of the respective studies.We extracted the best response after CAR-T infusion and during follow-up.Hazard ratios (HRs) were extracted directly from texts or reconstructed from Kaplan-Meier curves when unavailable.8 Statistical analysis was performed using Review Manager 5.4 and R Studio software.The study protocol was followed by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered in the International Prospective Register for Systematic Reviews (registration identity: CRD420251168280).After screening 2367 records, 10 articles 3-6,9-14 comprising 5006 enrolled patients were included (supplemental Figure 1A); end point-specific subsets differed by data availability.The baseline characteristics of the included studies are presented in supplemental Table 1.Sample sizes ranged from 25 to 844.In total, 1202 patients had tNHL, and 3804 patients had dn-LBCL.Bias assessment indicated moderate to good quality (supplemental Figure 1B), and the Egger publication bias test suggested no risk of publication bias (supplemental Table 2).
2026-06-17 | Outcomes of CAR T-Cell Therapy in transformed indolent Non-Hodgkin Lymphomas and de novo DLBCL: A comparative analysis from the Italian CAR T-SIE study.
Transformed indolent non-Hodgkin lymphoma (TiNHL) generally has poorer outcomes than de novo diffuse large B-cell lymphoma (dnDLBCL). Although anti-CD19 CAR T-cell therapy is standard for relapsed/refractory (R/R) large B-cell lymphoma (LBCL), its prognostic role across histologies remains unclear. We conducted a multicenter, retrospective/prospective observational study comparing R/R TiNHL and R/R dnDLBCL patients treated with commercial CAR T-cell therapy and enrolled in the Italian CART-SIE study. Among 438 patients, 107 had TiNHL (96 transformed follicular lymphoma [tFL], 11 transformed marginal zone lymphoma [tMZL]) and 331 had dnDLBCL. Baseline characteristics were comparable. TiNHL patients showed superior overall (83% vs 69%) and complete response rates (62% vs 53%) (both p < 0·01), with better 2-year progression-free survival (PFS: 44% vs 31%) and overall survival (OS: 61% vs 48%) (both p < 0·01). CAR-HEMATOTOX score predicted worse outcomes (PFS HR=2·10; OS HR=3·57). No significant differences were found between tFL and tMZL. Two-year relapse/progression incidence was lower in TiNHL (28% vs 47%, p < 0·01), with similar non-relapse mortality (11% vs 4%, p = 0·12). Safety profiles, including cytokine release syndrome and ICANS rates, were comparable. TiNHL patients receiving CAR T-cell therapy achieved better outcomes than dnDLBCL patients, with comparable safety, supporting its use as a standard treatment in TiNHL.
2026-06-03 | From CAR-T to CAAR-T: redefining targeting strategies in B-cell malignancies through idiotype-directed cellular therapy.
Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the management of selected hematologic malignancies, particularly relapsed or refractory large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma. However, currently approved CAR-T strategies largely rely on lineage-associated or differentiation antigens, such as CD19 or BCMA, and therefore do not selectively distinguish malignant B cells from their normal counterparts. This limitation contributes to on-target, off-tumor toxicity, including B-cell aplasia, hypogammaglobulinemia, infectious complications, and prolonged immune dysfunction. In addition, CAR-T therapy remains associated with cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, immune effector cell-associated hematotoxicity, manufacturing complexity, and variable efficacy across disease entities, particularly in chronic lymphocytic leukemia. Chimeric autoantibody receptor T-cell (CAAR-T) therapy represents a conceptually distinct approach in which engineered T cells are designed to recognize disease-defining immunoglobulin structures, including surface immunoglobulin or B-cell receptor idiotypes. This strategy has been most extensively explored in autoimmune diseases, where CAAR-T cells can selectively eliminate autoreactive B-cell populations while sparing the broader B-cell compartment. Its application in B-cell malignancies remains largely hypothetical, but the biological principle is attractive because many B-cell neoplasms are defined by clonotypic immunoglobulin rearrangements. In this review, we provide a disease-specific and translationally oriented assessment of idiotype-directed CAAR-T therapy in B-cell malignancies. We summarize the current evidence supporting CAAR-T biology, critically evaluate its potential in chronic lymphocytic leukemia, indolent lymphomas, multiple myeloma, and minimal residual disease, and discuss key biological, economic, manufacturing, and regulatory barriers. At present, CAAR-T should not be viewed as a near-term replacement for approved CAR-T therapies, but rather as a hypothesis-generating precision platform requiring rigorous disease-specific validation.
2026-04-16 | A Phase 2, Open-Label, Multicenter Study of the Safety and Efficacy of TAK-007 in Adult Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma
In relapsed/refractory large B-cell lymphoma (LBCL), chimeric antigen receptor (CAR)-natural killer (NK) cell therapies offer potential advantages over CAR-T-cell therapies, including off-the-shelf availability and scalable manufacturing. We performed a phase 2 study of single-dose TAK-007, a cryopreserved, cord blood-derived, off-the-shelf CD19 CAR-NK cell therapy, in 26 heavily pre-treated patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Adverse events were manageable, with limited grade 1–2 cytokine release syndrome (11.5%). Overall response rate with TAK-007 800 x106 CD19 CAR+ viable NK cells (n=14) was 60.9% (95% CI: 38.5–80.3). Median progression-free survival was 2.0 months (95% CI: 0.99–3.58) in LBCL (n=10) and 5.6 months (95% CI: 1.05–8.57) in indolent NHL (n=7) expansion cohorts. Deep molecular responses, including ctDNA-negative responses, were achieved. Not all TAK-007 products elicited clinical responses; single cell RNA-sequencing showed NK proliferating and NK-CD56dim cell enrichment in TAK-007 products eliciting/not eliciting responses, respectively, which could inform product selection. This is a single cell RNASeq dataset collected longitudinally during culturing and generation of CD19 CAR-NK cell therapies.
antibodies
2026-09-16 | Current and new approaches to the treatment landscape for adults with Waldenström macroglobulinemia.
Waldenström macroglobulinemia (WM) is an indolent B-cell lymphoma with unique clinical manifestations driven by both tumor infiltration of the bone marrow and extramedullary tissues, as well as IgM-related pathology. Recent therapeutic advances for WM have been largely driven by molecular discoveries, and current agents have significantly improved disease control and progression-free survival. However, WM remains incurable, and novel treatment strategies that balance efficacy with tolerability are needed. This review summarizes current treatment approaches, including chemoimmunotherapy and Bruton tyrosine kinase inhibitors, and discusses emerging therapeutic strategies with a focus on clinical efficacy, toxicity, and evolving treatment paradigms. We also examine the role of combination approaches and novel agents, considering their potential integration into the current treatment landscape. Despite substantial progress, key challenges remain, including the absence of definitive comparative data between various treatment strategies, the optimal sequencing of available agents, and an understanding of the impact of novel therapies on the depth of hematologic response, as well as long-term clinical and patient-reported outcomes. Future efforts should focus on biologically informed treatment selection and the development of strategies that reduce cumulative toxicities while achieving durable disease control.
2026-09-10 | Peripheral CD8⁺ T-cell clonality and NK-cell expansion mark early response to mosunetuzumab in indolent B-cell lymphoma.
Mosunetuzumab is highly effective against many B-cell lymphomas, but longitudinal immune changes induced by intermittently dosed CD20×CD3 bispecific antibodies remain incompletely characterized. We performed immune profiling of peripheral blood samples from patients receiving fixed-duration (6 months) subcutaneous mosunetuzumab for previously untreated follicular or marginal zone lymphoma on a phase 2 clinical trial (NCT04792502). Analyses included flow cytometry, cytokine profiling, and RNA-seq of isolated CD8+ T-cells with TCR repertoire inference. Early (at 3 weeks) on-treatment samples showed broad cytokine induction, CD8+ T-cell redistribution with decreased TEMRA cells and increased CD27+CD62L+ transitional effector memory-like cells, increased PD-1 and LAG-3 expression, and induction of CD8+ transcriptional programs consistent with activation, proliferation, exhaustion priming, and SREBF2-regulated cholesterol metabolism. By mid-treatment (at 3 months), activation-associated features contracted toward baseline, with no evidence of phenotypic exhaustion, though with persistent overexpression of LAG3, HAVCR2, and LAYN on RNA-seq, as well as sustained SREBF2 activation. CD8+ T-cell clonality increased at mid-treatment compared with baseline and higher clonality was associated with early clinical complete response. Mosunetuzumab also induced indirect NK-cell activation and expansion, including skewing toward CD56dimCD16bright effector state. HLA-DR upregulation on NK cells correlated with early increases in NK-activating plasma cytokines, and higher NK-cell count at mid-treatment was associated with complete response. Together, these findings define a CD8+ effector-remodeling state on mosunetuzumab therapy, characterized by clonal expansion, selective inhibitory receptor expression, sustained activation of cholesterol biosynthesis, and cytokine-linked engagement of innate immune mechanisms, providing a framework for potential strategies to support T-cell function and enhance bispecific antibody efficacy.
2026-09-08 | Follicular lymphoma and the microenvironment: potential targets and biomarkers.
Follicular lymphoma (FL) is an indolent B cell malignancy characterized by recurrent genetic alterations, yet its clinical course is highly variable and not fully explained by tumor-intrinsic features alone. Increasing evidence highlights the tumor microenvironment (TME) as a critical regulator of disease progression, therapeutic response, and immune escape. FL TME is composed of diverse cellular elements, including T cell subsets, tumor-associated macrophages, stromal cells, and follicular dendritic cells, which collectively provide survival signals and shape immune dysfunction. These interactions have led to the identification of potential therapeutic targets, such as immune checkpoint molecules, macrophage polarization pathways, and stromal-tumor signaling axes. In parallel, microenvironment-derived biomarkers, including specific immune cell compositions, spatial organization patterns, and gene expression signatures, are emerging as important predictors of prognosis and treatment outcomes. Advances in single-cell and spatial profiling technologies have further refined our understanding of TME heterogeneity, enabling the discovery of clinically relevant targets and biomarkers. Together, these insights support a more integrated model of FL biology and provide a foundation for developing microenvironment-directed therapies and precision medicine approaches.
2026-07-30 | Comparison of H1 versus combined H1/H2 antagonist premedication on incidence of rituximab infusion-related reaction: A retrospective cohort study.
IntroductionRituximab, an anti-CD20 monoclonal antibody used in B-cell malignancies, is associated with infusion-related reactions (IRRs) during the initial infusion. Standard premedication includes acetaminophen, corticosteroids, and a histamine-1 (H1) antagonist, typically diphenhydramine. Second-generation H1 antagonists offer similar efficacy with less sedation. Some institutions also incorporate histamine-2 (H2) antagonists despite limited supporting evidence. This study evaluated whether dual H1/H2 antagonist premedication reduces IRRs compared with H1-antagonist monotherapy when given with standard premedication.MethodsThis retrospective study reviewed health records of adults with a hematologic malignancy who received their first rituximab infusion at Brown University Health system between January 1, 2022 and June 30, 2025. Patients received premedication with either an H1-antagonist alone or dual H1/H2 receptor-antagonists with acetaminophen and a corticosteroid. The primary endpoint was IRR incidence during or within 24 h of infusion initiation. Secondary endpoints included IRR severity, incidence of grade 3-4 IRRs across subgroups, and time to IRR onset.ResultsAmong 299 patients (mean age 65; 55% male), 62% had aggressive lymphoma, 28% indolent lymphoma, and 10% leukemia. Baseline features included bone marrow involvement (38%), bone disease (39%), advanced-stage nodal disease (54%), B symptoms (48%), and >2 extranodal sites (28%). IRRs occurred in 38% of patients receiving dual H1/H2 antagonist premedication versus 36.5% with H1-antagonist monotherapy, with no difference in grade 3-4 IRRs. Most IRRs occurred 30 to 60 min after infusion initiation.ConclusionDual H1/H2-antagonist premedication was not associated with differences in the incidence or severity of rituximab IRRs compared with H1-antagonist monotherapy in addition to standard premedication.
2026-07-23 | Multifunctional CD38 in the pathogenesis and treatment of B-cell lymphomas.
B-cell lymphoma is a group of non-Hodgkin lymphomas with high heterogeneity. Despite advancement in therapeutics, the clinical outcomes of B-cell lymphomas need to be improved. CD38, a transmembrane multifunctional protein, is widely expressed across various B-cell lymphoma subtypes. Research indicates that CD38 plays multiple pathogenic roles in B-cell lymphomas, including regulation of proliferation, apoptosis, immune modulation, primarily through its enzymatic activity and its influence on signaling pathways in malignant lymphoma cells and immunosuppressive cells, making it a valuable therapeutic target. In recent years, CD38-targeted therapies, such as anti-CD38 antibodies and CD38-directed CAR-T cell therapies, have been explored for B-cell lymphomas. This review summarizes the knowledge on CD38 molecular functions, data of CD38 heterogeneous expression and prognostic role in B-cell lymphomas (from indolent to aggressive subtypes), anti-CD38 antibody efficacy and mechanisms of action, current understanding of the treatment resistance mechanisms, frontier advances in CD38-targeted therapies, and the challenges of novel targeted and immunotherapies in clinical applications, thereby seeking to provide a deep understanding of the role of CD38 in the pathogenesis and treatment of B-cell lymphomas. CD38-targed therapy is especially promising as a novel and optional treatment for CD20-negative lymphomas, for which standard treatment has not been established. Although the efficacy of anti-CD38 antibodies in most other B-cell lymphomas is low in previous clinical trials, in contrast to the remarkable efficacy of daratumumab in multiple myeloma, novel therapeutic strategies and combination therapies in ongoing clinical trials have the potential to overcome the counteracting actions and to improve the clinical outcomes of patients with relapsed/refractory B-cell lymphoma.
small molecules
2026-08-01 | The efficacy and safety of zanubrutinib combined with BR regimen in B-cell chronic lymphoproliferative disorder
ObjectiveTo explore the efficacy and safety of a zanubrutinib-based combination regimen as first-line treatment for patients with B-cell chronic lymphoproliferative disorder (B-CLPD). MethodsA retrospective analysis was performed on 26 patients with B-CLPD, including indolent B-cell non-Hodgkin lymphoma (B-iNHL), mantle cell lymphoma (MCL), and other unclassifiable B-CLPD, who were newly diagnosed and treated at the Department of Hematology, Zhongshan Hospital (Xiamen), Fudan University between January 2021 and January 2025. Patients were divided into two groups according to the treatment regimen: BR (bendamustine plus rituximab) and ZBR (zanubrutinib combined with BR regimen). Baseline characteristics, treatment responses, and the incidence of treatment-related adverse events (TRAE) were compared between the two groups. ResultsNo statistically significant differences in baseline characteristics were observed between the two groups. All patients completed at least four cycles of treatment. There were no significant differences between the BR and ZBR groups in partial response rate (46.2% vs 53.8%), complete response rate (53.8% vs 15.4%), overall response rate (100.0% vs 84.6%), or TRAE incidence. After the first cycle, the lymphocyte count was higher in the ZBR group than in the BR group (P＝0.002); no other statistically significant differences in other hematologic parameters were observed at any treatment cycle. ConclusionsIn patients with B-iNHL, MCL, and other unclassifiable B-CLPD, the ZBR regimen demonstrates similar safety and response rates to the BR regimen. These findings support further investigation into the clinical value of ZBR as first-line treatment regimen in a limited course for indolent lymphoid malignancies.
2026-07-07 | Bendamustine in indolent lymphoma: Letting the dust settle down.
In a large population‐based cohort of patients with indolent B‐cell lymphoma, bendamustine–rituximab was not associated with a statistically significant excess risk of secondary primary malignancies compared with cyclophosphamide‐based regimens after adjustment for confounders. These data contextualize prior safety concerns and support thoughtful optimization rather than abandonment of bendamustine‐based frontline therapies in indolent B‐cell lymphomas.
2026-07-03 | Diagnostic challenge of occult ER-positive breast carcinoma within bone marrow indolent B-cell lymphoma and response to CDK4/6 inhibitor: a case report.
Bone marrow metastasis from hormone receptor-positive breast cancer can be challenging to detect, especially in patients with concurrent hematologic malignancies, where isolated epithelial cells may be hidden by a dominant lymphoid infiltrate. This situation requires careful histopathologic and immunophenotypic evaluation to prevent misdiagnosis. We report a 74-year-old White woman with Waldenström's macroglobulinemia carrying the MYD88 L265P mutation and bone marrow infiltration by indolent B-cell non-Hodgkin lymphoma. She was evaluated for suspected skeletal disease progression due to rising tumor markers and inconclusive PET findings. Bone marrow biopsy revealed small clusters of epithelial cells positive for estrogen receptor (ER), cytokeratin AE1/AE3, and GATA3, consistent with metastatic breast carcinoma within a lymphoid background. Notably, ER positivity was the only marker indicating epithelial origin. The patient had previously received empirical aromatase inhibitor therapy after the initial detection of scattered ER-positive epithelial cells in 2018. Following disease progression in December 2024, she was treated with palbociclib and fulvestrant, while the indolent lymphoma was managed with active surveillance. At 6-month follow-up, the patient showed clinical stability, a biochemical response, and radiologic evidence of stable disease. This case emphasizes the importance of maintaining a high level of clinical and pathological suspicion when assessing bone marrow infiltration, especially in patients with a history of malignancy. The presence of isolated ER-positive epithelial cells within a lymphoid marrow environment should raise suspicion of occult breast carcinoma metastasis. Due to the rarity of this coexistence, the underlying mechanisms and optimal management strategies are still unclear. To our knowledge, this is one of the few reported cases of occult ER-positive breast carcinoma presenting solely as bone marrow involvement in a patient with indolent B-cell lymphoma, with documented response to CDK4/6 inhibitor-based therapy. This case report was prepared in accordance with the CAse REport (CARE) guidelines.
2026-03-31 | Prognostic significance of clinical risk models and genomic alterations in Waldenström macroglobulinemia before or after the BTK inhibitor era.
Waldenström macroglobulinemia (WM) is a rare indolent B-cell lymphoma with marked clinical and molecular heterogeneity. Clinical risk models, including IPSSWM, rIPSSWM, and MSSWM, were developed prior to the widespread use of Bruton tyrosine kinase inhibitors (BTKi), and their performance in the BTKi era remains uncertain. In addition, the prognostic impact of various genomic alterations is controversial. We retrospectively analyzed 453 symptomatic WM patients, including 203 who received non-BTKi therapy and 250 who received BTKi-based therapy. All three models significantly stratified prognosis in the non-BTKi cohort, with rIPSSWM showing the highest predictive accuracy, but none effectively predicted survival in BTKi-treated patients. Notably, among patients receiving first-line BTKi-based therapy, high-risk patients by any model achieved survival outcomes comparable to those of lower-risk patients, suggesting that upfront BTKi can overcome the adverse impact of high-risk clinical features. At the molecular level, MYD88 mutation was significantly associated with favorable outcomes exclusively in patients treated with first-line BTKi-based therapy, while CXCR4 and TP53 mutations predicted significantly inferior prognosis in both BTKi-based and non-BTKi cohorts. Our findings indicate that although clinical risk models remain relevant for patients receiving non-BTKi therapy, molecular features, especially MYD88, CXCR4, and TP53 mutations, provide superior prognostic insights for patients with BTKi-based regimens.
2026-03-30 | [IgG-κ lymphoplasmacytic lymphoma complicated by bilateral femoral neck fractures secondary to bone involvement].
Lymphoplasmacytic lymphoma (LPL) is a type of indolent B-cell lymphoma typically associated with IgM paraproteinemia and does not require immediate treatment until symptoms appear. However, non-IgM LPL has a higher frequency of extramedullary involvement and requires more aggressive therapy than IgM-LPL. A 51-year-old woman in treatment-free follow-up for LPL with IgG-κ paraproteinemia was referred to our hospital with a chief complaint of right coxalgia. A plain MRI scan showed multiple osteolytic bone lesions, including bilateral femoral incomplete fractures. Similar bone lesions were also detected in the right shoulder joint. Pathological examination of the bilateral femurs and the right shoulder revealed LPL lesions with amyloid deposits. MYD88 L265P gene mutations were confirmed by genetic analysis, and all lesions were considered identical. Ibrutinib plus rituximab therapy was administered, resulting in a partial response sustained to date. Bone involvement and amyloidosis are rare but critical extranodal manifestations of LPL, necessitating careful screening and follow-up even in asymptomatic patients. When these manifestations are suspected, prompt pathological and genetic evaluation is warranted, especially in non-IgM LPL cases.
other
2026-06-02 | Obinutuzumab plus bendamustine as first-line therapy for indolent B-cell lymphomas: a prospective multicenter open-label study.
This study evaluated the efficacy and safety of obinutuzumab plus bendamustine (GB) as first-line treatment for indolent B-cell lymphomas. In this prospective, multicenter, single-arm trial (NCT06415708), adults with newly diagnosed indolent B-cell lymphomas-including follicular lymphoma (FL), marginal zone lymphoma (MZL), Waldenström macroglobulinemia (WM), hairy cell leukemia variant (HCL-v), and unclassified B-cell lymphoproliferative disorder (BCLPD-U)-received six induction cycles of GB followed by 2 years of obinutuzumab maintenance in responders (⩾ partial response). The primary endpoint was overall response rate (ORR), whereas secondary endpoints included complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Among 220 enrolled patients (149 with FL and 71 with non-FL), 210 completed ⩾ 3 treatment cycles. At a median follow-up of 13.1 months, ORRs in the different patient subgroups were 96.6% (FL), 100% (MZL, HCL-v), 92.9% (WM), and 88.9% (BCLPD-U). The median DOR was 16.7 months in the FL group and was not reached in the non-FL group. PFS and OS were not reached in any subgroup. The FL and non-FL groups had comparable ORRs (P = 0.435); however, the FL group showed a higher CRR (92.4% vs. 78.5%; P = 0.004) and shorter PFS (P = 0.020). Treatment-emergent adverse events occurred in 42 patients and were more frequent in the non-FL group than in the FL group (26.8% vs. 15.4%; P = 0.046), particularly infections (18.3% vs. 6.0%; P = 0.005). Overall, the GB regimen demonstrated high response rates and manageable safety in Chinese patients with indolent B-cell lymphoma.
2026-01-08 | Non-gastric mucosa-associated lymphoid tissue lymphomas: a narrative review of pathogenesis, diagnosis, and treatment strategies.
Extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) are indolent non-Hodgkin lymphomas (NHLs) that can arise in various extranodal organs, often due to chronic inflammation. Gastric MALT lymphomas are well characterized; however, MALT lymphomas may occur in diverse sites such as the ocular adnexa, salivary glands, thyroid, lung, skin, and the small intestine. These site-specific MALT lymphomas have distinct etiologic associations, clinical presentation, and management considerations. This review provides an updated, site-specific overview to guide the diagnostic and therapeutic approach to non-gastric MALT lymphoma in adults. We reviewed peer-reviewed articles [2015-2025] on non-gastric MALT lymphomas, focusing on pathophysiology/etiology, diagnostic workup, and treatment strategies for each site. Key sources include recent reviews and guidelines from high-impact journals. Chronic antigenic stimulation is a unifying theme in MALT lymphoma genesis, either through infectious etiologies or autoimmune conditions. Ocular adnexal MALT lymphoma (OAML) is linked to Chlamydia psittaci (C. psittaci) infection in certain regions; salivary MALT lymphoma is related to Sjogren's syndrome (SS); thyroid MALT lymphoma develops in the background of Hashimoto's thyroiditis; pulmonary MALT lymphoma can be linked to chronic airway inflammation due to Achromobacter xylosoxidans (A. xylosoxidans); small intestinal MALT lymphoma can be associated with Campylobacter jejuni (C. jejuni) infection; and cutaneous MALT lymphoma can be linked to Borrelia burgdorferi (B. burgdorferi) infection. Diagnostic evaluation requires adequate tissue biopsy for histopathology and immunohistochemistry. MALT lymphomas exhibit an immunophenotype consistent with CD20+, CD79a+, IgM+ with light chain restriction, BCL2+, and negative for CD5, CD10, and cyclin D1. Staging for OAML and cutaneous lymphomas is tumor-node-metastasis (TNM)-based, while the others utilize an Ann Arbor staging system. Computed tomography (CT)/magnetic resonance imaging (MRI) and positron emission tomography (PET)/CT are used to determine the staging and spread of tumors. Treatments are not standardized but consist of therapy with radiotherapy and surgical excision for localized disease, and chemotherapy/for disseminated disease. Intestinal MALT lymphoma differs, as first-line treatment consists of antibiotics and then chemotherapy/immunotherapy. The non-gastric MALT lymphomas have an excellent prognosis as a whole; relapses are common but manageable, and disseminated disease is rare. Long-term follow-up is recommended in all cases.
2025-06-17 | The anti-CD47 antibody magrolimab with obinutuzumab and venetoclax in relapsed or refractory indolent B-cell lymphomas.
Follicular lymphoma (FL), marginal zone lymphoma (MZL), chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL) are characterized by a continuous incidence of relapse and increasing resistance to therapy. Novel immunotherapy approaches are needed. Magrolimab, a CD47-blocking antibody, disrupts CD47:SIRPα-mediated antiphagocytic signalling. When combined with a prophagocytic signal from an anti-CD20 antibody rituximab, it has shown activity in relapsed or refractory FL and MZL. In this phase 1 study, adding the BCL2-inhibitor venetoclax to magrolimab and the anti-CD20 antibody obinutuzumab resulted in complete responses in 6 of 10 (60%) evaluable patients with FL, MZL or CLL. Notably, we did not observe increased risk of infections previously reported from studies of magrolimab in acute myeloid leukaemia and higher risk myelodysplastic syndromes.
2025-06-01 | 591 | NOVEL CHEMOTHERAPY‐FREE INITIAL TREATMENT OF RITUXIMAB PLUS PEGYLATED INTERFERON Α‐2B IN UNTREATED ADVANCED INDOLENT B‐CELL LYMPHOMA: 4‐YEAR FOLLOW‐UP STUDY
G. Yan and L. Ping equally contributing author. Background: Indolent B-cell lymphomas (iBCL), accounting for 10%–15% of non-Hodgkin lymphoma (NHL) subtypes in China, exhibit clinical heterogeneity. While generally associated with favorable survival, most iBCL cases remain incurable. Rituximab monotherapy demonstrates efficacy in initial treatment, and preclinical studies suggest interferon-alpha (IFN-α) may synergistically enhance rituximab activity through immune modulation. Pegylated IFN-α2 (Peg-IFN-α2) offers improved pharmacokinetics with reduced toxicity compared to conventional IFN-α and is utilized in chronic hepatitis B (CHB) management. The phase II RIPPLE trial (NCT04246359) evaluates rituximab biosimilar combined with Peg-IFN-α2b in treatment-naïve iBCL. Methods: Newly diagnosed iBCL (follicular lymphoma [FL] grades 1–2/3a, marginal zone lymphoma [MZL], lymphoplasmacytic lymphoma [LPL], small lymphocytic lymphoma [SLL]); ECOG ≤ 2; adequate organ function; measurable disease. Patients with chronic hepatitis B co-infection (HBsAg+, HBV DNA < 3000 IU/mL, ALT < 5 × ULN) were permitted for enrollment. Induction therapy consisted of rituximab biosimilar (Henliritux; 375 mg/m2 IV day 1) plus Peg-IFN-α2b (Pegberon; 135μg SC days 1, 8) every 21 days for 6 cycles. Responders received maintenance (rituximab every 8 weeks; Peg-IFN-α2b monthly) for ≤ 2 years. CHB patients received entecavir prophylaxis. Primary endpoint: investigator-assessed ORR and CR (Lugano 2014). Secondary endpoints: TTR, DOR, PFS, OS, HBV clearance, safety (CTCAE v5.0). Results: Between September 2018 and July 2021, 57 eligible patients (median age 54 years; 56.1% female) were enrolled across six Chinese centers. 21 (36.8%) pts were symptomatic. The cohort comprised 45.6% (n = 26) FL grade 1–2, 36.8% (n = 21) MALT lymphoma, 12.3% (n = 7) FL grade 3a, 3.5% (n = 2) SLL, and 1.8% (n = 1) LPL, with 38.6% having FLIPI ≥ 3 and 10.5% being HBsAg-positive. At a median follow-up of 52.1 months (IQR 47.6–58.7), the overall response rate (ORR) was 71.9% (41/57) with 56.1% (32/57) achieving complete response (CR). Subtype-specific analyses revealed ORR/CR rates of 74.1%/48.1% in FL grade 1–2, 71.4%/71.4% in FL grade 3a, 61.9%/57.1% in MALT, 100%/50% in SLL, and 0/0 in LPL. Survival outcomes demonstrated 4-year progression-free survival (PFS) and overall survival (OS) rates of 61.6% and 93%, respectively, with medians not reached (Figure 1A,B). Treatment-emergent adverse events (TEAEs) were predominantly grade 1–2, including neutropenia (63.2%), anemia (36.5%), thrombocytopenia (29.8%), fever (28.1%), transaminase elevation (26.3%), fatigue (26.3%), and infusion reaction (21.7%, 10/46). No treatment-related deaths occurred. Conclusion: Rituximab biosimilar with Peg-IFN-α2b demonstrates durable efficacy and manageable toxicity in treatment-naïve iBCL, particularly in FL and MALT subtypes. The combination shows synergistic HBV suppression without reactivation risks. These results support further evaluation in larger randomized trials. Research funding declaration: No funding was received. Keywords: molecular targeted therapies; immunotherapy; indolent non-Hodgkin lymphoma No potential sources of conflict of interest.
2025-04-01 | A RARE DETERMINATION OF SMALL LYMPHOCYTIC LYMPHOMA ASSOCIATED WITH UNFAVORABLE EVOLUTION AND REVIEW OF THE LITERATURE.
Small lymphocytic lymphoma (SLL) is an indolent lymphoma. Hypercalcemia is rarely associated with this type of lymphoma and was reported as a Richter`s transformation sign of SLL in the literature. We report a case of a 64-year-old man, with many comorbidities, including cardiac and renal pathologies, known with hepatitis B. Small lymphocytic B lymphoma with genetic risk factors, such as TP53, 17p and unmutated IGHV was diagnosed by laterocervical node biopsy. During chemotherapy, the patient initially presented sciatic pain, leading to the suspicion of a new associated malignancy, but the lumbar MRI excluded osteolysis. A few weeks later, the patient presented with neurological symptoms and dangerous hypercalcemia and high levels of iPTH were discovered. Parathyroid determination was discovered and the second line therapy with Venetoclax- Rituximab was chosen, but unfavorable evolution was noted, with activated macrophage syndrome, disseminated intravascular coagulation and multiple organ dysfunction syndrome. The genetic risk factors and the presence of hypercalcemia are markers of negative prognosis and unfavorable evolution of the disease.
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Drug Discovery Landscape
2 orphan drug designations for Indolent B-cell non-Hodgkin lymphoma.
2 orphan drug designations for Indolent B-cell non-Hodgkin lymphoma.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
blinatumomab | antibodies | FDA | Amgen, Inc. | |
Cladribine [Litak] | small molecules | EMA | Lipomed GmbH |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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