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B-cell receptor (BCR) activation is a pivotal step in the progression of B-cell cancer. BCR signaling requires Bruton's tyrosine kinase (BTK). Ibrutinib (PCI-32765) is a small medication that covalently and permanently inhibits BTK. BTK's defining properties are its high potency and selectivity. The FDA and EMA have authorized ibrutinib for the second-line therapy for Mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL) individuals who have had a minimum of one previous anti-CD20 (cluster of differentiate 20) based drug. It has been authorized by the FDA and the EMA for the management of Wald Enstrom's Patients with macroglobulinemia who have already had therapy or are unsuitable for immunochemotherapy. Ibrutinib nano formulations include nanoparticles composed of chitosan (CS) and sulfobutylether (SBE) ether-b-cyclodextrin that have been packed with the medication ibrutinib. Because of the inclusion of cyclodextrin, Nanoparticles have a high loading efficiency for the hydrophobic drug. Other nano versions of ibrutinib are also available, which improves Ibrutinib bioavailability. In addition, we combined clinical outcomes and side effects induced by ibrutinib in patients from several clinical and preclinical trials in one study. [Display omitted] • In B-cell receptor (BCR) signaling, Bruton's tyrosine kinase (BTK) plays key role. • Ibrutinib (PCI-32765) is a tiny drug that inhibits BTK covalently and irreversibly. • Great potency and great selectivity for BTK is its distinguishing features. • Various nanoformulations, pre-clinical & clinical findings have also been discussed. [ABSTRACT FROM AUTHOR]

Background: Ibrutinib is a Bruton's tyrosine kinase inhibitor indicated for the first-line treatment and relapse of chronic lymphocytic leukaemia (CLL), Waldenström's macroglobulinemia (WM) and mantle cell lymphoma (MCL). This study aimed to describe the characteristics of CLL patients treated with ibrutinib and its effectiveness, safety, and treatment pattern in real life. Methods: All patients covered by the general health scheme (approximately 80% of the French population) with a first ibrutinib dispensation from August 1, 2017 (date of reimbursement in France) to December 31, 2020, were identified in the French National Health Insurance database (SNDS). An algorithm was developed to identify the disease (CLL, MCL or WM) for which ibrutinib was prescribed. This article focused on CLL patients. The time to next treatment (TTNT) was plotted using Kaplan‒Meier curves. Results: During this period, 6,083 patients initiated ibrutinib, among whom 2,771 (45.6%) patients had CLL (mean age of 74 years; 61% of men). At ibrutinib initiation, 46.6% of patients had a cardiovascular comorbidity. Most patients (91.7%) were not hospitalized during the exposure period for one of the cardiovascular or bleeding events studied. Hospitalizations were more frequent in patients with a cardiovascular comorbidity (5.9% versus 11.0%, p-value < 0.0001) and aged over 70 (5.9% versus 9.4%, p-value < 0.0001). The median TTNT was not reached. Conclusion: This is one of the largest cohorts of ibrutinib-treated patients in the world. The profile of CLL patients treated with ibrutinib was in accordance with the marketing authorization and reimbursement. This study confirmed effectiveness and safety data. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) pathogenesis is strongly related to the role of the tumor immune microenvironment (TIME) in which MCL cells proliferate. TIME cells can produce growth signals influencing MCL cells' survival and exert an antitumoral immune response suppression. The activity of TIME cells might be mirrored by some ratios of peripheral blood cell subpopulations, such as the monocyte-to-platelet ratio (MPR). We reviewed the clinical features of 165 consecutive MCL patients newly diagnosed and not eligible for autologous stem cell transplantation (both for age or comorbidities) who accessed two Italian Centers between 2006 and 2020. MPR was calculated using data obtained from the complete blood cell count at diagnosis before any cytotoxic treatment and correlated with PFS. Univariate analysis showed that MPR ≥ 3 was associated with inferior PFS (p = 0.02). Multivariate analysis confirmed that MPR ≥ 3, LDH > 2.5 ULN, and bone marrow involvement were significant independent variables in predicting PFS. For these reasons, MPR ≥ 3 seems the most promising prognostic factor in patients with MCL, and it could be considered a variable in new predictive models. [ABSTRACT FROM AUTHOR]

Cyclin D1 protein-positive diffuse large B cell lymphoma (DLBCL) has an immunophenotype of CD5(−) cyclin D1(+) SOX11(−), and most cases lack a CCND1 rearrangement and have a gene expression profile of DLBCL. Rarely, cyclin D1 protein-positive DLBCL harbors a CCND1 rearrangement, and some genetic copy number features typical of mantle cell lymphoma (MCL) have been detected. Since gene expression studies have not been performed, whether such CCND1-rearranged cases represent cyclin D1 protein-positive DLBCL or CD5/SOX11 double-negative pleomorphic MCL remains unclear. To date, no cases of CD5/SOX11 double-negative MCL have been reported. In this study, we collected eight cases initially diagnosed as cyclin D1 protein-positive DLBCL, including four with a CCND1 rearrangement and four without. Immunohistochemically, all four CCND1-rearranged cases had >50% of tumor cells positive for cyclin D1 protein, whereas only one (25%) non-rearranged case had >50% positive tumor cells. Analysis of genome-wide copy number, mutational, and gene expression profiles revealed that CCND1-rearranged cases were similar to MCL, whereas CCND1-non-rearranged cases resembled DLBCL. Despite the SOX11 negativity by immunohistochemistry, CCND1-rearranged cases had a notable trend (P = 0.064) of higher SOX11 mRNA levels compared to non-rearranged cases. Here, we show for the first time that CCND1 rearrangement could be useful for identifying CD5/SOX11 double-negative pleomorphic MCL in cases diagnosed as cyclin D1 protein-positive DLBCL. Cases with >50% cyclin D1 protein-positive tumor cells immunohistochemically and higher SOX11 mRNA levels are more likely to have a CCND1 rearrangement, and fluorescence in situ hybridization can be used to detect the rearrangement. [ABSTRACT FROM AUTHOR]

The patient we present here had many clinical, morphological, and laboratory findings characteristic of acute leukemia. During the course of the disease, the diagnosis changed from acute leukemia to chronic small B-cell lymphoproliferative disease, a blastoid variant of mantle cell lymphoma, and finally to atypical plasma cell leukemia. Atypical plasma cell leukemia is a rare condition with aggressive biological behavior. Our patient relapsed a short time after achieving complete remission, in spite of aggressive therapy and autologous stem cell transplantation. During relapse, it was possible to morphologically identify malignant cells as being of plasma cell origin, although immature and atypical. Atypical plasma cell leukemia presents a diagnostic challenge as it may mimic other neoplasms both morphologically and clinically. It is also recognized that plasma cell neoplasm immunophenotype may not be entirely specific for its lineage where common diagnostic biomarkers are applied by immunohistochemistry or flow cytometry. Where this is the case, only focused investigation for plasma cell lineage will be more informative. This patient has unusual clinical presentation, a nondescript morphology of the circulating plasma cells, as well as an immunophenotype, detected by the initial panels used for flow cytometry and immunohistochemistry, that was not entirely specific for plasma cells. Such cases present a good reminder of the diagnostic complexity of atypical plasma cell leukemia and emphasize that plasma cell differentiation needs to be interrogated in cases where the initial work-up shows unusual results. [ABSTRACT FROM AUTHOR]

In the frontline high-dose phase 3 FIL-MCL0208 trial (NCT02354313), 8% of enrolled mantle cell lymphoma (MCL) patients could not be randomised to receive lenalidomide (LEN) maintenance vs observation after autologous stem cell transplantation (ASCT) due to inadequate hematological recovery and 52% of those who started LEN, needed a dose reduction due to toxicity. We therefore focused on the role played by CD34 + hematopoietic stem cells (PBSC) harvesting and reinfusion on toxicity and outcome. Overall, 90% (n = 245) of enrolled patients who underwent the first leukapheresis collected ≥ 4 × 106 PBSC/kg, 2.6% (n = 7) mobilized < 4 × 106 PBSC/kg and 7.7% (n = 21) failed the collection. Similar results were obtained for the planned second leukapheresis, with only one patient failing both attempts. Median count of reinfused PBSC was 5 × 106/kg and median time to recovery from neutropenia G4 was 10 days from ASCT. No impact of mobilizing subtype or number of reinfused PBSC on hematological recovery and LEN dose reduction was noted. At a median follow-up of 75 months from ASCT, PFS and OS of transplanted patients were 50% and 73%, respectively. A long lasting G4 neutropenia after ASCT (> 10 days) was associated with a worse outcome, both in terms of PFS and OS. In conclusion, although the harvesting procedures proved feasible for younger MCL patients, long-lasting cytopenia following ASCT remains a significant issue: this can hinder the administration of effective maintenance therapies, potentially increasing the relapse rate and negatively affecting survival outcomes. [ABSTRACT FROM AUTHOR]

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase crucial for B cell development and function, acts downstream of the B cell receptor (BCR) in the BCR pathway. Other kinases involved downstream of the BCR besides BTK such as Syk, Lyn, PI3K, and Mitogen-activated protein (MAP) kinases also play roles in relaying signals from the BCR to provide pro-survival, activation, and proliferation cues. BTK signaling is implicated in various B-cell lymphomas such as mantle cell lymphoma, Waldenström Macroglobulinemia, follicular lymphoma, and diffuse large B cell lymphoma, leading to the development of transformative treatments like ibrutinib, the first-in-class covalent BTK inhibitor, and pirtobrutinib, the first-in-class noncovalent BTK inhibitor. However, kinase-deficient mutations C481F, C481Y, C481R, and L528W in the BTK gene confer resistance to both covalent and non-covalent BTK inhibitors, facilitating B cell survival and lymphomagenesis despite kinase inactivation. Further studies have revealed BTK's non-catalytic scaffolding function, mediating the assembly and activation of proteins including Toll-like receptor 9 (TLR9), vascular cell adhesion protein 1 (VCAM-1), hematopoietic cell kinase (HCK), and integrin-linked kinase (ILK). This non-enzymatic role promotes cell survival and proliferation independently of kinase activity. Understanding BTK's dual roles unveils opportunities for therapeutics targeting its scaffolding function, promising advancements in disrupting lymphomagenesis and refining B cell lymphoma treatments. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary approach in the treatment of lymphoma. This review article provides an overview of the four FDA-approved CAR T-cell products for aggressive B-cell lymphoma, including diffuse large B-cell lymphoma and mantle cell lymphoma, highlighting their efficacy and toxicity as well as discussing future directions. [ABSTRACT FROM AUTHOR]

Background: Membranous nephropathy (MN) is a common type of nephrotic syndrome (NS) in adults, accounting for about 20–30% of cases. Although secondary to specific factors, the coexistence of MN and mantle cell lymphoma (MCL) has been scarcely reported in clinical literature. Case presentation: A 59-year-old Chinese male was admitted to the hospital with a generalized pruritic rash with bilateral lower extremity edema, which did not improve significantly after symptomatic treatment. He had undergone renal biopsy, and the diagnosis was thought to be secondary MN (SMN), therefore, we did a lymph node biopsy on the patient and found that MN was complicated with MCL. Soon after, the patient was admitted to the hematology department for a BR chemotherapy regimen (composed of bendamustine 90 mg/m2 BSA (body surface area), rituximab 375 mg/m2 BSA and dexamethasone 5 mg), and during the post-treatment follow-up, both his symptoms and renal function improved. Conclusions: The mechanism underlying the combination of SMN and MCL remains elusive and exceedingly rare, consequently often overlooked in clinical practice. This case serves to offer valuable clinical insights for diagnosis and treatment, while emphasizing the pivotal role of renal pathology in clinical assessment. [ABSTRACT FROM AUTHOR]

Background: The present study reviewed the clinicopathological features and outcomes of bilateral lacrimal gland lesions. Methods: The data of 113 patients who underwent lacrimal gland biopsy at the West China Hospital of Sichuan University, China, between January 1, 2010, and December 31, 2021, are presented in this case series. The patients all presented with bilateral lacrimal gland lesions. The collected data included patient demographics, clinical features, the results of laboratory examinations, imaging presentations, histopathological diagnoses, treatments, and outcomes. Results: The mean age of the 113 enrolled patients was 47.4 ± 14.9 years (range, 11–77 years) with a predominance of females (54.9%, n = 62). The lacrimal gland was the source of the majority of biopsy tissue (98.2%, n = 111). The most prevalent etiology was immunoglobulin G4-related ophthalmic disease (IgG4-ROD) (32.7%, n = 37), followed by idiopathic orbital inflammation (IOI) (28.3%, n = 32), mucosa-associated lymphoid tissue (MALT) lymphoma (17.7%, n = 20), reactive lymphoid hyperplasia (RLH) (10.6%, n = 12), and mantle cell lymphoma (4.4%, n = 5). Patients with IOI were significantly younger than those with IgG4-ROD and MALT lymphoma (t = 2.932, P = 0.005; t = 3.865, P<0.001, respectively). Systemic symptoms were more prevalent among patients with IgG4-ROD (χ2 = 7.916, P = 0.005). The majority of patients were treated with surgery (53.1%, n = 60), with surgery combined with corticosteroid therapy (21.2%, n = 24) being the second most common treatment. The majority of patients (91.2%, n = 103) attained complete resolution, stable disease, or significant improvement. Conclusion: In conclusion, there are several aetiologies associated with bilateral lacrimal gland lesions, the most prevalent being IgG4-ROD, IOI, and MALT lymphoma. Systemic symptoms were more common in patients with IgG4-ROD. The majority of patients who presented with bilateral lesions of the lacrimal glands responded satisfactorily to treatment, with favorable results. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a subtype of B-cell lymphoma derived from CD5-positive antigen-naïve pre-germinal center B-cells within the mantle zone that surrounds normal germinal center follicles. MCL comprises approximately 5 to 10% of all lymphomas. Tonsil is the most common location of MCL in the head and neck region, followed by the nasopharynx. Primary MCL involving the nasopharynx is extremely rare. Its clinical course is very aggressive with frequent relapses after conventional chemotherapy. It always presents as a protruding mass on the mucosal lining of the pharyngeal cavity. Here, we report a new nodular type of MCL in the nasopharynx. Endoscopically, this case showed multiple nodular lesions of primary MCL on the nasopharyngeal mucosa. This unique finding has not been reported yet in the English literature. These lesions should be differentiated from simple pharyngeal infections or benign lymphoid hyperplasia in the nasopharynx. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a rare, incurable, and aggressive B-cell non-Hodgkin lymphoma (NHL). Early MCL diagnosis and treatment is critical and puzzling due to inter/intra-tumoral heterogeneity and limited understanding of the underlying molecular mechanisms. We developed and applied a multifaceted analysis of selected publicly available transcriptomic data of well-defined MCL stages, integrating network-based methods for pathway enrichment analysis, co-expression module alignment, drug repurposing, and prediction of effective drug combinations. We demonstrate the "butterfly effect" emerging from a small set of initially differentially expressed genes, rapidly expanding into numerous deregulated cellular processes, signaling pathways, and core machineries as MCL becomes aggressive. We explore pathogenicity-related signaling circuits by detecting common co-expression modules in MCL stages, pointing out, among others, the role of VEGFA and SPARC proteins in MCL progression and recommend further study of precise drug combinations. Our findings highlight the benefit that can be leveraged by such an approach for better understanding pathobiology and identifying high-priority novel diagnostic and prognostic biomarkers, drug targets, and efficacious combination therapies against MCL that should be further validated for their clinical impact. [ABSTRACT FROM AUTHOR]

Rituximab, gemcitabine and oxaliplatin (R-GemOx) has demonstrated to be effective and safe in lymphoma patients. We aimed to determine the maximum tolerated dose (MTD) of oxaliplatin in combination with rituximab and gemcitabine and to explore the efficacy and safety of R-GemOx in relapsed or refractory (r/r) indolent and mantle cell lymphoma (MCL). In this single-arm, phase I/II trial, we enrolled 55 patients with r/r indolent lymphoma and MCL not suitable for autologous stem-cell transplantation. Patients received 4 cycles of R-GemOx. In the dose escalation group, 70 mg/m2 of oxaliplatin was applied and interindividually increased by 10 mg/m2 until the MTD was reached together with fixed doses of rituximab and gemcitabine. At the oxaliplatin MTD, an extension cohort was opened. Primary aim was to detect an overall response rate (ORR) greater than 65% (α = 0.05). Oxaliplatin 70 mg/m2 (MTD) was chosen for the extension cohort after 3 of 6 patients experienced a DLT at 80 mg/m2. Among 46 patients evaluable for the efficacy analysis ORR was 72% (33/46), missing the primary aim of the study (p = 0.21). After a median follow-up of 7.9 years, median PFS and OS were 1.0 and 2.1 years. Most frequent grade ≥ 3 adverse events were cytopenias. R-GemOx induces decent response rates in r/r indolent lymphoma and MCL, though novel targeted therapies have largely replaced chemotherapy in the relapse setting. Particularly in MCL, R-GemOx might be an alternative option in late relapses or as bridging to CAR-T-cells. This study was registered with ClinicalTrials.gov on Aug 4th, 2009, number NCT00954005. [ABSTRACT FROM AUTHOR]

Blastoid or pleomorphic mantle cell lymphoma (B/P-MCL) is characterized by high invasiveness and unfavorable outcomes, which is still a challenge for treating MCL. This retrospective study was performed to comprehensively analyze the clinical, genomic characteristics and treatment options of patients with B/PMCL from multicenter in China. Data were obtained from 693 patients with B/PMCL from three centers in China between April 1999 and December 2019. Seventy-four patients with BMCL (n = 43) or PMCL (n = 31) were included in the analysis. The median age of the cohort was 60.0 years with a male-to-female ratio of 2.89:1. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 44.1% and 46.0%, respectively. Mutations of TP53, ATM, NOTCH1, NOTCH2, NSD2, SMARCA4, CREBBP, KMT2D, FAT1, and TRAF2 genes were the most common genetic changes in B/P-MCL. Progression of disease within 12 months (POD12) could independently predict the poor prognosis of patients with blastoid and pleomorphic variants. Patients with POD12 carried a distinct mutation profile (TP53, SMARCA4, NSD2, NOTCH2, KMT2D, PTPRD, CREBBP, and CDKN2A mutations) compared to patients with non-POD12. First-line high-dose cytosine arabinoside exposure obtained survival benefits in these populations, and BTKi combination therapy as the front-line treatment had somewhat improvement in survival with no significant difference in the statistic. In conclusion, B/P-MCL had inferior outcomes and a distinct genomic profile. Patients with POD12 displayed a distinct mutation profile and a poor prognosis. New therapeutic drugs and clinical trials for B/P-MCL need to be further explored. [ABSTRACT FROM AUTHOR]

Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers. Here, we demonstrated that cyclin D1 is SUMOylated, and we identified Itch as a specific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and proteasome degradation of cyclin D1. We generated cyclin D1 mutant mice with mutations in the SUMOylation site, phosphorylation site, or both sites of cyclin D1, and found that double mutant mice developed a Mantle cell lymphoma (MCL)-like phenotype. We showed that arsenic trioxide (ATO) enhances cyclin D1 SUMOylation-mediated degradation through inhibition of cyclin D1 deSUMOylation enzymes, leading to MCL cell apoptosis. Treatment of severe combined immunodeficiency (SCID) mice grafted with MCL cells with ATO resulted in a significant reduction in tumor growth. In this study, we provide novel insights into the mechanisms of MCL tumor development and cyclin D1 regulation and discover a new strategy for MCL treatment. Steady-state protein levels of cyclin D1 are controlled by phosphorylation- and SUMOylation-mediated proteasome degradation. Inhibition of cyclin D1 degradation leads to B lymphocyte transformation and develops Mantle cell lymphoma-like phenotype. [Display omitted] [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Blastoid variant‐mantle cell lymphoma (BV‐MCL) represents an aggressive subset of patients with no established standard of care treatment approach. Methods We performed a retrospective analysis of the clinical characteristics and outcomes of 17 de novo BV‐MCL patients treated at our institution between May 2009 and September 2023. In addition, we reviewed the literature supporting 2nd/3rd generation Bruton's Tyrosine‐kinase (BTKi)‐based therapies for upfront management. Results The complete response rate to frontline and salvage therapy was 66.7% and 25%, respectively. Two‐year overall survival (OS) was low at 62.5% (95% CI, 34.7%–81.1%). Variables associated with higher OS included receipt of consolidative HSCT (p = 0.017), TP53‐wild type (p = 0.031), intermediate‐ versus high‐risk Mantle Cell Lymphoma Prognostic Index score (p = 0.026), and achieving complete response with induction therapy (p = 0.027). Discussion Treatment outcomes with chemo‐immunotherapy in BV‐MCL patients are poor, especially among TP53‐mutated patients. Recent findings describing positive outcomes with novel BTKi‐based therapies are encouraging and should be considered in this high‐risk population.

This letter to the editor discusses a rare case of acute macular neuroretinopathy (AMN) as an atypical immune effector cell-associated neurotoxicity syndrome (ICANS) manifestation following CAR-T cell infusion. The patient, a 64-year-old woman with refractory mantle cell lymphoma, developed ocular symptoms after CAR-T cell therapy, including vision loss and floaters. Treatment with anakinra and dexamethasone led to symptom improvement, suggesting a potential lifelong adverse event related to CAR-T infusion. Ophthalmologists should be involved in cases of ocular symptoms post-CAR-T infusion, especially when accompanied by classical ICANS manifestations. [Extracted from the article]

This document discusses the diagnosis of lymphoma through cytology, which involves examining cells extracted from the body. The process includes sample collection, preparation of samples, microscopic examination, immunocytochemistry, flow cytometry, and molecular tests. The document emphasizes the importance of using ancillary techniques to differentiate between different causes of lymphocyte-rich effusions. It also mentions that B-cell lymphomas can manifest as effusions, particularly in advanced stage disease. The document provides a case history and includes a morphology quiz with answers. [Extracted from the article]

Abstract Inhibitors of Bruton’s tyrosine kinase (BTKi) and chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 are paradigm-shifting advances in treating patients with aggressive mantle cell lymphoma (MCL). However, clinical relapses following BTKi and CD19-directed CAR-T treatments are a fast-growing medical challenge. Development of novel therapies to overcome BTKi resistance (BTKi-R) and BTKi-CAR-T dual resistance (Dual-R) are urgently needed. Our single-cell RNA sequencing data revealed major transcriptomic reprogramming, with great enrichment of MYC-targets evolving as resistance to these therapies developed. Interestingly, cyclin-dependent kinase 9 (CDK9), a critical component of the positive transcription elongation factor-b complex, was among the top upregulated genes in Dual-R vs. BTKi-R samples. We therefore hypothesized that targeting CDK9 may turn off MYC-driven tumor survival and drug resistance. Enitociclib (formerly VIP152) is a selective CDK9 inhibitor whose potency against MCL has not been assessed. In this study, we found that enitociclib was highly potent in targeting lymphoma cells, with the half-maximal inhibitory concentration (IC50) ranging from 32 to 172 nM in MCL and diffuse large B-cell lymphoma cell lines. It inhibited CDK9 phosphorylation and downstream events including de novo synthesis of the short-lived proteins c-MYC, MCL-1, and cyclin D1, and induced apoptosis in a caspase-3-dependent manner. Enitociclib potently inhibited in vivo tumor growth of cell line-derived and patient-derived xenografts having therapeutic resistance. Our data demonstrate the potency of enitociclib in overcoming therapeutic resistance in MCL models and provide evidence in favor of its clinical investigation.

Juan-Manuel Sancho,1 Marc Sorigué,1 Eva Rubio-Azpeitia2 1Clinical Hematology Department, ICO-IJC-Hospital Germans Trias I Pujol. Badalona, Universitat Autònoma de Barcelona, Barcelona, Spain; 2Medical Department-Hematology, Janssen-Cilag, S.A, Madrid, SpainCorrespondence: Eva Rubio-Azpeitia, Johnson and Johnson SA, Medical Affairs Hematology, Paseo de las Doce Estrellas, 5-7, Madrid, Spain, Email eva.rubioazpeitia@gmail.comIntroduction: Mantle cell lymphoma (MCL) is an incurable disease with an aggressive clinical course, and most patients eventually relapse after chemotherapy. Targeted therapies developed for relapsed/refractory MCL have been approved based on clinical trial data. However, real-world setting data are scarce and scattered.Areas Covered: This systematic review aimed to collect, synthesize, and describe the characteristics and treatment outcomes of patients with relapsed/refractory MCL after receiving a second or subsequent line of therapy in the real-world setting.Expert Opinion: R/R MCL is clinically and biologically heterogeneous and still represents a therapeutic challenge, with high-risk and early relapsed patients remaining an unmet medical need. This systematic review is limited by the quality of the available data and the difficulty of comparing outcomes in R/R MCL due to the heterogeneity of the disease, but the results suggest that covalent BTKis should be positioned as second-line therapy, followed by CAR T-cells in BTK-i-relapsed patients. Chemo-free and combination therapies with established chemoimmunotherapy backbones in the relapsed and front-line settings have been recently developed, and front-line options are being improved to move targeted and cellular therapies to earlier lines, including front-line therapy, in elderly and younger fit patients. In the upcoming years, many new targeted agents will play an important role and will be incorporated to the routine practice as their sequence, and outcomes in unselected patients are determined.Keywords: CAR-T cells, ibrutinib, mantle cell lymphoma, real-world evidence, relapsed/refractory mantle cell lymphoma (R/R MCL), treatment efficacy

Abstract Introduction Mantle cell lymphoma is a rare lymphoma of the gastrointestinal tract that may present as multiple lymphomatous polyposis. We report a case of lymphomatous polyposis with a review of the literature. Case report A 56-year-old man of Black ethnicity and Ivorian nationality with no relevant past medical history, consulted for a sudden onset symptoms of gastrointestinal obstruction, which evolved over 2 days. Macroscopic examination revealed the presence of multiple polyploid formations of the colonic mucosa. Histology showed diffuse lymphomatous proliferation of submucosa consisting off small lymphoid cells with a hyperchromatic crenelated nucleus, suggesting lymphomatous polyposis. Immunohistochemical examination showed expression by the tumor cells of antibodies to CD20, CD5, Bcl2, and cyclin D1. They did not express antibodies to CD10 and CD23. The Ki67 proliferation index was 25%. We have thus retained the diagnosis of mantle cell lymphomatous polyposis. Conclusion Multiple lymphomatous polyposis is a rare entity characterized by the presence of numerous gastrointestinal polyploid lesions sometimes involving several segments of the gastrointestinal tract. Typical lymphoma presenting as lymphomatous polyposis is mantle cell lymphoma; although, other tumors may have this aspect.

Abstract Background The combination of rituximab and chemotherapy is a first-line treatment for patients with B-cell non-Hodgkin lymphoma. Lenalidomide is an immunomodulatory drug that has shown promising properties and activity in a variety of hematological malignancies. This study evaluated the efficacy and safety of lenalidomide-based regimens in the treatment of B-cell non-Hodgkin lymphoma. Methods The PubMed, Science Direct, ClinicalTrials.gov, and Web of Science databases were searched for relevant studies published up to May 2022. Studies with patients diagnosed with non-Hodgkin B-cell lymphoma, who were randomly assigned to a lenalidomide treatment group or a non-lenalidomide control group were considered for inclusion in this review and meta-analysis. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of the time-to-event outcomes and risk ratios (RRs) with 95% CIs of dichotomous data were estimated. Results A total of 3593 patients from 10 studies were evaluated. The results of the pooled analysis indicated that the lenalidomide-based regimen was associated with prolonged overall survival (HR, 0.85; 95% CI 0.74–0.97; P = 0.02) and progression-free survival (HR, 0.70; 95% CI 0.57–0.88; P = 0.002). Significant differences were found in the overall response rate (RR, 1.18; 95% CI 1.04–1.33; P = 0.01) and complete response rate (RR, 1.18; 95% CI 1.00–1.39; P = 0.05) between the treatment and control groups. Conclusions Lenalidomide appears to be a promising therapeutic agent that offers the possibility of a novel combination of chemotherapy free regimen for patients with B-cell non-Hodgkin lymphoma.

Background Blastoid mantle cell lymphoma (B-MCL) is a rare aggressive lymphoma. It is characterized by blastoid morphology with high proliferation and inconsistent immunohistochemistry (IHC), making it a diagnostic challenge for the pathologist. Methods This is a retrospective analytical cohort study. We reviewed biopsy confirmed cases of B-MCL diagnosed over a period of 10 years (January 2012 to December 2022). The clinical presentation, histopathological and IHC findings, treatment received, and survival outcomes were studied. Randomly selected cases of classic MCL (n=12), diagnosed during the same period served as controls. Results A total of 12 cases were studied. Four cases were transformed from previously diagnosed MCL; 8 cases arose de novo. Mean age was 61.17 years and the male: female ratio was 5:1. Half of the cases showed extra nodal extension and 81.8% had bone marrow involvement. Gastrointestinal tract was the most common site of extra nodal involvement. Histopathological examination showed diffuse involvement of the lymph node with medium sized cells. On immunohistochemistry, one of the cases showed loss of CD5 expression while the other had aberrant CD10 expression. Mean Ki-67 index was 58.09% in the cases and 16.33% in controls and was statistically significant ( p=0.005). The median overall survival (OS) for cases was 2 years vs 8 years in controls. The p53 over expression (>30% nuclear positivity) was seen in 66.6% cases (4/6). Conclusion There are several factors that contribute to the aggressiveness of B-MCL, and new treatment approaches might be required to improve patient outcomes.

Inhibitors of Bruton's tyrosine kinase (BTKi) and chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 are paradigm-shifting advances in treating patients with aggressive mantle cell lymphoma (MCL). However, clinical relapses following BTKi and CD19-directed CAR-T treatments are a fast-growing medical challenge. Development of novel therapies to overcome BTKi resistance (BTKi-R) and BTKi-CAR-T dual resistance (Dual-R) are urgently needed. Our single-cell RNA sequencing data revealed major transcriptomic reprogramming, with great enrichment of MYC-targets evolving as resistance to these therapies developed. Interestingly, cyclin-dependent kinase 9 (CDK9), a critical component of the positive transcription elongation factor-b complex, was among the top upregulated genes in Dual-R vs. BTKi-R samples. We therefore hypothesized that targeting CDK9 may turn off MYC-driven tumor survival and drug resistance. Enitociclib (formerly VIP152) is a selective CDK9 inhibitor whose potency against MCL has not been assessed. In this study, we found that enitociclib was highly potent in targeting lymphoma cells, with the half-maximal inhibitory concentration (IC50) ranging from 32 to 172 nM in MCL and diffuse large B-cell lymphoma cell lines. It inhibited CDK9 phosphorylation and downstream events including de novo synthesis of the short-lived proteins c-MYC, MCL-1, and cyclin D1, and induced apoptosis in a caspase-3-dependent manner. Enitociclib potently inhibited in vivo tumor growth of cell line-derived and patient-derived xenografts having therapeutic resistance. Our data demonstrate the potency of enitociclib in overcoming therapeutic resistance in MCL models and provide evidence in favor of its clinical investigation. [ABSTRACT FROM AUTHOR]

Splenic rupture and hematoma are significant complications that can occur in patients with non-Hodgkin lymphoma (NHL). Understanding these associated complications is essential for optimal patient management and enhanced patient outcomes. Histopathological and immunohistochemical analyses are crucial in diagnosing NHL and assessing splenic involvement. In this study, a judicial autopsy had been requested by the Prosecutor's Office for a malpractice claim due to a fall in the hospital. In the Emergency Department, a 72-year-old man fell from a gurney and reported sustaining a wound to his forehead. No other symptoms were reported. A face and brain CT scan showed no abnormalities. Nine days after discharge, the patient presented with abdominal pain. An abdominal CT revealed splenic rupture and hemoperitoneum. The patient underwent open splenectomy but showed signs of hemodynamic shock and subsequently died. The evidence from the autopsy allowed us to diagnose mantle cell non-Hodgkin lymphoma with spleen involvement, previously unknown. Histopathological and immunohistochemical analyses were performed to assess the diagnosis of splenic rupture and estimate its timing. The findings strongly suggest that the splenic rupture was associated with the patient's fall and the pre-existing malignancy. This case highlights the importance of considering an underlying hematological malignancy when investigating delayed splenic rupture. An immunohistochemical study of spleen samples allowed the timing of splenic hematoma and rupture to be assessed, leading to the establishment of a causal relationship with trauma. [ABSTRACT FROM AUTHOR]

Numerous variable selection techniques have been developed for complete high-dimensional data but very few of them for censored data. The techniques for complete data must be modified if censoring is present. In this paper, we consider the variable selection technique for accelerated failure time (AFT) models by extending the ranking-based variable selection (RBVS) algorithm and its iterative procedure as proposed in the work of Baranowski et al. through the Stute's weighted least square technique. Simulation studies are conducted to demonstrate the performance of the proposed methods. We further illustrate the performance of this method with a mantle cell lymphoma microarray example. When there is no correlation among the covariates, the proposed method outperforms the iterative sure independence screening and stability selection methods in terms of overall performance for high-dimensional data. Real data analysis also suggests that the proposed method can be chosen for high-dimensional censored data analysis in parallel to other methods in the literature. [ABSTRACT FROM AUTHOR]

We herein report a middle-aged gentleman who initially presented with ocular adnexal mantle cell lymphoma (MCL) on the right eyelid. The lesion was excised and the patient was treated with radiation therapy. During the initial presentation, a PET CT was performed and did not reveal disease involvement beyond the eyelid. The patient presented 3 months later with ocular adnexal MCL of the contralateral eye. Re-evaluation using PET CT revealed a slight increase in the uptake in several lymph nodes and the spleen, which, after biopsy, confirmed systemic MCL. The patient was started on six cycles of chemotherapy. The patient also underwent autologous hematopoietic stem cell transplant. Approximately 80% of primary ocular adnexal lymphomas are B-cell in origin, with MCL being the rarest subtype constituting only 5% of B-cell ocular adnexal lymphomas. Despite its rarity, it is crucial for clinicians to detect the entity early and ensure rapid initiation of appropriate therapy. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Patients presenting with abdominal pain and retroperitoneal mass in radiographic images may be in the early stages of primary adrenal mantle cell lymphoma, which requires histological studies for a definite diagnosis. This report presents a 37‐year‐old woman complaining of ambiguous abdominal pain, with imaging findings revealing a retroperitoneal abdominal mass on the left side of the aorta, and a possible diagnosis of non‐functional retroperitoneal paraganglioma. Total laparoscopic excision was performed. Surprisingly, histological examinations revealed features in favor of mantle cell lymphoma. [ABSTRACT FROM AUTHOR]

To explore the optimal treatment for young patients with untreated mantle cell lymphoma (MCL), we compared the efficacy and safety of R-CHOP/R-DHAP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone/rituximab, dexamethasone, cytarabine and cisplatin) and R-BAP (rituximab, bendamustine, cytarabine, and prednisone) plus BTK (Bruton's tyrosine kinase) inhibitors in newly diagnosed patients. Eighty-three young patients (≤ 65 years old) with newly diagnosed MCL admitted to the First Affiliated Hospital of Zhengzhou University from January 1, 2014, to June 1, 2023, using R-CHOP/R-DHAP or R-BAP plus BTK inhibitor were assessed in this study. The median age at presentation was 60 (42–65) years in 83 patients, including 64 males and 19 females; 59 were treated with R-CHOP/R-DHAP regimen chemotherapy, and 24 were treated with R-BAP in combination with the BTK inhibitor regimen. The median follow-up was 17 months (2–86 months) in 83 patients, and the median PFS (progression-free survival) time was not reached. The CRR (complete response rate) of the R-BAP group was higher than that of the R-CHOP/R-DHAP group (87.5% vs. 54.2%, P = 0.005). The ORR (overall response rate) was not significantly different between the two groups (ORR: 91.7% vs. 84.7%, P = 0.497). The PFS (progression-free survival) of the R-BAP group was longer than that of the R-CHOP/R-DHAP group (P = 0.013), whereas OS was not significantly different between the two groups (P = 0.499). The most common adverse effect in both groups was hematotoxicity, with a higher incidence of grade 3–4 lymphopenia and grade 3–4 thrombocytopenia in the R-BAP group than in the R-CHOP/R-DHAP group (P = 0.015 and P = 0.039). Male sex (HR = 4.257, P = 0.013), LDH (lactate dehydrogenase) ≥ 245 U/L (HR = 3.221, P = 0.012), pleomorphic-blastoid (HR = 2.802, P = 0.043) and R-CHOP/R-DHAP regimen (HR = 7.704, P = 0.047) were independent risk factors for PFS. Ki67 ≥ 30% (HR = 8.539, P = 0.005) was an independent risk factor for OS. First-line treatment with R-BAP in combination with BTK inhibitor improved CRR and prolonged PFS in young patients with mantle cell lymphoma and adverse events were tolerable. [ABSTRACT FROM AUTHOR]

Mucosal‐associated invariant T‐cells (MAIT) are unconventional T‐cells with cytotoxic and pro‐inflammatory properties. Previous research has reported contradictory findings on their role in cancerogenesis with data being even scarcer in haematological malignancies. Here, we report the results of a systematic analysis of MAIT cells in treatment‐naïve patients with a broad range of haematological malignancies. We analysed peripheral blood of 204 patients and 50 healthy subjects. The pool of haematological patients had a statistically significant lower both the absolute value (median values, 0.01 × 109/L vs. 0.05 × 109/L) of MAIT cells and their percentage (median values 0.94% vs. 2.56%) among T‐cells compared to the control group. Separate analysis showed that the decrease in the absolute number of MAIT cells is significant in patients with acute myeloid leukaemia, myeloproliferative neoplasms, plasma cell myeloma, B‐cell non‐Hodgkin lymphomas, otherwise not specified, diffuse large B‐cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma compared to the control population. Furthermore, in haematological malignancies, MAIT cells overexpress PD‐1 (average values, 51.7% vs. 6.7%), HLA‐DR (average values, 40.2% vs. 7%), CD38 (average values, 25.9% vs. 4.9%) and CD69 (average values, 40.2% vs. 9.2%). Similar results were obtained when comparing patients with individual malignancies to the control population. Our data show that the depletion of circulating MAIT cells is a common observation in a broad spectrum of haematological malignancies. In addition to their reduced numbers, MAIT cells acquire an activated/exhausted phenotype. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapies have dramatically improved treatment outcomes for patients with relapsed or refractory B-cell acute lymphoblastic leukemia, large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma. Despite unprecedented efficacy, treatment with CAR T cell therapies can cause a multitude of adverse effects which require monitoring and management at specialized centers and contribute to morbidity and non-relapse mortality. Such toxicities include cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, neurotoxicity distinct from ICANS, immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, and immune effector cell-associated hematotoxicity that can lead to prolonged cytopenias and infectious complications. This review will discuss the current understanding of the underlying pathophysiologic mechanisms and provide guidelines for the grading and management of such toxicities. [ABSTRACT FROM AUTHOR]

Digital pathology involves the conversion of histology slides into digital format to generate high-resolution images. Tissue classification, particularly for identifying common types of non-Hodgkin lymphomas like mantle cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia, is a crucial application of this technology. Due to the complexity of these lymphomas, pathologists often encounter challenges in their diagnosis. However, the limited availability of image data in the dataset poses a significant challenge. To solve this issue, we present a new technique for augmenting the dataset and enabling more efficient model training. In this article, we propose a technique capable of approaching lymphoma images. Our idea is to generate lymphoma images by adding a segmented image. The reference images are taken from the available dataset. We use two re neural networks. The first neural network is image-to-image translation, a technique used to transform the appearance or style of images, particularly adversarial neural networks, facilitates this process by using inputs from the source domain to produce images that closely match the target domain. The second neural network, we use an improved convolutional neural network (CNN) algorithm for classifying non-Hodgkin lymphomas. Trained on this augmented dataset, the proposed model achieves a classification accuracy of 99.91%. This precision is higher than that reported by Khelil et al. in their study. Moreover, we acknowledge the ethical implications of generating synthetic medical images and propose guidelines for ensuring the ethical conduct of our proposed technique. [ABSTRACT FROM AUTHOR]

Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT. The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II–IV mantle cell lymphoma, aged 18–65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m2 on day 1, intravenous doxorubicin 50 mg/m2 on day 1, intravenous vincristine 1·4 mg/m2 on day 1, and oral prednisone 100 mg on days 1–5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1–4, intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1–19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov , NCT02858258. Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84–92) versus 72% (67–79; hazard ratio 0·52 [one-sided 98·3% CI 0–0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67–79) versus 86% (82–91; hazard ratio 1·77 [one-sided 98·3% CI 0–3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3–5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3–5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238). Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined. Janssen and Leukemia & Lymphoma Society. [ABSTRACT FROM AUTHOR]

Simple Summary: Discussed here is a review of the changing landscape in the treatment of mantle cell lymphoma (MCL) regarding the emergence and use of targeted therapy. Targeted therapy is the use of small molecules designed to interrupt specific mechanisms within the cancer cell to exert anti-tumor efficacy. Targeting such mechanisms relies upon our understanding of what makes a cancer cell malignant. MCL is a difficult-to-treat lymphoid cancer that relies heavily upon constitutive intracellular signaling, promoting its growth and survival. The mainstay of MCL treatment has been to treat it with cytotoxic chemotherapy; however, targeted therapies have allowed for improved treatment outcomes and continue to change the way we manage this disease. This review aims to describe what targeted therapies are being utilized in MCL treatment and their mechanisms of action, safety, and efficacy, as well as future directions for their use in MCL treatment. Mantle cell lymphoma (MCL) is a rare, heterogeneous B-cell non-Hodgkin's lymphoma. The standard front-line treatment utilizes chemotherapy, often followed by consolidation with an autologous hematopoietic cell transplant; however, in most patients, the lymphoma will recur and require subsequent treatments. Additionally, mantle cell lymphoma primarily affects older patients and is frequently chemotherapy-resistant, which has further fostered the necessity for new, chemotherapy-free treatment options. In the past decade, targeted therapies in mantle cell lymphoma have been practice-changing as the treatment paradigm shifts further away from relying primarily on cytotoxic agents. Here, we will review the pathophysiology of mantle cell lymphoma and discuss the emergence of targeted, chemotherapy-free treatments aimed at disrupting the abnormal biology driving its lymphomagenesis. Treatments targeting the constitutive activation of NF-kB, Bruton's Tyrosine Kinase signaling, and anti-apoptosis will be the primary focus as we discuss their clinical data and toxicities. Our review will also focus primarily on the emergence and use of targeted therapies in the relapsed/refractory setting but will also discuss the emergence of their use in front-line therapy and in combination with other agents. [ABSTRACT FROM AUTHOR]

Background: Mantle cell lymphoma (MCL) is a type of B‐cell lymphoma that is currently incurable. Pirtobrutinib shows promising response rates in heavily pretreated MCL patients according to the approval study, but the real‐world data are scarce. Methods: In this study, we retrospectively analyzed the efficacy and safety profile of pirtobrutinib in 10 relapsed/refractory MCL patients from compassionate use program (CUP). Results: On average, the patients underwent three lines of systemic therapy prior to pirtobrutinib and were predominantly BTKi exposed (9/10). The best overall response rate (BORR) was 67%. In a median follow‐up of 8.6 months, the mean duration of response (DOR), progression‐free survival (PFS), and overall survival (OS) were not reached. No new safety signals were documented. Conclusions: In summary, pirtobrutinib represented a safe and effective treatment option in a small real‐world population. [ABSTRACT FROM AUTHOR]

Summary: The combination of the phosphatidylinositol 3‐kinase delta (PI3Kδ) inhibitor zandelisib with the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib was hypothesized to be synergistic and prevent resistance to single‐agent therapy. This phase 1 study (NCT02914938) included a dose‐finding stage in patients with relapsed/refractory (R/R) B‐cell malignancies (n = 20) and disease‐specific expansion cohorts in follicular lymphoma (FL; n = 31) or mantle cell lymphoma (MCL; n = 19). The recommended phase 2 dose was zandelisib 60 mg on Days 1–7 plus zanubrutinib 80 mg twice daily continuously in 28‐day cycle. In the total population, the most common adverse events (AEs; all grades/grade 3–4) were neutropenia (35%/24%), diarrhoea (33%/2%), thrombocytopenia (32%/8%), anaemia (27%/8%), increased creatinine (25%/0%), contusion (21%/0%), fatigue (21%/2%), nausea (21%/2%) and increased aspartate aminotransferase (24%/6%). Three patients discontinued due to AEs. The overall response rate was 87% (complete response [CR] = 33%) for FL and 74% (CR = 47%) for MCL. The median duration of response and progression‐free survival (PFS) were not reached in either group. The estimated 1‐year PFS was 72.3% (95% confidence interval [CI], 51.9–85.1) for FL and 56.3% (95% CI, 28.9–76.7) for MCL (median follow‐up: 16.5 and 10.9 months respectively). Zandelisib plus zanubrutinib was associated with high response rates and no increased toxicity compared to either agent alone. [ABSTRACT FROM AUTHOR]

Summary: We report the outcome of 563 cases of newly diagnosed lymphoma registered in 2019–2021, including 176 cases (31.2%) of Hodgkin lymphoma (HL), 130 (23.1%) of diffuse large B‐cell lymphoma (DLBCL), 28 (5%) of follicular lymphoma (FL), 16 (2.9%) of mantle cell lymphoma (MCL) and 20 (3.5%) of peripheral T‐cell lymphoma (PTCL). After a median follow‐up of 30.1 months (95% CI: 28.8–31.3), the 3‐year overall survival rates were 95%, 83%, 86%, 100%, 61% and 42% for HL, DLBCL, CLL, FL, MCL and PTCL respectively. These data offer valuable information on the curability of lymphoma patients in Ukraine, in a real‐world setting. [ABSTRACT FROM AUTHOR]

Acalabrutinib studies have limited Asian participation. This phase 1/2 study (NCT03932331) assessed acalabrutinib in Chinese patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL). Primary endpoint was blinded independent central review (BICR)-assessed overall response rate (ORR). Overall, 34 patients were enrolled. Most patients were men (88%); median age was 63 years and 59% had ≥3 prior treatments. Median treatment duration was 14 months (range, 1–24). Any-grade adverse events (AEs) and grade ≥3 AEs occurred in 85.3% and 44.1% of patients, respectively. AEs causing treatment discontinuation were aplastic anemia, thrombocytopenia, and gastrointestinal infection (n = 1 each). Fatal AEs occurred in 2 patients (aplastic anemia and multiple organ dysfunction syndrome [n = 1 each]). BICR-assessed ORR was 82.4% (95% confidence interval [CI]: 65.5, 93.2); 12 (35.3%) patients achieved complete response. Estimated 12-month OS was 84.5% (95% CI: 66.6, 93.3). Acalabrutinib yielded tolerable safety and high response rates in Chinese patients with R/R MCL. [ABSTRACT FROM AUTHOR]

This document presents a case series of four patients with relapsed mantle cell lymphoma (MCL) and central nervous system (CNS) involvement who were treated with a combination of bridging therapy, CAR-T cell therapy (BA), and Bruton's tyrosine kinase inhibitors (BTKi). The patients showed remission of CNS disease after BA, with a complete response rate of 75%. The use of BTKi as bridging therapy and maintenance treatment following BA was found to be effective and safe, with no severe side effects reported. These findings suggest that this treatment approach may be a promising option for patients with relapsed MCL and CNS involvement. [Extracted from the article]

This article discusses a rare case of secondary histiocytic sarcoma (HS) that developed rapidly following chimeric antigen receptor T-cell (CAR-T) therapy for relapsed diffuse large B-cell lymphoma (DLBCL). The patient initially presented with DLBCL and underwent various treatments, including CAR-T therapy, which resulted in a partial remission. However, PET/CT scans later revealed progression of the disease, and biopsies confirmed the presence of HS. Genetic testing showed a clonal relationship between the DLBCL and HS, supporting the hypothesis of divergent evolution. The article suggests that CAR-T therapy may have played a role in the development of HS, although further research is needed to confirm this. [Extracted from the article]

This document summarizes a study on the outcomes of patients with mantle cell lymphoma (MCL) who received different treatments. The study found that the overall survival rates at two and four years were 91% and 68% respectively. Patients who received rituximab maintenance therapy had higher survival rates compared to those who did not. The blastoid variant of MCL was associated with lower survival rates. The study also found that autologous hematopoietic stem cell transplant (HSCT) in an outpatient setting was safe and effective. Overall, the study suggests that the best available care, including rituximab maintenance therapy and HSCT, should be provided for MCL patients. [Extracted from the article]

Mantle cell lymphoma (MCL) is an uncommon and incurable B‐cell lymphoma subtype that has an aggressive course. Hepatitis B virus (HBV) infection has been associated with an increased risk for B‐cell lymphomas, and is characterized by distinct clinical and genetic features. Here, we showed that 9.5% of MCL Chinese patients were hepatitis B surface antigen positive (HBsAg+). Compared to HBsAg‐negative (HBsAg−) patients, HBsAg+ MCL patients had a greater incidence of elevated lactate dehydrogenase (LDH), but no difference was observed in the other clinical characteristics, including sex, age, ECOG ps, Ann Arbor stage, MIPI, extranodal involvement and Ki‐67. The HD‐AraC (high‐dose cytarabine) regimen was the main first‐line induction regimen for younger HBsAg+ patients, and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) were used for elderly patients. HBsAg seropositivity was associated with a significantly shorter PFS than HBsAg seronegativity when patients were treated with rituximab or CHOP‐based regimens. Compared with CHOP, the HD‐AraC regimen was associated with longer PFS in HBsAg+ patients. Treatment with a Bruton tyrosine kinase inhibitor (BTKi) alone can also cause HBV reactivation. Among the 74 patients who underwent targeted deep sequencing (TDS), the nonsynonymous mutation load of HBsAg+ MCL patients was greater than that of HBsAg− MCL patients. HDAC1, TRAF5, FGFR4, SMAD2, JAK3, SMC1A, ZAP70, BLM, CDK12, PLCG2, SMO, TP63, NF1, PTPR, EPHA2, RPTOR and FIP1L1 were significantly enriched in HBsAg+ MCL patients. [ABSTRACT FROM AUTHOR]

This editorial discusses the use of Pentixather, a radiopharmaceutical labeled with gallium-68, in the treatment of hematological disorders such as multiple myeloma and lymphomas. The studies reviewed showed that Pentixather radioligand therapy (RLT) was effective and tolerable in heavily pretreated patients, with neutropenia and infections being the most common adverse effects. However, further research and validation through multicenter studies are needed to fully understand the potential of Pentixather RLT in these conditions. Clinical trials are currently underway to investigate the efficacy of different radioligands in managing lymphomatous central nervous system involvement and multiple myeloma. [Extracted from the article]

Introduction: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) often require multiple lines of treatment and have a poor prognosis, particularly after failing covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. Newer treatments such as brexucabtagene autoleucel (brexu-cel, chimeric antigen receptor T cell therapy) and pirtobrutinib (non-covalent BTKi) show promise in improving outcomes. Methods: Without direct comparative evidence, an unanchored matching-adjusted indirect comparison was conducted to estimate the relative treatment effects of brexu-cel and pirtobrutinib for post-cBTKi R/R MCL. Using logistic propensity score models, individual patient-level data from ZUMA-2 brexu-cel-infused population (N = 68) were weighted to match pre-specified clinically relevant prognostic factors based on study-level data from the BRUIN cBTKi pre-treated cohort (N = 90). The base-case model incorporated the five most pertinent factors reported in ≥ 50% of both trial populations: morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplant. A sensitivity analysis additionally incorporated TP53 mutation and Ki-67 proliferation. Relative treatment effects were expressed as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). Results: In the base-case model, brexu-cel was associated with higher rates of objective response (OR 10.39 [95% CI 2.81–38.46]) and complete response (OR 10.11 [95% CI 4.26–24.00]), and improved progression-free survival (HR 0.44 [95% CI 0.25–0.75]), compared to pirtobrutinib. Overall survival and duration of response favored brexu-cel over pirtobrutinib but the differences crossed the bounds for statistical significance. Findings were consistent across the adjusted and unadjusted analyses. Conclusions: Findings suggest that brexu-cel may offer clinically and statistically significant benefits regarding objective response, complete response, and progression-free survival compared to pirtobrutinib among patients with R/R MCL after prior cBTKi therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive overall survival results. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) has a poor prognosis and high relapse rates despite current therapies, necessitating novel treatment regimens. Inhibition of SRC-3 show effectiveness in vivo and in vitro in other B cell lymphomas. Additionally, previous studies have shown that SRC-3 is highly expressed in the lymph nodes of B cell non-Hodgkin's lymphoma patients, suggesting SRC-3 may play a role in the progression of B cell lymphoma. This study aimed to investigate novel SRC-3 inhibitors, SI-10 and SI-12, in mantle cell lymphoma. The cytotoxic effects of SI-10 and SI-12 were evaluated in vitro and demonstrated dose-dependent cytotoxicity in a panel of MCL cell lines. The in vivo efficacy of SI-10 was confirmed in two ibrutinib-resistant models: an immunocompetent disseminated A20 mouse model of B-cell lymphoma and a human PDX model of MCL. Notably, SI-10 treatment also resulted in a significant extension of survival in vivo with low toxicity in both ibrutinib-resistant murine models. We have investigated SI-10 as a novel anti-lymphoma compound via the inhibition of SRC-3 activity. These findings indicate that targeting SRC-3 should be investigated in combination with current clinical therapeutics as a novel strategy to expand the therapeutic index and to improve lymphoma outcomes. [ABSTRACT FROM AUTHOR]

Aims: MNDA (myeloid nuclear differentiation antigen) has been considered as a potential diagnostic marker for marginal zone lymphoma (MZL), but its utility in distinguishing MZL from other B-cell non-Hodgkin lymphomas (B-NHLs) and its clinicopathologic relevance in diffuse large B-cell lymphoma (DLBCL) are ambiguous. We comprehensively investigated MNDA expression in a large series of B-NHLs and evaluated its diagnostic value. Methods: MNDA expression in a cohort of 1293 cases of B-NHLs and 338 cases of reactive lymphoid hyperplasia (RLH) was determined using immunohistochemistry and compared among different types of B-NHL. The clinicopathologic relevance of MNDA in DLBCL was investigated. Results: MNDA was highly expressed in MZLs (437/663, 65.9%), compared with the confined staining in marginal zone B-cells in RLH; whereas neoplastic cells with plasmacytic differentiation lost MNDA expression. MNDA expression was significantly higher in mantle cell lymphoma (MCL, 79.6%, p = 0.006), whereas lower in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, 44.8%, p = 0.001) and lymphoplasmacytic lymphoma (LPL, 25%, p = 0.016), and dramatically lower in follicular lymphoma (FL, 5.2%, p < 0.001), compared with MZL. 29.6% (63/213) of DLBCLs were positive for MNDA. The cases in non-GCB group exhibited a higher rate of MNDA positivity (39.8%) compared to those in GCB group (16.3%) (p < 0.001), and MNDA staining was more frequently observed in DLBCLs with BCL2/MYC double-expression (50%) than those without BCL2/MYC double-expression (24.8%) (p = 0.001). Furthermore, there was a significant correlation between MNDA and CD5 expression in DLBCL (p = 0.036). Conclusions: MNDA was highly expressed in MZL with a potential utility in differential diagnosis between MZL and RLH as well as FL, whereas its value in distinguishing MZL from MCL, CLL/SLL is limited. In addition, MNDA expression in DLBCL was more frequently seen in the non-GCB group and the BCL2/MYC double-expression group, and demonstrated a correlation with CD5, which deserves further investigation. The clinical relevance of MNDA and its correlation with the prognosis of these lymphomas also warrant to be fully elucidated. [ABSTRACT FROM AUTHOR]