Diagnosis Of Diffuse Large B-cell Lymphoma Research Articles

Correlation Analysis of Peripheral Blood B Cell Count with Clinical Features and Prognosis in Patients Newly Diagnosed with Diffuse Large B-Cell Lymphoma

To explore the correlation between peripheral blood B cell count and clinical features and prognosis of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). The relationship of peripheral blood B cell count with clinical features, laboratory indexes and prognosis in 67 patients with newly diagnosed DLBCL was retrospectively analyzed. Patients were divided into low B-cell count group (B cell＜0.1×109/L, n=34) and high B-cell count group (B cell≥0.1×109/L, n=33) according to the median B cell count values. Compared with the high B cell count group, the low B cell count group had a higher proportion of patients with Lugano stage III-IV, elevated LDH, elevated β2-MG and IPI score 3-5 and increased CRP (P =0.033, 0.000, 0.023, 0.001, 0.033). The peripheral CD3+ and CD4+ cell counts of patients in the low B cell count group were significantly lower than those in the high B cell count group (P =0.010, 0.017). After initial treatment, overall response rate (ORR) and complete remission (CR) rate in high B cell count group were significantly higher than those in low B cell count group (P =0.032, 0.013). The median follow-up time of patients was 23(2-77) months, progression-free survival (PFS) and overall survival (OS) of patients in the high B cell count group were significantly better than those in the low B cell count group (P =0.001, 0.002). Univariate analysis showed that pretreatment low B cell count in the peripheral blood was associated with shortened PFS and OS (HR=4.108, P =0.002; HR=8.218, P =0.006). Multivariate analysis showed that low B cell count was an independent prognostic factor for shortened PFS (HR=3.116, P =0.037). Decreased peripheral blood B cell count in newly diagnosed DLBCL patients is associated with high-risk clinical features and may affect the efficacy of immunochemotherapy, which is associated with poor clinical prognosis.

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.

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%. 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. 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. Tumor hypoxia modulation led to a significant decrease in serum sIL-2R levels, potentially through improvements in the crosstalk between hypoxia and inflammation pathways.

457 A Phase I Trial of Tazemetostat and Venetoclax in Relapsed and Refractory non-Hodgkin Lymphoma

OBJECTIVES/GOALS: Primary Objective: To evaluate the safety of venetoclax plus tazemetostat in patients with relapsed and refractory (R/R) Follicular lymphoma (FL) or Diffuse large B-cell lymphoma (DLBCL) Secondary Objectives: 1. To evaluate the tolerability of the combination of T+V using patient reported outcomes (PROs) 2. To evaluate the efficacy of T+V METHODS/STUDY POPULATION: Study design: A phase I trial in two parts: Part 1: a single-arm, open-label sequential dose escalation (3+3) of venetoclax in combination with tazemetostat, given at its recommended phase II dose (RP2D) of 800mg BID, to determine the maximum tolerated dose (MTD) of venetoclax. Part 2: two expansion cohorts (R/R DLBCL and R/R FL) to further characterize the safety and tolerability of the combination, and to estimate the preliminary efficacy. We will perform additional exploratory studies to determine if there are biologic features that correlate with responses. Eligibility: up to 38 patients aged >/=18 years old with histologically confirmed diagnosis of FL or DLBCL who have received at least 2 prior lines of therapy for lymphoma with evidence of disease progression and meet inclusion criteria RESULTS/ANTICIPATED RESULTS: Primary Endpoints: 1. Incidence and severity of adverse events as per CTCAEv5 2. Dose-limiting toxicity (DLT) of T+V, and to establish the maximum tolerated dose (MTD) of V plus fixed dose T Secondary Endpoints: 1. Incidence and Severity of toxicity and quality of life as per PRO-CTCAE and FACT-Lym 2. Overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, as per Lugano criteria 3. Duration of response (DOR), progression-free survival (PFS), overall survival (OS)Exploratory Endpoints: 1. Characterization of tumor cells pre-treatment (including EZH2 mutations and BCL2 translocations) 2. Phenotypic analysis (including BCL2 expression) and quantification of the tumor microenvironment in pre-treatment samples (using image mass cytometry)Explorato DISCUSSION/SIGNIFICANCE: There is a need for novel therapeutic approaches to improve the prognosis for patients with R/R NHL. Preclinical data suggests synergism between the pair.5 Importantly, this represents a chemotherapy-free, oral regimen. If well tolerated, this could present an alternative therapeutic option for patients ineligible for more intensive therapies.

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

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. 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. 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. 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.

Comparative Review of the Current and Future Strategies to Evaluate Bone Marrow Infiltration at Diffuse Large B-Cell Lymphoma Diagnosis.

Diffuse large B-cell lymphoma (DLBCL) requires a complete staging at diagnosis that may have prognostic and therapeutic implications. The role of bone marrow (BM) biopsy (BMB) is controversial in the era of nuclear imaging techniques. We performed a comparative review of 25 studies focused on BM evaluation at DLBCL diagnosis, including at least two of the following techniques: BMB, flow cytometry, and positron emission tomography (PET-FDG). The report about BM involvement (BMi), diagnostic accuracy, and prognostic significance was collected and compared among techniques. A concordance analysis between BMB, FCM, and PET was also performed, and we deeply evaluated the implications of the different types of BMi: concordant by LBCL or discordant by low-grade B-cell lymphoma for both BMB and FCM, and focal or diffuse uptake pattern for PET. As a main conclusion, BMB, FCM, and PET are complementary tools that provide different and clinically relevant information in the assessment of BMi in newly diagnosed DLBCL.

Characterization of primary small intestinal lymphoma: a retrospective study based on double balloon endoscopy

BackgroundThe diagnosis of primary small intestinal lymphoma (PSIL) is difficult. This study aimed to evaluate the clinical, radiological and endoscopic characteristics of PSIL and provide clue for diagnosis.MethodsA total of 30 patients diagnosed with PSIL who underwent double balloon endoscopy (DBE) in the First Affiliated Hospital of Zhejiang University were retrospectively analyzed. Clinical, radiological and endoscopic data were collected. Univariate analysis was used to determine significant indicators for differentiating three main subtypes of PSIL. Cox regression analysis was performed to assess the risk factors for survival.ResultsIn this study, 10 patients were pathologically diagnosed as diffuse large B-cell lymphoma (DLBCL), 11 were indolent B-cell lymphoma (BCL) and 9 were T-cell lymphoma (TCL). Compared with DLBCL patients, the body mass index (BMI) of TCL patients was significantly lower (p = 0.004). Meanwhile, compared with patients with DLBCL, the patients with indolent BCL had lower levels of C-reactive protein, lactate dehydrogenase (LDH), fibrinogen and D-Dimer (p = 0.004, p = 0.004, p = 0.006, and p = 0.002, respectively), and lower proportion of thicker intestinal wall and aneurysmal dilation in CT scan (p = 0.003 and p = 0.020, respectively). In terms of ulcer morphology, patients with DLBCL had significantly higher proportion of deep ulcers than patients with indolent BCL (p = 0.020, respectively). Cox regression analysis showed that drink (p = 0.034), concomitant colonic ulcers (p = 0.034) and elevated LDH (p = 0.043) are risk factors for mortality in patients with PSIL.ConclusionsThis study provides clinical characteristics of patients with PSIL. Thicker intestinal wall and aneurismal dilation detected on CT scan and deeper ulcer on DBE examination helps to establish a diagnosis of DLBCL.

Predicting central nervous system relapse in primary breast diffuse large B-cell lymphoma using the stage-modified IPI score: A retrospective cohort study

ObjectiveThe existing Central Nervous System-International Prognostic Index (CNS-IPI) provides insufficient guidance for predicting central nervous system (CNS) relapse in individuals with primary breast diffuse large B-cell lymphoma (DLBCL). This retrospective cohort study sought to examine the potential of the stage-modified IPI in predicting CNS relapse within this specific patient population. Patients and methodsWe examined the baseline characteristics of 76 consecutive patients diagnosed with primary breast DLBCL, calculating the stage-modified IPI score for each individual. Utilizing a competing risk regression (CRR) model, we conducted both univariate and multivariate analyses to explore the relationship between potential prognostic factors and the occurrence of CNS relapse. ResultsIn our cohort, the rates of CNS disease at 2 and 5 years since the diagnosis of primary breast DLBCL are 3.9% and 7.8%, respectively. Among patients experiencing CNS relapse, 80% presented with a parenchymal brain mass. Individuals with a high stage-modified IPI score (1–3 points) had a significantly higher incidence of CNS relapse (p = 0.031), a shorter time from the initial diagnosis of primary breast DLBCL to the first CNS relapse (p = 0.010), as well as relapse at any site (p = 0.012), compared to those with a low score (0 points). Univariate analysis identified stage (Hazard Ratio (HR): 4.098, p = 0.024), stage-modified IPI score (HR: 11.582, p = 0.012), and radiation therapy (HR: 5.784, p = 0.026) as significant risk factors. In multivariate analysis, in addition to radiation therapy (HR: 7.258, p = 0.012), the stage-modified IPI score (1–3 points versus 0 points) emerged as an independent and reliable predictor for CNS relapse (HR: 12.945, p = 0.016). ConclusionOur study underscores the significance of stage-modified IPI scores in predicting CNS relapse for patients with primary breast DLBCL. Validation of these findings through further research is essential, along with exploring potential prevention and intervention approaches.

Epidemiology and Real-World Treatment of Incident Diffuse Large B-cell Lymphoma (DLBCL): A German Claims Data Analysis.

The objective of this study was to investigate the prevalence, incidence, and treatment patterns (treatment regimens, switches, duration) for diffuse large B-cell lymphoma (DLBCL) in a real-world setting. This was a retrospective German claims data analysis of patients with DLBCL diagnosed between January 1, 2012, and December 31, 2020. The prevalence and cumulative incidence of DLBCL were found for 2019/2020. Line of treatment (LOT) and treatment setting from first DLBCL diagnosis to end of follow-up were described. Kaplan-Meier overall survival (OS) estimates since DLBCL diagnosis and start of treatment lines were calculated. Overall, 2633 incident DLBCL cases were identified (median age 75years, 51% male). Of these, 2119 patients received at least one DLBCL-related treatment (LOT1), and 1567 patients died during follow-up. In 2019/2020, the prevalence and cumulative incidence of DLBCL was 34.8/36.7 per 100,000 patients and 14.0/12.7 per 100,000 patients, respectively. For LOT1, 1922 patients were given a chemotherapy-based regimen (1530 with CD20 antibodies). A total of 403 patients were administered a second line (LOT2), of which 183 patients received a CD20 antibody-containing chemotherapy regimen and 100 patients received stem cell transplantation or chimeric antigen receptor (CAR)-T therapy. Of the 136 LOT3+ treatments, 74 were chemotherapy regimens (54 with CD20 antibodies) and 18 were kinase inhibitors. The median time between treatment lines was less than 6 months. Among patients with at least LOT2, approximately 50% received more than one LOT during the first year after diagnosis. Approximately 25% of treated patients died within 6months of treatment initiation. Of the 2633 included patients, the median OS from diagnosis was 31.0months (treated patients: 46.8months, untreated patients: 3.0months). Despite advances in the field, high unmet medical need in DLBCL remains. The treatment landscape is very heterogeneous, particularly in second- or later-line treatments, with few patients receiving potentially curative treatment beyond the first line. Treatment for DLBCL, particularly for transplant-ineligible patients, remains challenging.

Development and validation of a nomogram for predicting cardiovascular mortality risk for diffuse large B-cell lymphoma in children, adolescents, and adults.

This study aimed to construct and validate a nomogram for predicting cardiovascular mortality (CVM) for child, adolescent, and adult patients with diffuse large B-cell lymphoma (DLBCL). Patients with only one primary tumor of DLBCL first diagnosed between 2000 and 2019 in the SEER database were extracted. We used the cumulative incidence function (CIF) to evaluate the cumulative rate of CVM. The outcome of interest was CVM, which was analyzed using a competing risk model, accounting for death due to other causes. The total database was randomly divided into a training cohort and an internal validation cohort at a ratio of 7:3. Adjustments were for demographics, tumor characteristics, and treatment modalities. Nomograms were constructed according to these risk factors to predict CVM risk at 5, 10, and 15 years. Validation included receiver operating characteristic (ROC) curves, time-dependent ROC, C-index, calibration curves, and decision curve analysis. One hundred four thousand six hundred six patients following initial diagnosis of DLBCL were included (58.3% male, median age 64 years, range 0-80, White 83.98%). Among them, 5.02% died of CVM, with a median follow-up time of 61 (31-98) months. Nomograms based on the seven risk factors (age at diagnosis, gender, race, tumor grade, Ann Arbor stage, radiation, chemotherapy) with hazard ratios ranging from 0.19-1.17 showed excellent discrimination, and calibration plots demonstrated satisfactory prediction. The 5-, 10-, and 15-year AUC and C-index of CVM in the training set were 0.716 (0.714-0.718), 0.713 (0.711-0.715), 0.706 (0.704-0.708), 0.731, 0.727, and 0.719; the corresponding figures for the validation set were 0.705 (0.688-0.722), 0.704 (0.689-0.718), 0.707 (0.693-0.722), 0.698, 0.698, and 0.699. Decision curve analysis revealed a clinically beneficial net benefit. We first built the nomogram model for DLBCL patients with satisfactory prediction and excellent discrimination, which might play an essential role in helping physicians enact better treatment strategies at the time of initial diagnosis.

Expression of MCP-1 and CCR2 in Newly Diagnosed Diffuse Large B-Cell Lymphoma and Clinical Significance

To analyze the expression of MCP-1 and CCR2 in newly diagnosed diffuse large B-cell lymphoma (DLBCL), and to evaluate their correlation with clinicopathological features and prognosis. A total of 141 patients with DLBCL diagnosed and treated in the Department of Hematology, the First Affiliated Hospital of Bengbu Medical College from January 2017 to May 2022 were retrospectively collected. The clinical characteristics, pathological data and prognostic factors of the patients were collected. Immunohistochemical staining was used to detect the expression of MCP-1 and CCR2 in the tissues of newly treated DLBCL patients, and to analyze the relationship between MCP-1 and clinical characteristics, prognosis and survival of patients. The expression of MCP-1 and CCR2 were correlated with Ann Arbor stage, IPI score, lactate dehydrogenase (LDH), Ki-67 index and therapeutic effect. There were no significant correlation between the expression of MCP-1 or CCR2 and other clinical histopathological parameters such as gender, age, β2-microglobulin, BCL-2, BCL-6, Hans classification, initial location, B symptoms, bone marrow involvement. There was a statistical difference in OS and PFS between the MCP-1 or CCR2 positive group and the negative group, which was associated to poor prognosis.Univariate Cox regression analysis showed that β2-microglobulin, Ki-67 index, IPI score, MCP-1, CCR2 expression levels and disease remission affected the PFS and OS of DLBCL patients (P < 0.05). Gender, age, LDH, BCL-2, BCL-6, Hans classification, primary tumor site, B symptoms, bone marrow involvement, Ann Arbor stage had no effect on PFS and OS (P >0.05). Multivariate analysis showed that β2-microglobulin, Ki-67 index, IPI score, MCP-1, CCR2 expression levels and disease remission were independent influencing factors of patients (P < 0.05). The expression rate of MCP-1 or CCR2 in newly treated DLBCL is high, and it is correlated with the clinical features of poor prognosis such as stage and LDH of DLBCL patients, which is a poor prognostic factor affecting PFS and OS.

Primary Skeletal Muscle Diffuse Large B Cell Lymphoma in Lumbar Region – A Rare Occurrence

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma worldwide. Patients most often present with a rapidly growing tumour mass in single or multiple, nodal, or extranodal sites. Extranodal involvement is seen in up to 40% cases. Initial presentation as soft tissue lesion is rare. We report a case of extranodal DLBCL in an elderly male, presenting as a soft tissue mass in the left lumbar region, clinically suggestive of lipoma. The patient had no palpable lymphadenopathy. Complete blood counts were within normal limits. Initial ultrasonography was suggestive of abscess, possibly of tubercular origin. On fine needle aspiration cytology, features were of a malignant neoplasm; a lymphomatous process. Subsequent histopathological evaluation followed by IHC confirmed the diagnosis of DLBCL. Primary extranodal DLBCL involving the soft tissue is rare. Owing to its non- specific and unusual clinical presentation, accurate diagnosis may be delayed. Besides, imaging modalities are also diagnostically challenging due to a wide range of differentials, thereby emphasising the need for tissue diagnosis. Histopathological examination and immunohistochemistry are paramount in accurate diagnosis and tailoring treatment options.International Journal of Human and Health Sciences Vol. 08 No. 01 Jan’24 Page: 95-98

CD70 is a potential prognostic marker and significantly regulates cellular function in diffuse large B-cell lymphoma.

Extensive research has demonstrated that dysregulation of costimulatory molecule expression plays a pivotal role in cancer biology. However, the impact of intratumoral CD70 on the initiation, progression, and immune response in diffuse large B-cell lymphoma (DLBCL) remains poorly understood. This study aims to elucidate the clinical significance of CD70 in DLBCL diagnosis and prognosis, as well as its relationship with the immune microenvironment. We first analyzed CD70 expression across various cancers, including DLBCL, using multiple online databases (TIMER, GEPIA, GENT2, TNMPlot, GSCA, and GEO). We then evaluated the clinical correlations and prognostic value of CD70 in DLBCL. Additionally, we investigated the functional role of CD70 in DLBCL cells. Genomic alterations of CD70 were analyzed using the cBioPortal online tool. Co-expression network analysis was performed to assess the biological functions associated with CD70. Furthermore, we utilized TIMER2.0 to examine the correlation between CD70 expression and immune cell infiltration. Our results revealed that CD70 expression was significantly upregulated in DLBCL tissues compared to matched normal tissues, and high CD70 expression was associated with poor clinical outcomes in DLBCL patients. In vitro experiments demonstrated that CD70 inhibition promotes apoptosis and induces G1 phase arrest in DLBCL cells. Genomic alteration analysis showed that patients with CD70 alterations exhibited worse overall survival compared to those without such alterations. Co-expression and functional enrichment analyses indicated that CD70 is functionally related to tumor necrosis factor receptor binding and the NF-κB signaling pathway. Moreover, we found that CD70 expression levels were negatively correlated with B cell and NK cell infiltration in DLBCL. In conclusion, this study suggests that CD70 is a potential diagnostic and therapeutic biomarker for DLBCL. Our findings provide valuable insights for the development of novel therapeutic strategies targeting CD70 in DLBCL treatment.

Plasma long non-coding RNAs as biomarkers for bone marrow infiltration and stage in diffuse large B-cell lymphoma.

We aimed to evaluate the expression profiles of five circulating lncRNAs (HOTAIR, MALAT-1, XIST, SNHG15, and H19) in DLBCL patients and explore potential associations between their expression and different clinicopathological features. Diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma (NHL), exhibits marked genetic and clinical heterogeneity, emphasizing the need for improved tools for risk stratification. Long non-coding RNAs (lncRNAs) emerged as regulators in different cellular processes and have been linked to cancer pathogenesis. Real-time quantitative PCR (qRT-PCR) was used to evaluate lncRNA expression in the plasma of 65 newly diagnosed adult DLBCL patients and 30 age-matched controls. HOTAIR expression was significantly elevated in DLBCL patients, while SNHG15 was significantly downregulated. Interestingly, both HOTAIR and SNHG15 demonstrated robust discriminatory power between DLBCL and healthy individuals, achieving area under the curve (AUC) values of 69% and 71%, respectively. H19 expression displayed a significant association with early-stage (stage I) DLBCL. While upregulated HOTAIR was a significant independent predictor of poor prognosis, high SNHG15 expression appeared to have a protective effect on mortality rates. Our findings suggest that circulating lncRNA expression patterns are promising tools as non-invasive biomarkers for diagnosis of DLBCL. Specific lncRNAs, such as HOTAIR, SNHG15, and H19, could offer potential for disease staging and patient prognosis. Long-term follow-up studies are recommended to further elucidate the interplay between these lncRNAs and survival rates, as well as their interactions with other genetic and pathological features of DLBCL.

Performance of the cobas EZH2 mutation test on clinical samples from non-Hodgkin lymphoma patients

Objective To present the technical verification and clinical validation of the companion diagnostic assay, cobas® EZH2 Mutation Test (cobas EZH2 Test), targeting gain-of-function EZH2 mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). The focus is on patient clinical samples proving that the test met the performance criteria required for FDA approval of a companion diagnostic test. Design Epizyme, Inc., Eisai Co., Ltd., and Roche Molecular Systems, Inc., collaborated to develop the cobas EZH2 Test on an RT-PCR platform. The assay design needed to detect the gain-of-function EZH2 mutations found in FL and DLBCL indications. Thus, the test was optimized for investigational purposes in a clinical trial setting. Part of its technical verification included testing of patient tumor samples with a documented diagnosis of FL and DLBCL procured from commercial vendors, and the clinical validation used patient samples from the Epizyme clinical study. Both the technical performance verification method correlation study (104 clinical commercially acquired samples) and the clinical validation accuracy study (341 patient samples from the therapeutic study) used next-generation sequencing as a reference method to establish true vs. false results by cobas EZH2 Test. The reproducibility study used a 15-member panel of DNA samples with varying EZH2 mutation status from procured clinical FL and DLBCL patient samples under multiple variables. Results Single and rare, infrequent double EZH2 mutations were detected in FL and DLBCL samples. Agreements between results from cobas EZH2 and sequencing were &gt;98% from commercial clinical samples and from the therapeutic study clinical samples. The reproducibility study obtained 178 to 180 valid results for each panel member, with an overall invalid rate of 0.37%. The agreement for each per panel member was 100%. Conclusion cobas EZH2 Test data demonstrated that the test is reliable and will perform well in a commercial customer environment.

Incidence of venous thromboembolism and predictive ability of age-adjusted international prognostic index for prediction of venous thromboembolism in Asian patients with diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is one of the malignancies at high risk for the development of venous thromboembolism (VTE). We aimed to evaluate the incidence of VTE and the predictive ability of the age-adjusted international prognostic index (aaIPI) for the prediction of VTE among DLBCL patients.This was a retrospective cohort study including adult patients with newly diagnosed DLBCL. Differences in VTE occurrence within one year after diagnosis of DLBCL were estimated across aaIPI groups using the Kaplan-Meier model, Cox's model, and Gray's model with deaths regarded as competing events.Five hundred and ninety-one newly diagnosed DLBCL patients with a median age of 58 (range 16-93) years were included in this study. At a median follow-up time of 365 (range 2-365) days, VTE events were objectively diagnosed in 32 patients, giving a one-year cumulative incidence of VTE of 5.4% (95% confidence interval [CI], 3.7-7.6). Patients with aaIPI ≥ 2 had a significantly higher risk of VTE than patients with aaIPI < 2 (hazard ratio, 3.5; 95% CI, 1.6-7.8; p = 0.001 based on Cox's model and sub-distribution hazard ratio, 3.0; 95% CI, 1.3-6.7; p = 0.007 using Gray's model). The C-statistic of aaIPI was 0.65 (95% CI, 0.58-0.72).We demonstrated thatthe incidence of VTE in Asian DLBCL patients was not uncommon. The aaIPI was effective in determining the risk of VTE in DLBCL patients, even when including death as a competing event. aaIPI may be helpful in identifying patients at higher risk of VTE in DLBCL patients.

The Relapse-to-Therapy Interval in Relapsed or Refractory Diffuse Large B Cell Lymphoma Is Associated with Clinical Outcomes

Introduction In newly diagnosed diffuse large B cell lymphoma (DLBCL), the diagnosis-to-treatment (DTI) interval is associated with clinical outcomes: patients who initiated therapy early after DLBCL diagnosis have significantly worse event free survival (EFS) (Maurer JM et al. J Clin Oncol 2018;36:1603-1610). In relapsed or refractory (R/R) DLBCL, the relapse-to-treatment interval (RTI) has gained more relevance with the recent approvals of several novel therapies including chimeric antigen receptor (CAR) T-cell therapies, which require several weeks of manufacturing time, and bispecific antibody therapies that require several weeks of desensitization through dose ramp-up to achieve therapeutic levels. The association between RTI and patient outcomes in R/R DLBCL has not yet been reported. Methods We conducted an IRB-approved retrospective review of r/r DLBCL patients treated with rituximab, ifosfamide, carboplatin, etoposide (R-ICE) as second line treatment at three academic medical centers between 2010-2020. Characteristics at the time of relapse, including RTI and treatment outcomes were collected from the electronic medical record. Outcomes evaluated included disease response to R-ICE, subsequent autologous stem cell transplant (ASCT) and CAR T cell therapy, progression free survival (PFS) and OS. All analyses were done using R and its packages. The optimal cutoff values for RTI were determined using maximally selected rank test from MaxStat and survminer packages. The association between RTI and clinical outcomes was evaluated using Fisher test and Wilcoxon rank-sum test. Survival was calculated using the Kaplan Meier method, comparisons done using log-rank. Results We identified 249 patients treated with second line R-ICE for r/r DLBCL with available RTI data. The median RTI was 18 days (IQR 9-31). The optimal RTI cutoffs calculated with maximally selected rank test were 7 days for PFS and 11 days for OS. An intermediate value of 10 days was chosen. At the time of relapse, age, gender, cell of origin and double expressor / double hit features were comparable among groups, but patients with an RTI of ≤ 10 days were more likely to have B symptoms, elevated lactate dehydrogenase, and intermediate or high IPI scores compared to those with longer RTI (table 1). The RTI had a strong association with patient outcomes. Patients with RTI of 10 days or less had a lower rate of complete remission (20% vs. 45%, p = 0.003). After a median follow up of 53 months (IQR 36-73), median PFS for patients with RTI ≤ 10 days was 5.1 vs. 12.7 months for patients with RTI &amp;gt; 10 days (p &amp;lt;0.001). Four-year PFS estimates were 17.3% for patients with RTI ≤ 10 days vs. 35.3% for patients with RTI &amp;gt; 10 days. Median OS was 26 months for patients with RTI 10 days vs. 85 months for patients with RTI &amp;gt; 10 days (figure 1). Among patients with RTI of ≤ 10 days, 46% went on to receive ASCT, whereas 64% of patients with RTI &amp;gt; 10days had ASCT (p = 0.048). On multivariate Cox proportional hazards analysis including RTI ≤10 days, age &amp;gt; 60 years at time of relapse, elevated LDH, and ECOG ≥ 2, the proportional hazards condition was met for both PFS and OS. Shorter RTI had a statistically significant association with PFS and OS, with hazard ratios (HR) of 1.80 (95% CI 1.27-2.56, p = 0.001) and 1.97 (95% CI 1.29-3.03, p = 0.002), respectively. Conclusions There is a strong association between RTI and the outcomes of R/R DLBCL patients treated with second line R-ICE chemotherapy. Our findings highlight the worse outcomes of patients with rapidly progressive, symptomatic R/R DLBCL and are particularly impactful in the era of CAR T-cells and novel immunotherapies, which can take many weeks to become available or effective. As with the DTI, clinical trials of DLBCL therapies should report RTI whenever possible. More effective and rapidly available treatment approaches should be designed to improve the outcomes of this high-risk patient population.

Impact of Progression-Free Survival at 24 Months on Subsequent Survival in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP Therapy: A Supplementary Analysis of JCOG0601

Introduction The impact of progression-free survival status at 24 months (PFS24) or event-free survival status at 24 months (EFS24) on subsequent survival has been evaluated in patients with various lymphoma subtypes. Patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who achieve PFS24 or EFS24 generally have excellent outcomes. It has been observed that the overall survival (OS) after achieving EFS24 was not significantly different from that of the general population (M.J. Maurer. J Clin Oncol, 2014). However, the OS after achieving PFS24 was significantly worse than that of the general population (M.J. Maurer. Ann Oncol, 2018). Consequently, the impact of achieving PFS24 for DLBCL patients remains controversial. In this supplementary analysis, we evaluated the impact of achieving PFS24 on the subsequent survival of untreated DLBCL patients by using data from JCOG0601, a randomized phase2/3 study assessing the schedule of rituximab administration in combination with tri-weekly CHOP (Ohmachi K. Blood Adv, 2021). Methods Among 422 patients enrolled between Dec 2007 and Dec 2014 in JCOG0601, 409 patients were eligible for this analysis (Data cutoff date: Dec 19, 2017). PFS24 was defined as being alive without progression or relapse for 24 months from randomization. The protocol treatment was initiated within 7 days after randomization. OS from PFS24 was defined as the time from achieving PFS24 or the date of progression or relapse to death from any cause. We compared OS from PFS24 with that of age-, sex-, and calendar period-matched Japanese general population using standardized mortality ratios (SMRs). Similarly, PFS12 and PFS60, as well as OS from PFS12 and PFS60, were defined in the same manner as PFS24 and OS from PFS24. The log-rank P-values for OS were calculated. Results The baseline characteristics of the 409 patients were as follows: a median age of 62 years (range, 20-79), with males accounting for 56% (n=227) of the patients. At diagnosis, 46% (n=188) of the patients were Ann Arbor stage III or IV. The majority of patients (82%; n=335) were classified as international prognostic index low or low-intermediate risk. Based on the Hans algorithm for cell-of-origin, 51% (n=210) of the patients were categorized as non-germinal center B-cell type (non-GCB). At a median follow-up of 5.3 years among all patients, a total of 334 patients (82%) achieved PFS24, while 66 patients (16%) failed to achieve PFS24. Five patients died without progression within 24 months, and four patients were lost to follow-up within 24 months. Multivariable analysis revealed that risk factors for failing to achieve PFS24 included serum LDH levels higher than the upper normal limit and two or more extranodal lesions. Patients who achieved PFS24 had a significantly better OS than those who failed to achieve PFS24 (median OS, not reached vs. 1.3 years; P &amp;lt; 0.001). Similar results were observed when using PFS12 and PFS60, regardless of the cell-of-origin. Among the patients who failed to achieve PFS24, non-GCB type patients more frequently had relapsed or refractory diseases in extranodal sites (72%: n=26/36) compared to GCB type patients (43%; n=6/14). The OS after achieving PFS24 or PFS60 was not remarkably different from that of the general population (PFS24: SMR 1.29, 95% confidence interval [CI] 0.72-2.12, P = 0.39; PFS60: SMR 1.43, 95% CI 0.47-3.33, P = 0.55). However, the OS after achieving PFS12 was significantly worse than that of the general population (SMR 2.30, 95%CI 1.59-3.22, P &amp;lt; 0.001). The primary cause of death for patients achieving PFS12 was DLBCL with the cumulative incidence of more than 5% at 5 years, while the incidence of death due to DLBCL was less than 5% for those achieving PFS24. The primary cause of death for the patients achieving PFS24 was other diseases except for DLBCL and treatment-related toxicity, including secondary malignancies (n=4/7) and pneumonia (n=3/7). Conclusion Newly diagnosed DLBCL patients treated with R-CHOP who achieved PFS24 exhibited an excellent subsequent outcome, which did not differ from those of age-, sex-, calendar-period matched individuals in the general population. Our findings suggest that PFS24 achievement could serve as a surrogate endpoint for OS in DLBCL patients. Further research is warranted to establish the utility of PFS24 achievement as a reliable milestone in clinical practice.

Mutational Landscape of Diffuse Large B-Cell Lymphoma (DLBCL) in Mexican Patients

Background. Diffuse Large B Cell Lymphoma (DLBCL) is the most common B-cell malignancy (1), recently classified with genomic sequencing and exome analysis into clusters with clinical implications (2,3). However, this analysis has not been informed neither in Mexican, or Latin-American population. The aim of this study was to describe the mutational landscape and its correlation with the clinical outcome in Mexican patients with DLBCL. Material and methods. A prospective, observational study of patients with diagnosis of DLBCL, attended at the National Cancer Institute in Mexico City. Inclusion criteria: patients &amp;gt; 18 years, diagnosis of DLBCL, without previous treatment and candidate to be treated with RCHOP. IRB approval was: Register number CEI/966/15. All signed informed consent. Clinical &amp; pathological variables were analyzed. All patients were treated with 6 cycles of RCHOP. Clinical response was evaluated by PET-CT. Samples: DNA was extracted from paraffin-embedded tissue of the primary neoplasm using the kit Quick-DNA/RNA FFPE kit (Zymo Research). A custom panel (6,026 oligos) was used for the sequencing of coding regions and splicing sites of 79 genes associated with lymphomas. Therafter, the bioinformatic analysiswas carried out using Ion Torrent Suite Browser version 5.0 and Ion Reporter version 5.18. Variant calling was performed with Torrent Variant Caller. The following databases were used: Cancer Genome Interprteter (CGI), ClinVar (201706), COSMIC (v86), PolyPhen (v2.2.2), SIFT (v5.2.2), FATHMM (v2.1), gnomAD (r2.0.1), and the Variant Effect Predictor (v93.2). All variants had a depth greater than 500X. Statistical analysis. Descriptive statistics for clinical variables. Associations between clinical and pathological characteristics were assessed with the frequency of SNVs and InDels. Survival curves were estimated using the Kaplan-Meier method. The association of the overall survival (OS) and the recurrence-free survival (RFS) was evaluated with Log-Rank test. Statistical significance was set at p-value &amp;lt; 0.05. Cox proportional-hazard regression analysis was used to identify the variables predicting overall survival (OS). All statistical analyses were performed using R software (v4.2.2) (https://cran.r-project.org, accessed on 23rd May 2023) and SPSS version 25 software (IBM, Corp., Armonk, NY). Results We included 185 patients, median + SD age 59.3 + 14.1 years. Most (n=128, 69.2 %) were in ECOG score &amp;lt; 2, without B symptoms (n=131, 70.8 %), in advanced disease (n=134, 72.4%), and were germinal-center (GC) (n=126, 68.1 %), and 26 (14.1 %) were double hit lymphomas. At least a driver mutation was found in 110 cases (59.4 %). The genes with driver mutations most frequently were: TP53, EZH2, CREBBP, NOTCH1 and KMT2D. ( figure 1). The EZH2 mutations and KMT2D mutations were more frequent in female: ( EZH2 mutated [n=22/34, 64.7%], p=0.047]) ( KMT2D mutated, 75%, p=0.034), and had a higher frequency of bulky disease (63.3 %, p= 0.05). In contrast, MYD88 mutations were more frequent in male (MYD88 mutations: 76.9 %], p= 0.042). Response to R-CHOP treatment was: Complete (n= 129 (69.7%), partial (n=10, 5.4 %), or stable disease (n=3, 1.6 %); 26 patients (14 %) progressed during treatment. Median follow-up + SD was 41.99 + 21.4 months. The RFS was 60 % to 80 months and OS was 70 % to 84 months. ECOG &amp;gt;2 (p=0.002 [95 %CI: 1.52-3.97]), mutations at genes EZH2 (p=0.007 [95% CI: 0.193 -0.0.58), CREBBP (p=0.004 [95 % CI: 1.59 - 11.85]), and ARID1A (p= 0.027 [95 % CI: 1.34 - 131.45] were factors influencing on OS by univariate analysis. The multivariate analysis confirmed that an ECOG &amp;gt;2 (p=0.001 [95 CI: 1.46-3.34]) had a negative impact on OS. In contrast, EZH2 mutations (p=0.025 [95 % CI: 0.12 -0.86]) were a protective factor. Conclusions: This is the first approach to describe the genomic landscape in Latino-american population. The presence of EZH2 and KMT2 mutations were more frequent in female patients with mediastinal and bulky disease. After multivariate analysis, only the presence of EZH2 mutations was the only genomic factor influencing on OS. These results require to be confirmed by further studies.

Pomalidomide, Rituximab, Orelabrutinib, and Minichop-like (PRO-miniCHOP) in Elderly Patients with Newly Diagnosed Diffuse Large-B Cell Lymphoma: Preliminary Results from a Phase II Study

Introduction: Owing to comorbidities and poor tolerance to standard-dose chemotherapy, elderly patients with newly diagnosed diffuse large-B cell lymphoma (DLBCL) have to reduce their chemotherapy dose, ultimately leading to a poor prognosis (Di M, et al. Oncologist, 2021). Therefore, new therapeutic strategies with superior efficacy and less toxicity are urgently needed. The Smart Start study demonstrated that induction therapy with rituximab (R), lenalidomide, and ibrutinib resulted in a high overall response rate (ORR) in patients with newly diagnosed DLBCL (Westin J, et al. J Clin Oncol, 2023). Orelabrutinib (O), as a novel covalent Bruton's kinase inhibitor (BTKi) with high target selection, was reported to preserve the NK-cell-mediated antibody-dependent cellular cytotoxicity induced by R and thus boosted the antitumor effect of R-based regimen (Yu H, et al. Mol Ther-Oncolytics, 2021). The responders to OR induction therapy have been reported to attain synergistic antitumor effect and high complete remission (CR) rate (CRR) when receiving subsequent treatment (Qu C, et al. Hematol Oncol, 2023). Here, a prospective study was conducted to investigate the efficacy and safety of pomalidomide (P; a third-generation immunomodulatory drug), R, O, and miniCHOP-like (PRO-miniCHOP) in elderly patients with newly diagnosed DLBCL. Methods: Patients aged ≥70 years with newly diagnosed DLBCLwere enrolled in this open-label, single-arm, phase II study (NCT05809180). All eligible patients received one 21-day cycle of induction therapy with PRO (P, 4 mg, d1-7; R, 375 mg/m 2, d1; O, 150 mg, QD). Subsequently, patients who achieved at least mini response (miniR, a reduction in tumor lesions by 25%-50%) were administered additional 6 cycles of PRO-miniCHOP regimen (PRO with reduced-dose CHOP regimen [cyclophosphamide, 400 mg/m 2, d2; doxorubicin/liposomal doxorubicin, 25 mg/m 2/15 mg/m 2, d2; vindesine, 2 mg, d2; and dexamethasone, 7.5 mg/m 2, d2-6]). The subsequent treatment was administrated according to the tumor response after 6 cycles of the PRO-miniCHOP regimen, including the end of treatment for CR, 2 years of pomalidomide maintenance therapy for partial remission (PR), and discharge from the study for stable disease or progression disease. The primary endpoints were ORR and CRR after 6 cycles of the PRO-miniCHOP regimen. Secondary endpoints were ORR and CRR at the end of the induction therapy, as well as 2-year progression-free survival, 2-year overall survival and safety. Results: From January 01, 2023 to July 30, 2023, 10 patients were enrolled in this study. The median age was 76.0 (range, 70.0-84.0) years (Table 1). The majority of patients had an Ann Arbor stage of III or IV (7/10, 70.0%), International Prognostic Index score of ≥3 (6/10, 60.0%), and non-germinal center B-cell-like subtype (6/10, 60.0%). Five (50.0%) patients had hypertension, 4 (40.0%) patients presented with extranodal involvement, and MYC/BCL-2 double expression lymphoma (40.0%). After one cycle of induction therapy with PRO, all (10/10, 100.0%) patients achieved at least miniR, including 3 CR, 6 PR, and 1 miniR (Figure 1). Five patients completed ≥3 cycles of the PRO-miniCHOP regimen, among whom 4 (80.0%) achieved a CR and 1 (20.0%) had a PR, with the best ORR of 100%; of these, one sustained CR at the end of cycle 6. During the induction therapy with PRO, 50.0% (5/10) of patients reported adverse events (AEs) of any grade, the majority of which were grade 1-2, with only 2 patients experiencing grade 3-4 neutropenia. Grade ≥3 AEs during the whole treatment period were neutropenia (6/10, 60.0%), thrombocytopenia (1/10, 10.0%), and lymphopenia (1/10, 10.0%), of which one (1/10, 10.0%) patient developed febrile neutropenia. Notably, the use of prophylactic pegylated recombinant human granulocyte colony stimulating factor significantly reduced the recurrence rate of severe neutropenia in the subsequent treatment, and no treatment-associated death was observed. Moreover, despite half of the patients having the comorbidity of hypertension, no off-target related cardiac events such as atrial fibrillation or atrial flutter were observed. At the time of data cutoff, 9 patients were still under treatment. Conclusions: The present study provided preliminary evidence supporting the use of the PRO-miniCHOP regimen in elderly patients with newly diagnosed DLBCL. More clinical data will be updated from this ongoing study.

Zanubrutinib Combined with R-CHOP As the First-Line Treatment for Newly Diagnosed Diffuse Large B-Cell Lymphoma with Extranodal Involvement: A Prospective Phase II Trial in China

BACKGROUND About one-third of Diffuse large B-cell lymphoma (DLBCL) arises primarily from extranodal sites, patients with extranodal involvement indicates poor clinical outcomes.There is an urgent need to find new treatments for DLBCL patients with extranodal involvement. METHODS We conducted a single-arm, prospective phase II trial for newly diagnosed DLBCL with extranodal involvement to evaluate the efficacy and safety of the zanubrutinib combined with R-CHOP. Patients received therapies: R-CHOP intravenously Rituximab (375mg/m2 on Day0), Cyclophosphamide (750mg/m2on Day1), Doxorubicin (50mg/m2 on Day1), Vincristine(1.4mg/m2 on Day1), and oral Prednisone(50mg/day Day1-5) with Zanubrutinib (160mg bid Day1-21) regimen.This trail was registered at Chinese Clinical Trial Registry(ChiCTR2100053056). RESULTS 31 patients received ZR-CHOP regimen treatments at least 2 cycles, 26 patients completed 6 cycles. Patients had a median age of 68 years(38-79). 18 patients (58%) had intermediate and high risk of IPI score, 20 patients (65%) had stage III~IV disease, 22 patients (71%) were Non-GCB types, 19 patients (61%) Ki-67 More than 80%. 7 patients (23%) were double-expression lymphoma，5 patients (16%) with positive CD5 and 4 patients (13%) TP53 more than 80%. The objective response rate(ORR) was 96%(26/27), 12 patients(44%) reached complete remission(CR). 1 patient(3%) died for progression disease(PD) and 4 patients(13%) withdrew the trial. The most common adverse events of hematological toxicity were neutropenia, thrombocytopenia and anemia with 19%，13% and 10% grade 3/4 AEs respectively. The most common non-hematological toxicity were pneumonia, nausea and fatigue with 16%，6% and 3% grade 3/4 AEs . CONCLUSIONS Our results showed that Zanubrutinib plus R-CHOP(ZR-CHOP) is a safe and effective scheme for DLBCL patients with extranodal involvement. It indicate that the addition of zanubrutinib to the standard first-line treatment can enable these patients to achieve remission in the early stage of treatment and without significantly increasing toxicity.