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

Chimeric Antigen Receptor T-cell (CAR-T) therapy uses genetically engineered T-cells with specific binding sites. This therapy allows for tumor specificity and durable treatment responses for patients with hematological malignancies. In this review, we study the risk of venous thromboembolism (VTE) associated with CAR-T therapy. We searched the National Institutes of Health library, Cochrane Library Databases, ClinicalTrials.gov database, and medical literature search engines PubMed and Google Scholar for Phase 2 and Phase 3 drug-efficacy and safety trials to determine the aggregate incidence and risk of VTE treated with CAR-T. Of 1127 search results, nine studies were identified and included in our meta-analysis. Of the 1017 patients who received therapy, 805 patients (79.15%) experienced some degree of CRS, and 122 patients (11.9%) experienced severe CRS (higher than grade 3). Only three out of one thousand and seventeen patients were reported to have experienced venous thromboembolism. Our study did not find a statistically significant association between increased VTE incidence (OR = 0.0005, 95% CI [0.0001, 0.0017]) and CRS/ICANS (p < 0.0001). There was a 0.0050 (95% confidence interval [0.0019, 0.0132]) relative risk for VTE. In our study, we did not find a statistically significantly increased risk of developing VTE despite CRS and underlying malignancy, which have been associated with increased risk of VTE. [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]

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]

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]

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]

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]

The B cell receptor (BCR) signaling pathway plays a crucial role in B cell development and contributes to the pathogenesis of B cell neoplasms. In B cell malignancies, the BCR is constitutively active through both ligand-dependent and ligand-independent mechanisms, resulting in continuous Bruton tyrosine kinase (BTK) signaling activation, which provides a survival and proliferation advantage to the neoplastic clone. Among B cell malignancies, those in which the most significant results were obtained by treatment with BTK inhibitors (BTKi) include chronic lymphocytic leukemia, mantle cell lymphoma, lymphoplasmacytic lymphoma, and diffuse large B cell lymphoma. Covalent BTKi (namely ibrutinib, acalabrutinib, and zanubrutinib) functions by irreversibly blocking BTK through covalent binding to the cysteine residue 481 (Cys-481) in the ATP-binding domain. Despite the high efficacy and safety of BTKi treatment, a significant fraction of patients affected by B cell malignancies who are treated with these drugs experience disease relapse. Several mechanisms of resistance to covalent BTKi, including Cys-481 mutations of BTK, have been investigated in B cell malignancies. Non-covalent BTKi, such as pirtobrutinib, have been developed and proven effective in patients carrying both Cys-481-mutated and unmutated BTK. Moreover, targeting BTK with proteolysis-targeting chimeras (PROTACs) represents a promising strategy to overcome resistance to BTKi in B cell neoplasms. [ABSTRACT FROM AUTHOR]

Malignant lymphoma, which impacts the lymphatic system, presents diverse challenges in accurate diagnosis due to its varied subtypes—chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). Lymphoma is a form of cancer that begins in the lymphatic system, impacting lymphocytes, which are a specific type of white blood cell. This research addresses these challenges by proposing ensemble and non-ensemble transfer learning models employing pre-trained weights from VGG16, VGG19, DenseNet201, InceptionV3, and Xception. For the ensemble technique, this paper adopts a stack-based ensemble approach. It is a two-level classification approach and best suited for accuracy improvement. Testing on a multiclass dataset of CLL, FL, and MCL reveals exceptional diagnostic accuracy, with DenseNet201, InceptionV3, and Xception exceeding 90% accuracy. The proposed ensemble model, leveraging InceptionV3 and Xception, achieves an outstanding 99% accuracy over 300 epochs, surpassing previous prediction methods. This study demonstrates the feasibility and efficiency of the proposed approach, showcasing its potential in real-world medical applications for precise lymphoma diagnosis. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) prognosis has significantly improved in recent years; however, the possible survival benefit of new treatment options should be evaluated outside of clinical trials. We investigated 73 consecutive MCL patients managed from 2006 to 2020. For younger patients <65 years old, the median PFS was 72 months and we reported a 2-year, 5-year, and 10-year PFS of 73%, 62%, and 41%; median OS was not reached and we reported a 2-year, 5-year, and 10-year OS of 88%, 82%, and 66%. For patients aged 75 years or older, the median PFS was 36 months and we reported a 2-year, 5-year, and 10-year PFS of 52%, 37%, and 37%; median OS was not reached and we reported a 2-year, 5-year, and 10-year OS of 72%, 55%, and 55%. The median PFS was significantly reduced for patients treated between 2006 and 2010 compared to patients treated between 2011 and 2015 (p = 0.04). Interestingly, there was a trend towards improved OS for patients treated between 2016 and 2020 compared to between 2006 and 2010 and between 2011 and 2015 (5-year OS was 91%, 44%, and 33%). These findings could be due to the introduction of BR as a first-line regimen for elderly patients and to the introduction of ibrutinib as a second-line regimen. [ABSTRACT FROM AUTHOR]

NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca2+-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients. [ABSTRACT FROM AUTHOR]

Bruton tyrosine kinase (BTK) is an essential enzyme in the signaling pathway of the B-cell receptor (BCR) and is vital for the growth and activation of B-cells. Dysfunction of BTK has been linked to different types of B-cell cancers, autoimmune conditions, and inflammatory ailments. Therefore, focusing on BTK has become a hopeful approach in the field of therapeutics. Small-molecule inhibitors of BTK have been developed to selectively inhibit its activity and disrupt B-cell signaling pathways. These inhibitors bind to the active site of BTK and prevent its phosphorylation, leading to the inhibition of downstream signaling cascades. Regulatory authorities have granted approval to treat B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with multiple small-molecule BTK inhibitors. This review offers a comprehensive analysis of the synthesis and clinical application of conventional small-molecule BTK inhibitors at various clinical stages, as well as presents promising prospects for the advancement of new small-molecule BTK inhibitors. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is an intermediate-grade B-cell lymphoma, representing 2.8% of all non-Hodgkin lymphomas in the US. It is associated with t(11;14)(q13; q23), which leads to the overexpression of cyclin D1, consequently promoting cell proliferation. MCL usually expresses CD19, CD20, CD43, surface immunoglobulins, FMC7, BCL2, cyclin D1, CD5, and SOX11. Herein is a case of a 67-year-old male, referred to our facility with shortness of breath, anemia (hemoglobin of 5.3 g/dL), thrombocytopenia (12 × 109/L), and leukocytosis (283 × 109/L). A peripheral blood smear showed marked lymphocytosis with blastoid morphology. Morphologic examination of the bone marrow biopsy revealed a diffuse sheet of blastoid cells expressing CD20 and CD10, but without CD5 or cyclin D1. Given these features, a differential diagnosis of diffuse large B-cell lymphoma (DLBCL) with germinal center derivation, high-grade follicular lymphoma, and Burkitt lymphoma was considered, with the latter not favored due to morphology. Additional studies revealed positive SOX11, and fluorescence in situ hybridization (FISH) studies detected t(11;14). These additional studies supported diagnosis of the blastoid variant of MCL. In conclusion, we present a unique and challenging case of MCL without cyclin D1 or CD5, but with an expression of CD10 and SOX11, along with t(11;14). Pathologists should explicitly consider the blastoid variant of MCL when dealing with mature B-cell neoplasms with blastoid morphology in adults, and utilize a broad panel of ancillary studies, including FISH and SOX11. [ABSTRACT FROM AUTHOR]

Hodgkin's lymphomas (HL) and the majority of non-Hodgkin's lymphomas (NHL) derive from different stages of B-cell differentiation. MicroRNA (miRNA) expression profiles change during lymphopoiesis. Thus, miRNA expression analysis can be used as a reliable diagnostic tool to differentiate tumors. In addition, the identification of miRNA's role in lymphopoiesis impairment is an important fundamental task. The aim of this study was to analyze unique miRNA expression profiles in different types of B-cell lymphomas. We analyzed the expression levels of miRNA-18a, -20a, -96, -182, -183, -26b, -34a, -148b, -9, -150, -451a, -23b, -141, and -128 in lymph nodes (LNs) in the following cancer samples: HL (n = 41), diffuse large B-cell lymphoma (DLBCL) (n = 51), mantle cell lymphoma (MCL) (n = 15), follicular lymphoma (FL) (n = 12), and lymphadenopathy (LA) (n = 37), as well as bone marrow (BM) samples: HL (n = 11), DLBCL (n = 42), MCL (n = 14), FL (n = 16), and non-cancerous blood diseases (NCBD) (n = 43). The real-time RT-PCR method was used for analysis. An increase in BM expression levels of miRNA-26b, -150, and -141 in MCL (p < 0.01) and a decrease in BM levels of the miR-183-96-182 cluster and miRNA-451a in DLBCL (p < 0.01) were observed in comparison to NCBD. We also obtained data on increased LN levels of the miR-183-96-182 cluster in MCL (p < 0.01) and miRNA-18a, miRNA-96, and miRNA-9 in FL (p < 0.01), as well as decreased LN expression of miRNA-150 in DLBCL (p < 0.01), and miRNA-182, miRNA-150, and miRNA-128 in HL (p < 0.01). We showed that miRNA expression profile differs between BM and LNs depending on the type of B-cell lymphoma. This can be due to the effect of the tumor microenvironment. [ABSTRACT FROM AUTHOR]

T lymphoblastic leukemia (T-ALL) is an aggressive haematolymphoid malignancy comprising 15% of acute lymphoblastic leukemia (ALL). Although its prognosis has improved with intensive chemotherapy, the relapse/refractory disease still carries a dismal prognosis. Thus, there is an urgent need to develop novel therapy for T-ALL. Bortezomib, a 26S proteasome inhibitor, is licensed to treat plasma cell myeloma and mantle cell lymphoma. Due to its favorable side effect profile, it is a novel agent of research interest in the treatment of ALL. Despite an increasing number of clinical trials of bortezomib in T-ALL, its detailed mechanistic study in terms of DNA damage, cell cycle, and mitotic catastrophe remains elusive. Moreover, WEE1, a protein kinase overexpressed in ALL and involved in cell-cycle regulation, has been known to be a novel therapeutic target in many cancers. But the role of bortezomib in modulating WEE1 expression in ALL still remains elusive. In this study, we demonstrate the therapeutic efficacy of bortezomib on T-ALL primary samples and cell lines. Our findings reveal that bortezomib treatment induces DNA damage and downregulates WEE1, leading to G2-M cell-cycle progression with damaged DNA. This abnormal mitotic entry induced by bortezomib leads to mitotic catastrophe in T-ALL. In conclusion, our findings dissect the mechanism of action of bortezomib and provide further insights into the use of bortezomib to treat T-ALL. Our findings suggest the possibility of novel combination therapy using proteasome inhibitors together with DNA-damaging agents in the future, which may fill the research gaps and unmet clinical needs in treating ALL. [ABSTRACT FROM AUTHOR]

Non-Hodgkin lymphoma's (NHL) incidence is rising over time, and B cell lymphomas comprise the majority of lymphomas. The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue 1 (Akt)/mammalian target of the rapamycin (mTOR) signaling pathway plays a critical role in a variety of cellular processes, such as cell proliferation and survival. Its role in lymphomagenesis is confirmed in many different types of B cell lymphomas. This review is mainly focused on the PI3K/v-akt/mTOR pathway-related oncogenic mechanisms in B cell NHLs with an emphasis on common B cell lymphoma types [diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL)]. Furthermore, it summarizes the literature regarding the clinical applications of the mTOR inhibitors temsirolimus and everolimus in B cell NHLs, which have been tested in a range of clinical trials enrolling patients with B cell malignancies, either as monotherapy or in combination with other agents or regimens. [ABSTRACT FROM AUTHOR]

Background: Extranodal non-Hodgkin lymphoma (NHL) is more prevalent in the gastrointestinal (GI) tract than in other sites. This study aimed to determine the endoscopic characteristics of primary gastrointestinal non-Hodgkin lymphomas. Methods: We investigated 140 patients from three tertiary referral hospitals with primary malignant lymphoma of the gastrointestinal tract. Characteristics of the lesions were evaluated and analyzed using image-enhanced endoscopy, endoscopic ultrasound, and histopathology. Results: The median age was 60.5 (range: 11–99), and 59 (42.1%) were female. The most frequent complaint was abdominal pain (74.3%), followed by bloody feces (10%) and diarrhea (2.9%). B symptoms were observed in 15 (10.7%) patients. GI obstruction was the most common complication (10.0%), followed by hemorrhage (7.9%) and perforation (1.5%). Regarding endoscopic findings, the identified sites were the following: the stomach (61.4%), colon (10%), small intestine (10%), ileocecum (8.6%), rectum (6.4%), and duodenum (3.6%). Diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma are most prevalent in the stomach. Helicobacter pylori was identified in 46 cases (39.0%), with MALT lymphoma being the most infected subtype. Nearly all gastrointestinal non-Hodgkin lymphomas manifested as superficial type (25–59.6%) and ulcer type (15.6–50%) under endoscopy. We found that fungating type and protruding with ulcer type were more frequent types of aggressive lymphomas (diffuse large B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma) compared to the indolent types (MALT lymphoma, follicular lymphoma, duodenal-type follicular lymphoma, and small lymphocytic lymphoma) (p < 0.05). Conclusions: This study showed that most subtypes of gastrointestinal non-Hodgkin lymphomas exhibited same endoscopic features (superficial type and ulcer type). Aggressive gastrointestinal non-Hodgkin lymphomas (diffuse large B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma) were highly suspected when fungating lesions and protruding with ulcer lesions were encountered under endoscopy. Endoscopists should be aware of the connection between enhanced endoscopic characteristics and histological varieties of gastrointestinal lymphoma to improve diagnosis. [ABSTRACT FROM AUTHOR]

The diagnosis and treatment of lymphoid neoplasms have undergone a continuously progressive positive change in the last three decades, with accelerated progress in the previous decade due to the advent of genomics in cancer diagnosis. Significantly, there has been an increasing emphasis on integrating molecular genetics with clinical, morphologic, immunophenotypic, and cytogenetic evaluation for diagnosis. As we think of moving forward with further advances in the genomics era, it is first helpful to understand our current state of knowledge and how we achieved it in the challenging and complex field of lymphoid neoplasms, which comprise very heterogeneous neoplastic diseases in children and adults, including clinically acute lymphoblastic leukemias (ALLs) arising from precursor lymphoid cells and clinically indolent and aggressive lymphomas arising from mature lymphoid cells. This work aims to provide an overview of the historical evolution and the current state of knowledge to anyone interested in the field of lymphoid neoplasms, including students, physicians, and researchers. Therefore, I discuss this complex topic in three review manuscripts, designated Parts 1–3. In Part 1, I explain the basis of the diagnostic classification of lymphoid neoplasms and its evolution up to the current fifth edition of the World Health Organization classification of hematolymphoid neoplasms, and the crucial importance of diagnostic tumor classifications in achieving and advancing patient care and precision medicine. In the second and third manuscripts, I discuss current diagnostic considerations for B-ALL and T-ALL (Part 2) and common indolent and aggressive mature leukemias/lymphomas (Part 3), including significant updates in the WHO 2022 classification, newly described entities, and concepts, including genetic predisposition to ALLs and lymphomas, and throughout emphasizing the essential integration of molecular genetics with clinical, morphologic (pathologic), immunophenotypic, and cytogenetic evaluation, as is required for precise diagnosis of the type of lymphoma/leukemia in any patient. [ABSTRACT FROM AUTHOR]

Simple Summary: Pathologists working with skin biopsies of different hematological malignancies via blastic morphology need to consider a broad spectrum of diseases that, despite similar blastic features, have different outcomes and require distinct therapeutic strategies. Therefore, a precise and prompt diagnosis is critical for patient management. The aim of our paper is to discuss, in detail, the clinical and pathological features of lymphoblastic lymphoma of B- or T-cell origin and mantle cell lymphoma, in particular its aggressive blastoid variant. Although mantle cell lymphoma rarely involves the skin, its blastoid variant is commonly encountered in cutaneous infiltrates, possibly due to the increased tendency of aggressive subtypes for skin involvement. When aggressive lymphomas are detected at cutaneous sites, a complete systemic work-up is critical. Besides blastoid mantle cell lymphoma and lymphoblastic lymphoma, other hematological malignancies with blastic characteristics and skin involvement are discussed. Hematological neoplasms sharing a blastic morphology may involve the skin. The skin may be either the primary site of occurrence of hematological malignancies with blastic features or cutaneous lesions are the first manifestation of an underlying systemic malignancy. The assessment of skin biopsies of hematological neoplasms with blastic features poses diagnostic problems and requires expert hematopathologists considering a wide range of differential diagnoses. The precise diagnosis of diseases sharing blastic features but with different outcomes and requiring distinct therapies is essential for patient management. The present paper mainly focuses on cutaneous involvement of the blastoid variant of mantle cell lymphoma and lymphoblastic lymphoma of B-cell or T-cell origin. The relevant literature has been reviewed and the clinical aspects, pathological features, prognosis, and therapy of both blastoid mantle cell lymphoma and lymphoblastic lymphoma involving the skin are discussed. A focus on other hematological entities with blastic features, which may involve the skin, to be taken into consideration in differential diagnosis is also given. [ABSTRACT FROM AUTHOR]

Multiple signaling pathways facilitate the survival and drug resistance of malignant B-cells by regulating their migration and adhesion to microenvironmental niches. NF-κB pathways are commonly dysregulated in mantle cell lymphoma (MCL), but the exact underlying mechanisms are not well understood. Here, using a co-culture model system, we show that the adhesion of MCL cells to stromal cells is associated with elevated levels of KDM6B histone demethylase mRNA in adherent cells. The inhibition of KDM6B activity, using either a selective inhibitor (GSK-J4) or siRNA-mediated knockdown, reduces MCL adhesion to stromal cells. We showed that KDM6B is required both for the removal of repressive chromatin marks (H3K27me3) at the promoter region of NF-κB encoding genes and for inducing the expression of NF-κB genes in adherent MCL cells. GSK-J4 reduced protein levels of the RELA NF-κB subunit and impaired its nuclear localization. We further demonstrated that some adhesion-induced target genes require both induced NF-κB and KDM6B activity for their induction (e.g., IL-10 cytokine gene), while others require induction of NF-κB but not KDM6B (e.g., CCR7 chemokine gene). In conclusion, KDM6B induces the NF-κB pathway at different levels in MCL, thereby facilitating MCL cell adhesion, survival, and drug resistance. KDM6B represents a novel potential therapeutic target for MCL. [ABSTRACT FROM AUTHOR]

Despite major progress in mantle cell lymphoma (MCL) therapeutics, MCL remains a deadly disease with a median survival not exceeding four years. No single driver genetic lesion has been described to solely give rise to MCL. The hallmark translocation t(11;14)(q13;q32) requires additional genetic alterations for the malignant transformation. A short list of recurrently mutated genes including ATM, CCND1, UBR5, TP53, BIRC3, NOTCH1, NOTCH2, and TRAF2 recently emerged as contributors to the pathogenesis of MCL. Notably, NOTCH1 and NOTCH2 were found to be mutated in multiple B cell lymphomas, including 5–10% of MCL, with most of these mutations occurring within the PEST domain of the protein. The NOTCH genes play a critical role in the early and late phases of normal B cell differentiation. In MCL, mutations in the PEST domain stabilize NOTCH proteins, rendering them resistant to degradation, which subsequently results in the upregulation of genes involved in angiogenesis, cell cycle progression, and cell migration and adhesion. At the clinical level, mutated NOTCH genes are associated with aggressive features in MCL, such as the blastoid and pleomorphic variants, a shorter response to treatment, and inferior survival. In this article, we explore in detail the role of NOTCH signaling in MCL biology and the ongoing efforts toward targeted therapeutic interventions. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma (NHL) characterized by a hallmark translocation of t (11; 14). CD10 negativity has been used to differentiate MCL from other NHL types; however, recently, there has been an increase in the number of reported cases of CD10-positive MCL. This warrants further investigation into this rarer immunophenotype and its clinical significance. BCL6, which is a master transcription factor for the regulation of cell proliferation and key oncogene in B cell lymphomagenesis, has been reported to have co-expression with CD10 in MCL. The clinical significance of this aberrant antigen expression remains unknown. We conducted a systematic review by searching four databases and selected five retrospective analyses and five case series. Two survival analyses were conducted to determine if BCL6 positivity conferred a survival difference: 1. BCL6+ vs. BCL6− MCL. 2. BCL6+/CD10+ vs. BCL6−/CD10+ MCL. Correlation analysis was conducted to determine if BCL6 positivity correlated with the Ki67 proliferation index (PI). Overall survival (OS) rates were performed by the Kaplan–Meier method and log-rank test. Our analyses revealed that BCL6+ MCL had significantly shorter overall survival (median OS: 14 months vs. 43 months; p = 0.01), BCL6+/CD10+ MCL had an inferior outcome vs. BCL6+/CD10− MCL (median OS: 20 months vs. 55 months p = 0.1828), BCL6+ MCL had significantly higher percentages of Ki67% (Ki67% difference: 24.29; p = 0.0094), and BCL6 positivity had a positive correlation with CD10+ status with an odds ratio 5.11 (2.49, 10.46; p = 0.0000286). Our analysis showed that BCL6 expression is correlated with CD10 positivity in MCL, and BCL6 expression demonstrated an inferior overall survival. The higher Ki67 PI in BCL6+ MCL compared to BCL6− MCL further supports the idea that the BCL6+ immunophenotype may have prognostic value in MCL. MCL management should consider incorporating prognostic scoring systems adjusted for BCL6 expression. Targeted therapies against BCL6 may offer potential therapeutic options for managing MCL with aberrant immunophenotypes. [ABSTRACT FROM AUTHOR]

Background: With the emergence of therapies for mantle cell lymphoma (MCL), understanding the treatment patterns and burden of illness among older patients with MCL in Canada is essential to inform decision making. Methods: A retrospective study using administrative data matched individuals aged ≥65 who were newly diagnosed with MCL between 1 January 2013 and 31 December 2016 with general population controls. Cases were followed for up to 3 years in order to assess healthcare resource utilization (HCRU), healthcare costs, time to next treatment or death (TTNTD), and overall survival (OS); all were stratified according to first-line treatment. Results: This study matched 159 MCL patients to 636 controls. Direct healthcare costs were highest among MCL patients in the first year following diagnosis (Y1: CAD 77,555 ± 40,789), decreased subsequently (Y2: CAD 40,093 ± 28,720; Y3: CAD 36,059 ± 36,303), and were consistently higher than the costs for controls. The 3-year OS after MCL diagnosis was 68.6%, with patients receiving bendamustine + rituximab (BR) experiencing a significantly higher OS compared to patients treated with other regimens (72.4% vs. 55.6%, p = 0.041). Approximately 40.9% of MCL patients initiated a second-line therapy or died within 3 years. Conclusion: Newly diagnosed MCL presents a substantial burden to the healthcare system, with almost half of all patients progressing to a second-line therapy or death within 3 years. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy has greatly transformed the treatment and prognosis of B-cell hematological malignancies. As CAR T-cell therapy continues to be more readily adopted and indications increase, the field's recognition of emerging toxicities will continue to grow. Among the adverse events associated with CAR T-cell therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are the most common toxicities, while thrombotic events represent an under-reported, life-endangering complication. To determine thrombosis incidence post CAR T-cell therapy, we performed a multi-center, retrospective study on CAR T-cell therapy adult patients (N = 140) from Indiana University Simon Cancer Center and the University of North Carolina Medical Center treated from 2017 to 2022 for relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL, N = 3), diffuse large B-cell lymphoma (DLBCL, N = 92), follicular lymphoma (FL, N = 9), mantle cell lymphoma (MCL, N = 2), and multiple myeloma (MM, N = 34). We report 10 (7.14%) thrombotic events related to CAR T-cell therapy (DLBCL: N = 8, FL: N = 1, MM: N = 1) including 9 primary venous events and 1 arterial event that occurred with median time of 23.5 days post CAR T-cell infusion. In search of parameters associated with such events, we performed multivariate analyses of coagulation parameters (i.e., PT, PTT, and D-Dimer), scoring for adverse events (Padua Score and ISTH DIC Score) and grading for CAR T-cell toxicity severity (CRS grade and ICANS grade) and found that D-Dimer peak elevation and ICANS grade were significantly associated with post-CAR T-cell infusion thrombosis. While the pathophysiology of CAR T-cell associated coagulopathy remains unknown, our study serves to develop awareness of these emerging and unusual complications. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) is a heterogeneous disease in Western and Chinese populations, and it is still not well characterized in Chinese patients. Based on a large cohort of newly diagnosed CLL/SLL patients from China, we investigated immunophenotypes, genetic abnormalities, and their correlations. Eighty-four percent of the CLL/SLL patients showed typical immunophenotypes with scores of 4 or 5 points in the Royal Marsden Hospital (RMH) scoring system (classic group), and the remaining 16% of patients were atypical with scores lower than 4 points (atypical group). Trisomy 12 and variants of TP53, NOTCH1, SF3B1, ATM, and MYD88 were the most recurrent genetic aberrations. Additionally, unsupervised genomic analysis based on molecular genetics revealed distinctive characteristics of MYD88 variants in CLL/SLL. By overlapping different correlation grouping analysis from genetics to immunophenotypes, the results showed MYD88 variants to be highly related to atypical CLL/SLL immunophenotypes. Furthermore, compared with mantle cell lymphoma (MCL), the genetic landscape showed potential value in clinical differential diagnosis of atypical CLL/SLL and MCL patients. These results reveal immunophenotypic and genetic features, and may provide insights into the tumorigenesis and clinical management of Chinese CLL/SLL patients. [ABSTRACT FROM AUTHOR]

Simple Summary: In patients with mantle cell lymphoma (MCL), an effective and safe high-dose chemotherapy regimen as consolidation of first-line treatment prior to ASCT is a matter of ongoing exploration due to unsatisfying outcomes with a relevant rate of relapse in the following course of disease. In our study, we evaluated the use of bortezomib together with standard HDCT of BeEAM (2BeEAM) in 11 patients with an MCL in a single institution study, assessing feasibility, toxicities, and survival rates. More than half of the patients presented with peripheral sensory and/or motor neuropathy. Progression-free survival and overall survival were 64% after a median follow-up time of 22 months. Moreover, 55% of the patients were in complete remission. These findings suggest the addition of bortezomib is associated with substantial toxicities without having a superior benefit in MCL therapy. Thus, we could not identify an obvious clinical benefit compared to standard treatment. (1) Background: First-line therapy in fit MCL patients may comprise high-dose chemotherapy (HDCT) with autologous transplantation to consolidate remission before maintenance treatment. However, optimization of HDCT is an unmet clinical need given the substantial relapse rate of first-line treatment, while the use of bortezomib is a promising candidate to be added to standard HDCT. (2) Methods: We analyzed 11 consecutive patients with MCL who received bortezomib added to standard BeEAM (2BeEAM) HDCT at a single academic institution. We assessed safety, feasibility, toxicities, and survival rates. (3) Results: All patients had stage III or IV disease. We found that six patients (55%) developed new or worsening of preexisting peripheral neuropathy following administration of 2BeEAM HDCT. One patient relapsed within the first six months after HDCT, whereas three patients never reached complete remission. After a median follow-up of 22 months, the PFS was 64% and the OS 64% at the last follow-up assessment. At this time, 55% of patients were in CR. (4) Conclusions: The use of bortezomib added to standard BeEAM HDCT is associated with relevant toxicities, particularly with regards to additional neuropathy. Moreover, the anti-lymphoma efficacy of 2BeEAM HDCT appears to be modest; therefore, other therapeutic options should be evaluated for consolidation in this patient group. [ABSTRACT FROM AUTHOR]

Simple Summary: Mantle cell lymphoma (MCL) is a very rare subtype of non-Hodgkin's lymphoma, predominantly affecting men, where most patients at initial presentation show an advanced spread of the disease with poor prognosis. We analyzed the long-term outcome of 22 patients treated with total body irradiation (TBI)-based conditioning prior to stem cell transplantation (SCT) at the University Hospital of Muenster, Germany. The present results of multimodal treatment support the published reports that TBI-based high-dose therapy followed by SCT is highly effective in this unfavorable disease. Both recently approved agents and traditional SCT open up possibilities of a personalized treatment approach for MCL with the aim of a cure. Introduction: In patients with mantle cell lymphoma (MCL), long-term remissions can be achieved by stem cell transplantation (SCT). Different conditioning treatment protocols exist with or without total body irradiation (TBI). There are few data published on the role of TBI before autologous stem cell transplantation (autoSCT) or allogenic stem cell transplantation (alloSCT). We report on the long-term survival data of patients treated by TBI prior to autologous or allogenic SCT at our center. Patients: In a retrospective analysis, the data of patients treated at the University Hospital of Muenster from May 2004 to February 2015 were collected and evaluated. For the analysis, all data of patients who were histopathologically diagnosed with MCL and underwent TBI prior to stem cell transplantation (SCT) were evaluated. Results: A total of 22 patients (19 men and 3 women) were treated with a TBI-based conditioning prior to SCT. The median age at initial diagnosis was 57.5 years (38–65 years). Seventeen patients had Ann Arbor stage IV, two patients had Ann Arbor stage III, and three patients Ann Arbor stage II disease. AutoSCT was performed in 19 patients and alloSCT was performed in 3 patients. In 18 patients, autoSCT was applied as part of first-line therapy, and in one patient after relapse. Two patients received alloSCT after relapse of MCL, and one patient received alloSCT during first-line therapy after an inadequate treatment response. TBI was performed in 12 patients with 10 Gy and in 6 patients with 12 Gy, these patients subsequently received autoSCT. In the group of four patients who received TBI with four Gy, four patients subsequently received alloSCT and one patient received autoSCT. Median overall survival after autoSCT and previous TBI was 11.4 years (142 months). In total, 11 out of 19 patients treated with autoSCT lived longer than 6.8 years (82–202 months). After alloSCT and previous TBI, the median overall survival was 3.25 years (14–59 months). Conclusions: A large proportion of patients with advanced MCL survived remarkably longer than 11.4 years after high-dose chemotherapy, TBI, and SCT. The present results of multimodal treatment support the published reports that TBI-based high-dose therapy followed by autoSCT is highly effective in this prognostically unfavorable disease situation. [ABSTRACT FROM AUTHOR]

Simple Summary: Targeting BCL-2 through venetoclax is an effective therapy for a series of hematological cancers, such as mantle cell lymphoma (MCL), but resistance to venetoclax is an increasing challenge that needs to be overcome. In order to elucidate the resistance mechanisms to venetoclax in MCL at a molecular level, we used an in vitro model of acquired resistance and performed genetic, epigenetic and transcriptomic analyses. We found that venetoclax-resistant (VR) cells acquired a TP53 mutation and consequently exhibited a reduced apoptotic response. In addition, transcriptomic analysis showed an upregulation of the PI3K/Akt pathway in the VR cells, and an extensive drug screen revealed that Akt and ERK inhibition with TIC10 could induce apoptosis in VR cells with both acquired and intrinsic venetoclax resistance. Thus, TIC-10 might be a possible treatment option for VR patients that requires further investigation. Venetoclax, a BCL-2 inhibitor, has proven to be effective in several hematological malignancies, including mantle cell lymphoma (MCL). However, development of venetoclax resistance is inevitable and understanding its underlying molecular mechanisms can optimize treatment response. We performed a thorough genetic, epigenetic and transcriptomic analysis of venetoclax-sensitive and resistant MCL cell lines, also evaluating the role of the stromal microenvironment using human and murine co-cultures. In our model, venetoclax resistance was associated with abrogated TP53 activity through an acquired mutation and transcriptional downregulation leading to a diminished apoptotic response. Venetoclax-resistant cells also exhibited an upregulation of the PI3K/Akt pathway, and pharmacological inhibition of Akt and ERK with TIC-10 led to cell death in all venetoclax-resistant cell lines. Overall, we highlight the importance of targeted therapies, such as TIC-10, against venetoclax resistance-related pathways, which might represent future therapeutic prospects. [ABSTRACT FROM AUTHOR]

Cancer-associated factors have been largely identified in the understanding of tumorigenesis and progression. However, aminoacyl-transfer RNA (tRNA) synthetases (aaRSs) have so far been neglected in cancer research due to their canonical activities in protein translation and synthesis. FARSA, the alpha subunit of the phenylalanyl-tRNA synthetase is elevated across many cancer types, but its function in mantle cell lymphoma (MCL) remains undetermined. Herein, we found the lowest levels of FARSA in patients with MCL compared with other subtypes of lymphomas, and the same lower levels of FARSA were observed in chemoresistant MCL cell lines. Unexpectedly, despite the essential catalytic roles of FARSA, knockdown of FARSA in MCL cells did not lead to cell death but resulted in accelerated cell proliferation and cell cycle, whereas overexpression of FARSA induced remarkable cell-cycle arrest and overwhelming apoptosis. Further RNA sequencing (RNA-seq) analysis and validation experiments confirmed a strong connection between FARSA and cell cycle in MCL cells. Importantly, FARSA leads to the alteration of cell cycle and survival via both PI3K-AKT and FOXO1-RAG1 axes, highlighting a FARSA-mediated regulatory network in MCL cells. Our findings, for the first time, reveal the noncanonical roles of FARSA in MCL cells, and provide novel insights into understanding the pathogenesis and progression of B-cell malignancies. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplantation (allo-SCT) represented the first immunotherapy to treat hematologic malignancies: it has been considered as a cure for the disease and never as an approach to extend the life of patients. The success of allo-SCT derives both from the ability to treat patients with intensive chemoradiotherapy and from the potent graft-versus-leukemia effects mediated by donor immunity. Although considerable progress has been made in the last years, significant barriers still remain in the form of disease relapse, graft-versus-host disease, infectious complications, and regimen-related toxicities. Moreover, the treatment of hematologic malignancies, particularly acute lymphoblastic leukemia and certain forms of lymphomas, has been revolutionized by the commercial introduction of genetically modified autologous T-lymphocyte therapy (CAR-T). Our review discusses current standards and the shifting paradigms in the indications for allo-SCT and the role of CAR-T cell therapy for lymphoid neoplasms. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma is a B-cell malignancy, which, in its classic form, usually involves lymph nodes and extranodal sites, and, among the extranodal sites, the gastrointestinal tract and the Waldeyer's ring are most prevalent. MCL is rarely reported in the ocular adnexa, a site more frequently affected by extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, which is a form of low-grade malignancy. The diagnosis of MCL presenting in the ocular adnexa requires special attention as its rarity in this location combined with the not uncommon CD5 negativity of the disease when occurring in the ocular adnexa, may lead the pathologist to overlook the diagnosis and misinterpret MCL as marginal zone B cell lymphoma, which has a totally different behavior. Herein, we present a case of primary bilateral conjunctival CD5-negative MCL in a patient having no other sites affected by lymphoma and we discuss possible diagnostic pitfalls. [ABSTRACT FROM AUTHOR]

Simple Summary: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma that remains incurable with standard therapy. A promising approach to overcome the low life expectancy of patients with MCL is drug repurposing, a strategy focused on finding novel therapeutic weapons in approved drugs. Statins are well-tolerated, inexpensive, and widely prescribed as cholesterol-lowering agents that have also shown anti-cancer activity. The present study aimed to elucidate the effect of simvastatin on MCL cells. Our preclinical data demonstrate for the first time that simvastatin treatment impairs MCL proliferation and triggers a caspase-independent, ROS-mediated death of MCL cultures. Furthermore, we show that simvastatin significantly inhibits MCL migration and invasion ability, thereby impairing the growth of MCL tumors, suggesting that the use of statins might be considered for repurpose as a precise MCL therapy. Background: Mantle cell lymphoma (MCL) is a rare and aggressive subtype of B-cell non-Hodgkin lymphoma that remains incurable with standard therapy. Statins are well-tolerated, inexpensive, and widely prescribed as cholesterol-lowering agents to treat hyperlipidemia and to prevent cardiovascular diseases through the blockage of the mevalonate metabolic pathway. These drugs have also shown promising anti-cancer activity through pleiotropic effects including the induction of lymphoma cell death. However, their potential use as anti-MCL agents has not been evaluated so far. Aim: The present study aimed to investigate the activity of simvastatin on MCL cells. Methods: We evaluated the cytotoxicity of simvastatin in MCL cell lines by CellTiter-Glo and lactate dehydrogenase (LDH) release assays. Cell proliferation and mitotic index were assessed by direct cell recounting and histone H3-pSer10 immunostaining. Apoptosis induction and reactive oxygen species (ROS) generation were evaluated by flow cytometry. Cell migration and invasion properties were determined by transwell assay. The antitumoral effect of simvastatin in vivo was evaluated in a chick embryo chorioallantoic membrane (CAM) MCL xenograft model. Results: We show that treatment with simvastatin induced a 2 to 6-fold LDH release, inhibited more than 50% of cell proliferation, and enhanced the caspase-independent ROS-mediated death of MCL cells. The effective impairment of MCL cell survival was accompanied by the inhibition of AKT and mTOR phosphorylation. Moreover, simvastatin strongly decreased MCL cell migration and invasion ability, leading to a 55% tumor growth inhibition and a consistent diminution of bone marrow and spleen metastasis in vivo. Conclusion: Altogether, these data provide the first preclinical insight into the effect of simvastatin against MCL cells, suggesting that this agent might be considered for repurpose as a precise MCL therapy. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma with poor prognosis, due to the inevitable development of drug resistance. Despite being the first-in-class proteasome inhibitor for relapsed/refractory MCL, resistance to bortezomib (BTZ) in MCL patients remains a major hurdle of effective therapy, and relapse following BTZ is frequent. Understanding the mechanisms underlying BTZ resistance is, therefore, important for improving the clinical outcome and developing novel therapeutic strategies. Here, we established de novo BTZ-resistant human MCL-derived cells with the highest resistance index of 300-fold compared to parental cells. We provided compelling evidence that both Bcl-xL and Bax are key mediators in determining BTZ sensitivity in MCL cells. Overexpression of antiapoptotic Bcl-xL and depletion of proapoptotic Bax cooperatively protected MCL cells against BTZ-induced apoptosis, causing acquired BTZ resistance, likely by tilting the balance of Bcl-2 family proteins toward antiapoptotic signaling. Bioinformatics analyses suggested that high BCL2L1 (encoded Bcl-xL) and low BAX were, in part, associated with poor prognosis of MCL patients, e.g., when combined with low OGT, which regulates cellular O-GlcNAcylation. Our findings support recent strategies in small molecule drug discovery co-targeting antiapoptotic Bcl-2 family proteins using BH3 mimetics and Bax using Bax activators to overcome cancer drug resistance. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) subtype characterized by overexpression of CCND1 and SOX11 genes. It is generally associated with clinically poor outcomes despite recent improvements in therapeutic approaches. The genes associated with the development and prognosis of MCL are still largely unknown. Through whole transcriptome sequencing (WTS), we identified mRNAs, lncRNAs, and alternative transcripts differentially expressed in MCL cases compared with reactive tonsil B-cell subsets. CCND1, VCAM1, and VWF mRNAs, as well as MIR100HG and ROR1-AS1 lncRNAs, were among the top 10 most significantly overexpressed, oncogenesis-related transcripts. Survival analyses with each of the top upregulated transcripts showed that MCL cases with high expression of VWF mRNA and low expression of FTX lncRNA were associated with poor overall survival. Similarly, high expression of MSTRG.153013.3, an overexpressed alternative transcript, was associated with shortened MCL survival. Known tumor suppressor candidates (e.g., PI3KIP1, UBXN) were significantly downregulated in MCL cases. Top differentially expressed protein-coding genes were enriched in signaling pathways related to invasion and metastasis. Survival analyses based on the abundance of tumor-infiltrating immunocytes estimated with CIBERSORTx showed that high ratios of CD8+ T-cells or resting NK cells and low ratios of eosinophils are associated with poor overall survival in diagnostic MCL cases. Integrative analysis of tumor-infiltrating CD8+ T-cell abundance and overexpressed oncogene candidates showed that MCL cases with high ratio CD8+ T-cells and low expression of FTX or PCA3 can potentially predict high-risk MCL patients. WTS results were cross-validated with qRT-PCR of selected transcripts as well as linear correlation analyses. In conclusion, expression levels of oncogenesis-associated transcripts and/or the ratios of microenvironmental immunocytes in MCL tumors may be used to improve prognostication, thereby leading to better patient management and outcomes. [ABSTRACT FROM AUTHOR]

The receptor tyrosine kinase orphan receptor 1 (ROR1) is absent in most normal adult tissues but overexpressed in various malignancies and is of importance for tumor cell survival, proliferation, and metastasis. In this study, we evaluated the apoptotic effects of a novel small molecule inhibitor of ROR1 (KAN0441571C) as well as venetoclax (BCL-2 inhibitor), bendamustine, idelalisib (PI3Kδ inhibitor), everolimus (mTOR inhibitor), and ibrutinib (BTK inhibitor) alone or in combination in human MCL primary cells and cell lines. ROR1 expression was evaluated by flow cytometry and Western blot (WB). Cytotoxicity was analyzed by MTT and apoptosis by Annexin V/PI staining as well as signaling and apoptotic proteins (WB). ROR1 was expressed both in patient-derived MCL cells and human MCL cell lines. KAN0441571C alone induced significant time- and dose-dependent apoptosis of MCL cells. Apoptosis was accompanied by decreased expression of MCL-1 and BCL-2 and cleavage of PARP and caspase 3. ROR1 was dephosphorylated as well as ROR1-associated signaling pathway molecules, including the non-canonical WNT signaling pathway (PI3Kδ/AKT/mTOR). The combination of KAN0441571C and ibrutinib, venetoclax, idelalisib, everolimus, or bendamustine had a synergistic apoptotic effect and significantly prevented phosphorylation of ROR1-associated signaling molecules as compared to KAN0441571C alone. Our results suggest that targeting ROR1 by a small molecule inhibitor, KAN0441571C, should be further evaluated particularly in combination with other targeting drugs as a new therapeutic approach for MCL. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is an uncommon subcategory of non-Hodgkin lymphoma (NHL). Pathogenesis primarily includes overexpression of CCND1 and SOX11 along with other molecular aberrations. Lutetium 177Lu-DOTATATE is a radiolabeled somatostatin analogue used for the treatment of gastrointestinal neuroendocrine tumors. There are no clinical data supporting the use of Lutetium 177Lu-DOTATATE in the treatment of lymphoma. We describe the case of an 84-year-old man with a history of MCL and carcinoid tumor of the lung. Following progression of the carcinoid malignancy, the patient was treated with Lutetium 177Lu-DOTATATE. After treatment, there was an overall improvement of the patient's MCL that was demonstrated by stable lymphadenopathy on serial CT scans and down-trend of the absolute lymphocyte count. Therefore, we hypothesize that 177Lu-DOTATATE might have a role and can be repurposed for treating MCL. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a rare type of B-cell Non-Hodgkin lymphoma (NHL) affecting predominantly male patients. While complete remissions following first-line treatment are frequent, most patients ultimately relapse, with a usually aggressive further disease course. The use of cytarabine-comprising induction chemotherapy and autologous stem cell transplantation, Rituximab maintenance, Bruton's tyrosine kinase (BTK) inhibitors and CAR T therapy has substantially improved survival. Still, options for patients relapsing after CAR T therapy are limited and recommendations for the treatment of these patients are lacking. We report two cases of patients with mantle cell lymphoma who relapsed after CAR T therapy and were treated with the bispecific CD20/CD3 T cell engaging antibody glofitamab. Both patients showed marked increases of circulating CAR T cells and objective responses after glofitamab administration. Therapy was tolerated without relevant side effects in both patients. One patient completed all 12 planned cycles of glofitamab therapy and was alive and without clinical progression at the last follow-up. The second patient declined further treatment after the first cycle and succumbed to disease progression. We review the literature and investigate possible mechanisms involved in the observed responses after administration of glofitamab, such as proliferation of CAR T cells, anti-tumor effects of the bispecific antibody and the role of other possibly contributing factors. Therapy with bispecific antibodies might offer an effective and well-tolerated option for patients with mantle cell lymphoma relapsing after CAR T therapy. [ABSTRACT FROM AUTHOR]

An expert panel convened by the European Alliance for Personalized Medicine (EAPM) reflected on achievements and outstanding challenges in Europe in mantle cell lymphoma (MCL). Through the prism of member state experience, the panel noted advances in outcomes over the last decade, but highlighted issues constituting barriers to better care. The list notably included availability of newer treatments, infrastructure and funding for related testing, and shortages of relevant skills and of research support. The prospect of improvements was held to reside in closer coordination and cooperation within and between individual countries, and in changes in policy and scale of investment at both national and EU levels. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL), a type of B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13q32) translocation, is a clinically heterogenous disease which can range from indolent to highly aggressive. Numerous prognostic factors have been identified, including blastoid histology, the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, high proliferation index, p53 deletions and/or mutations, complex karyotype, minimal residual disease, and several others. However, using these prognostic factors to guide treatment selection has largely remained elusive. Given the heterogeneous behavior of this disease and varying patient characteristics, we suggest that the time has come for a more risk-adapted approach to this disease. In this article, we review the numerous prognostic factors that have been described for MCL, both at the time of diagnosis and following first-line treatment. We then propose a risk-adapted approach to first-line therapy for MCL, which would reserve intensive therapy for the highest risk patients and spare others excessive toxicity. [ABSTRACT FROM AUTHOR]

Simple Summary: Mantle cell lymphoma (MCL) is associated with poor response to anthracycline-based chemotherapy, and high-dose cytarabine offers a durable response. Recently, multiple targeted therapies have been approved for the treatment of MCL, highlighting the role of the tumor microenvironment (TME) in the expansion and resistance of the disease. We review herein the TME in MCL and the different therapeutic strategies of treatment. Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t(11;14) (q13;q32) and a poor response to rituximab–anthracycline-based chemotherapy. High-dose cytarabine-based regimens offer a durable response, but an important number of MCL patients are not eligible for intensive treatment and are ideal candidates for novel targeted therapies (such as BTK, proteasome or BCL2 inhibitors, Immunomodulatory Drugs (IMiDs), bispecific antibodies, or CAR-T cell therapy). On the bench side, several studies aiming to integrate the tumor within its ecosystem highlighted a critical role of the tumor microenvironment (TME) in the expansion and resistance of MCL. This led to important insights into the role of the TME in the management of MCL, including potential targets and biomarkers. Indeed, targeted agents often have a combined mechanism of action on the tumor B cell but also on the tumor microenvironment. The aim of this review is to briefly describe the current knowledge on the biology of the TME in MCL and expose the results of the different therapeutic strategies integrating the TME in this disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Mantle cell lymphoma (MCL) is much more common in males than in females. The reason for this is not clear, but research has indicated that the female sex hormones, estrogens, have a protective effect on MCL development. To study this further, mice were transplanted with MCL cells and treated with an estrogen that selectively activates ESR2, the main nuclear estrogen receptor in lymphoma cells. The activation of ESR2 resulted in reduced MCL tumor growth of MCL tumors that were both sensitive and resistant to a newly developed drug (ibrutinib). The mechanism for this effect was investigated by analyzing gene expression and ESR2 binding to target genes. The results show that the affected genes were enriched in several malignancy-related biological processes, including MCL. Furthermore, the results suggested an interplay between the lymphoma cells and the tumor microenvironment in response to ESR2 activation. Altogether, the results clarify the mechanisms of ESR2-mediated MCL growth impairment by estrogens and provide a possible explanation for the sex difference in incidence. Furthermore, targeting ESR2 may be an option when considering the treatment of MCL. Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma with one of the highest male-to-female incidence ratios. The reason for this is not clear, but epidemiological as well as experimental data have suggested a role for estrogens, particularly acting through estrogen receptor β (ESR2). To study the ESR2 effects on MCL progression, MCL cells sensitive and resistant to the Bruton tyrosine kinase inhibitor ibrutinib were grafted to mice and treated with the ESR2-selective agonist diarylpropionitrile (DPN). The results showed that the DPN treatment of mice grafted with both ibrutinib-sensitive and -resistant MCL tumors resulted in impaired tumor progression. To identify the signaling pathways involved in the impaired tumor progression following ESR2 agonist treatment, the transcriptome and ESR2 binding to target genes were investigated by genome-wide chromatin immunoprecipitation in Granta-519 MCL tumors. DPN-regulated genes were enriched in several biological processes that included cell–cell adhesion, endothelial–mesenchymal transition, nuclear factor-kappaB signaling, vasculogenesis, lymphocyte proliferation, and apoptosis. In addition, downregulation of individual genes, such as SOX11 and MALAT1, that play a role in MCL progression was also observed. Furthermore, the data suggested an interplay between the lymphoma cells and the tumor microenvironment in response to the ESR2 agonist. In conclusion, the results clarify the mechanisms by which estrogens, via ESR2, impair MCL tumor progression and provide a possible explanation for the sex-dependent difference in incidence. Furthermore, targeting ESR2 with a selective agonist may be an additional option when considering the treatment of both ibrutinib-sensitive and -resistant MCL tumors. [ABSTRACT FROM AUTHOR]

The anti-diabetic drug metformin is currently tested for the treatment of hematological and solid cancers. Proteasome inhibitors, e.g., Bortezomib, are approved for the treatment of multiple myeloma and mantle cell lymphoma but are also studied for lung cancer therapy. We here analyzed the interaction of the two drugs in two cell lines, namely the mantle cell lymphoma Jeko-1 and the non-small-cell lung cancer (NSCLC) H1299 cells, using proliferation and survival assays, native-gel analysis for proteasome activity and assembly, and expression analysis of proteasome assembly factors. Our results demonstrate that metformin treatment induces resistance of cancer cells to the proteasome inhibitor Bortezomib by impairing the activity and assembly of the 26S proteasome complexes. These effects of metformin on proteasome inhibitor sensitivity in cancer cells are of potential relevance for patients that receive proteasome inhibitor therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: We present the long-term results of patients receiving allogeneic stem cell transplantation (allo-SCT) for relapsed/refractory mantle cell lymphoma (R/R MCL) in the last 25 years in Spain. We conclude that allo-SCT may be a curative option in R/R MCL with a low cumulative incidence (CI) of relapse, although non-relapse mortality (NRM) is still high, which is mainly secondary to acute graft-versus-host disease (aGVHD). Results are better for fit patients, using HLA-identical (related or unrelated) or haploidentical related donors and without previous ASCT. However, the arrival of new highly effective and low toxic immunotherapeutic or targeted therapies inevitably will relegate allo-SCT to those fit patients who fail these therapies, being administered far away from the optimal timing. Allo-SCT is a curative option for selected patients with relapsed/refractory (R/R) MCL, but with significant NRM. We present the long-term results of patients receiving allo-SCT in Spain from March 1995 to February 2020. The primary endpoints were EFS, OS, and cumulative incidence (CI) of NRM, relapse, and GVHD. We included 135 patients, most (85%) receiving RIC. After a median follow-up of 68 months, 5-year EFS and OS were 47 and 50%, respectively. Overall and CR rates were 86 and 80%. The CI of relapse at 1 and 3 years were 7 and 12%. NRM at day 100 and 1 year were 17 and 32%. Previous ASCT and Grade 3–4 aGVHD were associated with a higher NRM. Grade 3–4 aGVHD, donor type (mismatch non-related), and the time-period 2006–2020 were independently related to worse EFS. Patients from 1995–2005 were younger, most from HLA-identical sibling donors, and were pretreated less. Our data confirmed that allo-SCT may be a curative option in R/R MCL with low a CI of relapse, although NRM is still high, being mainly secondary to aGVHD. The arrival of new, highly effective and low toxic immunotherapeutic or targeted therapies inevitably will relegate allo-SCT to those fit patients who fail these therapies, far away from the optimal timing of treatment. [ABSTRACT FROM AUTHOR]

CD24 and its ligand Siglec-10 were described as an innate immune checkpoint in carcinoma. Here, we investigated this axis in B-cell lymphoma by assessing CD24 expression and evaluating pro-phagocytic effects of CD24 antibody treatment in comparison to hallmark immune checkpoint CD47. In mantle cell lymphoma (MCL) and follicular lymphoma patients, high mRNA expression of CD24 correlated with poor overall survival, whereas CD47 expression did not. Conversely, CD24 expression did not correlate with survival in diffuse large B-cell lymphoma (DLBCL), whereas CD47 did. CD24 was also highly expressed on MCL cell lines, where treatment with CD24 antibody clones SN3 or ML5 potently induced phagocytosis, with SN3 yielding >90% removal of MCL cells and triggering phagocytosis of primary patient-derived MCL cells by autologous macrophages. Treatment with CD24 mAb was superior to CD47 mAb in MCL and was comparable in magnitude to the effect observed in carcinoma lines. Reversely, CD24 mAb treatment was less effective than CD47 mAb treatment in DLBCL. Finally, phagocytic activity of clone SN3 appeared at least partly independent of antibody-dependent cellular phagocytosis (ADCP), suggesting CD24/Siglec-10 checkpoint activity, whereas clone ML5 solely induced ADCP. In conclusion, CD24 is an immunotherapeutic target of potential clinical relevance for MCL, but not DLBCL. [ABSTRACT FROM AUTHOR]

Callerya speciosa is widely distributed in tropical and subtropical countries and is traditionally used for preventing numerous disorders. In this study, a bioguided fractionation of ethyl acetate extract (SE) from C. speciosa root was carried out to target antioxidant and cytotoxic activities. Of the four fractions (SE1-SE4) obtained by column chromatography, SE4 had the strongest anti-radical ability in the DPPH and ABTS assays (IC50 = 0.05 and 0.17 mg/mL, respectively), with results close to butylated hydroxytoluene (BHT), a common antioxidant agent. The cytotoxic activities against the selected cells were analyzed in this study by MTT assay. Accordingly, SE2, SE3, and SE4 significantly inhibited the viability of multiple myeloma cell lines, comprising U266 (IC50 = 0.38, 0.09, and 0.11 mg/mL, respectively) and KMS11 (IC50 = 0.09, 0.17, and 0.15 mg/mL, respectively), mantle cell lymphoma Mino (IC50 = 0.08, 0.16, and 0.15 mg/mL, respectively), and the noncancerous cell line LCL (IC50 = 0.40, 0.32, and 0.21 mg/mL, respectively). At a concentration of 125 µg/mL, SE2, SE3, and SE4 induced the cell apoptosis of U266 (32.2%, 53.2%, and 55.6%, respectively), KMS11 (36.9%, 40.8%, and 47.9%, respectively), Mino (36.6%, 39.8%, and 22.0%, respectively), and LCL (12.4%, 17.5%, and 23.5%, respectively) via annexin V assay. The dominant compounds detected in fractions by high-performance liquid chromatography–electrospray ionization–tandem mass spectrometry (HPLC-ESI-MS/MS), were identified as isoflavones. This is the first report describing C. speciosa as a promising natural source of antileukemia and antimyeloma agents, which may be useful for the development of blood cancer treatments. [ABSTRACT FROM AUTHOR]

Proteasome inhibitors have shown relevant clinical activity in several hematological malignancies, namely in multiple myeloma and mantle cell lymphoma, improving patient outcomes such as survival and quality of life, when compared with other therapies. However, initial response to the therapy is a challenge as most patients show an innate resistance to proteasome inhibitors, and those that respond to the therapy usually develop late relapses suggesting the development of acquired resistance. The mechanisms of resistance to proteasome inhibition are still controversial and scarce in the literature. In this review, we discuss the development of proteasome inhibitors and the mechanisms of innate and acquired resistance to their activity—a major challenge in preclinical and clinical therapeutics. An improved understanding of these mechanisms is crucial to guiding the design of new and more effective drugs to tackle these devastating diseases. In addition, we provide a comprehensive overview of proteasome inhibitors used in combination with other chemotherapeutic agents, as this is a key strategy to combat resistance. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a rare mature B-cell non-Hodgkin lymphoma (B-NHL) with historically poor outcomes. Virtually all patients will eventually experience refractory or relapsed (R/R) disease, with a virulent course of resistance and serial relapses, making treatment challenging. The available therapies for R/R MCL are not curative with conventional therapy, their goal being to palliate and prolong survival. A variety of agents approved for R/R MCL, including Bruton's tyrosine kinase inhibitors (BTKi), changed the treatment landscape of R/R MCL. In the pre-BTKi era, the median progression-free survival (PFS) in R/R disease was 4–9 months. With the introduction of ibrutinib, the median PFS improved to 13–14.6 months. Despite these impressive results, the duration of response is limited, and resistance to BTKi inevitably develops in a subset of patients. Outcomes after progression on BTKi are extremely poor, with a median overall survival (OS) of 6 to 10 months. Certain therapies, such as chimeric antigen receptor (CAR) T cells, have shown promising results after BTKi failure. The preferred combination and sequencing of therapies beyond BTKi remain unestablished and are currently being investigated. In this review, we describe the current evidence for the available treatment of R/R MCL after progression on BTKi. [ABSTRACT FROM AUTHOR]

Patients with CD5-expressing lymphomas presenting with splenomegaly are frequently diagnosed with chronic lymphocytic leukemia. The most important differential diagnosis is mantle cell lymphoma, both in its classical and leukemic, non-nodal forms, given its prognostic and therapeutic implications. Other small B-cell neoplasms that frequently involve the spleen and occasionally express CD5 include the splenic marginal zone lymphoma, hairy cell leukemia and, rarely, lymphoplasmacytic lymphoma. The frequency of CD5 positivity depends in part on the sensitivity of the detection methods employed. Usually, a combination of morphological, immunophenotypic and molecular findings allows for a precise sub-classification of CD5-positive, low-grade B-cell lymphomas of the spleen. Some of these tumors may display a mixture of small and larger B cells, raising the possibility of more aggressive lymphomas, such as diffuse large B-cell lymphomas (DLBCL). Approximately 5-10% of DLBCL are CD5-positive and some may manifest as primary splenic lesions. When available, the morphology of DLBCL in the splenic tissue is distinctive and a leukemic picture is very rare. In conclusion, the appropriate morphological and clinical context assisted by flow cytometry panels and/or immunohistochemistry allows the differential diagnosis of CD5-positive, non-Hodgkin, B-cell lymphomas involving the spleen. [ABSTRACT FROM AUTHOR]

Background: In Ontario, no clearly defined standard of care for the management of mantle cell lymphoma (mcl) has been developed, and substantial variability from centre to centre is evident. This guidance document was prompted by the need to harmonize practice in Ontario with respect to first-line, conditioning, and post transplantation maintenance therapy for patients newly diagnosed with transplantation-eligible mcl. Methods: The medline and embase databases were systematically searched from January 2013 to January 2020 for evidence, and the best available evidence was used to draft recommendations relevant to first-line therapy, autologous stem-cell transplantation, and post-transplantation maintenance in the management of transplantation-eligible newly diagnosed mcl. Final approval of this guidance document was obtained from the Stem Cell Transplant Advisory Committee. Recommendations: These recommendations apply to all cases of transplantation-eligible newly diagnosed mcl: Alternating cycles of r-chop (rituximab plus cyclophosphamide-doxorubicin-vincristine-prednisolone) and r-dhap [rituximab plus dexamethasone-high-dose cytarabine-cisplatin] is the recommended first-line treatment for symptomatic patients newly diagnosed with mcl before autologous stem-cell transplantation (asct). Rituximab plus hyperfractionated cyclophosphamide-vincristine-doxorubicin-dexamethasone (r-hypercvad), alternating with methotrexate and cytarabine, is not recommended for the treatment of patients with newly diagnosed mcl. beam (carmustine-etoposide-cytarabine-melphalan), beac (carmustine-etoposide-cytarabine-cyclophosphamide), and total-body irradiation-based regimens are reasonable conditioning options for patients with mcl who have responded to first-line therapy and who are undergoing asct. Maintenance therapy with rituximab is recommended for patients with newly diagnosed mcl who have undergone asct. [ABSTRACT FROM AUTHOR]