Subtype Of Lymphoma Research Articles

Cuproptosis-related gene <i>ATOX1</i> promotes MAPK signaling and diffuse large B-cell lymphoma proliferation via modulating copper transport

Diffuse Large B-cell lymphoma (DLBCL) is a common subtype of non-Hodgkin lymphoma, highlighting the importance of studying susceptibility genes to develop personalized treatment strategies. While cuproptosis, caused by high levels of copper ions induced by ionophores, has been shown to affect cancer survival, its specific role in lymphoma is not yet clear. To investigate the involvement of upregulation-related genes in DLBCL, we employed bioinformatics techniques. Specifically, we analyzed the differentially expressed genes (DEGs) in the GSE25638 dataset using Weighted Gene Co-expression Network Analysis (WGCNA) and performed functional enrichment analysis. By building a Protein-Protein Interaction (PPI) network, candidate genes were identified. Gene Set Enrichment Analysis (GSEA) and Receiver Operating Characteristic (ROC) curve analysis were used to confirm the clinical diagnostic use of these genes. The effects of Antioxidant 1 (ATOX1) knockdown, CuCl2, and DCAC50 treatments on DLBCL cells and the activation of the Mitogen-Activated Protein Kinase (MAPK) pathway were investigated by conducting in vitro experiments. Bioinformatics and in vitro experiments confirmed elevated expression of ATOX1 in DLBCL cells and tumor samples. ATOX1 knockdown led to decreased cell proliferation and G2 cell cycle arrest in vitro. Additionally, Phosphorylated Extracellular Signal-Regulated Kinases 1 and 2 (P-ERK1/2) protein levels within the MAPK pathway were reduced as a result of ATOX1 knockdown, but these levels were recovered by CuCl2. Treatment with DCAC50 showed a dose-dependent antiproliferative effect in DLBCL cells, which was strengthened by ATOX1 knockdown. Our study demonstrated that ATOX1 may be important in DLBCL via controlling the MAPK pathway through copper transport, providing new insights into potential therapeutic strategies for DLBCL.

Primary Cutaneous Diffuse Large B‑Cell Lymphoma, Leg Type: A Clinical Case

Introduction. Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type it is a rare variant of skin lymphoma that has an aggressive course and a high risk of extracutaneous manifestations.The purpose of this work is to familiarize a wide range of specialists with the clinical manifestations of a rare disease — primary cutaneous diffuse large B-cell lymphoma.Materials and methods. An interesting clinical case is presented and the medical history of a patient with B-cell lymphoma from the skin is analyzed.Results. A differential diagnosis of the disease was made. Based on the study of histological material, the final clinical diagnosis was established and further treatment tactics were determined.Discussion. The patient had spots and plaques on the lower extremities, the sole visible signs of the disease. These symptoms may suggest a positive prognosis and a gradual progression. Diagnostic measures should include gathering medical history, assessing the local condition, and carrying out an excision biopsy early in the examination process for an accurate and prompt diagnosisConclusion. Due to the rarity of this subtype of lymphoma and the limited number of domestic publications on the topic, a more detailed study and description of individual clinical cases can lead to a better understanding of the characteristics of the symptoms and the processes of pathological changes in cells, tissues, and organs. This could potentially lead to the development of more efficient methods for early diagnosis and timely treatment of the condition.

Quality of Life Evaluation in Patients with Follicular Cell Lymphoma: A Real-World Study in Europe and the United States.

Follicular lymphoma (FL) is an indolent subtype of non-Hodgkin's lymphoma (NHL), characterized by a long natural course of remissions/relapses. We aimed to evaluate real-world quality of life (QoL) in patients with FL, by line of therapy (LOT), and across countries. Data were drawn from the Adelphi FL Disease Specific Programme™, a cross-sectional survey of physicians and their patients in Europe [France, Germany, Italy, Spain, the United Kingdom (UK)], and the United States (US) from June 2021 to January 2022. Patients provided demographics and patient-reported outcomes via the European Organisation for Research and Treatment of Cancer QoL questionnaire (EORTC QLQ-C30). Bivariate analysis assessed QoL versus NHL, across LOT [first line (1L), second line (2L), third line or later (3L+)] and country. Patients (n=401) had a mean [standard deviation (SD)] age of 66.0 (9.24) years, 58.1% were male, and 41.9%/22.9% were Ann Arbor stage III/IV. Patients with FL mean EORTC global health status (GHS)/QoL, nausea/vomiting, pain, dyspnea, appetite loss, and diarrhea scores were statistically significantly worse (p<0.05) versus the NHL reference values. Mean (SD) GHS/QoL worsened from 1L [56.5 (22.21)] to 3L+[50.4 (20.11)]. Physical and role functioning, fatigue, pain, dyspnea, and diarrhea scores also significantly worsened across later LOTs (p<0.05). Across all functional domains, mean scores were significantly lower (p<0.05) and almost all symptom scores (excluding diarrhea) were significantly higher (p<0.05) for European versus US patients. Patients with FL at later LOTs had significantly worse scores in most QoL aspects than earlier LOTs. European patients had significantly lower functioning and higher symptom burden than in the US. These real-world findings highlight the need for novel FL therapies that alleviate patient burden, positively impacting QoL.

Performance Characteristics of Incisional and Core Needle Biopsies for Diagnosis in Parotid Gland: Single-Institutional Experience and Assessment of the Value of a Milan System for Reporting Salivary Gland Cytopathology-Like Risk Stratification Model.

Unlike parotid fine-needle aspiration biopsy, standardized reporting for core needle biopsy (CNB) and incisional biopsy (IB) is not established. To examine the value of risk stratification by a Milan System for Reporting Salivary Gland Cytopathology (MSRSGC)-like classifier for parotid CNB/IB. Five hundred ninety-two parotid biopsy records (CNB = 356, IB = 236) were retrieved (1994-2022) along with clinicopathologic data. Diagnoses were transformed to an MSRSGC-like classifier and compared with end points including risk of malignancy. Over time, CNB was progressively more used compared with IB. Overall malignancy call rate was 223 of 592 (37.7%). Common specific diagnoses included Warthin tumor, lymphoma subtypes, and metastatic squamous cell carcinoma for CNB and IB, in addition to pleomorphic adenoma for CNB. Descriptive diagnoses were still frequent. Nondiagnostic rates were higher in CNB (26 of 356; 7.30%) than IB (5 of 236; 2.12%; P <.001). Tissue volumes significantly influenced CNB adequacy, with minimum and optimal volumes of 4.76 mm³ (J index, receiver operating characteristic curve) and 12.92 mm³ (95th percentile of distribution), respectively. One hundred forty-four patients (112 CNBs) had follow-up resections; diagnoses were concordant for 66 of 73 adequate CNBs (90.41%). Our restructured risk grouping of MSRSGC categories performed robustly in terms of risk of malignancy (sensitivity = 85.5%, specificity = 100%, accuracy = 92.3%, area under the curve = 0.9677). Although CNB and IB are amenable to a risk stratification system, there are some differences as compared with fine-needle aspiration biopsy, particularly given the high baseline prevalence of malignancy. Specific diagnoses are often feasible and concordant with resection. CNB tissue volume can inform optimal and minimal sampling recommendations for adequacy.

Mantle Cell Lymphoma in the Oral Cavity: Exploring the Differential Microscopic Diagnosis of a Rare Case.

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin's lymphoma (NHL), which generally has an aggressive course. Its pathophysiology seems to be related with the malignant transformation of B-cell mantle zone lymphocytes due to the CCND1 rearrangement. The occurrence of MCL in the oral cavity is especially rare. In this report, we present an exceptional case of oral MCL diagnosed in the palate in a 56-year-old male patient, highlighting its distinct morphological and immunohistochemical features that may assist in the accurate diagnosis.

Cancer-related Fatigue and the Additive Effect of Treatment in the Context of Lymphoma: An Analysis of the Lymphoma Coalition's 2022 Global Patient Survey.

CRF is a highly incident phenomenon in lymphoma that can be ascribed to a combination of causes. We have demonstrated substantial variability across various subtypes of lymphoma and have estimated that nearly half of the reported fatigue comes from treatment. Increased screening for and monitoring of fatigue will yield favorable health-related quality of life that will benefit health technology assessment activities and yield improved outcomes for patients.

Plasma circulating tumour DNA is a better source for diagnosis and mutational analysis of IVLBCL than tissue DNA.

Diagnosis of intravascular large B-cell lymphoma (IVLBCL) is a challenge due to its heterogeneous clinical presentation and lack of specific markers. This retrospective study investigated the utility of circulating tumour DNA (ctDNA) sequencing for diagnosing IVLBCL and analysing its mutation landscape. A cohort of 34 IVLBCL patients enrolled and underwent plasma ctDNA targeted sequencing. The median plasma ctDNA concentration was 135.0 ng/mL, significantly higher than that in diffuse large B-cell lymphoma (DLBCL) controls. Correlations were found between ctDNA concentration and disease severity indicators, LDH and SF. Mutation analysis revealed frequent mutations in B-cell receptor and NF-κB signalling pathways, including MYD88 (56%), CD79B (44%), TNFAIP3 (38%) and IRF4 (29%). CNS involvement was significantly related with BCL6 and CD58 mutation. Patients with complicated hemophagocytic lymphohistiocytosis had significantly higher mutation rates in B2M. Comparison with DLBCL subtypes showed distinctive mutation profiles in IVLBCL. Moreover, plasma ctDNA detected more mutations with higher variant allele fraction than tissue DNA, suggesting its superiority in sensitivity and accessibility. Dynamic monitoring of ctDNA during treatment correlated with therapeutic responses. This study revealed the role of ctDNA in IVLBCL diagnosis, mutation analysis, and treatment monitoring, offering a promising avenue for improving patient diagnosis in this rare lymphoma subtype.

Oncogenic alterations in KIR3DL1 in cutaneous acral CD8+ lymphoproliferative disorder.

Primary cutaneous acral CD8+ T-cell lymphoproliferative disorder (TLPD) is a rare and indolent lymphoma entity. Although TLPD was first identified many years ago, the molecular pathogenesis is still not fully understood. In order to better understand the molecular pathogenesis of cutaneous acral CD8+ TLPD and to identify further discriminatory markers to differentiate this lymphoma subtype from other CD8+ cutaneous lymphomas, we analysed five cases of cutaneous acral CD8+ TLPD for putative molecular alterations. Somatic alterations were assessed using whole-exome and targeted sequencing of paraffin-embedded tissue. Results were evaluated using immunohistochemical staining of respective relevant proteins. CD8+ cutaneous T-cell lymphomas (n = 12) served as control for KIR3DL1 staining. Copy number variation analysis revealed a homozygous deletion of the KIR3DL1 gene in two of the analysed cases. This resulted in loss of KIR3DL1 protein expression, which was observed in all cases of cutaneous acral CD8+ TLPD. In contrast, KIR3DL1 expression was more variable in other CD8+ cutaneous T-cell lymphomas with 50% of analysed cases (n = 12) found to be positive. In addition, one further case of acral CD8+ TLPD harboured a loss-of-function mutation in the PIK3R1 gene, presumably activating the phosphoinositide 3-kinase-AKT pathway. Alterations of the KIR3DL1 gene may be of pathogenetic relevance for acral CD8+ TLPD. Loss of KIR3DL1 protein expression may support the diagnosis of this indolent lymphoma entity; however, this is not a subtype-specific discriminative feature.

Discovery of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates Targeting MYD88 Mutant Diffuse Large B-Cell Lymphoma.

Developing therapies for the activated B-cell like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL) remains an area of unmet medical need. A subset of ABC DLBCL tumors is driven by activating mutations in myeloid differentiation primary response protein 88 (MYD88), which lead to constitutive activation of interleukin-1 receptor associated kinase 4 (IRAK4) and cellular proliferation. IRAK4 signaling is driven by its catalytic and scaffolding functions, necessitating complete removal of this protein and its escape mechanisms for complete therapeutic suppression. Herein, we describe the identification and characterization of a dual-functioning molecule, KT-413 and show it efficiently degrades IRAK4 and the transcription factors Ikaros and Aiolos. KT-413 achieves concurrent degradation of these proteins by functioning as both a heterobifunctional degrader and a molecular glue. Based on the demonstrated activity and safety of KT-413 in preclinical studies, a phase 1 clinical trial in B-cell lymphomas, including MYD88 mutant ABC DLBCL, is currently underway.

Targeted inhibition of DHODH is synergistic with BCL2 blockade in HGBCL with concurrent MYC and BCL2 rearrangement

High-grade B-cell lymphoma (HGBCL), the subtype of non-Hodgkin lymphoma, to be relapsed or refractory in patients after initial therapy or salvage chemotherapy. Dual dysregulation of MYC and BCL2 is one of the important pathogenic mechanisms. Thus, combined targeting of MYC and BCL2 appears to be a promising strategy. Dihydroorotate dehydrogenase (DHODH) is the fourth rate-limiting enzyme for the de novo biosynthesis of pyrimidine. It has been shown to be a potential therapeutic target for multiple diseases. In this study, the DHODH inhibitor brequinar exhibited growth inhibition, cell cycle blockade, and apoptosis promotion in HGBCL cell lines with MYC and BCL2 rearrangements. The combination of brequinar and BCL2 inhibitors venetoclax had a synergistic inhibitory effect on the survival of DHL cells through different pathways. Venetoclax could upregulate MCL-1 and MYC expression, which has been reported as a resistance mechanism of BCL2 inhibitors. Brequinar downregulated MCL-1 and MYC, which could potentially overcome drug resistance to venetoclax in HGBCL cells. Furthermore, brequinar could downregulate a broad range of genes, including ribosome biosynthesis genes, which might contribute to its anti-tumor effects. In vivo studies demonstrated synergetic tumor growth inhibition in xenograft models with brequinar and venetoclax combination treatment. These results provide preliminary evidence for the rational combination of DHODH and BCL2 blockade in HGBCL with abnormal MYC and BCL2.

Abstract PO-022: Distinct intratumoral microbiome signatures enrichment in patients with different Anaplaplastic Large Cell Lymphoma (ALCL) subtypes

Abstract Background: The intratumoral microbiome is a tumor-specific component of the tumor microenvironment (TME), including microorganisms localized inside and around cancer cells and immune cells (Nejman Science2020), which was recently added to the “Hallmarks of Cancer” (Hanahan, Cancer Discovery 2022). Specific intratumoral microbiome signatures (IMS) can be detected using our targeted sequencing platform Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) (Prashkin Nat Comm 2023) data through the implementation of a specific bioinformatic pipeline (Vanderbilt J Mol Diagn 2022, Abate Ann Surg 2022). In lymphoma, where antigen stimulation is known to promote lymphomagenesis, studying the intratumoral microbiome might inform lymphoma biology and potentially new treatment strategies. In anaplastic large cell lymphoma (ALCL), a specific histologic phenotype can be found in a very diverse spectrum of diseases, ranging from smoldering lymphomas such as breast-implant associated (BIA-ALCL) and primary cutaneous (pcALCL) to systemic aggressive lymphomas such as ALK-positive or ALK-negative ALCL. We hypothesized that the different IMS might be present in different ALCL clinical presentations. Methods: We used metagenomic techniques to analyze IMS on MSK-IMPACT-HEME as previously described (Vanderbilt J Mol Diagn 2022) of patients with ALCL in our lymphoma database. All patients signed informed consent. We calculated the odds ratio (OR) of each intra-lymphoma IMS in one ALCL subtype compared to that of the same IMS in the other ALCL subtypes. We used several different analyses to process the data for commensals and contaminants. In this regard, we built a database of potentially pathogenic or commensal microorganisms integrated in the decontam (R package) pipeline dataset. For BIA-ALCL, we compared the IMS results with those of known components of explanted textured implant biofilm. Results: We re-analyzed the MSK-IMPACT-HEME BAM files of 58 patients with ALCL, including 12 BIA-ALCL, 11 pcALCL, and 35 systemic ALK+/- ALCL. After reviewing the data for commensals and contaminants, we could identify more than one potentially lymphoma-specific or site-specific microorganism in pcALCL (n=2) and in BIA-ALCL (n=14) (slow-growing subtypes) compared with systemic ALCL. Fewer differences were noted between pcALCL and BIA-ALCL; however, Achromobacter and Rothia were significantly enriched in BIA-ALCL compared to systemic ALCL and pcALCL (OR 14.9 p=0.001; OR=5, p=0.025) and Micromonospora in pcALCL compared to BIA-ALCL and systemic ALCL (OR=5.5, p=0.05). No specific IMS was found in systemic ALCL, as the only potentially enriched IMS (Delftiae) is likely a contaminant. Conclusions: This analysis of IMS using targeted sequencing data, highlighted some possible associations between intratumoral microorganisms and lymphoma-specific subtypes, especially in indolent subtypes of ALCL (BIA- and pc-) compared to systemic ALCL. Further analyses with more cases and confirmatory techniques might confirm these initial findings. Citation Format: Paola Ghione, Horwitz Steven, Peter Cordeiro, Maria Arcila, Natasha Galasso, Ahmet Dogan, Gilles Salles, Chad Vanderbilt. Distinct intratumoral microbiome signatures enrichment in patients with different Anaplaplastic Large Cell Lymphoma (ALCL) subtypes [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-022.

Clinical Approach to Advanced Mantle Cell Lymphoma: A Detailed Case Analysis

Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin lymphoma (NHL) originating from cells in the mantle zone. Herein, we present a case report of a 49-year-old male patient diagnosed with stage VI MCL, illustrating various diagnostic methods and procedures utilized in his evaluation. The patient presented with progressively enlarging cervical lymph nodes, fatigue, weight loss, anorexia, chronic diarrhea, abdominal pain, and rectal bleeding. Clinical examination revealed cutaneomucosal pallor, tachycardia, expiratory polypnea, bilateral jugulocarotid adenopathies, and splenomegaly. Laboratory investigations showed normocytic normochromic anemia, hyperleukocytosis, lymphocytic predominance, and thrombocytopenia. Peripheral blood smear analysis indicated a lymphoproliferative disorder, confirmed by flow cytometry revealing monotypic lymphoid cells. Bone marrow biopsy showed hypoplastic marrow with atypical cells. Immunohistochemistry confirmed mantle cell lymphoma localization. Subsequent thoraco-abdomino-pelvic CT scan revealed mediastinal and abdominal adenopathy with splenomegaly, leading to a diagnosis of stage IV MCL. The case highlights the importance of early and comprehensive diagnostic approaches in MCL management.

Abstract PO-031: Systematic discovery of chemotherapy response biomarkers in Peripheral T Cell Lymphomas

Abstract Background. Identifying which patients will benefit from individual therapies remains a general challenge in oncology. Predictive biomarkers of drug sensitivity, when known, can increase the rate of success of trials, and allow stratification of patients for targeted combination therapies, as recent shown by the GUIDANCE-01 trial in Large B-Cell Lymphoma. Peripheral T-Cell Lymphomas (PTCL) could particularly benefit from this approach, being heterogeneous diseases against which many therapies are active in unpredictable subsets of patients. A central challenge of biomarker discovery is finding true determinants of drug response, which may be multiple genes, among thousands of molecular features that may accidentally correlate. Here, we aim to mitigate this challenge by combining functional genetic screens and gene expression profiling in diverse PTCL cultures, to enable the systematic discovery of drug sensitivity biomarkers. Methods. To discover genes whose expression directly modifies drug sensitivity, we conducted genome-wide CRISPR screens with PTCL cells under treatment with five therapies with clinical activity in PTCL: Romidepsin, Pralatrexate, Gemcitabine, Oxaliplatin, and Bortezomib. To discover genes whose basal expression significantly correlates with specific drug sensitivities, we measured RNAseq and drug response functions for a diverse panel of 27 PTCL cultures. Genes in the intersection of both experiments are causally related to and correlate with drug responses in PTCL, and have the statistical benefit of detection by independent methods. Results. Functional genetic screens on therapy provided mechanistic insights for each drug of interest, and identified genes whose perturbation affects drug sensitivity. Whereas hundreds of genes nominally correlate with drug sensitivity in cell line panels, for each drug a shortlist of only 5 to 20 genes are both CRISPR hits and correlate with response across PTCL cultures. For each drug tested, multi-gene sensitivity scores constructed from hits stratify PTCL cultures into statistically distinct sensitive and non-sensitive subgroups (Mann Whitney P-Values &amp;lt;0.01). These genes’ relationships to drug mechanisms were often supported by prior studies, including functions in DNA repair, cell cycle regulation, and solute carriers required for cellular entry of specific therapies, such as SLC19A1 for Pralatrexate and SLC43A2 for Oxaliplatin. Conclusions. Combining functional genetic screens and correlative drug sensitivity measurements narrowed the search for predictive biomarkers of drug sensitivity, and may be a general means of refining biomarker hypotheses for validation in clinical datasets. Although chemotherapy sensitivity is commonly polygenic, multi-gene scores based on few mechanistically-related genes were able to significantly distinguish drug sensitive from resistant PTCLs. These approaches provide novel hypotheses for drug-gene relationships that may serve as the basis for molecular subtyping of individual lymphomas for precision regimens. Citation Format: Adam C Palmer, Jacob C Pantazis. Systematic discovery of chemotherapy response biomarkers in Peripheral T Cell Lymphomas [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-031.

Abstract PO-021: Modeling marginal zone lymphomagenesis

Abstract Introduction: Marginal zone lymphomas (MZL) are the second most prevalent subtype of indolent Non-Hodgkin Lymphomas (iNHL), yet lack a unique cytogenetic identifying abnormality. The B-cell receptor signaling pathway is activated in B-cell malignancy and mediates its activity mainly through the Phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR) pathway. PI3K inhibitors have demonstrated impressive clinical activity in several indolent lymphomas including MZL, underscoring the pivotal role of the PI3K-AKT-mTOR (PAM) pathway in MZL pathogenesis. Furthermore, iNHL overexpress the antiapoptotic protein Bcl-2. Methods: We developed a genetically engineered mouse model with heterozygous global knockout alleles of both the tumor suppressor genes Phosphatase and Tensin Homolog (PTEN) and Liver Kinase B1 (LKB1), resulting in heightened PAM pathway activation across all tissues. We closely monitored these mice for tumor formation via regular physical assessments over several months. Upon tumor detection, mice were euthanized, and tumors were histologically examined. For a more precise representation of B-cell biology akin to the human disease, we employed the Cre-LoxP system to create the CD19-Cre-PTENfl/fl/LKB1fl/fl and CD19-Cre-PTENfl/fl/Eµ-Bcl2. Results: Thirty mice of global KO PTEN+/- LKB1+/- succumbed to or were euthanized due to disease progression, defined as either lymph node enlargement and/or splenomegaly. By Kaplan-Meier analysis, we saw a steady decrease in both tumor-free and overall survival after 3 months of age. Median survival time was 6 months (95% CI: 6, 8). Immunohistochemical analysis of the 51 lymph nodes revealed iNHL in 61.5% (N=32), with all of the MZL subtype. The penetrance rate was 37%. Then, we looked at the absolute B cells, and the major B subtypes in age-matched mice (N=3 per group): WT, CD19-Cre-PTENfl/fl/LKB1fl/fl, CD19-Cre-PTENfl/fl/Eµ-Bcl2. We observed the following preliminary results in the absolute B cells (23,489,812; 1,550,430; 140,476,875), Marginal zone cells (1,087,883; 452,470; 42,658,701), follicular cells (19,078,598; 203,286; 57,212,627), B1 cells (962,192; 939,386; 1,803,060), and plasma cells (211,725; 202,790; 10,531,585) respectively. Then, Kruskal-Wallis tests were used to test the main effect of these three models (WT, CD19-Cre-PTENfl/fl/LKB1fl/fl and CD19-Cre-PTENfl/fl/Bcl2) on absolute cell counts for each cell type: B cells (p=0.027), follicular (p=0.061), Marginal zone (p=0.027), B1 (p=0.43), and plasma cell (p=0.066). The test results indicate that there were statistically discernible differences in absolute cell counts among the three models for B cells and MZ. Conclusion: Marginal zone lymphoma remains an incurable lymphoma with a dearth of reliable preclinical models. Our data provides, for the first time, evidence supporting the involvement of the PAM pathway in MZL pathogenesis, laying the groundwork for further research elucidating the disease biology and rational therapeutic strategies for this incurable malignancy. Citation Format: Emily Harris, Ariel Sindel, Jian He, Roy Sabo, Alden Chesney, Guanhua Lai, Adolpho Mauro, Rebecca Martins, Jennifer Koblinski, Joelene Windle, Victor Yazbeck. Modeling marginal zone lymphomagenesis [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-021.

Abstract PO-025: Identifying tissue-specific drivers of immune evasion in Mantle Cell Lymphoma at single cell level

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma that exhibits clinical, pathological, and genetic heterogeneity. While generally thought to be incurable, recently demonstrated clinical activity of both chimeric antigen receptor T (CAR-T) cells and bispecific antibodies suggest that immune-mediated therapies offer substantial benefit in this disease and underscores the value of understanding mechanisms of immune evasion in this disease. Aim: The aim of this project is to uncover distinct cellular networks driving immune evasion in MCL across disease sites. Methods: We analyzed 10 archival samples collected from 8 clinically annotated patients with untreated MCL, including mononuclear cells from peripheral blood (PB), lymph nodes (LN) and bone marrow (BM). After generating single-cell suspensions from tumors, we performed Cellular Indexing of Transcriptomes and Epitopes sequencing (CITE-seq) and identified malignant B cells based on the co-expression of cyclin D1 (CCND1) and B cell markers (MS4A1, CD79A, CD79B). B and T cells were then subclustered using a reference mapping geneset. Molecular signatures database was utilized to perform geneset enrichment analysis (GSEA). Results: Our study first confirms the heterogeneity of mantle cell lymphoma across compartments (i.e PB, LN, BM), showing 5 different clusters of malignant cells, with different abundance in cell proportion among patients. We found that malignant B cells expressed different levels of CCND1 expression across tissue compartments. Furthermore, we identified a specific cluster of malignant cells, enriched in the PB, marked by decreased expression of the costimulatory receptor CD40 and higher levels of B-cell receptor signaling. This may explain the rapid response of circulating MCL cells to Bruton Tyrosine Kinase (BTK) inhibition. Interestingly, the higher expression of CD40 on LN-resident MCL cells suggests that MCL cells may co-opt LN-resident T-cells to support their growth, as has been previously described. Consistent with this, T-cells from LN were phenotypically exhausted, suggesting that MCL cells within the LN leverage local interactions with T-cells to promote survival while avoiding T-cell-driven cytotoxicity. Finally, we also found that high level of Ki67 correlates with myeloid-cell abundance in the TME suggesting that monocytes may support tumor cell proliferation. Conclusion: These results provide a deeper understanding of tissue-specific heterogeneity in MCL, including distinct tumor-immune interactions at different tissue sites. In ongoing analyses, we will correlate these findings with patient outcomes and response to BTK inhibition and are currently analyzing samples from patients with relapsed disease to identify microenvironmental features associated with disease progression. Citation Format: Amira Marouf, Jahan Rahman, Ashlee Joseph, Irem Isgor, Ya-Hui Lin, Ronan Chaligne, Shenon Sethi, Ahmet Dogan, Gilles Salles, Anita Kumar, Santosha A Vardhana. Identifying tissue-specific drivers of immune evasion in Mantle Cell Lymphoma at single cell level [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-025.

Survival trend and outcome prediction for pediatric Hodgkin and non-Hodgkin lymphomas based on machine learning

Pediatric Hodgkin and non-Hodgkin lymphomas differ from adult cases in biology and management, yet there is a lack of survival analysis tailored to pediatric lymphoma. We analyzed lymphoma data from 1975 to 2018, comparing survival trends between 7,871 pediatric and 226,211 adult patients, identified key risk factors for pediatric lymphoma survival, developed a predictive nomogram, and utilized machine learning to predict long-term lymphoma-specific mortality risk. Between 1975 and 2018, we observed substantial increases in 1-year (19.3%), 5-year (41.9%), and 10-year (48.8%) overall survival rates in pediatric patients with lymphoma. Prognostic factors such as age, sex, race, Ann Arbor stage, lymphoma subtypes, and radiotherapy were incorporated into the nomogram. The nomogram exhibited excellent predictive performance with area under the curve (AUC) values of 0.766, 0.724, and 0.703 for one-year, five-year, and ten-year survival, respectively, in the training cohort, and AUC values of 0.776, 0.712, and 0.696 in the validation cohort. Importantly, the nomogram outperformed the Ann Arbor staging system in survival prediction. Machine learning models achieved AUC values of approximately 0.75, surpassing the conventional method (AUC = ~ 0.70) in predicting the risk of lymphoma-specific death. We also observed that pediatric lymphoma survivors had a substantially reduced risk of lymphoma after ten years b,ut faced an increasing risk of non-lymphoma diseases. The study highlights substantial improvements in pediatric lymphoma survival, offers reliable predictive tools, and underscores the importance of long-term monitoring for non-lymphoma health issues in pediatric patients.

Racial disparities in the incidence and survival outcomes in diffuse large B-cell lymphoma in adolescents and young adults.

Diffuse large B-cell Lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL). The disease generally occurs in older patients. Although at a lower prevalence, the disease also occurs in the adolescent and young adult group (AYA). There is paucity of data in the literature on racial and ethnic disparities in the incidence and survival outcomes of DLBCL in the AYA group. The objective of our study is to demonstrate the disparities in these outcomes. Utilizing SEER, we obtained data on patient demographics, incidence, and survival from 2000 to 2020. We observed statistically significant reduced incidence of DLBCL in all racial groups, except the non-Hispanic Asian and Pacific Islander group (NHAPI). The non-Hispanic Black group (NHB) had one of the lowest survival despite showing the largest decrease in incidence in DLBCL. The differences in the survival could be secondary to socioeconomic factors, however other reasons need to be explored. The increased incidence among the NHAPI group mirrors that of large population-based studies in East Asian countries, however, underlying reasons have not been elucidated.

Impact of genetic alterations on central nervous system progression of primary vitreoretinal lymphoma.

Primary vitreoretinal lymphoma (PVRL) is a rare malignant lymphoma subtype with an unfavorable prognosis due to frequent central nervous system (CNS) progression. Thus, identifying factors associated with CNS progression is essential for improving the prognosis of PVRL patients. Accordingly, we conducted a comprehensive genetic analysis using archived vitreous humor samples of 36 PVRL patients diagnosed and treated at our institution and retrospectively examined the relationship between genetic alterations and CNS progression. Whole-exome sequencing (n = 2) and amplicon sequencing using a custom panel of 107 lymphomagenesis-related genes (n = 34) were performed to assess mutations and copy number alterations. The median number of pathogenic genetic alterations per case was 12 (range: 0- 22). Pathogenic genetic alterations of CDKN2A, MYD88, CDKN2B, PRDM1, PIM1, ETV6, CD79B, and IGLL5, as well as aberrant somatic hypermutations, were frequently detected. The frequency of ETV6 loss and PRDM1 alteration (mutation and loss) was 23% and 49%, respectively. Multivariate analysis revealed ETV6 loss (hazard ratio [HR]: 3.26, 95% confidence interval [CI]: 1.08-9.85) and PRDM1 alteration (HR: 2.52, 95% CI: 1.03-6.16) as candidate risk factors associated with CNS progression of PVRL. Moreover, these two genetic factors defined slow-, intermediate-, and rapid-progression groups (0, 1, and 2 factors, respectively), and the median period to CNS progression differed significantly among them (52 vs. 33 vs. 20 months, respectively). Our findings suggest that genetic factors predict the CNS progression of PVRL effectively, and the genetics-based CNS progression model might lead to stratification of treatment.

Automated Lugano Metabolic Response Assessment in 18F-Fluorodeoxyglucose-Avid Non-Hodgkin Lymphoma With Deep Learning on 18F-Fluorodeoxyglucose-Positron Emission Tomography.

Artificial intelligence can reduce the time used by physicians on radiological assessments. For 18F-fluorodeoxyglucose-avid lymphomas, obtaining complete metabolic response (CMR) by end of treatment is prognostic. Here, we present a deep learning-based algorithm for fully automated treatment response assessments according to the Lugano 2014 classification. The proposed four-stage method, trained on a multicountry clinical trial (ClinicalTrials.gov identifier: NCT01287741) and tested in three independent multicenter and multicountry test sets on different non-Hodgkin lymphoma subtypes and different lines of treatment (ClinicalTrials.gov identifiers NCT02257567, NCT02500407; 20% holdout in ClinicalTrials.gov identifier NCT01287741), outputs the detected lesions at baseline and follow-up to enable focused radiologist review. The method's response assessment achieved high agreement with the adjudicated radiologic responses (eg, agreement for overall response assessment of 93%, 87%, and 85% in ClinicalTrials.gov identifiers NCT01287741, NCT02500407, and NCT02257567, respectively) similar to inter-radiologist agreement and was strongly prognostic of outcomes with a trend toward higher accuracy for death risk than adjudicated radiologic responses (hazard ratio for end of treatment by-model CMR of 0.123, 0.054, and 0.205 in ClinicalTrials.gov identifiers NCT01287741, NCT02500407, and NCT02257567, compared with, respectively, 0.226, 0.292, and 0.272 for CMR by the adjudicated responses). Furthermore, a radiologist review of the algorithm's assessments was conducted. The radiologist median review time was 1.38 minutes/assessment, and no statistically significant differences were observed in the level of agreement of the radiologist with the model's response compared with the level of agreement of the radiologist with the adjudicated responses. These results suggest that the proposed method can be incorporated into radiologic response assessment workflows in cancer imaging for significant time savings and with performance similar to trained medical experts.

Prevalence of adverse events following bispecific antibody therapy in non-Hodgkin lymphoma: A meta-analysis.

e19008 Background: Bispecific antibodies (BsAb) have emerged as a new treatment modality for relapsed/refractory non-Hodgkin lymphomas (R/R NHL). They exert their effect by binding to CD3 on T-cells and CD19 or CD20 on lymphoma cells, activating the T-cell to exert cytotoxic effects against the tumor and normal B-cells. Treatment related adverse events (TRAE) include infections, cytokine release syndrome (CRS), neurotoxicity (ICANS). This meta-analysis was conducted to assess prevalence of TRAEs from prospective clinical trials that evaluated BsAb in R/R NHL. Methods: A systematic review was conducted through PubMed, Embase, Scopus, Web of Science, and Cochrane to identify BsAb clinical trials in NHL through October 2023. Eligible studies included phase I-III trials evaluating BsAb in any type of NHL, either as monotherapy or combination therapy irrespective of prior lines of treatment. Primary outcomes of interest include infection, neutropenia, CRS, and ICANS. All studies were weighted equally. Pooled prevalence estimates of TRAE were calculated using common and random effects models. Heterogeneity tests were performed using Cochran’s Q test. Subgroup analysis examined infection rates in monotherapy versus combination therapy cohorts. Results: After screening 1039 studies, 36 clinical trials with 2162 patients were included. The lymphoma subtypes were diffuse-large B cell lymphoma, follicular lymphoma, and mantle cell lymphoma. The BsAbs included mosunetuzumab (13 studies), epcoritamab (10 studies), blinatumomab (5 studies), glofitamab (5 studies), odronextamab (2 studies), and AFM11 (1 study). The median age of patients was 66 years, and patients had received a median of two prior lines of therapy. Median follow-up duration was 9.1 months. The prevalence of all-grade infections was 35% (95% CI: 0.33-0.38; I2 = 79%). For grade ≥3 infections, the prevalence was 16% (95% CI: 0.14-0.18, (I2 = 77%). There were higher rates of all-grade infections in the combination therapy cohort (41%, 95% CI: 0.36-0.47) compared with the monotherapy cohort (33%, 95% CI: 0.30-0.36). All-grade and grade ≥3 neutropenia occurred in 31% (95% CI: 0.29-0.34; I2 = 80%) and 22% (95% CI: 0.20-0.24, I2 = 61%) of patients. CRS was observed in 45% of patients (95% CI: 0.43-0.48, I2 = 85%). Grade ≥3 CRS occurred in only 2% of patients (95% CI: 0.02-0.03, I2 = 0%, p = 0.99). ICANS occurred in 12% (95% CI: 0.10-0.14, I2 = 90%) while grade ≥3 ICANS was rare, at 3% (95% CI: 0.02-0.03, I2 = 0%, p = 0.99). Conclusions: BsAb is associated with nontrivial rates of infections and neutropenia. The rates of high grade CRS and ICANS are low. The heterogeneity of the findings could be attributed by an underreporting of TRAE and small sample sizes from various studies. These results highlight the need for vigilant practices to diagnose and treat infections early and consideration for antibacterial prophylaxis in this immunocompromised population.