Diagnosis Of Diffuse Large B-cell Lymphoma Research Articles

5-Hydroxymethylcytosine profilings in circulating cell-free DNA as diagnostic biomarkers for DLBCL

Background5-Hydroxymethylcytosine (5hmC) is an important DNA epigenetic modification that plays a vital role in tumorigenesis, progression and prognosis. Previous studies have shown that it plays an important role in the prognosis of diffuse large B-cell lymphoma (DLBCL) and in the prediction of the efficacy of R-CHOP therapy. However, its potential for diagnosing DLBCL has not been reported. Here, we investigated the utility of 5hmC in plasma cfDNA in the diagnosis of DLBCL.MethodsApplying 5hmC-Seal technique, we obtained genome-wide 5hmC profiles in plasma cell-free DNA (cfDNA) samples from 176 Chinese subjects, included 86 DLBCL patients and 90 healthy controls. To investigate whether 5hmC can be used as a diagnostic biomarker for DLBCL, we separated patients and healthy controls into training (DLBCL = 56, Healthy = 60) and validation (DLBCL = 30, Healthy = 30) cohorts and developed a 5hmC-based logistic regression model from the training cohort to diagnose the DLBCL patients in the validation cohort.ResultsIn this study, we found 10 5hmC biomarkers, and the models created by these differentially regulated 5hmC modified genes showed high accuracy in distinguishing DLBCL patients from healthy controls (validation cohort: AUC = 0.94; (95% CI 88.8%–99.4%)).ConclusionOur study suggested that 5hmC markers derived from plasma cfDNA can served as effective epigenetic biomarkers for minimally invasive diagnosis of DLBCL.

Usefulness of the 3-hydroxykynurenine/kynurenic acid ratio as a diagnostic biomarker for diffuse larger B-cell lymphoma.

Reports have shown that the kynurenine pathway, one of the pathways by which tryptophan is metabolized, is activated in patients with diffuse large B-cell lymphoma (DLBCL). Activation of the kynurenine pathway triggers the production of various metabolites, such as kynurenine (Kyn), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), kynurenic acid (KA) and anthranilic acid (AA), which contribute to immune tolerance. The current study aimed to investigate the changes in metabolites of kynurenine pathway in DLBCL patients and evaluate their performance predicting DLBCL. Changes in metabolites of kynurenine pathway were examined using high-performance liquid chromatography in 35 DLBCL patients (age 61.2 ± 13.5 years) and 44 healthy controls (age 58.5 ± 12.5 years). DLBCL patients had significantly higher levels of 3-HK, AA, and 3-HAA but lower levels of Tryptophan (Trp) and KA compared to healthy controls. Given that the ratio of each metabolite represents the change in the Kyn pathway, the 3-HK/KA ratio was examined. Notably, DLBCL patients had a significantly higher 3-HK/KA ratio compared to healthy controls. In DLBCL, the area under the receiver operative characteristic (ROC) curve for 3-HK/KA (0.999) was higher than that for lactate dehydrogenase (0.885) and comparable to that for soluble interleukin-2 receptor (sIL-2R) (0.997). Based on ROC curve analysis, the 3-HK/KA ratio was found to be useful biomarker for the diagnosis of DLBCL. Our results suggest that the 3-HK/KA ratio is a clinically useful biomarker of DLBCL. Moreover, its combination with existing markers, such as sIL-2R, can improve its effectiveness of diagnosing DLBCL.

A German perspective on the impact of socioeconomic status in diffuse large B-cell lymphoma

The prognostic influence of socioeconomic status (SES) on the survival of diffuse large B-cell lymphoma (DLBCL) patients remains controversial. This observational study examines the potential impact of regional SES inequalities on overall survival (OS) among DLBCL patients in Germany. We analyzed data from the German nationwide population-based dataset spanning 2004-2019 sourced from the German Center for Cancer Registry Data (n = 49,465). The primary objective was to assess the 5-year OS among patients with low SES compared to those living in middle and high SES areas. SES was grouped according to quintiles of the German Index of Socioeconomic Deprivation, which summarized nine indicators covering aspects of regional education, employment, and income. DLBCL patients in low SES areas had significantly impaired 5-year OS compared to those in middle and high SES regions (59.2% vs. 61.8% vs. 64.1%, p < 0.0001). Yet, additionally accounting for regional premature mortality removed the impact of SES on survival (Hazard Ratio 0.94, 95% CI 0.87–1.01). Our findings indicate that the prognostic impact of socioeconomic deprivation on long-term survival is not due to variations in diagnosis and treatment of DLBCL itself but rather a higher comorbidity burden.

Identification of ferroptosis-related genes associated with diffuse large B-cell lymphoma via bioinformatics and machine learning approaches

Ferroptosis has emerged as a critical mechanism in the development and progression of various tumors, particularly diffuse large B-cell lymphoma (DLBCL). However, the thorough characterization of ferroptosis-related genes in DLBCL remains inadequately explored. We retrieved datasets associated with DLBCL and ferroptosis gene sets from the Gene Expression Omnibus (GEO) database and the Ferroptosis Database (FerrDb), resulting in the identification of 27 differentially expressed ferroptosis-related genes (DE-FRGs) linked to DLBCL. Utilizing the LASSO and Support Vector Machine Recursive Feature Elimination (SVW-RFE) algorithms, we identified 10 genes—MT1G, MTOR, BRD4, ACO1, SAT1, PEBP1, LPIN1, ATM, SRXN1, and PRDX1—as key biomarker candidates with significant diagnostic potential. Functional enrichment analyses revealed that these biomarker genes are likely involved in regulating several critical biological pathways implicated in DLBCL pathogenesis, including immune response, oxidative phosphorylation, and cell cycle regulation. Moreover, we identified 246 potential therapeutic agents targeting these 10 biomarker genes. Concurrently, competitive endogenous RNA (ceRNA) network analysis uncovered a complex regulatory network centered on the identified biomarker genes. Additionally, CIBERSORT analysis highlighted notable alterations in the immune microenvironment of DLBCL patients. We propose a diagnostic strategy that provides novel insights into the molecular mechanisms underlying DLBCL. Nevertheless, further validation of the practical value of this strategy for DLBCL diagnosis is necessary before its clinical application.

A machine learning approach in a monocentric cohort for predicting primary refractory disease in Diffuse Large B-cell lymphoma patients.

Primary refractory disease affects 30-40% of patients diagnosed with DLBCL and is a significant challenge in disease management due to its poor prognosis. Predicting refractory status could greatly inform treatment strategies, enabling early intervention. Various options are now available based on patient and disease characteristics. Supervised machine-learning techniques, which can predict outcomes in a medical context, appear highly suitable for this purpose. Retrospective monocentric cohort study. Adult patients with a first diagnosis of DLBCL admitted to the hematology unit from 2017 to 2022. We evaluated in our Center five supervised machine-learning (ML) models as a tool for the prediction of primary refractory DLBCL. One hundred and thirty patients with Diffuse Large B-cell lymphoma (DLBCL) were included in this study between January 2017 and December 2022. The variables used for analysis included demographic characteristics, clinical condition, disease characteristics, first-line therapy and PET-CT scan realization after 2 cycles of treatment. We compared five supervised ML models: support vector machine (SVM), Random Forest Classifier (RFC), Logistic Regression (LR), Naïve Bayes (NB) Categorical classifier and eXtreme Gradient Boost (XGboost), to predict primary refractory disease. The performance of these models was evaluated using the area under the receiver operating characteristic curve (ROC-AUC), accuracy, false positive rate, sensitivity, and F1-score to identify the best model. After a median follow-up of 19.5 months, the overall survival rate was 60% in the cohort. The Overall Survival at 3 years was 58.5% (95%CI, 51-68.5) and the 3-years Progression Free Survival was 63% (95%CI, 54-71) using Kaplan-Meier method. Of the 124 patients who received a first line treatment, primary refractory disease occurred in 42 patients (33.8%) and 2 patients (1.6%) experienced relapse within 6 months. The univariate analysis on refractory disease status shows age (p = 0.009), Ann Arbor stage (p = 0.013), CMV infection (p = 0.012), comorbidity (p = 0.019), IPI score (p<0.001), first line of treatment (p<0.001), EBV infection (p = 0.008) and socio-economics status (p = 0.02) as influencing factors. The NB Categorical classifier emerged as the top-performing model, boasting a ROC-AUC of 0.81 (95% CI, 0.64-0.96), an accuracy of 83%, a F1-score of 0.82, and a low false positive rate at 10% on the validation set. The eXtreme Gradient Boost (XGboost) model and the Random Forest Classifier (RFC) followed with a ROC-AUC of 0.74 (95%CI, 0.52-0.93) and 0.67 (95%CI, 0.46-0.88) respectively, an accuracy of 78% and 72% respectively, a F1-score of 0.75 and 0.67 respectively, and a false positive rate of 10% for both. The other two models performed worse with ROC-AUC of 0.65 (95%CI, 0.40-0.87) and 0.45 (95%CI, 0.29-0.64) for SVM and LR respectively, an accuracy of 67% and 50% respectively, a f1-score of 0.64 and 0.43 respectively, and a false positive rate of 28% and 37% respectively. Machine learning algorithms, particularly the NB Categorical classifier, have the potential to improve the prediction of primary refractory disease in DLBCL patients, thereby providing a novel decision-making tool for managing this condition. To validate these results on a broader scale, multicenter studies are needed to confirm the results in larger cohorts.

Cannabinoid receptor-2 expression in canine multicentric diffuse large B-cell lymphoma: An immunohistochemical, digital pathology and clinical analysis

The cannabinoid 2 receptor (CB2R) is a crucial element of the endocannabinoid system (ECS), which is predominantly expressed on cells of the reticuloendothelial system. Alterations in CB2R expression have shown a prognostic role in various human neoplastic diseases and its expression has been studied in canine mast cell tumours (MCT). Canine diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in dogs and has a variable clinical behaviour. Expression of CB2R was assessed by means of immunohistochemistry in fifteen dogs with proven histological diagnosis of DLBCL. A semiquantitative and quantitative assessment of immunoreactivity (IR) by digital analysis was performed in all cases. Our results indicate that CB2R expression is conserved in canine DLBCL but does not correlate with clinical outcome.

A Real-World Data-Based Analysis of Prognostic Indices as Part of Trial Eligibility Criteria in Diffuse Large B-Cell Lymphoma Patients.

Recent front-line clinical trials used the International Prognostic Index (IPI) to identify trial-eligible patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). However, many IPI-like variants with improved accuracy have been developed over the years for rituximab-treated patients. We assessed the impact of International Prognostic Indices on patient enrolment in clinical trials, aiming to exclude low-risk IPI patients based on POLARIX/EPCORE DLBCL-2 trial criteria. We identified 2877 patients in the Danish Lymphoma Registry who would have been eligible for the POLARIX trial if patients with IPI 0-1 scores were included. IPI and NCCN-IPI assigned 33.3% and 11.9% of patients to the low-risk group, respectively. Shorter 5-year overall survival (91.4% vs. 97.5%), higher relapse rate (9.9% vs. 4.4%), and more deaths (16.1% vs. 4.4%) occurred in the low-risk IPI group compared with low-risk NCCN-IPI group. Analyzed models failed to identify true high-risk patients with poor prognosis. Similar results were found in the confirmatory cohort developed based on EPCORE DLBCL-2 trial eligibility criteria. True low-risk patients are more optimal identified by NCCN-IPI and should be excluded from front-line clinical trials due to their excellent prognosis. However, additional high-risk factors besides clinical prognostic models need to be considered when selecting trial-eligible patients.

Diffuse large B-cell lymphoma of the gallbladder with hepatoduodenal invasion exhibiting a necrotic tendency.

We report a case of diffuse large B-cell lymphoma (DLBCL) of the gallbladder with extensive hepatoduodenal invasion, which was challenging to diagnose histologically due to a strong tendency to be necrotic. An 71year-old man presented with upper abdominal pain and was referred to our hospital. Computed tomography revealed a distended gallbladder with air within the irregular gallbladder wall and an indistinct border with the hepatoduodenum, suggesting invasion. Esophagogastroduodenoscopy detected an ulceration in the duodenal bulb. However, histologic analysis failed to provide a definitive diagnosis due to the presence of necrotic tissue. Furthermore, direct biopsy from the gallbladder mucosa by endoscopic retrograde cholangiography revealed only necrotic tissue and no diagnosis. Contrast ultrasonography for the hepatic invasion revealed enhancement with blood flow, suggesting non-necrotic tissue. Subsequently, an ultrasound-guided core-needle biopsy was conducted to obtain tissue samples from the described lesion. The pathology showed atypical lymphocytes with irregular nuclei. Immunostaining indicated positive expression of CD10, CD20, Bcl-6, and C-Myc, consistent with a diagnosis of DLBCL. In our case, the lymphoma exhibited a strong tendency to be necrotic, making histologic diagnosis difficult. However, selective biopsy from the site of blood flow made the diagnosis possible and proved to be useful.

A case of diffused large B-cell lymphoma in an elderly patient successfully treated with R-mini-CHOP

Diffuse large B-cell lymphoma (DLBCL) is a diverse group of B-cell lymphomas that vary in their clinical characteristics. Usually manifesting as a rapidly progressing or advanced condition, it is often curable even at advanced stages. The illness originates in extranodal and extramedullary tissues in 40% of patients. Patients over the age of 80 who have comorbidities or fragile conditions may be eligible for Rituximab and Reduced Dose CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) (R-mini-CHOP) chemoimmunotherapy. We report a 75-year-old woman with a tumor on the right side of the nose that covers the eye, so it is easy to fall out. The diagnosis of DLBCL (sinonasal) was made on the basis of computed tomography (CT) scan of the paranasal sinuses with contrast and immunohistochemical examination. Due to the age of the patient, who was included in the very elderly category with moderate frailty based on instrumental activities of daily living (IADLs), the patient was given R-mini-CHOP chemoimmunotherapy for six cycles, followed by radiation as much as 20 × 18 Gray (Gy) where the patient in the final evaluation stated complete response.

Ibrutinib plus rituximab and mini-CHOP in older patients with newly diagnosed DLBCL: a phase 2 ALLG study

AbstractThe multicenter, prospective phase 2 Australasian Leukaemia & Lymphoma Group NHL29 trial was conducted to assess the addition of ibrutinib to R-mini-CHOP (dose attenuated R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients aged ≥75 years with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Treatment consisted of six 21-day cycles of ibrutinib–R-mini-CHOP followed by two 21-day cycles of R-ibrutinib. Coprimary end points were deliverability and 2-year overall survival (OS). The median average relative total dose and average relative dose intensity for the entire regimen were both 97% (interquartile range, 82-100 and 88-100, respectively). With a median follow-up of 35.5 months, the 2-year OS was 68% (95% confidence interval [CI], 55.6-77.4) with a 2-year progression-free survival (PFS) of 60.0% (95% CI, 47.7-70.3). Median OS and PFS were 72 months (95% CI, 35 to not reached) and 40 months (95% CI, 20.4 to not reached), respectively. The overall response rate was 76% (61/79) of patients, with a complete response rate of 71% (56/79). Deaths occurred in 34 of 79 patients (43%), including 17 from progressive disease and 5 treatment related. Overall, 67% patients experienced at least 1 serious adverse event. Most common adverse events were infections and diarrhea (the majority grade 1-2). In both health-related quality of life measures, there was an improvement in functional and symptom scales, median health state classification score, and median visual analogue scale in responders over time. In conclusion, this study showed that the addition of ibrutinib to R-mini-CHOP was both deliverable and efficacious in elderly DLBCL patients.

Treatment patterns, healthcare resource utilization, and costs in Medicare patients with diffuse large B-cell lymphoma: a retrospective claims analysis (2015–2020)

Aims To understand treatment patterns, healthcare resource utilization (HCRU), and the economic burden of diffuse large B-cell lymphoma (DLBCL) in elderly adults in the US. Materials and methods This retrospective database analysis utilized US Centers for Medicare and Medicaid Services Medicare fee-for-service administrative claims data from 2015 to 2020 to describe DLBCL patient characteristics, treatment patterns, HCRU, and costs among patients aged ≥66 years. Patients were indexed at DLBCL diagnosis and required to have continuous enrollment from 12 months pre-index until 3 months post-index. HCRU and costs (USD 2022) are reported as per-patient per-month (PPPM) estimates. Results A total of 11,893 patients received ≥1-line (L) therapy; 1,633 and 391 received ≥2 L and ≥3 L therapies, respectively. Median (Q1, Q3) age at 1 L, 2 L, and 3 L initiation, respectively, was 76 (71, 81), 77 (72, 82), and 77 (72, 82) years. The most common therapy was R-CHOP (70.9%) for 1 L and bendamustine ± rituximab for 2 L (18.7%) and 3 L (17.4%). CAR T was used by 14.8% of patients in 3 L. Overall, 39.6% (1 L), 42.1% (2 L), and 47.8% (3 L) of patients had all-cause hospitalizations. All-cause mean (median [Q1–Q3]) costs PPPM during each line were $22,060 ($20,121 [$16,676–$24,597]) in 1 L, $30,027 ($20,868 [$13,416–$31,016]) in 2 L, and $47,064 ($25,689 [$15,555–$44,149]) in 3 L, with increasing costs driven primarily by inpatient expenses. Total all-cause 3 L mean (median [Q1–Q3]) costs PPPM for patients with and without CAR T were $153,847 ($100,768 [$26,534–$253,630]) and $28,466 ($23,696 [$15,466–$39,107]), respectively. Conclusions No clear standard of care exists in 3 L therapy for older adults with relapsed/refractory DLBCL. The economic burden of DLBCL intensifies with each progressing line of therapy, thus underscoring the need for additional therapeutic options.

Specific Mutation Predict Relapse/Refractory Diffuse Large B-Cell Lymphoma.

The application of rituximab has significantly enhanced the overall survival rates in patients with diffuse large B-cell lymphoma (DLBCL). Regrettably, a significant number of patients still progress to relapse/refractory DLBCL (rrDLBCL). Herein, we employed targeted sequencing of 55 genes to investigate if gene mutations could predict the progression to rrDLBCL. Additionally, we compared the mutation profiles at the time of DLBCL diagnosis with those found in rrDLBCL cases. Our findings highlighted significantly elevated mutation frequencies of TP53, MEF2B and CD58 in diagnostic biopsies from patients who progressed to relapse or refractory disease, with CD58 mutations exclusively observed in the rrDLBCL group. In assessing the predictive power of mutation profiles for treatment responses in primary DLBCL patients, we found that the frequency of CARD11 mutations was substantially higher in non-response group as compared with those who responded to immunochemotherapy. In addition, we revealed mutations in HIST2H2AB, BCL2, NRXN3, FOXO1, HIST1H1C, LYN and TBL1XR1 genes were only detected in initial diagnostic biopsies, mutations in the EBF1 gene were solely detected in the rrDLBCL patients. Collectively, this study elucidates some of the genetic mechanisms contributing to the progression of rrDLBCL and suggests that the presence of CD58 mutations might serve as a powerful predictive marker for relapse/refractory outcomes in primary DLBCL patients.

Prognostic Role of Neutrophil to Lymphocyte Ratio at Diagnosis in Patients with Diffuse Large B-Cell Lymphoma.

Aim to investigate the prognostic value of neutrophil to lymphocyte ratio (NLR) at the time of diagnosis, which is an inexpensive and easily accessible parameter, compared to factors known as prognostic value (such as R-IPI and NCCN-IPI) in patients with diffuse large B-cell lymphoma (DLBCL). Prognostic value of NLR at diagnosis in DLBCL. A hundred (100) newly diagnosed DLBCL patients were included. The correlations between the NLR with clinical characteristics, treatment response, and survival were analyzed. The NLR cut-off value was taken at 3.5 accordıng to the receiver operating characteristic curve. There were 53 patients with an NLR of 3.5 and 47 patients with an NLR < 3.5. Patients with NLR ≥ 3.5 had a complete response (CR) rate of 66.0% (n = 31/47), and patients with NLR < 3.5 had a CR rate of 98.1% (n = 51/52). The median progression-free survival (PFS) was 132.5 months (95%CI 103.1-162.0). PFS in the NLR ≥ 3.5 group (36 months) was significantly (P < 0.000) shorter than in the NLR < 3.5 group (185 months). The median overall survival (OS) for NLR ≥ 3.5 and NLR < 3.5 was 79.2 months (95% CI 51.6-106.8) and 197.8 months (95% CI 173.2-222.5), respectively. NLR ≥ 3.5 was associated with worse OS than NLR < 3.5 (P = 0.000). The high value of NLR (≥3.5) had lower treatment response rates, higher relapse, and death rates. High NLR was associated with poor treatment response, PFS, and OS. NLR can be used as a cost-effective and easy-to-interpret prognostic marker in DLBCL patients.

Central Nervous System Prophylaxis Utilization in Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma Within a Large Community Health System.

The impact of central nervous system (CNS) prophylaxis in diffuse large B-cell lymphoma (DLBCL) is contentious. The CNS International Prognostic Index (IPI) calculator offers prognostic guidance in identifying those patients who may be at highest risk of disease progression or relapse to the CNS. However, it is unclear whether this tool has guided clinician decision-making in a real-world setting. Studies have suggested that CNS prophylaxis may not offer clinically significant benefit in terms of preventing CNS disease progression. Given this, we investigated the utilization of CNS prophylaxis within our own population and documentation of the CNS-IPI score. We retrospectively evaluated patients with newly diagnosed DLBCL between January 1, 2014, and December 31, 2017. Patients were assessed for receipt of CNS prophylaxis in the form of intrathecal (IT) chemotherapy and/or high-dose intravenous (IV) methotrexate. CNS-IPI scores were calculated for all patients who received CNS prophylaxis or those who experienced CNS disease. Long-term outcomes at five years from diagnosis included CNS progression/relapse and survival. Of 234 patients who met criteria, 20 (8.6%) received either IV methotrexate or IT chemotherapy; most received IT methotrexate. No patients in the IT prophylaxis group developed CNS disease, while two of eight IV methotrexate patients experienced CNS disease involvement. The incidence of CNS progression was 3.7% in the no prophylaxis group and 10% in those who received prophylaxis. This study revealed low utilization of CNS prophylaxis and CNS-IPI documentation in a community hospital system. Given large differences between groups, claims of CNS prophylaxis efficacy are unable to be made. CNS relapse rates were consistent with existing literature and promote continued evaluation of the utility of current CNS prophylaxis approaches in DLBCL. New unambiguously effective therapeutic approaches are needed and may encourage a higher rate of standardized use.

Ibrutinib in Combination with R-GemOx in Patients with Relapsed or Refractory Diffuse Large B-cell Lymphoma of Nongerminal Center B-cell-like Type: Phase II Clinical Trial of the Spanish GELTAMO Group.

This phase II clinical trial evaluated the combination of ibrutinib with rituximab, gemcitabine, and oxaliplatin (R-GemOx) in patients with nongerminal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL). The IBDCL trial (NCT02692248) included patients with histologic diagnosis of non-GCB DLBCL with relapsed or refractory disease and non-candidates for stem-cell transplantation. Patients received an induction treatment consisting of six or eight cycles of R-GemOx at standard doses every 2 weeks, in combination with ibrutinib (560 mg daily), followed by a maintenance treatment with ibrutinib for a maximum of 2 years. The primary objective was to evaluate the overall response rate after four cycles. Sixty-four patients were included, 72% of them refractory to the last regimen. The overall response rate and complete remission rate after the fourth cycle were 53% [95% confidence interval (CI), 41-65] and 34% (95% CI, 24-46), respectively. Twenty-four (37%) patients started maintenance, and 7 (11%) completed the planned 2 years. After a median follow-up of 29.7 months (range: 0.4-48.6), the estimated 2-year progression-free survival and overall survival were 18% (95% CI, 8-28) and 26% (95% CI, 14-37), respectively. The most common grade ≥3 treatment-related adverse events were thrombocytopenia (44%), neutropenia (30%), and anemia (14%). Grade ≥3 infectious and cardiovascular treatment-related adverse events were reported in 6 (9%) and 1 (2%) patient, respectively. Ibrutinib in combination with R-GemOx, followed by ibrutinib maintenance, demonstrated encouraging antitumor activity with durable responses and a manageable toxicity in patients with non-GCB DLBCL.

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

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

A Retrospective Study of R±DHAX Regimen versus R-CHOP Regimen First-Line Treatment of Elderly Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma

To investigate the clinical efficacy and prognosis of Rituximab combined with DHAX and CHOP regimen in the first-line treatment of elderly patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). A total of 36 elderly patients with DLBCL who were admitted and treated with 3 of more courses of treatment from August 2011 to August 2021 were retrospectively analyzed, and they were divided into rituximab±DHAX (R±DHAX) regimen group (18 cases) and rituximab±CHOP (R-CHOP) regimen group (18 cases) according to the treatment plan, and clinical features, efficacy and survival of the patients were observed. Compared with R-CHOP group, patients of the R±DHAX group were older, and had worse performance status and higher IPI score, the differences between two groups in age, ECOG score and IPI score were statistically significant ( P =0.005 P =0.018, P =0.035), but there were no significant differences beween two groups in gender, whether there were B symptoms, whether LDH was elevated, whether there was extranodal involvement, cell origin, bone marrow infiltration, and whether rituximab was combined ( P =0.738, P =1, P =0.315, P =0.305, P =0.413, P =0.177, P =0.711, P =0.229). The efficacy could be evaluated in 36 cases, including CR 14 (38.9%), PR 17 (47.2%), PD 5 (13.9%), and ORR of 86.1% (31/36). There were no statistically significant differences in CR［(27.8%（5/18） vs 50.0%（9/18）; P >0.05］ and PR ［44.4%（8/18） vs 50.0%（9/18）; P >0.05］ of R±DHAX group and R-CHOP group, there was statistically significant difference in ORR［72.2%（13/18） vs 100.0%（18/18）; P =0.045］ between two groups. The 1-year OS of R±DHAX group and R-CHOP group was (38.9±11.5%)% and (94.4±7.4%)%, respectively, 2-year OS was (16.7±8.8)% and (72.2±10.6)%, respectively, and the differences between two groups were statistically significant ( P =0.001, P =0.002). The median survival time in the R±DHAX group was 11 months(95%CI :8.9-13.1), and the median survival time in the R-CHOP group was not reached, and there was a statistically significant difference between the groups (P < 0.001). For elderly DLBCL patients, R±DHAX may not be superior to R-CHOP in OS, and ECOG score, IPI score and age may affect the survival of elderly DLBCL patients. However, R±DHAX regimen is safe, tolerable and has a certain efficacy, which can be used as one of the clinical treatment options for elderly DLBCL.

Chinese expert consensus on the diagnosis and management of elderly patients with diffuse large B-cell lymphoma (2024)

The general population in China is aging, and thus the number of older patients with diffuse large B-cell lymphoma (DLBCL) will continue to increase. Individualized treatment is required to maximize therapeutic potential while minimizing the risk of toxicity. To improve the diagnosis and treatment of DLBCL in older people in China, the Lymphocyte Disease Group of the Hematology Division of the Chinese Medical Association and Lymphoma Expert Commitee of Chinese Society of Clinical Oncology (CSCO) have organized relevant experts to formulate this consensus.

Prognostic relevance of tumor-infiltrating CD4+ cells and total metabolic tumor volume-based risk stratification in diffuse large B-cell lymphoma.

In order to elucidate the relationship between pretreatment radiomic parameters and the proportions of various tumor-infiltrating (TI) cells, we retrospectively analyzed the association of total metabolic tumor volume (TMTV) and TI cells on biopsied tumor lesions in 171 patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). The surface markers of TI cells were analyzed by multicolor flow cytometry using a dissected single-cell suspension. In examining the correlation between TI cells and positron-emission tomography-derived parameters (maximum standardized uptake value [SUVmax], total metabolic tumor volume [TMTV], and total lesion glycolysis), intratumoral cell types minimally influenced the results, except for a weak negative correlation between CD4+ cells and SUVmax (R=-0.16, P=0.045). Even for the lesion fluorodeoxyglucose uptake at the biopsied site, CD19+ cells (indicative of malignant burden) showed only a weak correlation with the highest SUV (R=0.21, P=0.009), whereas CD3+ (R=-0.25, P=0.002) and CD4+ cells (R=-0.29, P<0.001) demonstrated a similarly weak inverse correlation. High TMTV and low TI CD4+ cells were independently associated with poor prognosis and their combination identified the most adverse population (3-year progression-free survival: 32.3%, 95% confidence interval [CI]: 19.4-53.7; 3-year overall survival: 48.4%, 95% CI: 33.6-69.6). Moreover, radiomic parameters incorporating the international prognostic index significantly improved the 3-year survival prediction (area under the curve: 0.76, P<0.05) compared to their standalone use. This study underscores the prognostic impact of TI CD4+ cells on DLBCL and suggests that integration of TMTV and TI cell analysis enhances the accuracy of prognostic prediction.

Clinical Features and Prognostic Analysis of Newly Diagnosed Diffuse Large B-cell Lymphoma Combined with Hemophagocytic Syndrome

To compare the clinical features and prognosis between newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients with and without hemophagocytic syndrome (HPS). The clinical data of 45 DLBCL patients in Gansu Provincial Hospital from January 2012 to December 2021 were retrospectively analyzed. The patients were divided into HPS group (15 cases) and non-HPS group (30 cases). The clinical features and prognosis of the two groups were compared, and survival analysis was performed using Kaplan-Meier method. Patients with HSP were mostly characterized by fever, cytopenia and splenomegaly. The levels of ferritin and soluble CD25 increased in all patients. The level of fibrinogen decreased in 66.67% patients, while triglyceride increased in 53.33% patients, and bone marrow hemophagocytosis occurred in 80.00% patients. Compared with non-HSP group, the proportions of patients with advanced stage (Ann Arbor stage III/IV) and lactate dehydrogenase (LDH) ≥240 U/L were higher in HSP group (both P < 0.05). The median survival time of HSP group was 8.0 months, which was significantly shorter than 45.5 months of non-HSP group (P < 0.001). The DLBCL patients with HPS have later Ann Arbor stage, higher LDH and shorter overall survival time compared with patients without HPS.