Diffuse Large B-Cell Lymphoma With Cardiac Invasion Presented as Acute Myocardial Infarction and Left Ventricular Hypertrophy: A Case Report.

Primary cardiac lymphoma is an exceedingly rare malignant tumor, with diffuse large B-cell lymphoma (DLBCL) being the most prevalent histological subtype. This disease has non-specific clinical manifestations, making early diagnosis crucial. However, DLBCL diagnosis is commonly delayed, and its prognosis is typically poor. Herein, we report the case of a 51-year-old male patient with DLBCL who presented with recurrent chest tightness for 4 months as the primary clinical symptom. The patient was admitted to the hospital and diagnosed with acute myocardial infarction and left ventricular hypertrophy with heart failure. Echocardiography revealed a progression from left ventricular thickening to local pericardial thickening and adhesion in the inferior and lateral walls of the left ventricle. Finally, pathological analysis of myocardial biopsy confirmed the diagnosis of DLBCL. After treatment with the R-CHOP chemotherapy regimen, the patient's chest tightness improved, and he was discharged. After 2 months, the patient succumbed to death owing to sudden ventricular tachycardia, ventricular fibrillation, and decreased blood pressure despite rescue efforts. Transthoracic echocardiography is inevitable for the early diagnosis of DLBCL, as it can narrow the differential and guide further investigations and interventions, thereby improving the survival of these patients.

Prognostic significance of myeloid-derived suppressor cells and systemic inflammation in newly diagnosed diffuse large B cell lymphoma treated with chemoimmunotherapy.

The revised International Prognostic Index (R-IPI) is an important prognostic tool in diffuse large B cell lymphoma (DLBCL); however, outcomes can vary markedly within R-IPI groups, and additional prognostic markers are needed. We conducted a prospective observational study to evaluate the circulating immature myeloid (IM) cell subsets and cytokine profiles of 31 patients with newly diagnosed DLBCL before and after chemoimmunotherapy. Among circulating IM cells, myeloid-derived suppressor cells (MDSCs) were the predominant cell type (73.8% ± 26%). At baseline, circulating monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) were predominantly mutually exclusive. Patients with DLBCL clustered into three distinct immunotypes according to MDSC levels and subtype predominance: M-MDSChigh, PMN-MDSChigh, and MDSClow. The M-MDSChigh immunotype was associated with the germinal center B cell-like (GCB) subtype and elevated serum IL-8 and MIP-1α levels. PMN-MDSChigh was associated with the non-GCB subtype and elevated IL-8, MCP-1, IP-10, TNFα, and IL-1Ra levels. Standard chemoimmunotherapy partially reduced M-MDSC distribution across the MDSClow and M-MDSChigh groups. By contrast, among the MDSClow and PMN-MDSChigh groups, PMN-MDSCs persisted after treatment. Two high-risk patients with non-GCB DLBCL and MDSClow immunotype experienced early disease recurrence within 12 months of treatment completion. This study demonstrates that distinct types of MDSCs are associated with subtypes of DLBCL. MDSC levels are dynamic and may be associated with disease status. Persistence of PMN-MDSCs among high-risk patients with DLBCL may be associated with early relapse.

Are we closer to a standard of care for Richter's syndrome? Novel treatments on the horizon.

INTRODUCTION: The therapeutic landscape for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has significantly evolved over the past decade with dramatically improved outcomes with the introduction of targeted therapies. This unfortunately has not been the case for Richter transformation (RT), the histologic transformation to a more aggressive lymphoma, most typically diffuse large B-cell lymphoma (DLBCL). As such, RT continues to be one of the most challenging complications of CLL/SLL. Historically, RT has a poor response to treatment, with a minority reaching complete remission (CR) and overall survival (OS) being less than a year. AREAS COVERED: The focus of this review is to discuss the effectiveness of commonly used regimens, and review existing data for emerging regimens being examined in ongoing clinical trials to improve prognosis and outcomes in patients with RT. Despite extensive efforts to optimize therapies for RT, there is still no generalized consensus on either first-line treatment regimens or regimens in the relapsed/refractory setting. RT continues to carry a high mortality rate without durable response to current therapeutic agents. EXPERT OPINION: Ongoing and future research may identify novel treatment approaches that will eventually improve outcomes for patients with RT. The optimal care for RT patients is a clinical trial, when feasible.

Molecular targets of glucocorticoids that elucidate their therapeutic efficacy in aggressive lymphomas.

Glucocorticoids have been used for decades to treat lymphomas without an established mechanism of action. Using functional genomic, proteomic, and chemical screens, we discover that glucocorticoids inhibit oncogenic signaling by the B cell receptor (BCR), a recurrent feature of aggressive B cell malignancies, including diffuse large B cell lymphoma and Burkitt lymphoma. Glucocorticoids induce the glucocorticoid receptor (GR) to directly transactivate genes encoding negative regulators of BCR stability (LAPTM5; KLHL14) and the PI3 kinase pathway (INPP5D; DDIT4). GR directly represses transcription of CSK, a kinase that limits the activity of BCR-proximal Src-family kinases. CSK inhibition attenuates the constitutive BCR signaling of lymphomas by hyperactivating Src-family kinases, triggering their ubiquitination and degradation. With the knowledge that glucocorticoids disable oncogenic BCR signaling, they can now be deployed rationally to treat BCR-dependent aggressive lymphomas and used to construct mechanistically sound combination regimens with inhibitors of BTK, PI3 kinase, BCL2, and CSK.

Effective bridging strategies prior to infusion with tisagenlecleucel results in high response rates and long-term remission in relapsed/refractory large B-cell lymphoma: findings from a German monocentric study.

BACKGROUND: Incorporating chimeric antigen receptor (CAR)-T cell therapy into relapsed or refractory large B-cell lymphoma (rr LBCL) treatment algorithms has yielded remarkable response rates and durable remissions, yet a substantial portion of patients experience progression or relapse. Variations in outcomes across treatment centers may be attributed to different bridging strategies and remission statuses preceding CAR-T cell therapy. PATIENTS: Twenty-nine consecutive adult patients receiving tisagenlecleucel (tisa-cel) for rr LBCL from December 2019 to February 2023 at Jena University Hospital were analyzed. RESULTS: The median age was 63, with a median of 3 prior treatments. Twenty patients (69%) were refractory to any systemic therapy before CAR-T cell treatment. Following leukapheresis, 25 patients (86%) received bridging therapy with the majority undergoing chemotherapy (52%) or combined modality therapy (32%). Radiotherapy (RT) was part of the bridging strategy in 44%, with moderately hypofractionated involved site RT (30.0 Gy/2.5 Gy) being applied most frequently (64%). Post-CAR-T infusion, the objective response rate at 30 days was 83%, with 55% achieving complete response. Twelve-month progression-free (PFS) and overall survival (OS) were 60% and 74%, respectively, with a median follow up of 11.1 months for PFS and 17.9 months for OS. Factors significantly associated with PFS were chemotherapy sensitivity pre-leukapheresis and response to bridging. CONCLUSION: The study underscores the importance of minimal tumor burden at CAR-T initiation, emphasizing the need for suitable bridging regimens. The findings advocate for clinical trials and further real-world analyses to optimize CAR-T cell therapy outcomes by identifying the most effective bridging strategies.

Combination of chidamide and PD-1 blockade in Refractory/Relapsed aggressive large B-cell lymphomas with high risk of failing CAR-T therapy.

BACKGROUND: Refractoriness and relapse after chimeric antigen receptor T-cell therapy have emerged as major challenges for immunotherapy of aggressive large B-cell lymphoma. Thus far, there is no consensus on how to address treatment failure and whether to administer maintenance therapy following CAR-T cell therapy. METHODS: From August 2017 through November 2022, 52 patients with refractory/relapsed aggressive LBCL who had a high risk of resistance to CAR-T cell therapy were given chidamide in combination with a PD-1 inhibitor as maintenance therapy following either CAR19/22 T-cell cocktail therapy or CAR19/22 T-cell cocktail therapy plus autologous stem cell transplantation (ASCT). Another 52 aggressive LBCL patients who had comparable baseline characteristics and received similar therapeutic regimens but did not receive any interventions following CAR-T cell therapy or CAR-T cell therapy plus ASCT were regarded as the control group to evaluate the efficacy and safety of the combination of chidamide and a PD-1 inhibitor. RESULTS: Among the 52 patients who received chidamide and a PD-1 inhibitor as maintenance therapy, with a median follow-up of 26.5 months (range: 1.1-53.8), neither the median progression-free survival (PFS) nor overall survival (OS) was reached, and the expected 2-year OS and PFS rates were 89 % and 77 %, respectively, which were superior to those of the control group (p < 0.001). Long-term chidamide administration and a specific genetic subtype of EZB were strongly associated with a better response after chidamide plus PD-1 blockade therapy. Additionally, long-term chidamide administration was significantly associated with prolonged persistence and reactivation of CD19-directed CAR-T cells in the peripheral blood. Adverse effects (AEs) were moderate and reversible, and no treatment-related deaths occurred. CONCLUSION: Our results indicate that the combination of chidamide and PD-1 blockade as maintenance therapy could improve the outcomes of aggressive LBCL patients at high risk of failing CAR-T cell therapy.

Outcomes of the transformation of follicular lymphoma to diffuse large B-cell lymphoma in the rituximab era: A population-based study.

BACKGROUND: Histological transformation (HT) to diffuse large B-cell lymphoma (DLBCL) is a common complication of follicular lymphoma (FL) and is usually associated with a dismal outcome. However, the survival rate of these patients has improved over the last 20 years with the introduction of rituximab. This study aimed to access the outcome of transformation to DLBCL (t-DLBCL) from FL in a retrospective series that began after the widespread use of rituximab use. In addition, we also compared survival between t-DLBCL and primary DLBCL (p-DLBCL) in the same timeframe. METHODS: We utilized the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with primary FL and patients with p-DLBCL between 2000 and 2020. Patients who had a subsequent diagnosis of DLBCL at least 2 months after FL diagnosis were identified as t-DLBCL. RESULTS: Finally, we identified 50,332 FL and 95,933 p-DLBCL. With a median follow-up of 119 months, 1631 patients developed t-DLBCL. The median time from FL diagnosis to t-DLBCL was approximately 4 years. The post-transformation survival (PTS) rate at 5 years was 49.6%, with a median PTS of 56 months. Older age, advanced stage, and early transformation were associated with worse PTS. Furthermore, t-DLBCL receiving chemotherapy or combined modality as initial therapy before HT was also associated with worse PTS, while the result was inverse when taking the impact of initial management strategy at HT into account. Taking t-DLBCL and p-DLBCL as a whole, comparable survival was observed between p-DLBCL and t-DLBCL receiving radiation or watch-and-wait as initial therapy prior to HT. CONCLUSION: The outcome of t-DLBCL in the rituximab era was better than historical series before the rituximab era. Due to the good prognosis, we did not recommend autologous stem cell transplantation for t-DLBCL receiving watch-and-wait or radiation as initial therapy before HT.

Primary lymphoma of the female genital tract masquerading as gynecological malignancy.

BACKGROUND: Primary lymphoma of the female genital tract (PLFGT) is a rare malignant tumor in the female reproductive system, with a low incidence and few clinical reports. The aim of this study is to report our institutional experience with this rare malignancy and emphasize the need for increasing the awareness about PLFGT presenting with gynecologic symptoms. METHODS: The medical records of patients diagnosed with PLFGT from March 2014 to November 2022 in the First Affiliated Hospital of Wannan Medical College were reviewed. Histological classification and staging were based on the World Health Organization and Ann Arbor systems, respectively. RESULTS: There were 13 patients with diagnosis of PLFGT and the median length of follow-up was 31 months (0-102 months). The main clinical symptoms included postmenopausal vaginal bleeding, pelvic mass and abdominal pain. Serum LDH increased in 10 patients and serum CA125 elevated in 2 patients. The tumor of ovarian or uterine presented as solid masses in CT or MRI, and ascites was rare. The histological subtypes were diffuse large B-cell (n = 12) and follicular (n = 1) lymphoma. Tumors were located in ovary (n = 8), uterus (n = 3), and cervix (n = 2). According to the Ann Arbor staging system, 6 cases were classified as stage II and 7 cases were classified as stage IV, respectively. A total of 10 patients underwent surgery. Combination chemotherapy was used in 10 patients. Eight patients had tumor-free survival, 1 patient had recurrent disease, 3 patients died and 1 patient lost to follow-up. The median survival time was 32 months (1-102 months). CONCLUSION: PLFGT usually presents as gynecological symptoms and solid masses in pelvis. Surgery or biopsy was the way to obtain the pathologic diagnosis, and combination chemotherapy is the efficient method for PLFGT. Making an accurate preoperative diagnosis is of paramount importance to avoid radical gynecologic surgery.

Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel.

Bendamustine has been retrospectively shown to be an effective and safe lymphodepletion regimen prior to the anti-CD19 chimeric antigen receptor T cell (CART) products tisagenlecleucel and axicabtagene ciloleucel, as well as the anti-BCMA CART products idecabtagene vicleucel and ciltacabtagene autoleucel. However, bendamustine as lymphodepletion prior to lisocabtagene maraleucel (liso-cel), a 4-1BB co-stimulated, fixed CD4:CD8 ratio anti-CD19 CART product, has not been described yet. Thus, we studied a cohort of sequentially-treated patients with large B-cell lymphomas who received bendamustine lymphodepletion before liso-cel at the University of Pennsylvania between 5/2021 and 12/2023 (n = 31). Patients were evaluated for toxicities and responses. Of note, 7 patients (22.6%) would have dnot met the inclusion criteria for the registrational liso-cel clinical trials, mostly due to older age. Overall and complete response rates were 76.9% and 73.1%, respectively. At a median follow-up of 6.3 months, the 6-month progression-free and overall survival were 59.9% and 91.1%, respectively. Rates of cytokine-release syndrome (CRS) and neurotoxicity (ICANS) of any grade were 9.7% and 9.7%, respectively, with no grade ≥ 3 events. No infections were reported during the first 30 days following liso-cel infusion. Neutropenia ≥ grade 3 was observed in 29.0% of patients; thrombocytopenia ≥ grade 3 occurred in 9.7%. In conclusion, bendamustine lymphodepletion before liso-cel appears to be a strategy that can drive tumor responses while ensuring a mild toxicity profile.

[Successful polatuzumab vedotin and rituximab therapy for post-CAR-T relapse of diffuse large B-cell lymphoma].

Relapse or progressive disease after chimeric antigen receptor T-cell (CAR-T) treatment remains a major issue for poor-risk aggressive large B-cell lymphoma. However, limited data are available on post-CAR-T use of polatuzumab vedotin. Here we describe the case of a patient with diffuse large B-cell lymphoma (DLBCL) who experienced relapse three months after CD19-directed CAR-T therapy with tisagenlecleucel. However, the relapsed lesions rapidly disappeared following treatment with polatuzumab vedotin and rituximab. Notably, long-term remission was achieved without severe cytopenia, infections or peripheral neuropathy, showing the therapeutic benefit of polatuzumab vedotin for CAR-T failure.

Identification of a novel form of caspase-independent cell death triggered by BH3-mimetics in diffuse large B-cell lymphoma cell lines.

BH3-mimetics represent promising anti-cancer agents in tumors that rely on the anti-apoptotic function of B-Cell Lymphoma 2 (BCL2) proteins, particularly in leukemia and lymphoma cells primed for apoptosis. Mechanistically, BH3-mimetics may displace pro-apoptotic binding partners thus inducing BAX/BAK-mediated mitochondrial permeabilization followed by cytochrome c release, activation of the caspase cascade and apoptosis. Here, we describe a novel mode of caspase-independent cell death (CICD) induced by BH3-mimetics in a subset of diffuse large B-cell lymphoma (DLBCL) cells. Of note, rather than occurring via necroptosis, CICD induced immediately after mitochondrial permeabilization was associated with transcriptional reprogramming mediated by activation of c-Jun N-terminal Kinase (JNK) signaling and Activator Protein 1 (AP1). Thereby, CICD resulted in the JNK/AP1-mediated upregulation of inflammatory chemokines and increased migration of cytotoxic Natural Killer (NK) cells. Taken together, our study describes a novel mode of CICD triggered by BH3-mimetics that may alter the immune response towards dying cells.

Real-World Challenges of Managing Diffuse Large B-Cell Lymphoma in a Developing Country.

PURPOSE: To highlight challenges and cancer care disparities in patients of diffuse large B-cell lymphoma management in resource-constrained settings. MATERIALS AND METHODS: This multicenter retrospective study included 738 patients from 12 public and private sector hematology-oncology centers across Pakistan. Patients were divided into limited-resource and enhanced-resource settings as per national diffuse large B-cell lymphoma (DLBCL) guidelines. RESULTS: The median age at diagnosis was 47 years (range, 14-89). Male:female ratio was 2.5:1. Majority of the patients (69.3%) were treated in limited-resource settings. Computed tomography was used as a staging modality in 442 (60%) patients. Limited-stage DLBCL was present in 13.5% of patients, while 86.3% had advanced-stage disease at diagnosis. First-line regimens included rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in 56% and cyclophosphamide, doxorubicin, vincristine, prednisone in 34% of patients, while 10% of patients received palliative regimens upfront. Of evaluable data, complete remission was documented in 299 (74.4%) patients, 39 (9.8%) had partial response and 63 (13.5%) had progressive disease. Disease-free survival (DFS) and overall survival (OS) status were not available for 345 (46.8%) patients at the time of data collection. Overall study cohort had a median follow-up of 2.2 years with a median OS of 3.6 years (95% CI, 3.1 to 4.1), median DFS of 3.1 years (95% CI, 2.6 to 3.6), and a 5-year OS of 40% and DFS of 36%. CONCLUSION: Patients from low- and middle-income countries present at an earlier age and have more advanced disease. Patients were frequently lost to follow-up, and record keeping was inadequate more so in patients treated in limited-resource settings. There is a need to establish a national lymphoma registry, improve record keeping, and standardize treatments to ensure improvement in treatment outcomes.

The Impact of Tumor Hypoxia Modulation on sIL-2R Levels in Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL) Patients Undergoing Chemotherapy: A Randomized Clinical Trial.

OBJECTIVE: Tumor hypoxia induces the production of Hypoxia-Inducible Factor (HIF)-1 alpha, which interacts with NF-kB, leading to cancer proliferation and metastasis. This study investigated the effect of tumor hypoxia modulation using carbogen (95% O2 and 5% CO2) and nicotinamide on reducing soluble interleukin-2 receptor (sIL-2R) levels in newly diagnosed DLBCL patients with tissue overexpression of HIF-1α ≥10%. MATERIAL AND METHODS: A prospective randomized controlled clinical trial was conducted at Dr. Kariadi Hospital in Semarang, Indonesia, from 2021 to 2022. Newly diagnosed DLBCL patients with tissue HIF-1α ≥10% were randomized into an intervention group (nicotinamide 2,000 mg + carbogen 10 liters/min during R-CHOP) and a control group (R-CHOP alone) for one cycle. sIL-2R levels were measured in the blood before and after intervention. RESULTS: The intervention group showed a significant reduction in sIL-2R levels after chemotherapy (p=0.026), with 85% of samples exhibiting a decrease. In contrast, only 45% of samples in the control group demonstrated a decrease in sIL-2R levels (p=0.184). The median sIL-2R level decreased from 139.50 pg/mL to 70.50 pg/mL in the intervention group, while the control group exhibited an increase from 182.50 pg/mL to 250.00 pg/mL following one cycle of chemotherapy. CONCLUSION: Tumor hypoxia modulation led to a significant decrease in serum sIL-2R levels, potentially through improvements in the crosstalk between hypoxia and inflammation pathways.

Recombinant hirudin suppresses angiogenesis of diffuse large B-cell lymphoma through regulation of the PAR-1-VEGF.

Hirudin is one of the specific inhibitors of thrombin, which has been confirmed to have strong bioactivities, including inhibiting tumors. However, the function and mechanism of hirudin and protease-activated receptor 1 (PAR-1) in diffuse large B-cell lymphoma (DLBCL) have not been clear. Detecting the expression PAR-1 in DLBCL tissues and cells by RT-qPCR and IHC. Transfected sh-NC, sh-PAR-1, or pcDNA3.1-PAR-1 in DLBCL cells or processed DLBCL cells through added thrombin, Vorapaxar, Recombinant hirudin (RH), or Na2S2O4 and co-culture with EA.hy926. And built DLBCL mice observed tumor growth. Detecting the expression of related genes by RT-qPCR, Western blot, IHC, and immunofluorescence, measured the cellular hypoxia with Hypoxyprobe-1 Kit, and estimated the cell inflammatory factors, proliferation, migration, invasion, and apoptosis by ELISA, CCK-8, flow cytometry, wound-healing and Transwell. Co-immunoprecipitation and pull-down measurement were used to verify the relationship. PAR-1 was highly expressed in DLBCL tissues and cells, especially in SUDHL2. Na2S2O4 induced SUDHL2 hypoxia, and PAR-1 did not influence thrombin-activated hypoxia. PAR-1 could promote SUDHL2 proliferation, migration, and invasion, and it was unrelated to cellular hypoxia. PAR-1 promoted proliferation, migration, and angiogenesis of EA.hy926 or SUDHL2 through up-regulation vascular endothelial growth factor (VEGF). RH inhibited tumor growth, cell proliferation, and migration, promoted apoptosis of DLBCL, and inhibited angiogenesis by down-regulating PAR-1-VEGF. RH inhibits proliferation, migration, and angiogenesis of DLBCL cells by down-regulating PAR-1-VEGF.

Real-world patient characteristics, treatment patterns, and treatment outcomes of patients with diffuse large B-cell lymphoma by line of therapy.

BACKGROUND: Although initial treatment of diffuse large B-cell lymphoma (DLBCL) with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) can be effective, up to 50% of patients will develop refractory or relapsed (R/R) disease. This study aimed to provide contemporary data on characteristics, treatment patterns, and outcomes for R/R-DLBCL. METHODS: Patients with incident (January 2016 to March 2021) DLBCL age ≥18 years who initiated first-line (1L) therapy were identified from the COTA real-world database. Baseline characteristics, treatment patterns, and real-world outcomes, including time to next treatment (rwTTNT) and overall survival (rwOS), were assessed for the study population and by line of therapy (LOT). RESULTS: A total of 1347 eligible DLBCL patients were identified. Of these, 340 (25.2%) proceeded to receive 2L, of whom 141 (41.5%) proceeded to receive 3L, of whom 51 (36.2%) proceeded to receive 4L+. Most common treatments were R-CHOP in 1L (63.6%), stem cell transplant (SCT) in 2L (17.9%), polatuzumab vedotin, bendamustine, and rituximab (Pola-BR) in 3L (9.9%), and chimeric antigen receptor T-cell therapy (CAR-T) in 4L (11.8%). Treatment patterns were more variable in later LOTs. One- and 3-year rwOS from 1L initiation were 88.5% and 78.4%, respectively. Patients who received later LOTs experienced numerically lower 1- and 3-year rwOS (from 2L initiation: 62.4% and 46.4%, respectively). CONCLUSIONS: In this real-world analysis, 25.2% of patients experienced R/R-DLBCL after 1L with poor outcomes. Given the findings of this study, there is a high unmet need for novel, safe, and effective treatment options for patients with R/R DLBCL.

Eukaryotic initiation factor 3a promotes the development of diffuse large B-cell lymphoma through regulating cell proliferation.

BACKGROUND: One-third of diffuse large B-cell lymphoma (DLBCL) patients suffer relapse after standard treatment. Eukaryotic initiation factor 3a (eIF3a) is a key player in the initial stage of translation, which has been widely reported to be correlated with tumorigenesis and therapeutic response. This study aimed to explore the biological role of eIF3a, evaluate its prognostic and therapeutic potential in DLBCL. METHODS: RNA-seq datasets from GEO database were utilized to detect the expression and prognostic role of eIF3a in DLBCL patients. Protein level of eIF3a was estimated by western blot and immunohistochemical. Next, DLBCL cells were transfected with lentiviral vector either eIF3a-knockdown or empty to assess the biological role of eIF3a. Then, samples were divided into 2 clusters based on eIF3a expression and differentially expressed genes (DEGs) were identified. Function enrichment and mutation analysis of DEGs were employed to detect potential biological roles. Moreover, we also applied pan-cancer and chemosensitivity analysis for deep exploration. RESULTS: eIF3a expression was found to be higher in DLBCL than healthy controls, which was associated with worse prognosis. The expression of eIF3a protein was significantly increased in DLBCL cell lines compared with peripheral blood mononuclear cells (PBMCs) from healthy donors. eIF3a knockdown inhibited the proliferation of DLBCL cells and the expression of proliferation-related proteins and increase cell apoptosis rate. Besides, 114 DEGs were identified which had a close linkage to cell cycle and tumor immune. eIF3a and DEGs mutations were found to be correlated to chemosensitivity and vital signal pathways. Pan-cancer analysis demonstrated that high eIF3a expression was associated with worse prognosis in several tumors. Moreover, eIF3a expression was found to be related to chemosensitivity of several anti-tumor drugs in DLBCL, including Vincristine and Wee1 inhibitor. CONCLUSIONS: We firstly revealed the high expression and prognostic role of eIF3a in DLBCL, and eIF3a might promote the development of DLBCL through regulating cell proliferation and apoptosis. eIF3a expression was related to immune profile and chemosensitivity in DLBCL. These results suggest that eIF3a could serve as a potential prognostic biomarker and therapeutic target in DLBCL.

Real-world total cost of care by line of therapy in relapsed/refractory diffuse large B-cell lymphoma.

AIMS: There are multiple recently approved treatments and a lack of clear standard-of-care therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). While total cost of care (TCC) by the number of lines of therapy (LoTs) has been evaluated, more recent cost estimates using real-world data are needed. This analysis assessed real-world TCC of R/R DLBCL therapies by LoT using the IQVIA PharMetrics Plus database (1 January 2015-31 December 2021), in US patients aged ≥18 years treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or an R-CHOP-like regimen as first-line therapy. METHODS: Treatment costs and resources in the R/R setting were assessed by LoT. A sensitivity analysis identified any potential confounding of the results caused by the impact of the COVID-19 pandemic on healthcare utilization and costs. Overall, 310 patients receiving a second- or later-line treatment were included; baseline characteristics were similar across LoTs. Inpatient costs represented the highest percentage of total costs, followed by outpatient and pharmacy costs. RESULTS: Mean TCC per-patient-per-month generally increased by LoT ($40,604, $48,630, and $59,499 for second-, third- and fourth-line treatments, respectively). Costs were highest for fourth-line treatment for all healthcare resource utilization categories. Sensitivity analysis findings were consistent with the overall analysis, indicating results were not confounded by the COVID-19 pandemic. LIMITATIONS: There was potential misclassification of LoT; claims data were processed through an algorithm, possibly introducing errors. A low number of patients met the inclusion criteria. Patients who switched insurance plans, had insurance terminated, or whose enrollment period met the end of data availability may have had truncated follow-up, potentially resulting in underestimated costs. CONCLUSION: Total healthcare costs increased with each additional LoT in the R/R DLBCL setting. Further improvements of first-line treatments that reduce the need for subsequent LoTs would potentially lessen the economic burden of DLBCL.

Indicators describing the tumor lesion aggregation and dissemination and their impact on the prognosis of patients with diffuse large B cell lymphoma receiving chimeric antigen receptor T cell therapy.

INTRODUCTION: Chimeric antigen receptor (CAR) T cell therapy has markedly improved the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). The relative positioning of tumor lesions in lymphoma varies among patients, manifesting as either aggregation (clumped together) or dissemination (spread throughout the body). Prognostic significance of factors indicating the relative positioning of tumor lesions in CAR T cell therapy remains underexplored. For aggregation, prior research proposed the tumor volume surface ratio (TVSR), linking it to prognosis in chemotherapy. Regarding dissemination, indicators such as disease stage or extranodal involvement, commonly used in clinical practice, have not demonstrated prognostic significance in CAR T cell therapy. This study aims to analyze current indicators of tumor aggregation or dissemination and introduce a novel indicator to assess the prognostic value of tumor lesions' relative positioning in DLBCL patients undergoing CAR T cell therapy. METHODS: This retrospective study included 42 patients receiving CAR T cell therapy. Lesion image information was obtained from the last PET/CT scan prior to CAR T cell infusion, including total metabolic tumor volume, total tumor surface, diameter of lymphoma masses, and the sites of tumor lesions. We evaluated TVSR and bulky disease as descriptors of tumor aggregation. We refined existing indicators, stage III&IV and >1 site extranodal involvement, to distill a new indicator, termed 'extra stage', to better represent tumor dissemination. The study examined the prognostic significance of tumor aggregation and dissemination. RESULTS: Our findings indicate that TVSR, while prognostically valuable in chemotherapy, lacks practical prognostic value in CAR T cell therapy. Conversely, bulky disease emerged as an optimal prognostic indicator of tumor aggregation. Both bulky disease and extra stage were associated with poor prognosis and exhibiting synergistic prognostic impact in CAR T cell therapy. CONCLUSIONS: Overall, the relative positioning of tumor lesions significantly influences the prognosis of patients with DLBCL receiving CAR T cell therapy. The ideal scenario involves tumors with minimal dissemination and no aggregation.

Real-World Survival, Healthcare Resource Utilization, and Costs Among U.S. Elderly Patients With Diffuse Large B-Cell Lymphoma (DLBCL) Treated With R-GemOx in the Relapsed/Refractory Setting.

BACKGROUND: Little recent real-world evidence exists on overall survival, healthcare resource utilization (HCRU), and costs among R/R DLBCL patients treated with the combination of rituximab, gemcitabine, and oxaliplatin (R-GemOx), a widely-used regimen for patients ineligible for stem cell transplant due to age or comorbidities. PATIENTS AND METHODS: This retrospective analysis used 2014 to 2019 U.S. Medicare claims. Individuals aged ≥66 years with a new DLBCL diagnosis between October 1, 2015 and December 31, 2018 and continuous fee-for-service Medicare Part A, B, and D coverage in the 12 months pre- and postindex were followed to identify the sample of patients with evidence of R-GemOx treatment in the second-line (2L) or third-line (3L) setting. Outcomes included overall survival, all-cause and DLBCL-related HCRU, and costs after R-GemOx initiation. RESULTS: The final sample included 157 patients who received treatment with R-GemOx in the R/R settings (mean (SD) age 77.5 (6.0) years, 39.5% age>80 years; 66.9% male; 91.1% White). Of these, 126 received R-GemOx in the 2L setting and 31 received R-GemOx in the 3L setting. Median overall survival from R-GemOx initiation was 6.9 months and 6.8 months in the 2L and 3L setting, respectively. Rates of all-cause hospitalization (68.1% [2L] and >90% [3L]) and hospice use (42.9% [2L] and 51.7% [3L]) were high in the 12 months after R-GemOx initiation. All-cause total costs were substantial ($144,653 [2L] and $142,812 [3L]) and approximately 80% of costs were DLBCL-related within 12 months of R-GemOx initiation. CONCLUSION: Elderly U.S. Medicare beneficiaries diagnosed with DLBCL who initiated R-GemOx treatment in the R/R setting have poor overall survival, high rates of HCRU, and substantial costs.

Molecular assessment of intratumoral immune cell subsets and potential mechanisms of resistance to odronextamab, a CD20×CD3 bispecific antibody, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

BACKGROUND: Patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) have a significant need for effective treatment options. Odronextamab is an Fc-silenced, human, CD20×CD3 bispecific antibody that targets CD20-expressing cells via T-cell-mediated cytotoxicity independent of T-cell/major histocompatibility complex interaction. Phase I results in patients with R/R B-NHL demonstrated that odronextamab monotherapy could achieve deep and durable responses with a generally manageable safety profile (ELM-1; NCT02290951). As part of a biomarker analysis of the same study, we investigated potential biomarkers and mechanisms of resistance to odronextamab. METHODS: Patients with R/R B-NHL enrolled in ELM-1 received one time per week doses of intravenous odronextamab for 4×21 day cycles, then doses every 2 weeks thereafter. Patient tumor biopsies were obtained at baseline, on-treatment, and at progression. Immune cell markers were analyzed by immunohistochemistry, flow cytometry, single-cell RNA sequencing, and whole genome sequencing. RESULTS: Baseline tumor biopsies showed that almost all patients had high proportions of B cells that expressed the CD20 target antigen, whereas expression of other B-cell surface antigens (CD19, CD22, CD79b) was more variable. Responses to odronextamab in patients with diffuse large B-cell lymphoma were not related to the relative level of baseline CD20 expression, cell of origin, or high-risk molecular subtype. A potential link was observed between greater tumor programmed cell death-ligand 1 expression and increased likelihood of response to odronextamab. Similarly, a trend was observed between clinical response and increased levels of CD8 T cells and regulatory T cells at baseline. We also identified an on-treatment pharmacodynamic shift in intratumoral immune cell subsets. Finally, loss of CD20 expression through inactivating gene mutations was identified as a potential mechanism of resistance in patients who were treated with odronextamab until progression, as highlighted in two detailed patient cases reported here. CONCLUSIONS: This biomarker analysis expands on clinical findings of odronextamab in patients with R/R B-NHL, providing verification of the suitability of CD20 as a therapeutic target, as well as evidence for potential mechanisms of action and resistance.