Diffuse Large B-cell Research Articles

INNV-20. FLUORESCEIN GUIDED SURGERY FOR ATYPICAL BRAIN LESIONS: IS IT USEFULL? CASE SERIES USING A LOW-COST DEVICE

Abstract INTRODUCTION Sodium Fluorescein (SF) enhances in areas in the brain with a disrupted Blood brain barrier (BBB). In neurosurgery, SF is extensive used for malignant brain tumors. Solitary brain abscesses (BA) are characterized by the pathognomonic finding of BBB disruption. Consequently, FL may have the potential to improve the intra-operative visualization of BA. Other infections also disrupt BBB and SF may guide these surgeries. CASE SERIES A 32-year old male patient, previously diagnosed with HIV presented with headache and during investigation MRI disclosure an extensive leptomeningeal commitment. Leptomeningeal biopsy guided by fluorescein and using Varioguide system was performed and the diagnosis was primary central nervous system lymphoma (Diffuse large B-cell). During surgery, it was observed increased fluorescence in arachnoid. A 72-year old woman presented with headache, impairment of mental status and epilepsy and a KPS of 60. Her initial hypothesis was metastasis but patient did not have a primary situs diagnosis. An open biopsy was performed through temporal posterior craniotomy. During surgery no visible well delimited tumor was found, even with ultrasound use. Fluorescein guided biopsy was performed. Histological evaluation showed an Epstein-Barr virus infection causing encephalitis. This is an extremely rare presentation of this type of infection and SF was extremely helpful to guide the procedure. CONCLUSION This paper reported atypical uses of SF for brain mass lesions surgeries. One of our cases is a unique presentation of a virus encephalitis which mimicked metastasis and other of increased fluorescence in Lymphoma. These atypical use of SF are relevant for further neurosurgical plannings Keywords: Fluorescein, Lymphoma, Biopsy

From prediction to practice: mitigating bias and data shift in machine-learning models for chemotherapy-induced organ dysfunction across unseen cancers

ObjectivesRoutine monitoring of renal and hepatic function during chemotherapy ensures that treatment-related organ damage has not occurred and clearance of subsequent treatment is not hindered; however, frequency and timing are not optimal. Model bias and data heterogeneity concerns have hampered the ability of machine learning (ML) to be deployed into clinical practice. This study aims to develop models that could support individualised decisions on the timing of renal and hepatic monitoring while exploring the effect of data shift on model performance.Methods and analysisWe used retrospective data from three UK hospitals to develop and validate ML models predicting unacceptable rises in creatinine/bilirubin post cycle 3 for patients undergoing treatment for the following cancers: breast, colorectal, lung, ovarian and diffuse large B-cell lymphoma.ResultsWe extracted 3614 patients with no missing blood test data across cycles 1–6 of chemotherapy treatment. We improved on previous work by including predictions post cycle 3. Optimised for sensitivity, we achieve F2 scores of 0.7773 (bilirubin) and 0.6893 (creatinine) on unseen data. Performance is consistent on tumour types unseen during training (F2 bilirubin: 0.7423, F2 creatinine: 0.6820).ConclusionOur technique highlights the effectiveness of ML in clinical settings, demonstrating the potential to improve the delivery of care. Notably, our ML models can generalise to unseen tumour types. We propose gold-standard bias mitigation steps for ML models: evaluation on multisite data, thorough patient population analysis, and both formalised bias measures and model performance comparisons on patient subgroups. We demonstrate that data aggregation techniques have unintended consequences on model bias.

Access Barriers to Anti-CD19+ CART-Cell Therapy for NHL Across a Community Transplant and Cellular Therapy Network

We analyzed access barriers to anti-CD19+ chimeric antigen receptor T-cells (CART) for non-Hodgkin lymphoma (NHL) within a community-based transplant and cell therapy network registry. 357 intended recipients of FDA-approved anti-CD19+ CART were identified in the study period (2018 to 2022). Results showed that the median age at referral was 61 years, referral year was 2018 (4%), 2019 (14%), 2020 (18%), 2021 (26%), and 2022 (38%). Diagnoses were diffuse large B-cell (69%), follicular (13%), follicular/large (7%), mantle cell (4%), or other (7%). CART products infused were Axi-cel (62%), Tisa-cel (16%), Brexu-cel (13%) and Liso-cel (9%). 182 patients were infused with CART. The median durations between referral to consultation, consultation to apheresis, and collection to infusion were 11, 107, and 32 days, respectively. The median duration from consultation to CART infusion declined steadily from 207 days in 2019 to 108 days in 2022. [P <0.0001] 124 patients (41%) did not receive CART mostly for disease progression (34%) or poor health (15%). Multivariable logistic regression showed no significant differences in demographic, financial, or social determinants compared to those receiving CART. Notably, the proportion of ineligible patients declined from 53% in 2018-2020 to 34% by 2021-2022 [P=0.001]. In conclusion, 41% of community patients were unable to access timely CART therapy for NHL, mostly related to attrition from disease-related causes while overall time to infusion exceeded four months. Time to infusion as well as the proportion receiving CART improved over time. Reducing time to apheresis, early referral, and careful attention to salvage/bridging strategies are necessary.

Sequencing of cellular therapy and bispecific antibodies for the management of diffuse large B-cell lymphoma.

Historically, the management of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) following first-line chemoimmunotherapy has been second-line chemotherapy, followed by high-dose chemotherapy and consolidative autologous hematopoietic stem cell transplantation (HSCT), resulting in durable remissions in approximately 40% of patients. In 2017, chimeric antigen receptor (CAR) T-cell therapy changed the landscape of treatment for patients with R/R DLBCL, with complete response rates ranging from 40-58% and long-term disease-free survival of >40% in the highest risk subgroups, including patients who relapsed after autologous HSCT. Since that time further studies have demonstrated improved overall response rates and survival outcomes in patients with primary refractory or early-relapsed (relapse within 1 year) DLBCL treated with CAR T-cell therapy compared with autologous HSCT, advancing CAR T-cell therapy into the second-line setting. However, >50% of patients will relapse in the post-CAR T-cell setting. In the past 2 years, two CD20 x CD3 bispecific antibodies were approved by the Food and Drug Administration for the treatment of R/R DLBCL after two or more lines of systemic therapy. These bispecific antibodies have demonstrated overall response rates exceeding 50% and durable remissions at >2 years of follow-up. Additionally, a notable treatment advantage of bispecific antibodies is their ability to be administered in the community setting, making treatment more accessible for patients. The development and advancement of these novel therapies raise questions regarding the ongoing role of HSCT in the management of R/R DLBCL and the best sequence of cellular and bispecific therapies to optimize patients' outcomes.

Health-related quality of life profile of newly diagnosed patients with Hodgkin and non-Hodgkin lymphomas: A real-world study including 3922 patients from the French REALYSA cohort

IntroductionConsidering the notable advances made in the treatment of lymphoma, assessment of health-related quality of life (HRQoL) of lymphoma patients has become a critical aspect to consider both in clinical research and routine practice. However, there is paucity of information about lymphoma specific HRQoL profile at diagnosis. Patients and methodsHRQoL at diagnosis was assessed for 3922 adult patients with newly diagnosed high-grade (HG) (n = 1994), low-grade (LG) (n = 1053) non-Hodgkin (NHL) and Hodgkin (HL) (n = 875) lymphomas included in REal world dAta in LYmphoma and Survival in Adults (REALYSA, NCT03869619), a prospective non-interventional multicentric cohort in France. Disease-specific HRQoL aspects were assessed with three validated EORTC questionnaires, namely, the QLQ‐NHL‐HG29, the QLQ-NHL-LG20 and the QLQ-HL27, for patients with NHL-HG, NHL-LG and HL, respectively. ResultsWe confirmed the high-level of completion of these questionnaires in REALYSA cohort, ranging from 84 % for QLQ-HG29 to 88 % for QLQ-HL27. The proportion of patients with impaired global health status was as follows: T-cell NHL, 67 %; diffuse large B-cell (DLBCL), 62 %; Burkitt, 61 %; HL, 53 %; marginal zone, 49 %; mantle cell, 48 %; follicular, 47 %. Multivariable regression analyses for DLBCL, follicular and HL showed that gender, performance status and B symptoms were independently associated with all HRQoL dimensions. However, a variable effect of age and stage were observed among these three subtypes. ConclusionsA comprehensive analysis was made describing the HRQoL profile of newly diagnosed patients with different types of lymphomas. Our data may help to enhance the interpretation of HRQoL results in future studies using the recently validated EORTC lymphoma specific questionnaires.

Outcomes and relapse patterns in primary central nervous system lymphoma: Longitudinal analysis of 559 patients diagnosed from 1983 to 2020.

Contemporary outcomes and relapse patterns in primary CNS lymphoma (PCNSL) are lacking. We analyzed factors associated with relapse in a large cohort with extensive follow-up. T1-post-contrast-enhancing disease was characterized in immunocompetent PCNSL (diffuse large B-cell) patients from 1983 to 2020. Patients were stratified by response to induction and consolidation (complete/unconfirmed [CR/CRu], partial, stable, progression [POD]). Refractory was POD during (or relapse ≤3 months of) induction. Initial relapse site was categorized as local (involving/adjacent to baseline), distant intraparenchymal, leptomeningeal, or other. Progression-free (PFS) and overall survival (OS) were assessed with proportional hazards. Cumulative incidence with competing risks was used to assess local relapse. Median follow-up was 7.4 years (N = 559). Most (321, 57%) were recursive partitioning analysis class 2 (age ≥50, Karnosfky Performance Status [KPS] ≥70). Most had supratentorial (420, 81%), multifocal (274, 53%), bilateral (224, 43%), and deep structure involvement (314, 56%). Nearly all received methotrexate-based induction (532, 95%). There was no difference in PFS or OS from consolidation based on initial response to induction (CR/CRu vs PR) in patients who ultimately achieved a CR/CRu to consolidation. PFS at 1-, 5 years for 351 patients with CR/CRu to consolidation was 80% (95% confidence interval [95% CI]: 76%-84%) and 46% (95% CI: 41%-53%), respectively; 1-year cumulative incidence of local versus nonlocal relapse was 1.8% versus 15%, respectively. For 97 refractory patients, 1-year cumulative incidence of local versus nonlocal relapse was 57% versus 42%, respectively. Deep structure involvement (HR 1.89, 95% CI: 1.10%-3.27%) was associated with local relapse in refractory patients. We report the first comprehensive relapse patterns in a large PCNSL cohort. While relapses post-CR to consolidation are typically distant and unpredictable, refractory patients had a relatively high incidence of local relapse. These findings can help optimize multimodality therapy for this highest-risk population.

Long-Term Survival and Factors Associated with Increased Mortality in Patients with Ocular Adnexal Lymphomas.

Orbital and ocular adnexal lymphoma (OAL) affects the orbit and the surrounding structures and can arise as several subtypes with variable prognoses. We performed an observational study on the relationship between OAL subtype, diagnostic features, and prognosis to offer valuable insights into imaging techniques, such as Positron Emission Tomography with 2-deoxy-2-[fluorine-18] fluoro-D-glucose integrated with Computed Tomography (18F-FDG PET-CT), in predicting outcomes. With this aim, we retrospectively reviewed 99 patients with OALs, recording demographics, cancer subtype, location and treatment, 18FDG avidity, and bone marrow positivity. We divided patients into Group 1 (those presenting with extranodal marginal zone lymphoma-EMZL) and Group 2, including all other subtypes. The primary outcome was long-term cancer-specific survival (CSS) based on key predictors, performed through Kaplan-Meier curves and the log-rank test, with a p < 0.05 significance threshold. The mean patient age was 67 years (57-75.5). The most frequent histopathologic subtypes were EMZL lymphoma in 69 patients (69.7%), small lymphocytic lymphoma (11.1%) and diffuse-large B-cell lymphoma (10.1%). Patients of Group 1 showed a better prognosis (CSS = 80%) compared to those of Group 2 (CSS = 60%) (p = 0.01). In patients with high-grade lymphoma, the occurrence of 18FDG avidity (p = 0.003) and bone marrow positivity (p = 0.005) were related to a worse prognosis. In our group, EMZL was the most prominent subtype of OALs and exhibited the best prognosis, low 18FDG avidity, and bone marrow negativity. By observing specific patterns in radiological findings, it is possible to increase our understanding of disease progression, treatment response, and the overall prognosis in OAL patients.

Longitudinal patterns of patient-reported cognitive impairment in patients with non-Hodgkin lymphoma (NHL) treated with chemotherapy: A group-based trajectory analysis of a nationwide community-based cohort.

7071 Background: Cognitive problems are an important clinical concern for cancer patients. We previously published that patients with lymphoma experienced worsening in cognitive functions and perceived function from pre-to post-treatment. Limited data exists in NHL, importantly previously reported group means of cognitive function may not capture interindividual heterogeneity. Therefore, we identified distinct subgroups of NHL patients with similar trajectories of cognitive function over time and investigated potential predictors. Methods: We included 181 NHL patients receiving chemotherapy (mean age [SD]: 59.0 [11.8]; 63.5% male; 54% diffuse large B-cell, 22% follicular lymphoma) enrolled in the National Cancer Institute Community Oncology Research Program. Cognitive function was assessed by the patient-reported Functional Assessment of Cancer-Therapy-Cognitive Function (total score and perceived cognitive impairment [PCI]) prior to chemotherapy (T1), after chemotherapy (T2), and 6 months following T2 (T3). Patient and cancer characteristics were collected through questionnaires or medical records at T1. We utilized group-based trajectory modeling (GBTM) to identify latent clusters of individuals with similar cognitive function patterns over time. Model selection and assessment were based on the Bayes factor, group size, model diagnostics, and clinical interpretability. Multinomial logistic regression models were identified characteristics associated with group membership. Results: Four groups were identified by GBTM: Group A had high perceived impairment, which decreased at T2 and remained high at T3 (n=17, 9.4%); Group B had moderate perceived impairment, with a continuous decline at T2 and T3 (n=21, 11.6%); Group C had low perceived impairment and remained stable at T2 and T3 (n=95, 52.5%); Group D had moderate perceived impairment, without changes at T2 and T3 (n=48, 26.5%). Similar trajectory groups were identified for the PCI subscale. Compared to ≥ some college education, ≤ high school was associated with an increased odds of membership in Group D relative to Group C (OR 3.45, 95% CI 1.44, 8.30). Patients with a higher fatigue score (MFSI) were more likely to report worse cognitive impairment (Group A vs. C: OR 1.10, 95% CI 1.07, 1.14; Group B vs. C: OR 1.05, 95% CI 1.02, 1.08; Group D vs. C: 1.05, 95% CI 1.03, 1.07). Stage, lymphoma subtype, and treatment regimen were not associated with group membership. Conclusions: Our analysis revealed that patients with perceived impairment experienced stable impairment or further decline over time, which is associated with education and fatigue; a subgroup of patients did not experience cognitive worsening. These data help identify patients with different patterns of cognitive impairment to inform personalized interventions.

HTA73 Cured and Invisible? Rationale for Mixture-Cure Models As Base-Case for HTA in Diffuse-Large B-Cell Lymphoma (DLBCL)

HTA73 Cured and Invisible? Rationale for Mixture-Cure Models As Base-Case for HTA in Diffuse-Large B-Cell Lymphoma (DLBCL)

Management of paediatric monomorphic post-transplant lymphoproliferative disorders with low-intensity treatment: A multicentre international experience.

Monomorphic post-transplant lymphoproliferative disorder (mPTLD) is a major cause of morbidity/mortality following solid organ transplant (SOT), with infection, mPTLD progression and organ rejection presenting equal risks. Balancing these risks is challenging, and the intensity of therapy required by individual patients is not defined. Although an increasing body of evidence supports the use of a stepwise escalation of therapy through reduction in immunosuppression (RIS) to rituximab monotherapy and low-dose chemo-immunotherapy, many centres still use B-cell non-Hodgkin lymphoma (B-NHL) protocols, especially when managing Burkitt/Burkitt-like (BL) PTLD. This study sought to define outcomes for children managed in the UK or Spanish centres using low-intensity first-line treatments. Retrospective data were anonymously collected on patients younger than 18years of age, with post-SOT mPTLD diagnosed between 2000 and 2020. Only patients given low-intensity treatment at initial diagnosis were included. Fifty-six patients were identified. Age range was 0.9-18years (median 10.7). Most (62.5%) had early-onset PTLD. Haematopathological analysis showed 75% were diffuse large B-cell like, 14.3% were BL and nine of 33 (27%) harboured a MYC-rearrangement. Stage III-IV disease was present in 78.6%. All but one had RIS, 26 received rituximab monotherapy and 24 low-dose chemo-immunotherapy, mostly R-COP. Intensified B-NHL chemotherapy was required in 10/56 (17.9%). There were a total of 13 deaths in this cohort, three related to PTLD progression. The 1-year overall survival (OS), event-free survival (EFS) and progression-free survival (PFS) were 92.8%, 78.6% and 80.2%, respectively. R-COP provides an effective low-dose chemotherapy option. Escalation to more intensive therapies in the minority of inadequately controlled patients is an effective strategy.

Recombinant hirudin suppresses angiogenesis of diffuselarge 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.

Primary lymphoma of the female genital tract masquerading as gynecological malignancy

BackgroundPrimary 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.MethodsThe 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.ResultsThere 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).ConclusionPLFGT 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.

Abstract 4432: Molecular biomarkers of non-Hodgkin lymphomas and subtypes identified by mass spectrometry-based metabolomics

Abstract Non-Hodgkin lymphomas (NHLs) constitute a diverse collection of lymphoid neoplasms, each characterized by distinct biological features. Approximately 90% of all lymphomas in the United States stem from B lymphocytes, with the remainder originating from T cells. The therapeutic approach for NHLs hinges on the neoplastic histology and the tumor stage, guiding the determination of whether radiotherapy, chemotherapy, or a combination thereof represents the most effective treatment strategy. Following an indolent phase, 50% of patients experience disease transformation into an aggressive form of lymphoma, leading to rapid deterioration and patient demise. While extensive efforts have been directed towards understanding the genetics of transformation, the contribution of altered tumor metabolism, induced by these genetic lesions, to disease aggressiveness remains unclear. Therefore, there exists an urgent need to better understand the metabolic changes during lymphoma transformation and treatment. Given the metabolic adaptations supporting bioenergetics, biosynthesis, and redox in malignant cells, here in this study we aimed to identify unique metabolic signatures in prominent lymphoma subsets—diffuse large B-cell (DLBCL), mantle cell (MCL), and follicular lymphomas (FL). Employing unbiased mass spectrometry-based metabolomics, we screened sera samples from n=30 patients with lymphoma and n=25 aged and BMI-matched healthy controls for molecular biomarkers that may be indicative of the subtypes. Principal component analysis revealed distinct clustering of the disease and control groups, indicating unique metabolic profiles induced by lymphoma presence. A total of 36 metabolites, including adenine, trans-aconitic acid, and citric acid, were significantly deregulated between groups (FC &amp;gt; 2, FDR p &amp;lt; 0.05). Functionally, enriched pathways included tryptophan metabolism and the tricarboxylic cycle (FDR p &amp;lt; 0.05), supporting our previous findings that lymphomas rely on oxidative phosphorylation for sustained proliferation. Comparing metabolic profiles of different lymphomas subtypes demonstrated unique clustering, emphasizing the distinct metabolic flexibility of each malignancy. Interestingly, cystine was the primary metabolite driving separation of the groups in our partial least squares discriminant analysis (PLS-DA), with DLBCLs demonstrating the highest abundance of this amino acid. In summary, our research uncovered that there are distinctive metabolic shifts resulting from the transformation of lymphomas. The findings stemming from our unbiased metabolic screening enables a better understanding of the complex metabolic intricacies in lymphomas and paves the way for prominent biomarker detection for improved patient outcomes. Citation Format: Fouad Choueiry, Satishkumar Singh, Lalit Sehgal, Jiangjiang (Chris) Zhu. Molecular biomarkers of non-Hodgkin lymphomas and subtypes identified by mass spectrometry-based metabolomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4432.

Early CAR- CD4+ T-lymphocytes recovery following CAR-T cell infusion: A worse outcome in diffuse large B cell lymphoma.

CAR- CD4+ T cell lymphopenia is an emerging issue following CAR-T cell therapy. We analyzed the determinants of CD4+ T cell recovery and a possible association with survival in 31 consecutive patients treated with commercial CAR-T for diffuse large B-cell (DLBCL) or mantle cell lymphoma. Circulating immune subpopulations were characterized through multiparametric-flow cytometry. Six-month cumulative incidence of CAR- CD4+ T cell recovery (≥200 cells/μL) was 0.43 (95% confidence interval [CI]: 0.28-0.65). Among possible determinants of CD4+ T cell recovery, we recognized infusion of a 4-1BB product (tisagenlecleucel, TSA) in comparison with a CD28 (axicabtagene/brexucabtagene, AXI/BRX) (hazard ratio [HR] [95% CI]: 5.79 [1.16-24.12] p=0.016). Higher CD4+ T cell counts resulted with TSA at month-1, -2 and -3. Moderate-to-severe infections were registered with prolonged CD4+ T cell lymphopenia. Early, month-1 CD4+ T cell recovery was associated with a worse outcome in the DLBCL cohort, upheld in a multivariate regression model for overall survival (HR: 4.46 [95% CI: 1.12-17.71], p=0.03). We conclude that a faster CAR- CD4+ T cell recovery is associated with TSA as compared to AXI/BRX. Month-1 CAR- CD4+ T cell subset recovery could represent a "red flag" for CAR-T cell therapy failure in DLBCL patients.

Psychometric performance of EQ-5D-5L and SF-6Dv2 in patients with lymphoma in China.

To assess and compare the measurement properties of EQ-5D-5L and SF-6Dv2 among lymphoma patients in China. A face-to-face survey of Chinese lymphoma patients was conducted at baseline (all types) and follow-up (diffuse large B-cell). EQ-5D-5L and SF-6Dv2 health utility scores (HUSs) were calculated using the respective Chinese value sets. Ceiling effect was assessed by calculating the percentage of respondents reporting the optimal health state. Convergent validity of EQ-5D-5L and SF-6Dv2 was assessed using the Spearman rank correlation coefficient (r) with QLQ-C30 as a calibration standard. Known-groups validity of the two HUSs was evaluated by comparing their scores of patients with different conditions; and their sensitivity was further assessed in the known-groups using relative efficiency (RE). Test-retest reliability and responsiveness was tested using ICC and standardized response mean (SRM), respectively. Altogether 200 patients were enrolled at baseline and 78 were followed up. No ceiling effect was found for SF-6Dv2 compared to 24.5% for EQ-5D-5L. Correlation between the two HUSs and with QLQ-C30 score was strong (r > 0.5). Each dimension of EQ-5D-5L and SF-6Dv2 had moderate or greater correlations with similar dimensions of QLQ-C30 (r > 0.35). Both EQ-5D-5L and SF-6Dv2 could only a minority known-groups, and the latter may have better sensitivity. EQ-5D-5L had better test-retest reliability (ICC = 0.939); while both of them were responsive to patients with worsened and improved clinical status. EQ-5D-5L and SF-6Dv2 were found to have good convergent validity and responsiveness, while EQ-5D-5L had better test-retest reliability and higher ceiling effect. Not enough evidence indicates which of the two measures has better known-group validity and sensitivity.

Свободно циркулирующая ДНК в плазме у пациентов с диффузной В-крупноклеточной лимфомой и В-клеточной лимфомой высокой степени злокачественности (‘double hit’/’triple hit’)

Aim. To study plasma cell-free DNA (pcfDNA) concentration and B-cell clonality in patients with diffuse large B-cell (DLBCL) and B-cell high-grade lymphomas prior to and at different stages of chemotherapy as well as the correlation between the data obtained and clinical and laboratory parameters.&#x0D; Materials &amp; Methods. The study enrolled 23 DLBCL patients and 7 healthy donors (HD). Plasma was prepared from whole blood by centrifugation, pcfDNA was isolated with the commercial kit Qiagen (Germany). The concentration of pcfDNA was determined using fluorometer Qubit (USA). В-cell clonality was estimated by immunoglobulin gene analysis (BIOMED-2 protocol) in the tumor tissue and bone marrow core biopsy specimens obtained on diagnosis date as well as in the pcfDNA at 5 end points: prior to chemotherapy and after cycles 1, 2, 3, and 4.&#x0D; Results. Prior to therapy, all DLBCL patients showed significantly higher pcfDNA concentration than HD. Immunochemotherapy cycle 1 resulted in considerable increase in pcfDNA concentration. After cycle 2 and subsequent cycles, pcfDNA concentration gradually decreased. After cycle 4, the mean pcfDNA concentration was comparable with that of HD. In 95 % of patients В-cell clonality in pcfDNA corresponded to that identified in the tumor specimen. After immunochemotherapy cycle 1, В-cell clonality was detected in 50 % of patients, after cycle 2 it was shown by 15 %. Only 1 female patient retained В-cell clonality after therapy cycles 3 and 4. In HD, no В-cell clonality in pcfDNA was identified. Prior to therapy, the analysis revealed no correlation of either pcfDNA concentration or В-cell clonality in pcfDNA with age, sex, tumor spread, presence or absence of extranodal lesions, proliferation index Ki-67, and lactate dehydrogenase concentration.&#x0D; Conclusion. In patients with malignant hematological tumors, pcfDNA seems to be an interesting, easily accessible biological material deserving further investigation. Any studies of pcfDNA require long-term dynamical analysis and standardized methods of collection, storage and processing of the data obtained. In the long run, with more and more information, pcfDNA can become an important diagnostic marker of tumor heterogeneity and a reliable relapse predictor.

The Lymphoma Epidemiology of Outcomes cohort study: Design, baseline characteristics, and early outcomes.

To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18-99). Participants came from 49 US states and included 538 Black/African-Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 years, and 1513 rural residents. At study baseline, we abstracted clinical, pathology, and treatment data; banked serum/plasma (N = 5883, 76.0%) and germline DNA (N = 5465, 70.7%); constructed tissue microarrays for four major NHL subtypes (N = 1189); and collected quality of life (N = 5281, 68.3%) and epidemiologic risk factor (N = 4489, 58.0%) data. Through August 2022, there were 1492 deaths. Compared to population-based SEER data (2015-2019), LEO participants had a similar distribution of gender, AA race, Hispanic ethnicity, and NHL subtype, while LEO was underrepresented for patients who were Asian and aged 80 years and above. Observed overall survival rates for LEO at 1 and 2 years were similar to population-based SEER rates for indolent B-cell (follicular and marginal zone) and T-cell lymphomas, but were 10%-15% higher than SEER rates for aggressive B-cell subtypes (diffuse large B-cell and mantle cell). The LEO cohort is a robust and comprehensive national resource to address the role of clinical, tumor, host genetic, epidemiologic, and other biologic factors in NHL prognosis and survivorship.

CNS Radiotherapy As Bridging Prior to CAR T-Cell Therapy for Non-Hodgkin B-Cell Lymphoma

Introduction: Up to 80% of patients who receive CAR T-cell therapy (CAR T) for central nervous system lymphoma (CNSL) require bridging therapy, yet optimal regimens remain undefined. Radiotherapy is an established strategy for extracranial lymphoma that provides beneficial cytoreduction. However, CNS bridging radiotherapy (CNS-BRT) prior to CAR T is controversial due to concerns of potential enhanced neurotoxicity. We explored the safety and response profiles in patients treated with CNS-BRT prior to CAR T. Methods: We identified patients with non-hodgkin B-cell lymphoma who received CNS-BRT at our institution prior to commercial CAR T infusion. CNS-BRT was defined as treatment delivered between apheresis and CAR T infusion or within 30 days prior to apheresis, targeting the CNS parenchyma, leptomeninges, or epidural spine. Patients with epidural spine disease were included since the adjacent spinal cord is part of the treatment field. Safety was evaluated by rate of cytokine release syndrome (CRS) and immune effector associated neurotoxicity syndrome (ICANS) after CAR T. Best CNS response post CAR T was evaluated using the International Primary CNS Lymphoma Collaborative Group (IPCG) or Response Assessment in Neuro-Oncology (RANO) for parenchymal or leptomeningeal lesions, respectively. Cytoreduction from CNS-BRT was estimated by calculating the change in lesion size (sum of product diameter) from before and after CNS-BRT, but before CAR T infusion. Risk of any CNS relapse after CAR T was estimated using the Gray's method with death as a competing risk. Patients with epidural spine disease were not evaluate for CNS response or relapse. Results: 12 patients received CNS-BRT with median follow up of 8.5 months (range: 3.2 - 30.2), median age of 60 (30-76), median Karnofsky Performance Status (KPS) of 80 (range: 50 - 90). Histologies included diffuse large B cell (DLBCL) (n = 9), mantle cell (n = 2), and Burkitt lymphoma (n = 1), with disease localizing to the brain parenchyma (n = 6), leptomeninges (n = 4), and epidural spine (n = 2). 9 patients had secondary CNSL and 1 patient had primary CNSL. Prior to CNS-BRT, 11/12 patients had progressive disease. 5/12 patients had disease outside of the CNS. 5/12 patients received prior autologous hematopoietic stem cell transplantation. 9/12 patients received prior high dose methotrexate with median 46-day interval to CNS-BRT (range: 0 - 393). RT targets included whole brain (n = 3), involved site (partial) brain (n = 4), involved site spine (n = 4), and orbits (n = 1) with median dose 24 Gy (range: 15 - 33). CAR T products included Tisagenlecleucel (n = 4), Lisocabtagene maraleucel (n = 7), and Axicabtagene ciloleucel (n = 1). Among 10 patients with available toxicity grading, 6/10 experienced CRS (n = 1 grade (G) 1, n = 4 G2, and n = 1 G3), and 3/10 experienced ICANS (n = 1 G1, n = 1 G3, n = 1 G4). 6/10 patients required tocilizumab and/or steroids. CNS-BRT achieved a 74.4% (95% CI, 62.9 - 85.9) mean reduction in lesion size prior to CAR T infusion. Best CNS response after CAR T infusion included 3 complete responses (CR), 6 partial responses (PR), and 1 progressive disease (PD). The patients who achieved PR remained in PR at last follow up. The 12-month estimated risk of CNS progression after CNS-BRT and CAR T infusion was 20.0% (95% CI, 3- 49). CNS progression was not observed in patients who received involved site brain RT. Conclusion: Preliminary data suggest CNS-BRT achieves rapid cytoreduction prior to CAR T therapy and is associated with a favorable CNS response profile. While overall numbers are limited to date, the rate of severe CRS and ICANS is similar to that of historical series of CNSL patients treated with CAR T. However, a larger cohort will be required to determine the safety of CNS-BRT. These data support further study of RT, and exploration of involved site brain RT, as an effective bridging modality for CAR T-cell therapy in CNSL.

Primary Pancreatic Lymphoma: An Analysis of the National Cancer Database

Background: Primary pancreatic lymphoma (PPL) is a rare entity, accounting for fewer than 2% of extranodal malignant lymphomas and 0.5% of all pancreatic masses. Fewer than 150 cases of PPL have been reported in the English language medical literature. We aimed to utilize the National Cancer Database (NCDB) to investigate the clinicopathological features and prognostic factors in PPL. Methods: The NCDB for Non-Hodgkin lymphoma was used to identify 2130 patients diagnosed with PPL (2004 and 2020). The database was used to examine clinicopathological features. Survival analysis was done by Kaplan-Meier. Cox proportional hazards was adopted for prognostic variable evaluation. Results: Most PPL patients were males (58.5%) and white (87.7%), mean age at diagnosis was 67.38 years. Histologically 59.6% were diffuse large B-cell. 14.9% Follicular, 2.6 % Burkitt, &amp; 15.8% Lymphoma NOS. Regarding treatment 71.5% of patients received chemotherapy. Immunotherapy given in 21.9%. Radiation in 12.1%, and 7.3% received some form of surgical treatment. Median survival was 85.32 months (CI 79.79-90.84). Using Cox hazard regression, the following factors were statistically significant (p&amp;lt;0.001): Age &amp;gt;60 (HR: 2.36,CI 1.9-2.8), increasing Charlson-Deyo Score, DLBL histology (HR:0.57,CI 0.45-0.72), stage 3 (HR:1.9,CI 1.6-2.2), Chemotherapy (HR 0.4,CI 0.34-0.46),and immunotherapy (HR 0.61,CI0.62-0.89) Conclusion: This is the most comprehensive study to date to utilize the NCDB to study the characteristics and prognostic factors of patients with PPL. DLBL histology, chemotherapy and immunotherapy are associated with reduced risk of death.

No Discernable Dysfunction of Peripheral T-Cells and NK-Cells Despite Distinct Phenotypes in MYC Rearranged Versus Non Rearranged B-Cell Lymphoma Patients

Background: Patients with diffuse large B-cell lymphoma/high-grade B-cell lymphoma with MYC and BCL2 rearrangements (DLBCL/HGBL- MYC/BCL2, hereafter HGBL- MYC/BCL2) respond poorly to standard immunochemotherapy treatment compared with DLBCL not otherwise specified (LBCL-NOS) patients without a MYC rearrangement. This suggests a negative interaction between MYC and the immune system. As novel T-cell and NK-cell based immunotherapeutic approaches emerge as potential treatment options for aggressive lymphomas, we conducted comprehensive immune profiling to compare peripheral blood T-cells and NK-cells of HGBL- MYC/BCL2 with LBCL NOS patients. Methods: Peripheral blood mononuclear cells (PBMCs) were prospectively collected from HGBL- MYC/BCL2 patients (registered in the HOVON-152 trial, NCT03620578), LBCL-NOS (registered in the HOVON-902 cohort, NCT04139252) and age-matched healthy donors (HDs). Flow-cytometry-based immune profiling of T-cells and NK-cells was performed on baseline samples available from n=66 HGBL- MYC/BCL2 patients (median age 62 years), n=67 LBCL NOS patients (median age 69 years) and n=17 HDs (median age 64 years). The flow cytometry data were computationally analyzed using FlowSOM and UMAP. T-cells were also functionally assessed for intracellular cytokine secretion (ICS) after stimulation with PMA/ionomycin (4h) and proliferation after stimulation with CD3/CD28 beads (5 days) using CellTrace Violet. NK-cells were assessed for cytotoxicity against K562 and degranulation (CD107a/b upregulation) after 4h. Mann-Whitney's U tests were used to compare HGBL-MYC/BCL2 patients with LBCL-NOS patients (primary comparison), and for pairwise comparisons of the lymphoma groups with HDs. To correct for baseline characteristics (age), linear regression analysis was performed. Results: CD4 + helper T-cells did not significantly between the lymphoma subgroups, but were decreased in LBCL-NOS patients as compared to HDs. Frequencies of cytotoxic CD8 + and CD4 +CD8 + T-cells did not significantly between the lymphoma subgroups and were similar as in HDs. Regulatory T-cell (Treg) frequencies of HGBL- MYC/BCL2 patients were similar to that of HDs, but were decreased in LBCL NOS patients. The frequency of CD4 -CD8 - T-cells was increased in LBCL NOS patients. Previously activated (HLA-DR +) CD4 + and CD8 + T-cells, as well as recently activated CD25 +, CD38 + or CD127 + CD4 + T-cells (Figure 1A) or activated/exhausted (PD-1 +) CD4 + T-cells and PD1 + Tregs were increased in both lymphoma subtypes (Figure 1B), but only HGBL- MYC/BCL2 displayed an increase in PD1 + CD8 + T-cells (Figure 1B). Conversely, recently activated CD8 + T-cells were decreased exclusively in LBCL NOS. HGBL- MYC/BCL2 patients and HDs had similar percentages of T-cells with a senescent phenotype (CD28 -CD57 +KLRG1 +), but the frequency of T-cells with this senescent phenotype was increased in LBCL NOS patients (Figure 1A), also after adjustment for age. Despite all these phenotypic differences, functional in vitro assays detected no differences in proliferation or cytokine secretion of peripheral T-cells from HGBL- MYC/BCL2 patients, LBCL NOS patients and HDs. In the NK-cell compartment, both lymphoma subtypes contained lower frequencies of CD56 brightTim3 +, CD56 bright/dimDNAM-1 + NK-cells, but LBCL NOS patients expressed a higher amount of NK-cells expressing inhibitory receptor NKG2A compared with HDs. NK-cells of HGBL- MYC/BCL2 patients, LBCL NOS patients and HDs displayed similar cytotoxic activity, suggesting no apparent functional impairment. Conclusions: HGBL- MYC/BCL2 patients have a distinct peripheral T-cell and NK-cell phenotype from LBCL NOS patients without a MYC rearrangement, but show no apparent functional deficiencies in terms of proliferation, cytokine secretion or cytotoxic activity. These results are not contradicting the application of T-cell and NK-cell based immunotherapeutic approaches for patients with aggressive B-cell lymphoma. Simultaneously, it emphasize the need to investigate the potential immunomodulatory impact of lymphoma intrinsic MYC in the tumor microenvironment.