RARE DISEASE
Mantle cell lymphoma
Mantle cell lymphoma
Mantle cell lymphoma
Synonyms: LCM, MCL, Mantle zone lymphoma
Synonyms: LCM, MCL, Mantle zone lymphoma
Synonyms: LCM, MCL, Mantle zone lymphoma
Drug discovery
43
drugs
With orphan designations
Overview
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma characterized by cyclin D1 overexpression via t(11;14) translocation [1][12]. Typically diagnosed at advanced stages (70-80% stage IV) [6][17], it primarily affects older adults and is incurable but manageable with therapies like BTK inhibitors, CAR T-cell therapy, and risk-adapted chemoimmunotherapy [3][9][13]. Prognosis varies by molecular risk factors (e.g., TP53 mutations, Ki-67 index) and treatment access [2][8].
Burden
Median survival: 3–5 years historically, improving with novel therapies [1][17]; high relapse rates (median OS for R/R: 9–41 months) [9].
Economic impact: Hospitalizations account for 30–50% of costs; treatment toxicity increases healthcare utilization [4][14].
Disparities: Black patients face 30% higher mortality vs. White patients, driven by access barriers [2][19].
Therapies
Frontline: Bendamustine/rituximab (older patients) or high-dose cytarabine + ASCT (younger/fit patients) ± rituximab maintenance [3][13][18].
Relapsed/Refractory: BTK inhibitors (ibrutinib, acalabrutinib), CAR T-cell therapy (brexucabtagene autoleucel), and BCL-2 inhibitors (venetoclax) [1][9][13].
Emerging: Non-chemotherapy regimens (e.g., ibrutinib + rituximab) and risk-stratified approaches [3][8].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
3,048 drug discovery papers about Mantle cell lymphoma, with 3 first-in-class and 44 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,048 drug discovery papers about Mantle cell lymphoma, with 3 first-in-class and 44 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-08-07 | Long-term complete remission following treatment with polatuzumab vedotin, rituximab, and bendamustine in a patient with mantle cell lymphoma relapsing after CAR-T cell therapy: a case report.
Mantle cell lymphoma (MCL) remains an incurable B-cell malignancy despite major advances in its therapeutic management. While Bruton tyrosine kinase inhibitors (BTKi) and, more recently, CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy have significantly improved outcomes in relapsed or refractory MCL, relapse after CAR-T therapy is associated with a dismal prognosis and represents a major therapeutic challenge. Here, we report the case of a 43-year-old male diagnosed with stage IV common-type MCL, who achieved long-term complete remission (CR) after treatment with polatuzumab vedotin, rituximab, and bendamustine (Pola-R-Benda) following relapse after CAR-T therapy. The patient had previously received standard first-line immunochemotherapy (R-CHOP alternating with R-DHAP) and autologous stem-cell transplantation, resulting in durable CR, followed by ibrutinib at first relapse in 2017 with sustained remission until 2021. Eleven months after CAR-T therapy with brexucabtagene autoleucel, the patient experienced systemic relapse. Enrollment into a Pola-R-Benda clinical protocol resulted in complete metabolic remission after three cycles, confirmed by positron emission tomography/computer tomography. Treatment was well tolerated except for mild grade 2 diarrhea. The patient remains in ongoing CR >20 months after initiation of Pola-R-Benda. To our knowledge, this is among the first reports of long-term remission with Pola-R-Benda following CAR-T failure in MCL, suggesting that antibody-drug conjugate-based therapy may represent an effective salvage option in this highly refractory clinical setting.
2026-07-17 | Glofitamab in Heavily Pretreated Mantle Cell Lymphoma Patients: A Multicenter Real-World Case Series.
Relapsed or refractory mantle cell lymphoma (r/r MCL) remains difficult to treat despite therapeutic advances. This multicenter retrospective study included 10 patients with r/r MCL treated with glofitamab across five sites in Austria and Italy before European approval (January 2023-May 2024). Patients were heavily pretreated (median 4.5 prior lines; 5/10 post-CAR-T). After a median of five cycles, responses were observed in 7/9 evaluable patients, including complete response in 4/9. Cytokine-release syndrome occurred in 7/10 (mostly Grade 1-2), including grade 3 events in 2/10, while ICANS occurred in 2/10 patients, including one Grade 4 event. Three patients received glofitamab as bridging therapy and all proceeded to CAR-T infusion. Glofitamab showed encouraging activity and manageable toxicity in heavily pretreated MCL, including as bridging therapy to CAR-T-cell treatment. The authors have confirmed clinical trial registration is not needed for this submission.
2026-06-30 | Concurrent Mantle Cell Lymphoma and Paraneoplastic Membranous Nephropathy.
We report a rare case of synchronous stage IV mantle cell lymphoma (MCL) and paraneoplastic membranous nephropathy (MN) in a 48-year-old man. The patient presented with a nasopharyngeal mass; biopsy confirmed cyclin D1-positive MCL harboring the CCND1::IGH rearrangement, along with nephrotic syndrome. Kidney biopsy revealed MN with IgG1/IgG3-dominant glomerular deposits but was negative for PLA2R, THSD7A, and NELL-1 antigens in both renal and tumor tissues, with corresponding serum antibodies undetectable. After lymphoma-directed therapy alone (R-CHOP/R-DHAP induction, autologous hematopoietic stem cell transplantation consolidation, and extended rituximab maintenance), both conditions achieved sustained remission. Complete remission was confirmed per the Lugano 2014 criteria, and nephrotic syndrome resolved, with proteinuria decreasing from 7.38 to 0.29 g/24 hours and serum albumin improving from 26.2 to 35.5 g/L with preserved kidney function. Both MCL and MN remained in remission for >2 years. This case highlights MCL-associated MN as a PLA2R/THSD7A/NELL-1 triple-negative entity where antineoplastic therapy alone induces renal remission, demonstrating both the paraneoplastic mechanism and the feasibility of intensive lymphoma treatment, including transplantation without renal compromise.
2026-06-29 | CEACAM1 expression by immunohistochemistry in B-cell lymphomas and plasma cell myeloma.
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with limited curative treatment options. Carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) has recently been implicated in B-cell receptor signaling in MCL. We evaluated CEACAM1 expression by immunohistochemistry across MCL and other mature B-cell neoplasms, including small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM). We retrospectively analyzed 164 lymphoma cases, 35 MM cases, and 2 plasmacytomas. CEACAM1 expression was assessed on tissue microarrays by immunohistochemistry and scored using a prespecified dichotomous cutoff. In DLBCL, CEACAM1 status was correlated with cell-of-origin classification and targeted mutational data. CEACAM1 was expressed in 27 of 30 MCL cases (90%), higher than in the other lymphoma subtypes combined (35%; P < .0001). Expression was also seen in SLL (20/30, 67%), MM (23/35, 66%), MZL (8/22, 36%), and DLBCL (19/82, 23%). In DLBCL, expression was more frequent in germinal center B-cell subtype than activated B-cell subtype cases (30% vs 13%; P = .023). Within sequenced DLBCL cases, CEACAM1 expression was associated with BCL2 and TNFRSF14 mutations. In MM, CEACAM1 expression was not significantly associated with recurrent cytogenetic abnormalities, although a nonsignificant trend toward higher expression in t(11;14) cases (75% vs 53%, Fisher exact P = .28). CEACAM1 is frequently expressed in MCL and in subsets of other mature B-cell neoplasms and MM. These findings support further investigation of CEACAM1 as a biologically relevant marker and potential therapeutic target in selected lymphoid malignancies.
2026-05-20 | "Immunologic Dream Team": BiTEs peri-allotransplant to redirect donor lymphocytes towards GVL.
Bispecific T cell engagers (BiTEs) provide high rates of responses in patients with relapsed and refractory B cell lymphomas and multiple myeloma otherwise resistant to other therapies, but unfortunately the duration of response to these treatments is limited in time. Allogeneic stem cell transplantation is a potentially curative approach for those disorders, although its indication is limited to patients who achieve remission. While no established strategies to improve the "graft versus tumor effect" are available, relapses still account for the majority of the post-transplant failures. Herein, we report the first case in literature of a successful treatment with glofitamab, a CD20X2/CD3 BiTE, in a post-transplant relapse of mantle cell lymphoma with central nervous disease involvement. We propose the combination of BiTEs and allogeneic transplant as an integrated and sequential immunological approach to be tested in clinical trials.
cell therapies
2026-08-28 | CD19 CAR T-cell therapy (GLPG5101) for relapsed or refractory B-cell non-Hodgkin lymphoma (ATALANTA-1): phase 1 results from a single-arm, multicentre, phase 1/2 study.
Chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment of B-cell non-Hodgkin lymphoma, but centralised manufacturing-with its complex logistics and long vein-to-vein times-drives up costs and restricts access. We aimed to evaluate the safety of GLPG5101, a fresh, CD19 CAR T-cell product manufactured through a decentralised process, and determine the recommended phase 2 dose. This phase 1 dose-escalation part of the ATALANTA-1 phase 1/2, single-arm study, was executed in five hospitals in the Netherlands and Belgium. Patients aged 18 years or older, with histologically confirmed diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL) after two or more lines of therapy, measurable disease according to the Lugano classification, Eastern Cooperative Oncology Group Performance Status 0-2, and adequate organ function were enrolled. Patients were treated with a single intravenous infusion at one of three dose levels of GLPG5101 (dose level 1 [35-50 × 106 viable CAR+ T-cells], dose level 2 [85-110 × 106 viable CAR+ T-cells], and dose level 3 [200-250 × 106 viable CAR+ T-cells]). The phase 1 part of the study applied a Bayesian Optimal Interval design and the primary endpoints were safety (incidence of adverse events and serious adverse events until end of treatment [week 14], and dose-limiting toxicities [DLTs] until day 28) in patients who received fresh GLPG5101 at any dose (excluding recipients of non-conforming product [not meeting prespecified release criteria other than dose]) and determination of the recommended phase 2 dose. The study was registered with ClinicalTrials.gov (NCT06561425) and is closed for recruitment. From March 15, 2022, to Sept 10, 2024, 27 patients were screened for eligibility, 24 of whom were enrolled, underwent leukapheresis and lymphodepleting chemotherapy and received GLPG5101. Data cutoff was June 1, 2025. In the intention-to-treat population (n=24), the median age was 66·5 years (IQR 59·0-71·5), 15 (63%) patients were male, nine (38%) were female, and 21 (88%) were White. One of the 24 patients received a non-conforming product and was excluded from the safety analysis population. Median follow-up was 24·0 months (IQR 20·7-24·9). Five DLTs were reported: grade 3 thrombocytopenia (n=1, dose level 1), death from intra-abdominal haemorrhage (n=1, dose level 2), and grade 4 prolonged neutropenia not resolving to grade 2 or lower within 28 days (n=1 at dose level 1 and n=2 at dose level 2). All 23 patients in the safety analysis population had grade 3 or higher treatment-emergent adverse events; the most common were neutropenia (22 [96%]), leukopenia (nine [39%]), lymphopenia (seven [30%]), anaemia (six [26%]), and thrombocytopenia (five [22%]). Treatment-related deaths occurred in four patients: one during the 14-week treatment period due to intra-abdominal haemorrhage, and three after the treatment period due to Escherichia coli sepsis (n=1), immune-effector cell-associated haemophagocytic lymphohistiocytic syndrome (n=1), and COVID-19 (n=1). The safety review committee selected 110 × 106 (range 50-110 × 106) viable CAR T-cells as the recommended phase 2 dose. The results of this study showed the feasibility of rapid multicentre decentralised manufacturing and delivery of fresh CAR T-cell therapy in heavily pretreated B-cell non-Hodgkin lymphoma. The phase 2 part of ATALANTA-1 will provide further information on clinical activity and safety. CellPoint, Lakefront Biotherapeutics.
2026-08-26 | CAR T-cell vs bispecific antibodies in relapsed/refractory mantle cell lymphoma: a systematic review and meta-analysis.
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with limited treatment options for relapsed/refractory (R/R) cases. CAR T-cell therapy and CD20×CD3 bispecific antibodies are promising immunotherapies, but no study has systematically compared their efficacy and safety in R/R MCL. This systematic review and meta-analysis was conducted in accordance with the PRISMA 2020 guidelines and registered in PROSPERO (CRD42024622564). A comprehensive search of PubMed, Embase, and the Cochrane Library (from inception to October 27, 2024) was performed to identify studies evaluating CAR T-cell therapy and bispecific antibodies in R/R MCL (third-line or later). Random-effects and fixed-effects models were used to calculate pooled complete response (CR) rates, overall response (OR) rates, and Grade ≥3 adverse events. Sensitivity analyses were conducted to assess the robustness of the results. Five studies (237 patients) were included. Pooled CR rates were 0.63(95% CI, 0.51-0.74)for bispecific antibodies and 0.70(95%CI, 0.63-0.77) for CAR T-cell therapy (P <0.05). OR rates were similar (0.75 vs. 0.88). Grade ≥3 cytokine release syndrome rates were comparable (0.06 vs. 0.06), but neurotoxicity cannot be compared. CAR T-cell therapy demonstrated higher CR rates versus bispecific antibodies, supporting their role as effective third-line treatments for R/R MCL. Randomized trials are needed to confirm these findings. https://www.crd.york.ac.uk/prospero/, identifier CRD42024622564.
2026-07-30 | Allogeneic stem cell transplantation for mantle cell lymphoma can achieve durable remission and myeloablative conditioning is associated with inferior survival: an Australian and New Zealand Transplant & Cellular Therapies registry study.
Allogeneic stem cell transplantation (AlloSCT) has established curative potential in mantle cell lymphoma (MCL). As therapies for MCL evolve, outcomes with AlloSCT require reassessment. This study aimed to report the outcomes of AlloSCT for MCL across Australia and New Zealand. Data were collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for all patients undergoing AlloSCT for MCL between January 2009 and December 2019. Forty-six patients underwent AlloSCT for MCL between 2009 and 2014 and 40 between 2015 and 2019. The median patient age was 56 years (range 32-72), nine of 15 patients tested (60%) had TP53 mutation, and 14% of patients underwent myeloablative conditioning (MAC). A higher proportion of patients in the 2015-2019 period were BTKi-exposed (68% vs. 0%, P = 0.00). Non-relapse mortality (NRM) at 1 year and 5 years was 23% (95% confidence interval (95% CI) 14-32) and 31% (95% CI 21-42) respectively. The 100-day cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 21% (95% CI 13-30), and the 3-year cumulative incidence of chronic GVHD was 31% (95% CI 22-41). At 5 years, overall survival (OS) was 48% (95% CI 36-59) and progression free survival (PFS) was 38% (95% CI 27-50). The use of MAC was independently associated with inferior PFS (hazard ratio [HR] 2.33, 95% CI 1.05-5.17, P = 0.038) and OS (HR 3.11, 95% CI 1.39-7.00, P = 0.006). There was no difference in outcomes for patients transplanted between 2009 and 2014 versus 2015 and 2019. AlloSCT can achieve durable remissions for MCL in the modern era, and the use of MAC is associated with inferior outcomes.
2026-07-22 | Model-Based Analysis with Mechanistic Insights to CAR-T-Cell Therapy Kinetics: Case Study with Axicabtagene Ciloleucel and Brexucabtagene Autoleucel.
Model-informed drug development is increasingly used to support chimeric antigen receptor (CAR)-T-cell therapy programs. However, most population pharmacokinetic (PK) CAR-T-cell models available in literature are variations of an empirical piecewise-linear model, which accurately describes the observed data but lacks a mechanistic foundation. This limits its use for simulations of scenarios beyond the observed data. This work presents a mechanism-based population PK framework that aims to bridge existing empirical and mechanistic CAR-T-cell modeling approaches. The model was developed using a clinical database of 473 patients with various relapsed or refractory lymphomas (large B cell, follicular, marginal zone, or mantle cell) receiving axicabtagene ciloleucel or brexucabtagene autoleucel. The framework incorporates two CAR-T-cell compartments alongside a latent kinetic-pharmacodynamic tumor compartment, utilizing a continuous, mechanistically-driven approach to characterize the observed PK profiles. A covariate search identified five significant covariates impacting PK (P < 0.001). Among these, only product type/mantle cell lymphoma (MCL) disease type was deemed to have clinically relevant effects on exposure. Despite its mechanistic basis, the model remains parsimonious, requiring only seven structural parameters, and no additional data beyond post-infusion CAR-T-cell peripheral blood concentrations and covariate information routinely collected in clinical trials. With its mechanistic foundation but parsimonious structure, this model balances data-driven practicality with the integration of underlying biological processes. Its ability to identify relevant covariates could make it a valuable tool in supporting drug development decisions.
2026-07-16 | Expanding the Horizon of CAR-T Cell Therapy: Present Obstacles and New Strategies for Future CARs in Solid Tumors.
Chimeric antigen receptor (CAR)-T cells are synthetic receptors used for the recognition of specific antigens expressed by reprogrammed T cells for targeting tumors. CAR-T cell therapy has gained remarkable clinical success for the treatment of hematological malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), and primary intraocular lymphoma (PIL). The increasing number of preclinical investigations and clinical trials is focusing on extending CAR-T cell therapy to solid tumors due to its remarkable success in leukemia and lymphoma cancers. However, some limitations of CAR-T therapy still exist, including a lack of targetable antigen diversity, heterogeneous antigen expression, insufficient T-cell trafficking efficiency, and an immunosuppressive tumor microenvironment. This review explores the role of CAR-T cell therapy, current challenges, and emerging solutions for solid tumor malignancies. To overcome the existing limitations of CAR-T cell therapy, innovative strategies, including the optimization of novel CAR vectors with checkpoint inhibitors, have been designed to enhance the antitumor activity of CAR-T cells against solid tumors. It also explores the design of novel CAR-T cells and strategies for improving antitumor activity against solid tumors. Among the emerging strategies, universal CARs and combination approaches with checkpoint inhibitors are especially promising for extending CAR-T therapy to solid tumors.
small molecules
2026-09-25 | Survival benefit of chemoradiotherapy in limited-stage mantle cell lymphoma: a National Cancer Database analysis.
Limited-stage mantle cell lymphoma (MCL) is rare, and optimal management remains undefined because of limited representation in clinical studies. We conducted a large population-based analysis using the National Cancer Database to evaluate overall survival (OS) in patients with Ann Arbor stage I to II MCL diagnosed between 2004 and 2015. Initial treatment was categorized to chemotherapy alone, radiotherapy (RT) alone, or combined chemotherapy plus RT (Chemo+RT), and outcomes were further stratified by stage and era of diagnosis (2004-2009 vs 2010-2015) to account for advances in systemic therapy, such as the adoption of bendamustine-rituximab for frontline therapy and the availability of Bruton tyrosine kinase inhibitors for relapsed disease. Among 2428 patients included, median OS for the entire cohort was 8.1 years. Chemo+RT was associated with superior OS compared with chemotherapy alone or RT alone (median OS, 11.2 vs 7.4 vs 8.0 years, respectively; P < .001). This survival benefit was observed in both stage I and stage II diseases and in both eras. On multivariable analysis, treatment with chemotherapy alone (hazard ratio [HR], 1.50) or RT alone (HR, 1.33) was independently associated with inferior OS compared with Chemo+RT. In this, to our knowledge, largest real-world analysis of limited-stage MCL to date, combined chemoimmunotherapy and RT was associated with a clinically meaningful survival benefit, including in the modern treatment era. These findings suggest that combined-modality therapy may be preferred for appropriately selected patients with limited-stage MCL.
2026-09-21 | A Case of Leukemic Phase of Mantle Cell Lymphoma Diagnosed With Scarring Conjunctivitis and Bilateral Upper Palpebral Conjunctival Tumor.
Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma. Ocular adnexal involvement is rare as the initial symptom, and conjunctival involvement is particularly rare. An 84-year-old man was referred to our hospital with chronic conjunctivitis of the bulbar and tarsal conjunctiva with bilateral symblepharon, as well as a reddish-brown, cobblestone-like tumor. Suspecting malignancy, a tumor biopsy and systemic examination revealed the neoplastic lesion to be MCL. Leukocytosis and abnormal cells in peripheral blood (53%) were observed, and diffuse tumor cell infiltration was observed in the bone marrow. Both the bone marrow and tumor cells were positive for CD5, CD20, and cyclin D1, while the bone marrow tissue was negative for SOX11, confirming leukemic conversion (leukemic phase of mantle cell lymphoma). PET/CT revealed accumulation in systemic lymph nodes and extranodal organs, leading to a diagnosis of Ann Arbor stage IV disease. TP53 deletion was not detected. Following treatment with acalabrutinib in combination with bendamustine and rituximab, as reported in 2025, the conjunctivitis and eyelid tumor resolved, with no recurrence observed during follow-up. We report a case of leukemia-type MCL diagnosed with bilateral chronic cicatricial conjunctivitis and elevated lesions on the upper eyelid conjunctiva as initial findings. When encountering such findings, early pathological diagnosis and thorough systemic examination are important, with systemic malignant lymphoma in mind.
2026-09-14 | Targeting ROR1 with KAN571C disrupts resistance networks in mantle cell lymphoma.
Resistance to Bruton tyrosine kinase (TK) and BCL2 inhibitors, such as ibrutinib (Ibru) and venetoclax (Ven), remains a major therapeutic challenge in mantle cell lymphoma (MCL), which limits treatment options. Receptor TK-like orphan receptor 1 (ROR1), aberrantly expressed in MCL and other malignancies but largely absent in normal adult tissues, has been implicated in tumor cell proliferation, survival, and migration. This study aimed to elucidate the mechanisms underlying Ibru and Ven resistance in MCL and to investigate the therapeutic potential of targeting ROR1 using the small-molecule inhibitor KAN571C in Ibru- and/or Ven-resistant MCL cell lines. Ibru-, Ven-, and Ibru + Ven (Double)-resistant models were generated from the JEKO-1, Granta-519, and Z138 MCL cell lines. The cytotoxic effects of Ibru, Ven, and KAN571C were assessed in both naive and drug-resistant models using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. Western blotting was used to analyze downstream signaling alterations after exposure to KAN571C. KAN571C induced potent cytotoxicity in both naive and drug-resistant models, preferentially in Ven- and Ibru/Ven-resistant cells. Mechanistically, KAN571C dephosphorylated ROR1 at TK and proline-rich domains, suppressed downstream phosphatidylinositol 3-kinase/AKT and β-catenin signaling, and activated caspase-dependent apoptosis. Notably, long-term exposure (2 weeks) failed to establish KAN571C-resistant cell lines. Our findings identify ROR1 as a convergent mediator of resistance in MCL and highlight KAN571C as a potential therapeutic strategy to overcome treatment refractoriness.
2026-09-09 | Acalabrutinib Added To Rituximab, Bendamustine (ABR) in Newly Diagnosed High Risk Mantle Cell Lymphoma: an Early Indian Experience.
Conventionally chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) is the standard of care for newly diagnosed mantle cell lymphoma. The role of BTKi is emerging in upfront management of mantle cell lymphoma. It has redefined the role of upfront stem cell transplantation especially with achievement of deep sustained MRD negativity. Elderly population are not eligible for intensive chemotherapy for many reasons especially frailty, poor performance score and associated comorbidities. The use of upfront Ibrutinib and acalabrutinib with Rituximab, Bendamustine (BR) backbone has been studied in these transplant ineligible cohorts in Phase 3 SHINE and ECHO trial respectively. We reported the early outcome, efficacy of second generation BTKi (acalabrutinib) with BR from an Indian perspective. The online version contains supplementary material available at https://doi.org/10.1007/s12288-025-02257-8.
2026-09-09 | Preliminary study on efficacy and safety of pixantrone in relapsed/refractory aggressive B-cell lymphomas: multicenter, retrospective cohort study by Polish Lymphoma Research Group (PLRG).
Pixantrone (PIX) is an anthracycline derivative with reduced cardiotoxicity, registered in Poland for monotherapy in relapsed/refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL) in the third or fourth line of treatment. As R/R population is difficult to treat due to comorbidities including circulatory system pathologies we evaluate polish patients treated with PIX. This is the first real life study evaluating patients treated with PIX in Poland with emphasis on efficacy and cardiovascular toxicity. The retrospective study assessing safety and effectiveness of PIX administered in patients with aggressive de novo or transformed B-NHL [according to the Revised European American Lymphoma (REAL) and World Health Organization (WHO) classifications], who relapsed or were refractory to two or three previous lines of chemotherapy regimens, including at least one standard anthracycline-based regimen. Patients who did not remain sensitive to anthracyclines were excluded from this study. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), complete response (CR) rate, overall response rate (ORR) and safety. The data of 17 patients were collected in 6 study sites. The median age was 72 (range: 58-82) years old with male predominance (65%). In observed group10 patients had diffuse large B-cell lymphoma (DLBCL), 6 mantle cell lymphoma (MCL) and 1 patient had Richter syndrome. Five subjects responded to PIX (CR 2 and partial response 3)-ORR was 29%. The median of PFS was 12.9 months [standard error (SE) 2.2; 95% confidence interval (CI): 8.5, 17.2]. The median of survival time was 22.6 months (SE 7.3; 95% CI: 8.3, 36.8). The PIX compliance was good, with incidental dose omission or delay. The main reason for discontinuation was disease progression. Administration of PIX to patients with R/R aggressive B-NHL treated with multiple lines of chemotherapy containing maximal cumulative dose of anthracycline and with numerous concomitant diseases may be a potentially valuable therapeutic option but data from larger clinical studies will help in confirming PIX as an effective and safe option.
oligonucleotides
2024-02-14 | miR-17-92 cluster-BTG2 axis regulates B-cell receptor signaling in mantle cell lymphoma.
B-cell receptor (BCR) signaling is critically activated and stable for mantle cell lymphoma (MCL), but the underlying mechanism of the activated BCR signaling pathway is not clear. The pathogenic basis of miR-17-92 cluster remains unclear although the oncogenic microRNA (miRNA) miR-17-92 cluster is highly expressed in patients with MCL. We revealed that miR-17-92 cluster overexpression is partly dependent on SOX11 expression and chromatin acetylation of MIR17HG enhancer regions. Moreover, miR-17-92 cluster regulates not only cell proliferation but BCR signaling activation in MCL cell lines. To comprehensively identify miR-17-92 cluster target genes, we performed pulldown-seq, where target RNA of miRNA was captured using the biotinylated miRNA mimics and magnetic bead-coated streptavidin, and quantified using next-generation sequencing. The pulldown-seq identified novel miRNA target genes, including tumor suppressors such as BTG2 (miR-19b), CDKN2A (miR-17), SYNE1 (miR-20a), TET2 (miR-18, miR-19b, and miR-92a), TNFRSF10A (miR-92a), and TRAF3 (miR-17). Notably, the gene expression profile data of patients with MCL revealed that BTG2 expression was negatively associated with that of BCR signature genes, and low BTG2 expression was associated with poor overall survival. Moreover, BTG2 silencing in MCL cell lines significantly induced BCR signaling overactivation and cell proliferation. Our results suggest an oncogenic role of miR-17-92 cluster-activating BCR signaling throughout BTG2 deregulation in MCL. Furthermore, this may contribute to the prediction of the therapeutic efficacy and improved outcomes of MCL.
2023-05-29 | Long non-coding RNA as a novel biomarker and therapeutic target in aggressive B-cell non-Hodgkin lymphoma: A systematic review.
Abstract Cancer initiation and progression have been associated with dysregulated long non‐coding RNA (lncRNA) expression. However, the lncRNA expression profile in aggressive B‐cell non‐Hodgkin lymphoma (NHL) has not been comprehensively characterized. This systematic review aims to evaluate the role of lncRNAs as a biomarker to investigate their future potential in the diagnosis, real‐time measurement of response to therapy and prognosis in aggressive B‐cell NHL. We searched PubMed, Web of Science, Embase and Scopus databases using the keywords “long non‐coding RNA”, “Diffuse large B‐cell lymphoma”, “Burkitt's lymphoma” and “Mantle cell lymphoma”. We included studies on human subjects that measured the level of lncRNAs in samples from patients with aggressive B‐cell NHL. We screened 608 papers, and 51 papers were included. The most studied aggressive B‐cell NHL was diffuse large B‐cell lymphoma (DLBCL). At least 79 lncRNAs were involved in the pathogenesis of aggressive B‐cell NHL. Targeting lncRNAs could affect cell proliferation, viability, apoptosis, migration and invasion in aggressive B‐cell NHL cell lines. Dysregulation of lncRNAs had prognostic (e.g. overall survival) and diagnostic values in patients with DLBCL, Burkitt's lymphoma (BL), or mantle cell lymphoma (MCL). Furthermore, dysregulation of lncRNAs was associated with response to treatments, such as CHOP‐like chemotherapy regimens, in these patients. LncRNAs could be promising biomarkers for the diagnosis, prognosis and response to therapy in patients with aggressive B‐cell NHL. Additionally, lncRNAs could be potential therapeutic targets for patients with aggressive B‐cell NHL like DLBCL, MCL or BL.
2023-02-27 | RNA splicing factors in normal hematopoiesis and hematologic malignancies: novel therapeutic targets and strategies.
RNA splicing, a crucial transesterification-based process by which noncoding regions are removed from premature RNA to create mature mRNA, regulates various cellular functions, such as proliferation, survival, and differentiation. Clinical and functional studies over the past 10 y have confirmed that mutations in RNA splicing factors are among the most recurrent genetic abnormalities in hematologic neoplasms, including myeloid malignancies, chronic lymphocytic leukemia, mantle cell lymphoma, and clonal hematopoiesis. These findings indicate an important role for splicing factor mutations in the development of clonal hematopoietic disorders. Mutations in core or accessory components of the RNA spliceosome complex alter splicing sites in a manner of change of function. These changes can result in the dysregulation of cancer-associated gene expression and the generation of novel mRNA transcripts, some of which are not only critical to disease development but may be also serving as potential therapeutic targets. Furthermore, multiple studies have revealed that hematopoietic cells bearing mutations in splicing factors depend on the expression of the residual wild-type allele for survival, and these cells are more sensitive to reduced expression of wild-type splicing factors or chemical perturbations of the splicing machinery. These findings suggest a promising possibility for developing novel therapeutic opportunities in tumor cells based on mutations in splicing factors. Here, we combine current knowledge of the mechanistic and functional effects of frequently mutated splicing factors in normal hematopoiesis and the effects of their mutations in hematologic malignancies. Moreover, we discuss the development of potential therapeutic opportunities based on these mutations.
2022-05-06 | Integrated analysis of 14 lymphoma datasets revealed high expression of CXCL14 promotes cell migration in mantle cell lymphoma.
Lymphoma is accompanied by the impairment of multiple immune functions. Cytokines play an important role in a variety of immune-related functions and affect the tumor microenvironment. However, the exact regulatory mechanisms between them remain unclear. This study aimed to explore the cytokines expression and function in Hodgkin's lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL). We performed a transcriptome integration analysis of 14 lymphoma datasets including 240 Hodgkin's lymphoma, 891 diffuse large B-cell lymphoma, 216 mantle cell lymphoma, and 64 health samples. The results showed that multiple immune functions and signal pathway damage were shared by all three types of lymphoma, and these functions were related to cytokines. Furthermore, through co-expression network and functional interaction network analysis, we identified CXCL14 as a key regulator and it affects cell chemotaxis and migration functions. The functional experiment showed that CXCL14 knockdown inhibited cell migration in MCL cell lines. This study suggested that high expression of CXCL14 may aggravate MCL via promoting cell migration. Our findings provide novel insights into the biology of this disease and would be helpful for the pathogenesis study and drug discovery of lymphomas.
2022-04-07 | A Phase 2 Study of PNT2258 for Treatment of Relapsed or Refractory B-Cell Malignancies.
PNT2258 consists of a native, chemically unmodified, 24-base DNA oligonucleotide designed to target the regulatory region upstream of the BCL2 gene, delivered in a protective liposome. Derangement of BCL2-regulated control mechanisms is a defining characteristic of certain malignancies, and it was hypothesized that the oligonucleotide would promote anticancer activity via suppression of BCL2 transcription. PNT2258 was evaluated in this, multicenter, nonrandomized, open-label Phase 2 study in 13 participants with relapsed/refractory B-cell malignancies to investigate potential antitumor activity and safety. Participants with follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, or chronic lymphocytic leukemia received intravenous PNT2258 120 mg/m2 on Days 1 to 5 of a 21-day cycle for up to 8 cycles, followed by 100 mg/m2 on Days 1 to 2 of a 28-day cycle until study withdrawal. All 13 participants were treated with PNT2258 monotherapy and evaluable for response and safety and tolerability. The overall response rate was 53.8% (7/13; 95% confidence interval [CI], 25.1%-80.8%). Median duration of response was 23.4 months (range, 3, 31.5). The disease control rate of participants with stable disease or better was 84.6% (95% CI, 54.6%-98.1%). The most frequently (≥50%) observed adverse events (AEs) were nausea, chills, diarrhea, fatigue, headache, vomiting, and back pain. Hypertension (30.8%) and diarrhea (23.1%) were the most frequent grade ≥3 AEs. No deaths were observed. Clinically meaningful and durable activity with an acceptable safety profile was observed in participants with relapsed/refractory B-cell malignancies who received single-agent PNT2258. NCT01733238, first posted 26-Nov-2012. https://clinicaltrials.gov/ct2/show/NCT01733238.
other
2026-06-10 | LncRNA IRAIN inhibits mantle cell lymphoma progression by inducing cell cycle arrest and apoptosis: an in vitro study.
Long non-coding RNA (lncRNA) insulin-like growth factor 1 receptor antisense imprinted non-protein coding RNA (IRAIN) and lysine-specific demethylase 1 (LSD1) are aberrantly expressed in various malignancies. However, their roles in the progression of mantle cell lymphoma (MCL) remain unclear. This study aimed to investigate the expression pattern and biological role of IRAIN in MCL progression and to further explore the relationship between IRAIN and LSD1. In this study, the expression levels of IRAIN and LSD1 in MCL cells were detected by RT-qPCR. An IRAIN-overexpressing lentiviral vector (LV-IRAIN-up) was constructed and transduced into MCL cells, and the transduction efficiency was verified by flow cytometry (FACS) and RT-qPCR. The effects of IRAIN overexpression on cell viability, apoptosis, and cell cycle progression were evaluated using CCK-8 assays and FACS analysis. In addition, RT-qPCR and Western blot analyses were performed to determine the regulatory effects of IRAIN overexpression on LSD1 expression, apoptosis-related proteins (including Bax, Bcl-2, pro-caspase-3, and cleaved-caspase-3), and cell cycle-related proteins (Cyclin D1, CDK2, and p21). Furthermore, LSD1 was overexpressed in IRAIN-overexpressing MCL cells to investigate its effects on cell proliferation, apoptosis, and cell cycle progression. The results demonstrated that IRAIN expression was significantly downregulated, whereas LSD1 expression was markedly upregulated in MCL cells. IRAIN overexpression significantly inhibited cell viability, promoted apoptosis, and induced G1-phase cell cycle arrest. Meanwhile, IRAIN overexpression markedly downregulated the expression of LSD1, Bcl-2, pro-caspase-3/cleaved-caspase-3, Cyclin D1, and CDK2, while upregulating the expression of Bax and p21. Further experiments showed that LSD1 overexpression partially reversed the inhibitory effects of IRAIN overexpression on MCL cell proliferation, apoptosis induction, and G1-phase arrest. Collectively, these findings suggest that IRAIN may participate in the regulation of proliferation, apoptosis, and cell cycle progression in MCL cells, potentially through modulation of LSD1. These results provide preliminary experimental evidence for further understanding the potential biological function of IRAIN in MCL.
2025-12-13 | Identification and functional characterization of splicing factors implicated in mantle cell lymphoma aggressiveness.
Mantle cell lymphoma (MCL) is a clinically aggressive and incurable form of non-Hodgkin lymphoma with very heterogeneous clinical and biological behaviors. Dysregulation of RNA splicing machinery is common in various types of cancer, including hematologic malignancies, and is associated with cancer progression. However, whether and how splicing factors, the spliceosome components responsible for pre-mRNA splicing, regulate MCL aggressive behaviors remain largely unknown. Bioinformatics analyses were employed to profile the mRNA expression of two key families of splicing factors, that are serine/arginine-rich (SR) and heterogenous nuclear ribonucleoprotein (hnRNP) families, in clinical specimens of MCL patients in comparison to normal B cells. Functional roles of splicing factors in MCL aggressive phenotypes defined as hallmarks of cancer were investigated in MCL cell lines. Kaplan-Meier survival analyses were performed to determine the clinical significance of splicing factors according to their gene expression level. Depletion of SRSF1, hnRNP F, and PTBP1, which are highly expressed in MCL clinical specimens, by CRISPR/Cas9 system significantly inhibit cell growth and proliferation, motility, and angiogenesis of MCL cells. SRSF1, hnRNP F (for Z-138 cells), and PTBP1 were found to mediate BTZ sensitivity in MCL cells, in agreement with an increase in caspase-3 activation and the occurrence of splicing events that favor the expression of pro-apoptotic isoforms of apoptosis regulatory genes. We also found that depletion of SRSF1, hnRNP F, and PTBP1 induces the expression of autophagy-related genes and the accumulation of autophagic vacuoles, which may act as one of the tumor-suppressive mechanisms. Survival analyses revealed that co-high expression of SRSF1, HNRNPF, or PTBP1 and oncogenic MYC predicts poor clinical outcomes in MCL patients. Our data describe the clinical significance of aberrant SRSF1, hnRNP F, and PTBP1 in MCL and their tumor-promoting roles via the regulation of cancer hallmarks, which could be important in understanding MCL pathogenesis and therapeutic development.
2025-12-11 | Benefit of rituximab maintenance after first-line bendamustine-rituximab in patients with mantle cell lymphoma.
The benefit of rituximab maintenance after first-line (1L) bendamustine-rituximab (BR) in patients with mantle cell lymphoma (MCL) remains uncertain, with inconsistent results from the phase 2 MAINTAIN trial and several retrospective studies. We conducted a large retrospective study at 27 US and Canadian academic centers to examine the benefit of rituximab maintenance after BR. A total of 911 patients received 1L BR between 2010 and 2020, and 703 had an objective response and no evidence of disease progression at the 3-month post-BR landmark. Among those, 394 (56%) received rituximab maintenance and 309 (44%) did not, with largely similar baseline patient and disease characteristics. In the landmark analysis, rituximab maintenance was associated with improved event-free survival (EFS; median, 49.9 vs 29.7 months; P< .001) as well as overall survival (OS; median, 109.5 vs 74.2 months; P< .001). The EFS and OS benefits were observed across most of the subgroups. EFS and OS differences were statistically significant in those who achieved a complete response to 1L BR (n = 590; median EFS, 62.7 vs 31.1 months [P< .001]; median OS, 136.1 vs 75.3 months [P< .001]), but the analysis among those who achieved a partial response to 1L BR was limited by the small sample size. These results provide additional evidence for the survival benefit of rituximab maintenance after BR in MCL and support its use in clinical trial design and routine practice.
2025-11-10 | T-Cell-Redirecting Immunotherapies in Relapsed/Refractory Mantle Cell Lymphoma: Current Evidence, Sequencing, and Future Directions.
Relapsed/refractory (R/R) mantle cell lymphoma (MCL) remains a therapeutic challenge, particularly in patients with high-risk features or prior exposure to Bruton's tyrosine kinase inhibitors (BTKis). The advent of T-cell-redirecting immunotherapies, including chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies (BsAbs), has transformed the treatment landscape. CAR-T therapies, such as brexu-cel and liso-cel, induce high overall response rates and durable remissions, even in heavily pretreated or BTKi-refractory patients. However, CAR-T administration is limited by logistical constraints, the need for bridging therapy, and the risk of severe toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). BsAbs, targeting CD20 and CD3, offer an off-the-shelf, repeatable immunotherapeutic option suitable for outpatient use, with generally manageable toxicities. Step-up dosing, corticosteroids, and anti-IL6 therapy mitigate CRS, while hematologic toxicity and infections require vigilant monitoring. Clinical data indicate that BsAbs are active in both CAR-T-naïve and post-CAR-T settings, providing disease control in patients ineligible for immediate CAR-T therapy. Emerging evidence supports rational sequencing and combinatorial strategies to optimize outcomes. BsAbs may be employed as a bridge to CAR-T, or CAR-T may be used to consolidate BsAb-induced remissions. Combination regimens, including CAR-T or BsAbs with BTK inhibitors or other targeted agents, are under investigation to enhance the depth and durability of response. In conclusion, CAR-T and BsAbs are complementary modalities in R/R MCL. Individualized therapeutic sequencing and rational combinations, tailored to disease biology and patient characteristics, represent the next frontier for improving long-term outcomes in this historically high-risk population.
2025-10-01 | Chronic meningoencephalitis due to enterovirus A71 complicating rituximab therapy.
Rituximab and other anti-CD20 therapies are increasingly used in the treatment of autoimmune and hematologic disorders. These treatments are associated with persistent immune impairment, potentially leading to severe infections. We describe a resolutive case of proven chronic enterovirus A71 (EV A71) meningoencephalitis complicating rituximab maintenance therapy for non-Hodgkin lymphoma. This article combines an original case report and a literature review of cases of enteroviral meningoencephalitis complicating rituximab treatment. A 38-year-old man was treated with rituximab and chemotherapy for a mantle cell lymphoma. During maintenance treatment with rituximab, he developed a "hand-foot-mouth disease", and one month later severe neurological deterioration including quadriparesis and major neurocognitive disorder leading to a diagnosis of chronic enteroviral meningoencephalitis. A treatment associating monthly intravenous immunoglobulins (IVIg) and fluoxetine was initiated two months after neurological symptoms onset, resulting in dramatic clinical improvement within six months. A brief literature review shows that a treatment with high-dose IVIg often results in clinical improvement. Fluoxetine was added in recent reports based on in vitro evidence of anti-viral activity against enteroviruses. Enteroviral infection should be evoked in patients treated with rituximab presenting with an encephalitic symptomatology, and restoring humoral immunity with high-dose IVIg might improve their condition.
antibodies
2026-08-07 | Long-term complete remission following treatment with polatuzumab vedotin, rituximab, and bendamustine in a patient with mantle cell lymphoma relapsing after CAR-T cell therapy: a case report.
Mantle cell lymphoma (MCL) remains an incurable B-cell malignancy despite major advances in its therapeutic management. While Bruton tyrosine kinase inhibitors (BTKi) and, more recently, CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy have significantly improved outcomes in relapsed or refractory MCL, relapse after CAR-T therapy is associated with a dismal prognosis and represents a major therapeutic challenge. Here, we report the case of a 43-year-old male diagnosed with stage IV common-type MCL, who achieved long-term complete remission (CR) after treatment with polatuzumab vedotin, rituximab, and bendamustine (Pola-R-Benda) following relapse after CAR-T therapy. The patient had previously received standard first-line immunochemotherapy (R-CHOP alternating with R-DHAP) and autologous stem-cell transplantation, resulting in durable CR, followed by ibrutinib at first relapse in 2017 with sustained remission until 2021. Eleven months after CAR-T therapy with brexucabtagene autoleucel, the patient experienced systemic relapse. Enrollment into a Pola-R-Benda clinical protocol resulted in complete metabolic remission after three cycles, confirmed by positron emission tomography/computer tomography. Treatment was well tolerated except for mild grade 2 diarrhea. The patient remains in ongoing CR >20 months after initiation of Pola-R-Benda. To our knowledge, this is among the first reports of long-term remission with Pola-R-Benda following CAR-T failure in MCL, suggesting that antibody-drug conjugate-based therapy may represent an effective salvage option in this highly refractory clinical setting.
2026-07-17 | Glofitamab in Heavily Pretreated Mantle Cell Lymphoma Patients: A Multicenter Real-World Case Series.
Relapsed or refractory mantle cell lymphoma (r/r MCL) remains difficult to treat despite therapeutic advances. This multicenter retrospective study included 10 patients with r/r MCL treated with glofitamab across five sites in Austria and Italy before European approval (January 2023-May 2024). Patients were heavily pretreated (median 4.5 prior lines; 5/10 post-CAR-T). After a median of five cycles, responses were observed in 7/9 evaluable patients, including complete response in 4/9. Cytokine-release syndrome occurred in 7/10 (mostly Grade 1-2), including grade 3 events in 2/10, while ICANS occurred in 2/10 patients, including one Grade 4 event. Three patients received glofitamab as bridging therapy and all proceeded to CAR-T infusion. Glofitamab showed encouraging activity and manageable toxicity in heavily pretreated MCL, including as bridging therapy to CAR-T-cell treatment. The authors have confirmed clinical trial registration is not needed for this submission.
2026-06-30 | Concurrent Mantle Cell Lymphoma and Paraneoplastic Membranous Nephropathy.
We report a rare case of synchronous stage IV mantle cell lymphoma (MCL) and paraneoplastic membranous nephropathy (MN) in a 48-year-old man. The patient presented with a nasopharyngeal mass; biopsy confirmed cyclin D1-positive MCL harboring the CCND1::IGH rearrangement, along with nephrotic syndrome. Kidney biopsy revealed MN with IgG1/IgG3-dominant glomerular deposits but was negative for PLA2R, THSD7A, and NELL-1 antigens in both renal and tumor tissues, with corresponding serum antibodies undetectable. After lymphoma-directed therapy alone (R-CHOP/R-DHAP induction, autologous hematopoietic stem cell transplantation consolidation, and extended rituximab maintenance), both conditions achieved sustained remission. Complete remission was confirmed per the Lugano 2014 criteria, and nephrotic syndrome resolved, with proteinuria decreasing from 7.38 to 0.29 g/24 hours and serum albumin improving from 26.2 to 35.5 g/L with preserved kidney function. Both MCL and MN remained in remission for >2 years. This case highlights MCL-associated MN as a PLA2R/THSD7A/NELL-1 triple-negative entity where antineoplastic therapy alone induces renal remission, demonstrating both the paraneoplastic mechanism and the feasibility of intensive lymphoma treatment, including transplantation without renal compromise.
2026-06-29 | CEACAM1 expression by immunohistochemistry in B-cell lymphomas and plasma cell myeloma.
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with limited curative treatment options. Carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) has recently been implicated in B-cell receptor signaling in MCL. We evaluated CEACAM1 expression by immunohistochemistry across MCL and other mature B-cell neoplasms, including small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM). We retrospectively analyzed 164 lymphoma cases, 35 MM cases, and 2 plasmacytomas. CEACAM1 expression was assessed on tissue microarrays by immunohistochemistry and scored using a prespecified dichotomous cutoff. In DLBCL, CEACAM1 status was correlated with cell-of-origin classification and targeted mutational data. CEACAM1 was expressed in 27 of 30 MCL cases (90%), higher than in the other lymphoma subtypes combined (35%; P < .0001). Expression was also seen in SLL (20/30, 67%), MM (23/35, 66%), MZL (8/22, 36%), and DLBCL (19/82, 23%). In DLBCL, expression was more frequent in germinal center B-cell subtype than activated B-cell subtype cases (30% vs 13%; P = .023). Within sequenced DLBCL cases, CEACAM1 expression was associated with BCL2 and TNFRSF14 mutations. In MM, CEACAM1 expression was not significantly associated with recurrent cytogenetic abnormalities, although a nonsignificant trend toward higher expression in t(11;14) cases (75% vs 53%, Fisher exact P = .28). CEACAM1 is frequently expressed in MCL and in subsets of other mature B-cell neoplasms and MM. These findings support further investigation of CEACAM1 as a biologically relevant marker and potential therapeutic target in selected lymphoid malignancies.
2026-05-20 | "Immunologic Dream Team": BiTEs peri-allotransplant to redirect donor lymphocytes towards GVL.
Bispecific T cell engagers (BiTEs) provide high rates of responses in patients with relapsed and refractory B cell lymphomas and multiple myeloma otherwise resistant to other therapies, but unfortunately the duration of response to these treatments is limited in time. Allogeneic stem cell transplantation is a potentially curative approach for those disorders, although its indication is limited to patients who achieve remission. While no established strategies to improve the "graft versus tumor effect" are available, relapses still account for the majority of the post-transplant failures. Herein, we report the first case in literature of a successful treatment with glofitamab, a CD20X2/CD3 BiTE, in a post-transplant relapse of mantle cell lymphoma with central nervous disease involvement. We propose the combination of BiTEs and allogeneic transplant as an integrated and sequential immunological approach to be tested in clinical trials.
cell therapies
2026-08-28 | CD19 CAR T-cell therapy (GLPG5101) for relapsed or refractory B-cell non-Hodgkin lymphoma (ATALANTA-1): phase 1 results from a single-arm, multicentre, phase 1/2 study.
Chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment of B-cell non-Hodgkin lymphoma, but centralised manufacturing-with its complex logistics and long vein-to-vein times-drives up costs and restricts access. We aimed to evaluate the safety of GLPG5101, a fresh, CD19 CAR T-cell product manufactured through a decentralised process, and determine the recommended phase 2 dose. This phase 1 dose-escalation part of the ATALANTA-1 phase 1/2, single-arm study, was executed in five hospitals in the Netherlands and Belgium. Patients aged 18 years or older, with histologically confirmed diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL) after two or more lines of therapy, measurable disease according to the Lugano classification, Eastern Cooperative Oncology Group Performance Status 0-2, and adequate organ function were enrolled. Patients were treated with a single intravenous infusion at one of three dose levels of GLPG5101 (dose level 1 [35-50 × 106 viable CAR+ T-cells], dose level 2 [85-110 × 106 viable CAR+ T-cells], and dose level 3 [200-250 × 106 viable CAR+ T-cells]). The phase 1 part of the study applied a Bayesian Optimal Interval design and the primary endpoints were safety (incidence of adverse events and serious adverse events until end of treatment [week 14], and dose-limiting toxicities [DLTs] until day 28) in patients who received fresh GLPG5101 at any dose (excluding recipients of non-conforming product [not meeting prespecified release criteria other than dose]) and determination of the recommended phase 2 dose. The study was registered with ClinicalTrials.gov (NCT06561425) and is closed for recruitment. From March 15, 2022, to Sept 10, 2024, 27 patients were screened for eligibility, 24 of whom were enrolled, underwent leukapheresis and lymphodepleting chemotherapy and received GLPG5101. Data cutoff was June 1, 2025. In the intention-to-treat population (n=24), the median age was 66·5 years (IQR 59·0-71·5), 15 (63%) patients were male, nine (38%) were female, and 21 (88%) were White. One of the 24 patients received a non-conforming product and was excluded from the safety analysis population. Median follow-up was 24·0 months (IQR 20·7-24·9). Five DLTs were reported: grade 3 thrombocytopenia (n=1, dose level 1), death from intra-abdominal haemorrhage (n=1, dose level 2), and grade 4 prolonged neutropenia not resolving to grade 2 or lower within 28 days (n=1 at dose level 1 and n=2 at dose level 2). All 23 patients in the safety analysis population had grade 3 or higher treatment-emergent adverse events; the most common were neutropenia (22 [96%]), leukopenia (nine [39%]), lymphopenia (seven [30%]), anaemia (six [26%]), and thrombocytopenia (five [22%]). Treatment-related deaths occurred in four patients: one during the 14-week treatment period due to intra-abdominal haemorrhage, and three after the treatment period due to Escherichia coli sepsis (n=1), immune-effector cell-associated haemophagocytic lymphohistiocytic syndrome (n=1), and COVID-19 (n=1). The safety review committee selected 110 × 106 (range 50-110 × 106) viable CAR T-cells as the recommended phase 2 dose. The results of this study showed the feasibility of rapid multicentre decentralised manufacturing and delivery of fresh CAR T-cell therapy in heavily pretreated B-cell non-Hodgkin lymphoma. The phase 2 part of ATALANTA-1 will provide further information on clinical activity and safety. CellPoint, Lakefront Biotherapeutics.
2026-08-26 | CAR T-cell vs bispecific antibodies in relapsed/refractory mantle cell lymphoma: a systematic review and meta-analysis.
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with limited treatment options for relapsed/refractory (R/R) cases. CAR T-cell therapy and CD20×CD3 bispecific antibodies are promising immunotherapies, but no study has systematically compared their efficacy and safety in R/R MCL. This systematic review and meta-analysis was conducted in accordance with the PRISMA 2020 guidelines and registered in PROSPERO (CRD42024622564). A comprehensive search of PubMed, Embase, and the Cochrane Library (from inception to October 27, 2024) was performed to identify studies evaluating CAR T-cell therapy and bispecific antibodies in R/R MCL (third-line or later). Random-effects and fixed-effects models were used to calculate pooled complete response (CR) rates, overall response (OR) rates, and Grade ≥3 adverse events. Sensitivity analyses were conducted to assess the robustness of the results. Five studies (237 patients) were included. Pooled CR rates were 0.63(95% CI, 0.51-0.74)for bispecific antibodies and 0.70(95%CI, 0.63-0.77) for CAR T-cell therapy (P <0.05). OR rates were similar (0.75 vs. 0.88). Grade ≥3 cytokine release syndrome rates were comparable (0.06 vs. 0.06), but neurotoxicity cannot be compared. CAR T-cell therapy demonstrated higher CR rates versus bispecific antibodies, supporting their role as effective third-line treatments for R/R MCL. Randomized trials are needed to confirm these findings. https://www.crd.york.ac.uk/prospero/, identifier CRD42024622564.
2026-07-30 | Allogeneic stem cell transplantation for mantle cell lymphoma can achieve durable remission and myeloablative conditioning is associated with inferior survival: an Australian and New Zealand Transplant & Cellular Therapies registry study.
Allogeneic stem cell transplantation (AlloSCT) has established curative potential in mantle cell lymphoma (MCL). As therapies for MCL evolve, outcomes with AlloSCT require reassessment. This study aimed to report the outcomes of AlloSCT for MCL across Australia and New Zealand. Data were collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for all patients undergoing AlloSCT for MCL between January 2009 and December 2019. Forty-six patients underwent AlloSCT for MCL between 2009 and 2014 and 40 between 2015 and 2019. The median patient age was 56 years (range 32-72), nine of 15 patients tested (60%) had TP53 mutation, and 14% of patients underwent myeloablative conditioning (MAC). A higher proportion of patients in the 2015-2019 period were BTKi-exposed (68% vs. 0%, P = 0.00). Non-relapse mortality (NRM) at 1 year and 5 years was 23% (95% confidence interval (95% CI) 14-32) and 31% (95% CI 21-42) respectively. The 100-day cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 21% (95% CI 13-30), and the 3-year cumulative incidence of chronic GVHD was 31% (95% CI 22-41). At 5 years, overall survival (OS) was 48% (95% CI 36-59) and progression free survival (PFS) was 38% (95% CI 27-50). The use of MAC was independently associated with inferior PFS (hazard ratio [HR] 2.33, 95% CI 1.05-5.17, P = 0.038) and OS (HR 3.11, 95% CI 1.39-7.00, P = 0.006). There was no difference in outcomes for patients transplanted between 2009 and 2014 versus 2015 and 2019. AlloSCT can achieve durable remissions for MCL in the modern era, and the use of MAC is associated with inferior outcomes.
2026-07-22 | Model-Based Analysis with Mechanistic Insights to CAR-T-Cell Therapy Kinetics: Case Study with Axicabtagene Ciloleucel and Brexucabtagene Autoleucel.
Model-informed drug development is increasingly used to support chimeric antigen receptor (CAR)-T-cell therapy programs. However, most population pharmacokinetic (PK) CAR-T-cell models available in literature are variations of an empirical piecewise-linear model, which accurately describes the observed data but lacks a mechanistic foundation. This limits its use for simulations of scenarios beyond the observed data. This work presents a mechanism-based population PK framework that aims to bridge existing empirical and mechanistic CAR-T-cell modeling approaches. The model was developed using a clinical database of 473 patients with various relapsed or refractory lymphomas (large B cell, follicular, marginal zone, or mantle cell) receiving axicabtagene ciloleucel or brexucabtagene autoleucel. The framework incorporates two CAR-T-cell compartments alongside a latent kinetic-pharmacodynamic tumor compartment, utilizing a continuous, mechanistically-driven approach to characterize the observed PK profiles. A covariate search identified five significant covariates impacting PK (P < 0.001). Among these, only product type/mantle cell lymphoma (MCL) disease type was deemed to have clinically relevant effects on exposure. Despite its mechanistic basis, the model remains parsimonious, requiring only seven structural parameters, and no additional data beyond post-infusion CAR-T-cell peripheral blood concentrations and covariate information routinely collected in clinical trials. With its mechanistic foundation but parsimonious structure, this model balances data-driven practicality with the integration of underlying biological processes. Its ability to identify relevant covariates could make it a valuable tool in supporting drug development decisions.
2026-07-16 | Expanding the Horizon of CAR-T Cell Therapy: Present Obstacles and New Strategies for Future CARs in Solid Tumors.
Chimeric antigen receptor (CAR)-T cells are synthetic receptors used for the recognition of specific antigens expressed by reprogrammed T cells for targeting tumors. CAR-T cell therapy has gained remarkable clinical success for the treatment of hematological malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), and primary intraocular lymphoma (PIL). The increasing number of preclinical investigations and clinical trials is focusing on extending CAR-T cell therapy to solid tumors due to its remarkable success in leukemia and lymphoma cancers. However, some limitations of CAR-T therapy still exist, including a lack of targetable antigen diversity, heterogeneous antigen expression, insufficient T-cell trafficking efficiency, and an immunosuppressive tumor microenvironment. This review explores the role of CAR-T cell therapy, current challenges, and emerging solutions for solid tumor malignancies. To overcome the existing limitations of CAR-T cell therapy, innovative strategies, including the optimization of novel CAR vectors with checkpoint inhibitors, have been designed to enhance the antitumor activity of CAR-T cells against solid tumors. It also explores the design of novel CAR-T cells and strategies for improving antitumor activity against solid tumors. Among the emerging strategies, universal CARs and combination approaches with checkpoint inhibitors are especially promising for extending CAR-T therapy to solid tumors.
small molecules
2026-09-25 | Survival benefit of chemoradiotherapy in limited-stage mantle cell lymphoma: a National Cancer Database analysis.
Limited-stage mantle cell lymphoma (MCL) is rare, and optimal management remains undefined because of limited representation in clinical studies. We conducted a large population-based analysis using the National Cancer Database to evaluate overall survival (OS) in patients with Ann Arbor stage I to II MCL diagnosed between 2004 and 2015. Initial treatment was categorized to chemotherapy alone, radiotherapy (RT) alone, or combined chemotherapy plus RT (Chemo+RT), and outcomes were further stratified by stage and era of diagnosis (2004-2009 vs 2010-2015) to account for advances in systemic therapy, such as the adoption of bendamustine-rituximab for frontline therapy and the availability of Bruton tyrosine kinase inhibitors for relapsed disease. Among 2428 patients included, median OS for the entire cohort was 8.1 years. Chemo+RT was associated with superior OS compared with chemotherapy alone or RT alone (median OS, 11.2 vs 7.4 vs 8.0 years, respectively; P < .001). This survival benefit was observed in both stage I and stage II diseases and in both eras. On multivariable analysis, treatment with chemotherapy alone (hazard ratio [HR], 1.50) or RT alone (HR, 1.33) was independently associated with inferior OS compared with Chemo+RT. In this, to our knowledge, largest real-world analysis of limited-stage MCL to date, combined chemoimmunotherapy and RT was associated with a clinically meaningful survival benefit, including in the modern treatment era. These findings suggest that combined-modality therapy may be preferred for appropriately selected patients with limited-stage MCL.
2026-09-21 | A Case of Leukemic Phase of Mantle Cell Lymphoma Diagnosed With Scarring Conjunctivitis and Bilateral Upper Palpebral Conjunctival Tumor.
Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma. Ocular adnexal involvement is rare as the initial symptom, and conjunctival involvement is particularly rare. An 84-year-old man was referred to our hospital with chronic conjunctivitis of the bulbar and tarsal conjunctiva with bilateral symblepharon, as well as a reddish-brown, cobblestone-like tumor. Suspecting malignancy, a tumor biopsy and systemic examination revealed the neoplastic lesion to be MCL. Leukocytosis and abnormal cells in peripheral blood (53%) were observed, and diffuse tumor cell infiltration was observed in the bone marrow. Both the bone marrow and tumor cells were positive for CD5, CD20, and cyclin D1, while the bone marrow tissue was negative for SOX11, confirming leukemic conversion (leukemic phase of mantle cell lymphoma). PET/CT revealed accumulation in systemic lymph nodes and extranodal organs, leading to a diagnosis of Ann Arbor stage IV disease. TP53 deletion was not detected. Following treatment with acalabrutinib in combination with bendamustine and rituximab, as reported in 2025, the conjunctivitis and eyelid tumor resolved, with no recurrence observed during follow-up. We report a case of leukemia-type MCL diagnosed with bilateral chronic cicatricial conjunctivitis and elevated lesions on the upper eyelid conjunctiva as initial findings. When encountering such findings, early pathological diagnosis and thorough systemic examination are important, with systemic malignant lymphoma in mind.
2026-09-14 | Targeting ROR1 with KAN571C disrupts resistance networks in mantle cell lymphoma.
Resistance to Bruton tyrosine kinase (TK) and BCL2 inhibitors, such as ibrutinib (Ibru) and venetoclax (Ven), remains a major therapeutic challenge in mantle cell lymphoma (MCL), which limits treatment options. Receptor TK-like orphan receptor 1 (ROR1), aberrantly expressed in MCL and other malignancies but largely absent in normal adult tissues, has been implicated in tumor cell proliferation, survival, and migration. This study aimed to elucidate the mechanisms underlying Ibru and Ven resistance in MCL and to investigate the therapeutic potential of targeting ROR1 using the small-molecule inhibitor KAN571C in Ibru- and/or Ven-resistant MCL cell lines. Ibru-, Ven-, and Ibru + Ven (Double)-resistant models were generated from the JEKO-1, Granta-519, and Z138 MCL cell lines. The cytotoxic effects of Ibru, Ven, and KAN571C were assessed in both naive and drug-resistant models using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. Western blotting was used to analyze downstream signaling alterations after exposure to KAN571C. KAN571C induced potent cytotoxicity in both naive and drug-resistant models, preferentially in Ven- and Ibru/Ven-resistant cells. Mechanistically, KAN571C dephosphorylated ROR1 at TK and proline-rich domains, suppressed downstream phosphatidylinositol 3-kinase/AKT and β-catenin signaling, and activated caspase-dependent apoptosis. Notably, long-term exposure (2 weeks) failed to establish KAN571C-resistant cell lines. Our findings identify ROR1 as a convergent mediator of resistance in MCL and highlight KAN571C as a potential therapeutic strategy to overcome treatment refractoriness.
2026-09-09 | Acalabrutinib Added To Rituximab, Bendamustine (ABR) in Newly Diagnosed High Risk Mantle Cell Lymphoma: an Early Indian Experience.
Conventionally chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) is the standard of care for newly diagnosed mantle cell lymphoma. The role of BTKi is emerging in upfront management of mantle cell lymphoma. It has redefined the role of upfront stem cell transplantation especially with achievement of deep sustained MRD negativity. Elderly population are not eligible for intensive chemotherapy for many reasons especially frailty, poor performance score and associated comorbidities. The use of upfront Ibrutinib and acalabrutinib with Rituximab, Bendamustine (BR) backbone has been studied in these transplant ineligible cohorts in Phase 3 SHINE and ECHO trial respectively. We reported the early outcome, efficacy of second generation BTKi (acalabrutinib) with BR from an Indian perspective. The online version contains supplementary material available at https://doi.org/10.1007/s12288-025-02257-8.
2026-09-09 | Preliminary study on efficacy and safety of pixantrone in relapsed/refractory aggressive B-cell lymphomas: multicenter, retrospective cohort study by Polish Lymphoma Research Group (PLRG).
Pixantrone (PIX) is an anthracycline derivative with reduced cardiotoxicity, registered in Poland for monotherapy in relapsed/refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL) in the third or fourth line of treatment. As R/R population is difficult to treat due to comorbidities including circulatory system pathologies we evaluate polish patients treated with PIX. This is the first real life study evaluating patients treated with PIX in Poland with emphasis on efficacy and cardiovascular toxicity. The retrospective study assessing safety and effectiveness of PIX administered in patients with aggressive de novo or transformed B-NHL [according to the Revised European American Lymphoma (REAL) and World Health Organization (WHO) classifications], who relapsed or were refractory to two or three previous lines of chemotherapy regimens, including at least one standard anthracycline-based regimen. Patients who did not remain sensitive to anthracyclines were excluded from this study. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), complete response (CR) rate, overall response rate (ORR) and safety. The data of 17 patients were collected in 6 study sites. The median age was 72 (range: 58-82) years old with male predominance (65%). In observed group10 patients had diffuse large B-cell lymphoma (DLBCL), 6 mantle cell lymphoma (MCL) and 1 patient had Richter syndrome. Five subjects responded to PIX (CR 2 and partial response 3)-ORR was 29%. The median of PFS was 12.9 months [standard error (SE) 2.2; 95% confidence interval (CI): 8.5, 17.2]. The median of survival time was 22.6 months (SE 7.3; 95% CI: 8.3, 36.8). The PIX compliance was good, with incidental dose omission or delay. The main reason for discontinuation was disease progression. Administration of PIX to patients with R/R aggressive B-NHL treated with multiple lines of chemotherapy containing maximal cumulative dose of anthracycline and with numerous concomitant diseases may be a potentially valuable therapeutic option but data from larger clinical studies will help in confirming PIX as an effective and safe option.
oligonucleotides
2024-02-14 | miR-17-92 cluster-BTG2 axis regulates B-cell receptor signaling in mantle cell lymphoma.
B-cell receptor (BCR) signaling is critically activated and stable for mantle cell lymphoma (MCL), but the underlying mechanism of the activated BCR signaling pathway is not clear. The pathogenic basis of miR-17-92 cluster remains unclear although the oncogenic microRNA (miRNA) miR-17-92 cluster is highly expressed in patients with MCL. We revealed that miR-17-92 cluster overexpression is partly dependent on SOX11 expression and chromatin acetylation of MIR17HG enhancer regions. Moreover, miR-17-92 cluster regulates not only cell proliferation but BCR signaling activation in MCL cell lines. To comprehensively identify miR-17-92 cluster target genes, we performed pulldown-seq, where target RNA of miRNA was captured using the biotinylated miRNA mimics and magnetic bead-coated streptavidin, and quantified using next-generation sequencing. The pulldown-seq identified novel miRNA target genes, including tumor suppressors such as BTG2 (miR-19b), CDKN2A (miR-17), SYNE1 (miR-20a), TET2 (miR-18, miR-19b, and miR-92a), TNFRSF10A (miR-92a), and TRAF3 (miR-17). Notably, the gene expression profile data of patients with MCL revealed that BTG2 expression was negatively associated with that of BCR signature genes, and low BTG2 expression was associated with poor overall survival. Moreover, BTG2 silencing in MCL cell lines significantly induced BCR signaling overactivation and cell proliferation. Our results suggest an oncogenic role of miR-17-92 cluster-activating BCR signaling throughout BTG2 deregulation in MCL. Furthermore, this may contribute to the prediction of the therapeutic efficacy and improved outcomes of MCL.
2023-05-29 | Long non-coding RNA as a novel biomarker and therapeutic target in aggressive B-cell non-Hodgkin lymphoma: A systematic review.
Abstract Cancer initiation and progression have been associated with dysregulated long non‐coding RNA (lncRNA) expression. However, the lncRNA expression profile in aggressive B‐cell non‐Hodgkin lymphoma (NHL) has not been comprehensively characterized. This systematic review aims to evaluate the role of lncRNAs as a biomarker to investigate their future potential in the diagnosis, real‐time measurement of response to therapy and prognosis in aggressive B‐cell NHL. We searched PubMed, Web of Science, Embase and Scopus databases using the keywords “long non‐coding RNA”, “Diffuse large B‐cell lymphoma”, “Burkitt's lymphoma” and “Mantle cell lymphoma”. We included studies on human subjects that measured the level of lncRNAs in samples from patients with aggressive B‐cell NHL. We screened 608 papers, and 51 papers were included. The most studied aggressive B‐cell NHL was diffuse large B‐cell lymphoma (DLBCL). At least 79 lncRNAs were involved in the pathogenesis of aggressive B‐cell NHL. Targeting lncRNAs could affect cell proliferation, viability, apoptosis, migration and invasion in aggressive B‐cell NHL cell lines. Dysregulation of lncRNAs had prognostic (e.g. overall survival) and diagnostic values in patients with DLBCL, Burkitt's lymphoma (BL), or mantle cell lymphoma (MCL). Furthermore, dysregulation of lncRNAs was associated with response to treatments, such as CHOP‐like chemotherapy regimens, in these patients. LncRNAs could be promising biomarkers for the diagnosis, prognosis and response to therapy in patients with aggressive B‐cell NHL. Additionally, lncRNAs could be potential therapeutic targets for patients with aggressive B‐cell NHL like DLBCL, MCL or BL.
2023-02-27 | RNA splicing factors in normal hematopoiesis and hematologic malignancies: novel therapeutic targets and strategies.
RNA splicing, a crucial transesterification-based process by which noncoding regions are removed from premature RNA to create mature mRNA, regulates various cellular functions, such as proliferation, survival, and differentiation. Clinical and functional studies over the past 10 y have confirmed that mutations in RNA splicing factors are among the most recurrent genetic abnormalities in hematologic neoplasms, including myeloid malignancies, chronic lymphocytic leukemia, mantle cell lymphoma, and clonal hematopoiesis. These findings indicate an important role for splicing factor mutations in the development of clonal hematopoietic disorders. Mutations in core or accessory components of the RNA spliceosome complex alter splicing sites in a manner of change of function. These changes can result in the dysregulation of cancer-associated gene expression and the generation of novel mRNA transcripts, some of which are not only critical to disease development but may be also serving as potential therapeutic targets. Furthermore, multiple studies have revealed that hematopoietic cells bearing mutations in splicing factors depend on the expression of the residual wild-type allele for survival, and these cells are more sensitive to reduced expression of wild-type splicing factors or chemical perturbations of the splicing machinery. These findings suggest a promising possibility for developing novel therapeutic opportunities in tumor cells based on mutations in splicing factors. Here, we combine current knowledge of the mechanistic and functional effects of frequently mutated splicing factors in normal hematopoiesis and the effects of their mutations in hematologic malignancies. Moreover, we discuss the development of potential therapeutic opportunities based on these mutations.
2022-05-06 | Integrated analysis of 14 lymphoma datasets revealed high expression of CXCL14 promotes cell migration in mantle cell lymphoma.
Lymphoma is accompanied by the impairment of multiple immune functions. Cytokines play an important role in a variety of immune-related functions and affect the tumor microenvironment. However, the exact regulatory mechanisms between them remain unclear. This study aimed to explore the cytokines expression and function in Hodgkin's lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL). We performed a transcriptome integration analysis of 14 lymphoma datasets including 240 Hodgkin's lymphoma, 891 diffuse large B-cell lymphoma, 216 mantle cell lymphoma, and 64 health samples. The results showed that multiple immune functions and signal pathway damage were shared by all three types of lymphoma, and these functions were related to cytokines. Furthermore, through co-expression network and functional interaction network analysis, we identified CXCL14 as a key regulator and it affects cell chemotaxis and migration functions. The functional experiment showed that CXCL14 knockdown inhibited cell migration in MCL cell lines. This study suggested that high expression of CXCL14 may aggravate MCL via promoting cell migration. Our findings provide novel insights into the biology of this disease and would be helpful for the pathogenesis study and drug discovery of lymphomas.
2022-04-07 | A Phase 2 Study of PNT2258 for Treatment of Relapsed or Refractory B-Cell Malignancies.
PNT2258 consists of a native, chemically unmodified, 24-base DNA oligonucleotide designed to target the regulatory region upstream of the BCL2 gene, delivered in a protective liposome. Derangement of BCL2-regulated control mechanisms is a defining characteristic of certain malignancies, and it was hypothesized that the oligonucleotide would promote anticancer activity via suppression of BCL2 transcription. PNT2258 was evaluated in this, multicenter, nonrandomized, open-label Phase 2 study in 13 participants with relapsed/refractory B-cell malignancies to investigate potential antitumor activity and safety. Participants with follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, or chronic lymphocytic leukemia received intravenous PNT2258 120 mg/m2 on Days 1 to 5 of a 21-day cycle for up to 8 cycles, followed by 100 mg/m2 on Days 1 to 2 of a 28-day cycle until study withdrawal. All 13 participants were treated with PNT2258 monotherapy and evaluable for response and safety and tolerability. The overall response rate was 53.8% (7/13; 95% confidence interval [CI], 25.1%-80.8%). Median duration of response was 23.4 months (range, 3, 31.5). The disease control rate of participants with stable disease or better was 84.6% (95% CI, 54.6%-98.1%). The most frequently (≥50%) observed adverse events (AEs) were nausea, chills, diarrhea, fatigue, headache, vomiting, and back pain. Hypertension (30.8%) and diarrhea (23.1%) were the most frequent grade ≥3 AEs. No deaths were observed. Clinically meaningful and durable activity with an acceptable safety profile was observed in participants with relapsed/refractory B-cell malignancies who received single-agent PNT2258. NCT01733238, first posted 26-Nov-2012. https://clinicaltrials.gov/ct2/show/NCT01733238.
other
2026-06-10 | LncRNA IRAIN inhibits mantle cell lymphoma progression by inducing cell cycle arrest and apoptosis: an in vitro study.
Long non-coding RNA (lncRNA) insulin-like growth factor 1 receptor antisense imprinted non-protein coding RNA (IRAIN) and lysine-specific demethylase 1 (LSD1) are aberrantly expressed in various malignancies. However, their roles in the progression of mantle cell lymphoma (MCL) remain unclear. This study aimed to investigate the expression pattern and biological role of IRAIN in MCL progression and to further explore the relationship between IRAIN and LSD1. In this study, the expression levels of IRAIN and LSD1 in MCL cells were detected by RT-qPCR. An IRAIN-overexpressing lentiviral vector (LV-IRAIN-up) was constructed and transduced into MCL cells, and the transduction efficiency was verified by flow cytometry (FACS) and RT-qPCR. The effects of IRAIN overexpression on cell viability, apoptosis, and cell cycle progression were evaluated using CCK-8 assays and FACS analysis. In addition, RT-qPCR and Western blot analyses were performed to determine the regulatory effects of IRAIN overexpression on LSD1 expression, apoptosis-related proteins (including Bax, Bcl-2, pro-caspase-3, and cleaved-caspase-3), and cell cycle-related proteins (Cyclin D1, CDK2, and p21). Furthermore, LSD1 was overexpressed in IRAIN-overexpressing MCL cells to investigate its effects on cell proliferation, apoptosis, and cell cycle progression. The results demonstrated that IRAIN expression was significantly downregulated, whereas LSD1 expression was markedly upregulated in MCL cells. IRAIN overexpression significantly inhibited cell viability, promoted apoptosis, and induced G1-phase cell cycle arrest. Meanwhile, IRAIN overexpression markedly downregulated the expression of LSD1, Bcl-2, pro-caspase-3/cleaved-caspase-3, Cyclin D1, and CDK2, while upregulating the expression of Bax and p21. Further experiments showed that LSD1 overexpression partially reversed the inhibitory effects of IRAIN overexpression on MCL cell proliferation, apoptosis induction, and G1-phase arrest. Collectively, these findings suggest that IRAIN may participate in the regulation of proliferation, apoptosis, and cell cycle progression in MCL cells, potentially through modulation of LSD1. These results provide preliminary experimental evidence for further understanding the potential biological function of IRAIN in MCL.
2025-12-13 | Identification and functional characterization of splicing factors implicated in mantle cell lymphoma aggressiveness.
Mantle cell lymphoma (MCL) is a clinically aggressive and incurable form of non-Hodgkin lymphoma with very heterogeneous clinical and biological behaviors. Dysregulation of RNA splicing machinery is common in various types of cancer, including hematologic malignancies, and is associated with cancer progression. However, whether and how splicing factors, the spliceosome components responsible for pre-mRNA splicing, regulate MCL aggressive behaviors remain largely unknown. Bioinformatics analyses were employed to profile the mRNA expression of two key families of splicing factors, that are serine/arginine-rich (SR) and heterogenous nuclear ribonucleoprotein (hnRNP) families, in clinical specimens of MCL patients in comparison to normal B cells. Functional roles of splicing factors in MCL aggressive phenotypes defined as hallmarks of cancer were investigated in MCL cell lines. Kaplan-Meier survival analyses were performed to determine the clinical significance of splicing factors according to their gene expression level. Depletion of SRSF1, hnRNP F, and PTBP1, which are highly expressed in MCL clinical specimens, by CRISPR/Cas9 system significantly inhibit cell growth and proliferation, motility, and angiogenesis of MCL cells. SRSF1, hnRNP F (for Z-138 cells), and PTBP1 were found to mediate BTZ sensitivity in MCL cells, in agreement with an increase in caspase-3 activation and the occurrence of splicing events that favor the expression of pro-apoptotic isoforms of apoptosis regulatory genes. We also found that depletion of SRSF1, hnRNP F, and PTBP1 induces the expression of autophagy-related genes and the accumulation of autophagic vacuoles, which may act as one of the tumor-suppressive mechanisms. Survival analyses revealed that co-high expression of SRSF1, HNRNPF, or PTBP1 and oncogenic MYC predicts poor clinical outcomes in MCL patients. Our data describe the clinical significance of aberrant SRSF1, hnRNP F, and PTBP1 in MCL and their tumor-promoting roles via the regulation of cancer hallmarks, which could be important in understanding MCL pathogenesis and therapeutic development.
2025-12-11 | Benefit of rituximab maintenance after first-line bendamustine-rituximab in patients with mantle cell lymphoma.
The benefit of rituximab maintenance after first-line (1L) bendamustine-rituximab (BR) in patients with mantle cell lymphoma (MCL) remains uncertain, with inconsistent results from the phase 2 MAINTAIN trial and several retrospective studies. We conducted a large retrospective study at 27 US and Canadian academic centers to examine the benefit of rituximab maintenance after BR. A total of 911 patients received 1L BR between 2010 and 2020, and 703 had an objective response and no evidence of disease progression at the 3-month post-BR landmark. Among those, 394 (56%) received rituximab maintenance and 309 (44%) did not, with largely similar baseline patient and disease characteristics. In the landmark analysis, rituximab maintenance was associated with improved event-free survival (EFS; median, 49.9 vs 29.7 months; P< .001) as well as overall survival (OS; median, 109.5 vs 74.2 months; P< .001). The EFS and OS benefits were observed across most of the subgroups. EFS and OS differences were statistically significant in those who achieved a complete response to 1L BR (n = 590; median EFS, 62.7 vs 31.1 months [P< .001]; median OS, 136.1 vs 75.3 months [P< .001]), but the analysis among those who achieved a partial response to 1L BR was limited by the small sample size. These results provide additional evidence for the survival benefit of rituximab maintenance after BR in MCL and support its use in clinical trial design and routine practice.
2025-11-10 | T-Cell-Redirecting Immunotherapies in Relapsed/Refractory Mantle Cell Lymphoma: Current Evidence, Sequencing, and Future Directions.
Relapsed/refractory (R/R) mantle cell lymphoma (MCL) remains a therapeutic challenge, particularly in patients with high-risk features or prior exposure to Bruton's tyrosine kinase inhibitors (BTKis). The advent of T-cell-redirecting immunotherapies, including chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies (BsAbs), has transformed the treatment landscape. CAR-T therapies, such as brexu-cel and liso-cel, induce high overall response rates and durable remissions, even in heavily pretreated or BTKi-refractory patients. However, CAR-T administration is limited by logistical constraints, the need for bridging therapy, and the risk of severe toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). BsAbs, targeting CD20 and CD3, offer an off-the-shelf, repeatable immunotherapeutic option suitable for outpatient use, with generally manageable toxicities. Step-up dosing, corticosteroids, and anti-IL6 therapy mitigate CRS, while hematologic toxicity and infections require vigilant monitoring. Clinical data indicate that BsAbs are active in both CAR-T-naïve and post-CAR-T settings, providing disease control in patients ineligible for immediate CAR-T therapy. Emerging evidence supports rational sequencing and combinatorial strategies to optimize outcomes. BsAbs may be employed as a bridge to CAR-T, or CAR-T may be used to consolidate BsAb-induced remissions. Combination regimens, including CAR-T or BsAbs with BTK inhibitors or other targeted agents, are under investigation to enhance the depth and durability of response. In conclusion, CAR-T and BsAbs are complementary modalities in R/R MCL. Individualized therapeutic sequencing and rational combinations, tailored to disease biology and patient characteristics, represent the next frontier for improving long-term outcomes in this historically high-risk population.
2025-10-01 | Chronic meningoencephalitis due to enterovirus A71 complicating rituximab therapy.
Rituximab and other anti-CD20 therapies are increasingly used in the treatment of autoimmune and hematologic disorders. These treatments are associated with persistent immune impairment, potentially leading to severe infections. We describe a resolutive case of proven chronic enterovirus A71 (EV A71) meningoencephalitis complicating rituximab maintenance therapy for non-Hodgkin lymphoma. This article combines an original case report and a literature review of cases of enteroviral meningoencephalitis complicating rituximab treatment. A 38-year-old man was treated with rituximab and chemotherapy for a mantle cell lymphoma. During maintenance treatment with rituximab, he developed a "hand-foot-mouth disease", and one month later severe neurological deterioration including quadriparesis and major neurocognitive disorder leading to a diagnosis of chronic enteroviral meningoencephalitis. A treatment associating monthly intravenous immunoglobulins (IVIg) and fluoxetine was initiated two months after neurological symptoms onset, resulting in dramatic clinical improvement within six months. A brief literature review shows that a treatment with high-dose IVIg often results in clinical improvement. Fluoxetine was added in recent reports based on in vitro evidence of anti-viral activity against enteroviruses. Enteroviral infection should be evoked in patients treated with rituximab presenting with an encephalitic symptomatology, and restoring humoral immunity with high-dose IVIg might improve their condition.
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Drug Discovery Landscape
43 orphan drug designations for Mantle cell lymphoma, including 10 approved therapies.
43 orphan drug designations for Mantle cell lymphoma, including 10 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
an antibody-drug conjugate composed of the humanized monoclonal antibody against ROR1, conjugated to MMAE through a mc-vc-PAB cleavable linker | antibodies | FDA | Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd | |
CAR-T cell engager protein that links the CD19-directed CAR-T cell to a B cell antigen CD20 | cell therapies | FDA | Aleta Biotherapeutics | |
sonrotoclax [Beqalzi] | small molecules | FDA | Approved | BeOne Medicines USA, Inc. |
tacabrutideg | small molecules | FDA | BeOne Medicines USA, Inc. | |
an oral inhibitor of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) | small molecules | FDA | Schrödinger, Inc. | |
(+)N-hydroxy-N-(methylacylfulvene)urea | small molecules | FDA | Lantern Pharma | |
Glofitamab [Glofitamab Roche Registration GmbH] | antibodies | EMA | Roche Registration GmbH | |
Glofitamab | antibodies | FDA | Genentech, Inc. | |
Pirtobrutinib [Jaypirca] | small molecules | EMA | Eli Lilly Nederland B.V. | |
Orelabrutinib | small molecules | FDA | InnoCare Pharma Inc. | |
Humanised IgG1 monoclonal antibody against the extracellular domain of receptor tyrosine kinase-like orphan receptor 1 coupled via a proteolytically cleavable maleimidocaproyl-valine-citrulline-para-aminobenzoate linker to monomethyl auristatin E | antibodies | EMA | Merck Sharp & Dohme B.V. | |
pirtobrutinib [Jaypirca] | small molecules | FDA | Approved | Loxo Oncology, Inc. |
Antibody-drug conjugate (ADC) comprising an anti-ROR1 monoclonal antibody (UC-961), a proteolytically cleavable maleimidocaproyl-valine-citrulline-para-aminobenzoate linker (mc-vc-PAB), and a monomethyl auristatin E (MMAE) cytotoxin. | antibodies | FDA | Merck Sharp & Dohme, LLC | |
cirmtuzumab | antibodies | FDA | Ho’ola Therapeutics Inc. | |
Allogeneic gene-edited CD19-directed CAR T cells/azercabtagene zapreleucel | cell therapies | FDA | — | Imugene Limited |
lisocabtagene maraleucel [Breyanzi] | cell therapies | FDA | Approved | Juno Therapeutics, Inc. |
Autologous peripheral blood T cells CD4 and CD8 selected and CD3 and CD28 activated transduced with retroviral vector expressing anti CD19 CD28/CD3-zeta chimeric antigen receptor and cultured [Tecartus] | cell therapies | EMA | Approved | Kite Pharma EU B.V. |
allogeneic gene edited CD20-directed CAR (Chimeric Antigen Receptor) T cells | cell therapies | FDA | Precision BioSciences, Inc. | |
parsaclisib | small molecules | FDA | Incyte Corporation | |
Fully human immunoglobulin G1 monoclonal antibody that targets CD32b | antibodies | FDA | — | BioInvent International AB |
Venetoclax [Venclyxto] | small molecules | EMA | Abbvie Deutschland GmbH & Co. KG | |
venetoclax | small molecules | FDA | AbbVie Inc. | |
Humanized monoclonal immunoglobulin G1 antibody directed against human CD19 conjugated to SG3199 through a protease cleavable valine-alanine linker | antibodies | FDA | ADC Therapeutics SA | |
7-benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4H)-one-2HCL | small molecules | FDA | Chimerix, Inc. | |
zanubrutinib [BRUKINSA] | small molecules | FDA | Approved | BeOne Medicines USA, Inc. |
brexucabtagene autoleucel [TECARTUS™] | cell therapies | FDA | Approved | Kite Pharma, Inc. |
Acalabrutinib | small molecules | EMA | Acerta Pharma B.V. | |
Axicabtagene ciloleucel [Yescarta] | cell therapies | EMA | Kite Pharma EU B.V. | |
acalabrutinib [CALQUENCE] | small molecules | FDA | Approved | Acerta Pharma, LLC (a member of the AstraZeneca Group) |
daratumumab | antibodies | FDA | Janssen Research & Development, LLC | |
triterpenoid saponin | small molecules | FDA | — | Avicin Therapeutics, Ltd. |
Ibrutinib [Imbruvica] | small molecules | EMA | Janssen Cilag International | |
ibrutinib [Imbruvica] | small molecules | FDA | Approved | Pharmacyclics, LLC |
DNA plasmid vector expressing eIF5Ak50R protein, siRNA directed against the native eIF5A mRNA, and PEI (polyethyleneimine) | gene therapies | FDA | Senesco Technologies, Inc. | |
bortezomib [Velcade] | small molecules | FDA | Approved | Takeda Pharmaceuticals U.S.A., Inc. |
Lenalidomide [Revlimid] | small molecules | EMA | Celgene Europe B.V. | |
Autologous tumor-derived immunoglobulin idiotype coupled to keyhole limpet haemocyanin | vaccines | EMA | Biovest Europe Limited | |
Niraparib tosilate monohydrate [MK-4827] | small molecules | EMA | Tesaro UK Limited | |
dasiprotimut-T | vaccines | FDA | — | Biovest International, Inc. |
lenalidomide [Revlimid] | small molecules | FDA | Approved | Celgene Corporation |
Temsirolimus [Torisel] | small molecules | EMA | Pfizer Europe MA EEIG | |
Recombinant histidine-tagged idiotype immunoglobulin Fab fragment of clonal B-cell receptors | proteins | EMA | — | CellGenix GmbH |
Blinatumomab | antibodies | EMA | Amgen Europe B.V. |
“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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