Aggressive B-cell Research Articles

Single center, real-world retrospective study of CAR-T cell therapy for relapsed/refractory large B-cell lymphoma beyond second line: five-year results at the University Hospitals Leuven

ABSTRACT Introduction Large B-cell lymphomas (LBCL) are the most frequently aggressive B-cell non-Hodgkin lymphomas. Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has emerged as a new, powerful treatment for relapsed or refractory (R/R) disease. Two CAR-T cell products, tisagenlecleucel (tisa-cel,) and axicabtagene ciloleucel (axi-cel), are reimbursed in Belgium for R/R LBCL beyond second line. Objectives and methods We conducted a retrospective cohort study to report the outcome with tisa-cel and axi-cel for R/R LBCL beyond second line in the years 2019–2023 at the University Hospitals Leuven for 79 patients selected for apheresis and CAR-T infusion. Results Eleven patients (14%) did not proceed to CAR-T cell infusion. For infused patients (n = 68), the best overall response rate (ORR)/complete response (CR) rate was 64%/49% for tisa-cel and 88%/66% for axi-cel (p = 0.04 for ORR). After a median follow-up of 13.8 months, progression-free survival (PFS) and overall survival (OS) at 1 year were 30% and 43% for tisa-cel and 48% and 62% for axi-cel. Cytokine release syndrome (CRS) (all grades/grade ≥3) occurred in 82%/9% after tisa-cel and in 97%/0% after axi-cel. Immune effector cell-associated neurotoxicity syndrome (ICANS) (all grades/grade ≥3) occurred in 24%/18% after tisa-cel and in 54%/40% after axi-cel. The non-relapse mortality in the infusion cohort was 13%. Conclusion Our real-world data show high and durable response rates, with a non-significant trend towards a higher efficacy and higher toxicity for axi-cel compared to tisa-cel. Our results are in line with other real-world registries except for a shorter median OS and more high-grade ICANS.

Insight into Mantle Cell Lymphoma Pathobiology, Diagnosis, and Treatment Using Network-Based and Drug-Repurposing Approaches.

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.

Chimeric antigen receptor T-cell therapy for aggressive B-cell lymphomas.

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

Chromogenic LMO2 mRNA ISH Expression Correlates with LMO2 Protein and Gene Expression and Captures Their Survival Impact in Diffuse Large B-Cell Lymphoma, NOS.

LMO2 is a relevant gene involved in B-cell ontogeny and a survival predictor of aggressive large B-cell lymphomas (aLBCL). Most studies assessing LMO2 mRNA expression have relied on microarray platforms or qRT-PCR methods, overlooking tissue morphology. In this study, we evaluate LMO2 RNA expression by chromogenic in situ hybridization (CISH) in normal tissue and in a series of 82 aLBCL. LMO2 CISH was performed in formalin-fixed paraffin-embedded tissues, scored by three different methods, and correlated with a transcriptome panel. We obtained statistically significant results correlating the methods of evaluation with LMO2 protein expression and gene expression results. Normal tonsil tissue showed high levels of LMO2, particularly within the light zone of the germinal center. Conversely, in aLBCL, a notable reduction in LMO2 expression was noted, remarkably in cases carrying MYC rearrangements. Furthermore, significant results were obtained through overall survival and Cox regression survival analysis, incorporating International Prognostic Index data alongside LMO2 expression levels. We show a reliable method to identify LMO2 mRNA expression by CISH, effectively capturing many of the reported biologic features of LMO2.

Comparative Study on the Clinicopathologic and Molecular Characteristics of Primary and Secondary Diffuse Large B-cell Lymphoma in the Central Nervous System.

Diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL) is an aggressive B-cell lymphoma with clinical and molecular heterogeneity. Primary CNS-DLBCL (PCNSL) affects the brain, eyes, leptomeninges, or spinal cord without systemic involvement. Secondary CNS-DLBCL (SCNSL) manifests concurrently with systemic lymphoma or as an isolated CNS relapse with poor prognosis. Next-generation sequencing (NGS) was used to identify genomic alterations in 32 PCNSL and 9 SCNSL cases. Single nucleotide variants and copy number variations in addition to the clinicopathologic data and proposed risk predictive values were compared to aid in diagnostic differentiation between the two types of lymphomas. The MCD genotype, characterized by mutations in MYD88 and CD79B, is the most common alteration in PCNSL and is associated with lower survival rates. The frequency of MYD88 mutation was significantly higher in PCNSL compared to SCNSL (75.0% vs. 33.3%; p=0.042). Recurrent copy number loss of 6p21 occurred in 56.1% of cases, more often in PCNSL (65.6%) than in SCNSL (22.2%) (p=0.028). Diagnostic positive predictive values (PPV) of MYD88 mutation and 6p21 loss for PCNSL were 89% and 91%, respectively. PPV of both alterations was 93% for the diagnosis of PCNSL. MYD88 mutation and 6p21 loss were significantly higher in PCNSL than in SCNSL, and novel risk prediction models based on these distinct genomic profiles can aid in the clinical differentiation of PCNSL and SCNSL.

Salvage CD20-SD-CART therapy in aggressive B-cell lymphoma after CD19 CART treatment failure.

Patients with relapsed/refractory aggressive B-cell lymphoma(r/r aBCL)who progressed after CD19-specific chimeric antigen receptor T-cell therapy (CD19CART) had a poor prognosis. Application of CAR T-cells targeting a second different antigen (CD20) expressed on the surface of B-cell lymphoma as subsequent anti-cancer salvage therapy (CD20-SD-CART) is also an option. This study aimed to evaluate the survival outcome of CD20-SD-CART as a salvage therapy for CD19 CART treatment failure. This retrospective cohort study enrolled patients with aBCL after the failure of CD19 CART treatment at Beijing Gobroad Boren Hospital from December 2019 to May 2022. Patients were subsequently treated with CD20CART therapy or non-CART therapy (polatuzumab or non-polatuzumab). A total of 93 patients were included in the study, with 54 patients receiving CD20-SD-CART therapy. After a median follow-up of 18.54 months, the CD20-SD-CART group demonstrated significantly longer median progression-free survival (4.04 months vs. 2.27 months, p=0.0032) and median overall survival (8.15 months vs. 3.02 months, p<0.0001) compared to the non-CART group. The complete response rate in the CD20-SD-CART group (15/54, 27.8%) was also significantly higher than the non-CART group (3/38, 7.9%, p=0.03). Multivariate analysis further confirmed that CD20CART treatment was independently associated with improved overall survival (HR, 0.28; 95% CI, 0.16-0.51; p<0.0001) and progression-free survival (HR, 0.46; 95% CI, 0.27-0.8; p=0.005). CD20-SD-CART could serve as an effective therapeutic option for patients with relapsed or refractory aggressive B-cell lymphoma after CD19CART treatment failure.

Abstract PO-038: Unbiased discovery of novel antibody therapies that stimulate macrophage-mediated destruction of B-cell lymphoma

Abstract Monoclonal antibodies are among the most effective treatments for patients with blood cancers, and they primarily function by marking cells for destruction by the innate immune system. Macrophages are critical innate effectors of antibody therapies for lymphoma, but their anti-tumor capacity is limited by the CD47/SIRPa interaction. CD47 acts a “don’t eat me” signal that is highly expressed on the surface of many lymphomas, and it prevents phagocytosis by binding to the inhibitory receptor SIRPa expressed on macrophages. In multiple clinical trials, CD47-blocking therapies have demonstrated encouraging signs of efficacy for B-cell lymphomas, particularly when used in combination with rituximab, an opsonizing anti-CD20 antibody. However, the best antibodies and combination strategies to activate macrophages remains unknown. Here, we sought to define the repertoire of cell surface antigens that can be targeted to stimulate macrophage-mediated destruction of B-cell lymphomas. To achieve this goal, we developed a high-throughput functional screening platform to measure the ability of primary macrophages to attack B-cell lymphoma cells. We successfully applied this system to screen monoclonal antibody libraries targeting hundreds of distinct cell surface antigens across both mouse and human systems. We conducted screens using each antibody as a single agent, in combination with anti-CD20, or in combination with anti-CD47. From these efforts, we identified CD24, CD38, CXCR4, CD71, and multiple other novel and unique antigens that could be targeted alone or in combination to exert maximal macrophage-mediated destruction of B-cell lymphoma. Of note, some of the identified targets are predominantly expressed by the lymphoma cells, whereas others are expressed by the macrophages and act as unappreciated immune checkpoints. In validation studies, we defined a multitude of new antibody combinations that robustly stimulate macrophages to attack and eliminate lymphoma cells. Since some anti-CD47-antibodies have been limited by on-target hematologic toxicity, we also used the identified targets to engineer a collection of novel bispecific antibodies that induce macrophage phagocytosis without causing hematologic toxicity. We generated 156 bispecific antibodies, produced them recombinantly, and demonstrated they can maximize macrophage-mediated cytotoxicity of human B-cell lymphoma cells while minimizing binding to healthy blood cells. In mouse xenograft models, these bispecific antibodies exhibited significant single-agent activity in a model of aggressive B-cell lymphoma. Thus, our study has led to the development of a multitude of novel therapeutic candidates and combination strategies that can be developed further to maximize anti-tumor function and benefit patients with lymphoma. Furthermore, our approach can be rapidly applied to other hematologic malignancies to create innovative bispecific agents that maximize anti-tumor responses by macrophages or other innate immune cells. Citation Format: Juliano Ribeiro, Carlota Pages Geli, José Velarde, Anna Meglan, Jasmine Blandin, Kyle Vaccaro, Marta Crespo, Kipp Weiskopf. Unbiased discovery of novel antibody therapies that stimulate macrophage-mediated destruction of B-cell lymphoma [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-038.

Ciwujianoside E inhibits Burkitt lymphoma cell proliferation and invasion by blocking ENO1-plasminogen interaction and TGF-β1 activation

Burkitt's lymphoma (BL) is a rare and highly aggressive B-cell non-Hodgkin lymphoma. Although the outcomes of patients with BL have greatly improved, options for patients with relapsed and refractory BL are limited. Therefore, there is an urgent need to improve BL therapeutics and to develop novel drugs with reduced toxicity. In this study, we demonstrated that enolase 1 (ENO1) is a potential novel drug target for BL treatment. We determined that ENO1 was aberrantly upregulated in BL, which was closely related to its invasiveness and poor clinical outcomes. Furthermore, using RNA interference, we demonstrated that ENO1 depletion significantly inhibited cell proliferation and invasion both in vitro and in vivo. Mechanistically, we established that ENO1 knockdown suppressed the PI3K-AKT and epithelial-mesenchymal transition (EMT) signaling pathways by reducing plasminogen (PLG) recruitment, plasmin (PL) generation, and TGF-β1 activation. Addition of activated TGF-β1 protein to the culture medium of shENO1 cells reversed the inhibitory effects on cell proliferation and invasion, as well as those on the PI3K-AKT and EMT signaling pathways. Notably, our research led to the discovery of a novel ENO1-PLG interaction inhibitor, Ciwujianoside E (L-06). L-06 effectively disrupts the interaction between ENO1 and PLG, consequently reducing PL generation and suppressing TGF-β1 activation. In both in vitro and in vivo experiments, L-06 exerted impressive antitumor effects. In summary, our study elucidated the critical role of ENO1 in BL cell proliferation and invasion and introduced a novel ENO1 inhibitor, which holds promise for improving the treatment of patients with BL in the future.

Polatuzumab vedotin in diffuse large B-cell lymphoma therapy: Literature review and experience of the Oncohematology Division of the Lapino Clinical Hospital

Study of molecular and genetic features of diffuse large B-cell lymphoma (DLBCL) suggests differential approach to treatment of this aggressive B-cell disorder characterized by short remission after each subsequent therapy line. Therefore, more effective regimens should be used at earlier stages. Identification of biological markers and their integration into prognostic scales can help to personalize therapy, especially in patients with high risk of quick progression and increase survival.Our own experience of using immunoconjugate polatuzumab vedotin in therapy of patients with DLBCL. The use of Pola-BR combination in a patient with refractory non-GCB DLBCL allowed to achieve full remission alongside satisfactory tolerability and absence of significant adverse events. An evaluation of the Pola-R-CHP regimen in treatment of a patient with newly diagnosed generalized GCB DLBCL is presented.

CNS bridging radiotherapy achieves rapid cytoreduction before CAR T-cell therapy for aggressive B-cell lymphomas

AbstractChimeric antigen receptor (CAR) T-cell therapy (CART) for central nervous system lymphoma (CNSL) is a promising strategy, yet responses are frequently not durable. Bridging radiotherapy (BRT) is used for extracranial lymphoma in which it can improve CART outcomes through cytoreduction of high-risk lesions. We hypothesized that BRT would achieve similar, significant cytoreduction before CART for CNSL (CNS-BRT). We identified patients with CNSL with non-Hodgkin B-cell lymphoma who received CNS-BRT before commercial CART. Cytoreduction from CNS-BRT was calculated as change in lesion size before CART. Twelve patients received CNS-BRT, and the median follow-up among survivors is 11.8 months (interquartile range, 8.5-21.9). Ten patients had CNSL (9 secondary, 1 primary) and 2 patients had epidural disease (evaluable for toxicity). All 10 patients with CNSL had progressive disease at the time of CNS-BRT. Of 12 patients, 1 experienced grade ≥3 cytokine release syndrome, and 3 of 12 patients experienced grade ≥3 immune effector cell–associated neurotoxicity syndrome. CNS-BRT achieved a 74.0% (95% confidence interval, 62.0-86.0) mean reduction in lesion size from baseline (P = .014) at a median of 12 days from BRT completion and before CART infusion. Best CNS response included 8 complete responses, 1 partial response, and 1 progressive disease. Three patients experienced CNS relapse outside the BRT field. Preliminary data suggest CNS-BRT achieves rapid cytoreduction and is associated with a favorable CNS response and safety profile. These data support further study of BRT as a bridging modality for CNSL CART.

Diagnosis and differential diagnosis of large B-cell lymphoma with IRF4 rearrangement

Objective: To analyze the clinicopathological features and differential diagnosis of large B-cell lymphoma with IRF4 rearrangement, aiming enhance its recognition and prevent misdiagnosis. Methods: The clinicopathological features, immunophenotype, and fluorescence in situ hybridization (FISH) results of six cases diagnosed with IRF4 rearrangement-positive B-cell lymphoma at the Affiliated Hospital of Xuzhou Medical University from 2015 to 2023 were retrospectively analyzed. Additionally, a comprehensive review of the literature was conducted. Results: Six patients with IRF4 rearrangement-positive large B-cell lymphoma were included. Patients 1 to 5 included three males and two females with a median age of 19 years ranging from 11 to 34 years. Four patients presented with head and neck lesions, while the other one had a breast nodule; all were in clinical Ann Arbor stages I to Ⅱ. Morphologically, entirely diffuse pattern was present in two cases, purely follicular pattern in one case, and diffuse and follicular patterns in other two cases. The tumor cells, predominantly centroblasts mixed with some irregular centrocytes, were of medium to large size, with a starry sky appearance observed in two cases. Immunophenotyping revealed all cases were positive for bcl-6 and MUM1, with a Ki-67 index ranging from 70% to 90%, and CD10 was positive in two cases. IRF4 rearrangement was confirmed in all cases by FISH analysis, with dual IRF4/bcl-6 rearrangements identified in two cases, leading to a diagnosis of LBCL-IRF4. Case 6, a 39-year-old female with a tonsillar mass and classified as clinical Ann Arbor stage Ⅳ, displayed predominantly diffuse large B-cell lymphoma (DLBCL) morphology with 20% high-grade follicular lymphoma characteristics. Immunohistochemistry showed negative CD10 and positive bcl-6/MUM1, with a Ki-67 index of approximately 80%. Triple rearrangements of IRF4/bcl-2/bcl-6 were identified by FISH, leading to a diagnosis of DLBCL with 20% follicular lymphoma (FL). All six patients achieved complete remission after treatment, with no progression or relapse during a follow-up period of 31-100 months. Conclusions: Large B-cell lymphoma with IRF4 rearrangement is a rare entity with pathological features that overlap with those of FL and DLBCL. While IRF4 rearrangement is necessary for diagnosing LBCL-IRF4, it is not specific and requires differentiation from other aggressive B-cell lymphomas with IRF4 rearrangement.

Impact of military deployment on non-Hodgkin lymphoma subtype.

e19070 Background: Approximately 3.5 million activity duty service members (ADSM) have deployed to Afghanistan or Iraq from 2001-2022. During deployments, ADSMs are potentially exposed to deployment-related toxins and carcinogens, which could theoretically alter cancer biology. In terms of non-Hodgkin lymphoma (NHL), it is unclear whether deployment affects NHL subtype or cancer-specific survival. Methods: Deployment and occupation data from the Defense Manpower Data Center was merged with data from the Department of Defense Tumor Registry. Documented cases of NHL diagnosed from 2001-2022 were identified. ADSMs and retirees were included; dependents and those under the age of 18 were excluded. Differences in NHL subtype (aggressive B-cell, indolent B-cell, T-cell) and cancer-specific survival were assessed by deployment status (previously deployed vs. never deployed). Occupation was assessed among those who deployed. Propensity score matching (2:1) for age at diagnosis, year of diagnosis, and gender was performed to minimize confounding. All data were carried out using SAS and Jump statistical software. This study was approved by the IRB. Results: There were 2,599 ADSMs and retirees diagnosed with NHL between 2001-2022. Approximately 15% had previously deployed (n=398). Compared with never deployed, military personnel who had previously deployed were more likely to have aggressive B-cell NHL (45% vs. 34%) and less likely to have indolent B-cell NHL (50% vs. 54%) or T-cell NHL (6% vs. 12%), p&lt;0.001. Deployment to Iraq or Afghanistan did not impact NHL subtype. During deployment, occupations of Infantry, Engineering and Healthcare did not impact NHL subtype, whereas occupations of Pilot/Aircrew and Intelligence did, with less T-cell lymphoma diagnosed (0 vs. 7%, and 3% vs. 8%, respectively). When evaluating NHL subtype by race, it was noted that in comparison to White, Asian, Pacific Islander and Other Race, Black Race was associated with more T-cell NHL (21%), largely comprised of cutaneous T-cell lymphoma. Conclusions: After propensity score matching, prior deployment was associated with more aggressive B-cell lymphoma than military personnel who had never deployed. Deployment occupation affected NHL subtype diagnosed, with Pilots/Aircrew and Intelligence personnel being less likely to have T-cell lymphoma, whereas Black Race was associated with a higher likelihood of having T-cell lymphoma. This study sheds insights into the impact of deployment on cancer subtype. Ongoing investigations are assessing mortality differences by deployment as well as causes of death.

Interim results from the ELiPSE-1 study: A phase 1, multicenter, open-label study of CNTY-101 in subjects with relapsed or refractory CD19-positive B-cell malignancies.

7023 Background: CNTY-101 is an allogeneic, iPSC-derived anti-CD19 Chimeric Antigen Receptor NK (CAR-iNK) cell product with Allo-Evasion edits to avoid host rejection. Potential benefits of CNTY-101 include immediate availability for treatment, repeat dosing without the need for lymphodepletion, and the potential for improved safety over T-cell based therapies. The first-in-human Phase 1 clinical trial of CNTY-101, ELiPSE-1 (NCT05336409), evaluates safety, preliminary efficacy, PK, and translational biomarkers in patients with CD19-positive B-cell malignancies. Methods: Subjects with R/R aggressive and indolent B-cell NHL received lymphodepletion (LDC) followed by assignment to 100e6, 300e6 or 1e9 cells at either Day 1 (Schedule A) or Days 1, 8 and 15 (Schedule B). Eligible subjects (ie, achieved SD or better at Day 28 by PET/CT) can receive additional cycles, with or without one additional regimen of LDC. Subjects also receive daily subcutaneous injections of IL-2 for 8 days (A) or 4 days (B) following each infusion. Results: At time of abstract submission, 10 subjects have been treated (n=4 DL1A; n=3 DL2A; n=2 DL3A; n=1 DL2B). Three subjects (1 at DL1A, 2 at DL2A) received additional cycle(s) of CNTY-101. Three subjects have not yet been evaluated for full safety and efficacy within the DLT window. Seven subjects (n=5 DLBCL; n=1 FL; n=1 MZL) had data available as of the data cut (Nov 30, 2023). All had stage 4 disease, 6/7 were refractory to last line of therapy, with a median of 4 (2-5) prior lines of therapy including CAR T (3/7). No DLTs, GvHD or ICANs were observed. Two subjects had cytokine release syndrome (n=1 Gr 1, n=1 Gr 2), all responding promptly to treatment. ORR/CRR was 25%/25% for 100e6 cells (DL1A) and 67%/33% for 300e6 cells (DL2A). Dose escalation is ongoing. In subjects from all three dose levels, CNTY-101 rapidly traffics out of circulation after infusion and is observed via cell-free DNA on Day 3 and detected up to 28 days. CNTY-101 persistence was not adversely impacted when given without lymphodepletion in two subjects who received additional cycles of CNTY-101. Induction of functional humoral immunogenicity against CNTY-101 was not observed at any of the dose levels, regardless of single or multiple cycles of CNTY-101. Adaptive immune responses were observed in the tumor microenvironment on Day 8. Conclusions: CNTY-101 administered as a single dose in multiple cycles has demonstrated a manageable safety profile and preliminary evidence of efficacy. Allo-Evasion edits may allow for repeat dosing for multiple cycles without allorejection in the absence of lymphodepletion. Preliminary efficacy supports dosing at higher dose levels and with more dose-intense regimens. Updated safety, efficacy, PK, and CNTY-101's impact on tumor for DL3A and DL2B will be provided. Clinical trial information: NCT05336409 .

Incidence of any infections and SARS-CoV-2 infections in patients receiving treatment for follicular lymphoma and diffuse large B-cell lymphoma: Real-world evidence from a large US national claims database.

e19061 Background: Non-Hodgkin’s lymphoma is a heterogeneous group of conditions, including the indolent subtype follicular lymphoma (FL) and the aggressive subtype diffuse large B-cell lymphoma (DLBCL). Infections associated with NHL are a major concern due to effects of the underlying disease and its treatment and have been reported to increase with increasing lines of therapy (LoT). However, the risk of infections overall and SARS-COV-2 infections specifically is not well characterized in patients who have received multiple LoTs. The goal of the study was to estimate the exposure-adjusted incidence rates (EAIR) of infections during the COVID-19 pandemic by type, severity and LoT received in patients treated for FL or DLBCL in the real-world setting. Methods: We identified patients in the Optum Clinformatics claims data from October 1, 2015, to June 30, 2023. Patients were aged ≥18 years, enrolled continuously for 365 days before index (start of LoT), and had ≥2 ICD-10 diagnosis codes for FL or DLBCL in the 365 days before index. The EAIR (per 100 person-years, PY) was estimated for infections by type (any infections and SARS-COV-2 [after 1/1/2020]), severity (hospitalized or fatal hospitalizations), and number of LoTs received. Results: A total of 4,799, 1,025 and 510 FL patients were included in the 1L (1 LoT), 2L, and 3L+ cohorts, respectively. The EAIR of infections resulting in hospitalization in 1L, 2L, and 3L+ cohorts were 20.6 (95% confidence interval (CI): 19.0-22.3), 30.2 (25.5-35.9), and 44.2 (35.4-55.3) per 100-PY for any infection; and 4.6 (4.0-5.4), 4.4 (3.0-6.5) and 8.3 (5.3-13.2) per 100-PY for SARS-COV-2 infections, respectively. The EAIR of fatal hospitalizations were 4.0 (3.4-4.8), 8.6 (6.4-11.5), and 13.9 (9.7-20.0) per 100-PY for any infection; and 1.3 (1.0-1.7), 1.6 (0.8-3.0), and 4.1 (2.2-7.9) per 100-PY for SARS-COV-2 infections. A total of 8,058, 2,114 and 977 DLBCL patients were included in 1L, 2L, and 3L+ cohorts, respectively. The EAIR of infections resulting in hospitalization in 1L, 2L, and 3L+ cohorts were 64.2 (60.7-67.8), 85.2 (76.9-94.3), and 113.4 (98.4-130.7) per 100-PY for any infection; and 6.3 (5.5-7.2), 7.3 (5.6-9.6), and 15.1 (11.3-20.2) per 100-PY for SARS-COV-2 infections respectively. The EAIR of fatal hospitalizations were 12.0 (10.8-13.3), 23.0 (19.5-27.1), and 27.8 (22.1-34.9) per 100-PY for any infection; and 1.6 (1.2-2.1), 2.7 (1.7-4.2), and 4.8 (2.9-8.0) per 100-PY for SARS-COV-2 infections in 1L, 2L and 3L+ cohorts, respectively. Conclusions: This real-world analysis demonstrated substantial morbidity and mortality associated with overall and SARS-COV-2 infections among NHL patients, with a higher incidence in DLBCL compared to FL, and with increasing LoTs.

Incidence of central nervous system relapse in primary mediastinal B-cell lymphoma: Implications for central nervous system prophylaxis.

7080 Background: Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon type of aggressive B-cell non-Hodgkin lymphoma. PMBCL has distinct clinicopathologic features compared to diffuse large B-cell lymphoma but shares some clinical and biologic features with nodular sclerosis classic Hodgkin lymphoma (cHL). Central nervous system (CNS) relapse is exceedingly rare in cHL, therefore one may expect that CNS relapse in PMBCL is also uncommon. Herein, we examined the incidence of CNS relapse in patients with PMBCL. Methods: Patients with newly diagnosed PMBCL seen at Mayo Clinic between 1/2002 and 4/2023 were identified from the Mayo Clinic Lymphoma Database. Clinical features, treatment details and outcomes were abstracted from medical records. The CNS relapse rate was calculated using a competing risk model, with death considered as a competing risk. Results: A total of 154 PMBCL cases were identified. The median age at diagnosis was 38 years (range 18-77) and 60.4% were female. The distribution of CNS-IPI was low-risk in 80 (51.9%) patients, intermediate-risk in 43 (27.9%), and high-risk in 3 (1.9%), and data were missing for 28 patients (18.2%). 78 patients (50.6%) received R-CHOP and 76 patients (49.4%) received R-DA-EPOCH as frontline therapy. High-dose methotrexate (HD-MTX) for CNS prophylaxis was administered to 5 patients (all treated with R-CHOP). 20 patients received intrathecal (IT) chemotherapy (methotrexate and/or cytarabine) for CNS prophylaxis (4 with R-CHOP [1 received HD-MTX too],16 with R-DA-EPOCH). The median follow-up was 39 months (95% CI 28.2-49.8). Only 3 patients had CNS relapse, all associated with systemic relapse (1 concurrent, 1 had CNS relapse 8.8 months after systemic relapse, 1 had CNS relapse 2 months before systemic relapse). The cumulative incidence of CNS relapse for the entire cohort was 1.43% (95% CI 0.3%-4.6%) at 1 year and 2.21% (95% CI 0.6%-5.8%) at both 2 and 5 years. For those who did not receive CNS prophylaxis (n=130), the incidence was 0.86% (95% CI 0.1%-4.3%) at 1 year and 1.82% (95% CI 0.4%-5.8%) at both 2 and 5 years. All 3 patients who experienced CNS relapse had R-CHOP as frontline therapy; two patients did not receive any CNS prophylaxis, while 1 patient received IT CNS prophylaxis. Conclusions: The risk of isolated CNS relapse in PMBCL appears to be very low, even in patients who did not receive CNS prophylaxis. While some patients may experience CNS relapse associated with systemic relapse, the overall incidence was low (1.43% at 1 year and 2.21% at 2 and 5 years). The rarity of isolated CNS relapse in PMBCL suggests that routine CNS prophylaxis may not be necessary as part of initial therapy.

Clinical analysis of 18 children with aggressive mature B-cell lymphoma after liver transplantation

Objective: To summarize the clinical characteristics, prognostic factors and treatment outcomes of childhood aggressive mature B-cell lymphoma after liver transplantation. Methods: This retrospective study included 18 children with newly diagnosed aggressive mature B-cell lymphoma after liver transplantation and treated from June 2018 to June 2022 in the Department of Hematology and Oncology of Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine. Clinical characteristics, treatment and outcomes of patients at last evaluation were analyzed. Overall survival (OS) and event free survival (EFS) rates were calculated by Kaplan-Meier method and Log-Rank analysis was performed to find factors of poor prognosis. Results: Among all 18 patients, there were 6 males and 12 females, and the age of onset was 40 (35, 54) months. The interval from transplant to tumor diagnosis was 21 (17, 35) months and 5 patients had early onset disease (<1 year since transplant). Seventeen patients had abdominal lesions. Diarrhea, vomiting and abdominal masses were the main clinical manifestations. All patients were Epstein-Barr virus (EBV) related posttransplant lymphoproliferative disorders (PTLD). One patient received individualized therapy due to critical sick at diagnosis, and the remaining 17 patients received CP (cyclophosphamide, methylprednisolone plus rituximab) and/or modified EPOCH (prednisone, etoposide, doxorubicin, vincristine, cyclophosphamide plus rituximab) regimens. Of all 18 patients, 15 cases got complete response, 2 cases got partial response, 1 patient died of severe infection. The 2-year OS and EFS rates of 18 patients were (94±5)% and (83±8)%, respectively. None of age, gender or early onset disease had effect on OS and EFS rates in univariate analysis (all P>0.05). Conclusions: The symptoms of PTLD were atypical. Close surveillance of EBV-DNA for patients after liver transplantation was crucial to early stage PTLD diagnosis. CP or modified EPOCH regimen was efficient for pediatric patients with aggressive mature B cell lymphoma after liver transplantation.

Relapse after glofitamab has a poor prognosis and rates of CD20 loss are high.

We reviewed cases with aggressive B-cell non-Hodgkin lymphoma who relapsed or progressed following glofitamab. The prognosis was poor, with low rates of response to subsequent salvage therapies, and a median overall survival of 4.1 months from the time of progression. There were high rates of CD20 loss (59%) at the time of relapse. In a field where CD20 × CD3 bispecific antibodies are entering routine clinical use, our experience highlights a potential means of resistance. It illustrates both the need to further characterise mechanisms of CD20 loss, and to pursue clinical trials of novel non-CD20-directed treatments in this cohort.

Economic evaluation of anti-CD19 CAR T-cell pathway for large B-cell lymphomas in the real-life setting: the experience of an Italian hub center in the first three years of activity

Poor literature report actual and detailed costs of chimeric antigen receptor (CAR) T-cell pathway in a real-life setting. We retrospectively collect data for all patients with relapsed/refractory aggressive large B-cell lymphoma who underwent leukapheresis between August 2019 and August 2022. All costs and medical resource consumption accountability were calculated on an intention-to-treat (ITT) basis, starting from leukapheresis to the time when the patient (infused or not) exited the CAR T-cell pathway for any reason. Eighty patients were addressed to leukapheresis and 59 were finally infused. After excluding CAR-T product cost, the main driver of higher costs were hospitalizations followed by the examinations/procedures and other drugs, respectively 43.9%, 26.3% and 25.4% of the total. Regarding costs of drugs and medications other than CAR T products, the most expensive items are those referred to AEs, both infective and extra-infective within 30 days from infusion, that account for 63% of the total. Density plot of cost analyses did not show any statistically significant difference with respect to the years of leukapheresis or infusion. To achieve finally 59/80 infused patients the per capita patients without CAR-T products results 74,000 euros. This analysis covers a growing concern on health systems, the burden of expenses related to CAR T-cell therapy, which appears to provide significant clinical benefit despite its high cost, thus making economic evaluations highly relevant. The relevance of this study should be also viewed in light of continuously evolving indications for this therapy.

T-cell recruiting immunotherapies in B-cell lymphoma - the future backbone for all therapy lines?

The introduction of immunologically targeted therapies has represented a significant advancement in the treatment of B-cell lymphomas, particularly aggressive B-cell lymphoma. CD19 CAR-T cells such as Axicabtagen-Ciloleucel (Axi-cel) and Lisocabtagen Maraleucel (Liso-cel) have been approved since 2022 and 2023, respectively, for second-line therapy of Diffuse Large B-Cell Lymphomas (DLBCL), when there is primary refractory disease or relapse within 12 months after the end of first-line therapy. These therapies result in a significant improvement in progression-free survival compared to the previous standard therapy (salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation). Especially in elderly patients or patients with underlying medical conditions, CAR-T cell therapies like Axi-cel and Liso-cel demonstrate acceptable tolerability and high efficacy.Furthermore, bispecific T-cell-engaging antibodies ("bispecifics") such as Glofitamab, Epcoritamab, and Mosunetuzumab also represent promising treatment options for patients with relapsed disease after failure of second- or later line therapy and show efficacy even in a subset of patients relapsing after CD19 CAR-T cells. However, randomized study results for these substances are not yet available. They are expected to be used in earlier lines of therapy in the future, especially in combination with standard chemotherapy regimens. Common side effects of bispecific antibody therapies are cytokine release syndrome (CRS) and immune-mediated cytopenias, whereas immune-cell associated neurotoxicity syndrome (ICANS) is relatively rare compared to CD19 CAR T cells. In summary, bispecifics represent a novel, highly effective immunotherapy for the treatment of lymphomas with a very favourable toxicity profile.

New classifications of malignant lymphomas - What changes are relevant for practice?

An internationally uniform lymphoma classification is of fundamental importance for the comparability of clinical studies. There are currently 2 parallel classifications: the "International Consensus Classification" and the WHO-classification. Follicular lymphoma 3B is classified separately as follicular large cell lymphoma in WHO-HAEM5. The diagnostic criteria of lymphoplasmocytic lymphoma (LPL) have been adjusted, both classifications recommend molecular testing for MYD88 and CXCR4 mutations. There are no significant diagnostic changes in aggressive B-cell lymphomas. The ICC classify NLPBL and THRLBCL into the group of large B-cell lymphomas (LBCL). NLPHL/NLPBL-specific therapy must be considered, which differs greatly from the therapy of DLBCL, especially in the early stages. Peripheral T-cell lymphomas are a group of nodal T-cell lymphomas with a TFH phenotype and frequent mutations; peripheral T-cell lymphoma (NOS) is therefore a diagnosis of exclusion. Indolent T-cell lymphomas/lymphoproliferations of the GI tract are rare but must be differentiated from aggressive T-cell lymphomas. The WHO-HAEM5 also includes reactive/non-neoplastic lymph node lesions classified according to B or T cell predominance.