Up to 50% of diffuse large B-cell lymphoma (DLBCL) patients are ineligible for participation in clinical trials. Ineligible patients have inferior outcomes, but less is known about the impact of commonly used organ-function-based inclusion criteria on drug efficacy estimates. Data on DLBCL patients treated with CHOP+/-rituximab were retrieved from the Danish Lymphoma Registry. Trial inclusion criteria were extracted from four international DLBCL trials (REMoDL-B, GOYA, POLARIX, and HOVON-84). Differences in overall survival (OS) and 5-year restricted mean survival differences (5 y-RMSDs) between trial eligible and ineligible patients were computed. The effectiveness of adding rituximab to CHOP was quantified by the 5 y-RMSD between CHOP and R-CHOP-treated patients and the impact of individual trial criteria on estimated effectiveness was quantified by Shapley-values. In total, 4,083 R-CHOP-treated and 890 CHOP-treated DLBCL patients were included. Across the trials, 18.6-29.3% of the included R-CHOP-treated patients were deemed ineligible for trial based on organ function and performance status alone. Ineligible patients had significantly worse survival, with adjusted absolute differences in 5-year OS of 9-15%. The impact of individual criteria on the estimated effectiveness of adding rituximab to CHOP was small (Shapley-value range, -2.74-0.31). Using a smaller set of criteria derived from a data-driven approach, the number of eligible patients increased by 16-38% and the 5 y-RMSD increased by 0.7-3.1 months. In conclusion, OS among trial ineligible DLBCL patients is inferior as expected, but relaxing trial criteria would have increased the number of trial participants without making major changes in estimated efficacy for a hypothetical CHOP versus R-CHOP trial. This does not necessarily imply that trial findings based on selected patients are unreliable, as the estimated effectiveness of adding rituximab to CHOP was only slightly affected by omitting selected inclusion criteria.

OBJECTIVE: Selinexor is an oral selective inhibitor of exportine-1 (XPO1) with efficacy as a single agent in heavily pretreated diffuse large B-cell lymphoma (DLBCL). We conducted a study investigating the combination of selinexor with rituximab and platinum-based chemotherapy in B-cell lymphoma.
METHODS: We conducted a phase 1b, dose-escalation, and expansion trial, which enrolled patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Patients received oral selinexor according to a 3 + 3 design in combination with rituximab and dexamethasone, high-dose cytarabine, oxaliplatine (DHAOX) or gemcitabine, dexamethasone, and cisplatin (GDP) chemotherapy.
RESULTS: A total of 39 patients were enrolled, 27 during the escalation phase and 12 during the expansion phase. Most patients had diffuse large B-cell lymphoma (DLBCL; 77%). Group R-DHAOX was prematurely closed to inclusion due to a recommendation from the French drug agency, independent of this trial. A recommended phase 2 dose (RP2D) of selinexor in association with R-GPD was established at 40 mg on days 1, 8, and 15 of each 21-day cycle. In a population of 18 patients treated at this dose of selinexor, the most frequent grade 3-4 adverse events were hematological. With this regimen, seven obtained a complete metabolic response and five a partial response. The median PFS was 5.8 months.
CONCLUSIONS: Among the patients with R/R B-cell lymphoma, selinexor at a weekly dose of 40 mg with R-GDP is feasible for outpatients, with a generally acceptable safety profile.

OBJECTIVE: The aim of this study is to identify risk factors contributing to central nervous system (CNS) invasion and to validate the suitability of the Central Nervous System International Prognostic Index (CNS-IPI) for individuals afflicted with diffuse large B-cell lymphoma (DLBCL).
METHODS: Based on the presence or absence of CNS invasion, 365 patients were stratified into two groups: the CNS group and the non-CNS group. The clinical data of the patients were retrospectively analyzed using univariate and multivariate analysis, and the differences in survival curves were compared. The dependent variable in this study was the presence or absence of CNS invasion, while the independent variables included age, stage, extranodal involvement, renal/adrenal involvement, and others. Statistical methods included the chi-squared test and Fisher\'s exact test for intergroup comparison and binary logistic regression for multi-factor analysis. The related risk factors were modeled using the Cox proportional hazards model. The Kaplan-Meier method was used to generate survival curves, and the log-rank test was used to compare the differences between survival curves. The optimal cutoff value of beta-2 (β2)-microglobulin was determined through the utilization of a receiver operating characteristic (ROC) curve. All P values were bidirectional, and P < 0.05 was considered statistically significant. Both SPSS 23.0 (IBM Inc., Armonk, NY, USA) and RStudio (R software version 4.0.2, R Project for Statistical Computing) software were used for data processing RESULTS: The five factors of the CNS-IPI were related to the prognosis of patients with CNS invasion. Bone involvement, albumin < 40 g/L, and P53 protein (+) were the risk factors for CNS invasion in patients with DLBCL. However, prognostic factors such as double strike, testicular involvement, breast involvement, uterine involvement, and bone marrow involvement did not apply to these patients. It was also discovered that elderly patients with DLBCL with reduced albumin levels were more susceptible to CNS invasion. Furthermore, extranodal involvement at multiple sites and elevated beta-2 (β2) microglobulin were independent prognostic factors CONCLUSION: Patients older than 60 years with DLBCL and decreased albumin are at increased risk for CNS invasion. In addition to the five factors in the CNS-IPI, bone involvement, albumin levels < 40 g/L, and P53 protein expression are risk factors affecting the prognosis of CNS invasion in patients with DLBCL.

Approximately 40% of limited-stage (stage I and II) diffuse large B-cell lymphoma (LS-DLBCL) presents with extranodal disease. Extranodal LS-DLBCL may have significant biological differences and associated with worse outcomes than nodal disease. Although rituximab based chemoimmunotherapy is standard of first-line treatment, the role of consolidative radiotherapy (RT) in this particular subgroup is controversial. In this multicenter retrospective study, we evaluated the survival benefit of consolidative RT in patients diagnosed with extranodal LS-DLBCL and received rituximab-based chemoimmunotherapy with or without consolidative RT. A total of 328 patients were included, 129 patients (39.3%) received chemoimmunotherapy and consolidative RT, and 199 patients (60.7%) received chemoimmunotherapy alone. With a median follow-up of 5.1 years (range, 0.3-14.8 years), 5-year progression-free survival (PFS) and overall survival (OS) for all patients were 75.4% and 83.9%, respectively. In multivariate analyses, the addition of consolidative RT was associated with superior OS (P = 0.004) and PFS (P = 0.005). High stage-modified International Prognosis Index (SM-IPI) risk predicted worse OS (P = 0.001) and PFS (P = 0.005). Also, propensity score-matched analyses showed RT improved both OS (hazard ratio [HR] 0.228, 95% confidence index [CI] 0.111-0.467, P < 0.001) and PFS (HR 0.308, 95% CI 0.167-0.566, P < 0.001). Among patients who achieved CR, 49 patients (16.6%) developed disease relapse, of which 30.6% relapsed at local sites. Consolidative RT significantly reduced relapse risk (P = 0.002). Our results demonstrated that consolidative RT significantly improved outcomes in patients with extranodal LS-DLBCL in the rituximab era.

UNASSIGNED: Fluorescence in situ hybridization (FISH) is an essential ancillary study used to identify clinically aggressive subsets of large B-cell lymphomas that have MYC, BCL2, or BCL6 rearrangements. Small-volume biopsies such as fine needle aspiration biopsy (FNAB) and core needle biopsy (CNB) are increasingly used to diagnose lymphoma and obtain material for ancillary studies such as FISH. However, the performance of FISH in small biopsies has not been thoroughly evaluated or compared to surgical biopsies.
UNASSIGNED: We describe the results of MYC, BCL2, and BCL6 FISH in a series of 222 biopsy specimens, including FNAB with cell blocks, CNBs, and surgical excisional or incisional biopsies from 208 unique patients aggregated from 6 academic medical centers. A subset of patients had FNAB followed by a surgical biopsy (either CNB or excisional biopsy) obtained from the same or contiguous anatomic site as part of the same clinical workup; FISH results were compared for these paired specimens.
UNASSIGNED: FISH had a low hybridization failure rate of around 1% across all specimen types. FISH identified concurrent MYC and BCL2 rearrangements in 20 of 197 (10%) specimens and concurrent MYC and BCL6 rearrangements in 3 of 182 (1.6%) specimens. The paired FNAB and surgical biopsy specimens did not show any discrepancies for MYC or BCL2 FISH; of the 17 patients with 34 paired cytology and surgical specimens, only 2 of the 49 FISH probes compared (4% of all comparisons) showed any discrepancy and both were at the BCL6 locus. One discrepancy was due to necrosis of the CNB specimen causing a false negative BCL6 FISH result when compared to the FNAB cell block that demonstrated a BCL6 rearrangement.
UNASSIGNED: FISH showed a similar hybridization failure rate in all biopsy types. Ultimately, MYC, BCL2, or BCL6 FISH showed 96% concordance when compared across paired cytology and surgical specimens, suggesting FNAB with cell block is equivalent to other biopsy alternatives for evaluation of DLBCL or HGBCL FISH testing.

We aim to investigate cardiovascular mortality risk among diffuse large B-cell lymphoma (DLBCL) patients and explore cardiovascular mortality trends in the past decades in United States. We extracted data from the Surveillance, Epidemiology, and End Results database for adult patients diagnosed with DLBCL between 1975 and 2019. Standardized mortality ratio, joinpoint regression analysis, and competing risk model were analyzed. Overall, 49,918 patients were enrolled, of whom 4167 (8.3%) cardiovascular deaths were observed, which was 1.22 times the number expected (95%CI, 1.19-1.26). During 1985-2019, the incidence-based cardiovascular mortality rate increased by 0.98% per year (95%CI, 0.58-1.39%), with statistically significant increases in age groups younger than 75 years. The cumulative mortality from cardiovascular disease increased by age but never exceeded that from DLBCL. Older age, male sex, earlier year of diagnosis, lower tumor stage at diagnosis, chemotherapy, radiotherapy, and surgery were all poor prognostic factors for cardiovascular mortality.

UNASSIGNED: Studies have indicated an association between gut microbiota (GM) and non-Hodgkin lymphoma (NHL). However, the causality between GM and NHL remains unclear. This study aims to investigate the causality between GM and NHL using Mendelian randomization (MR).
UNASSIGNED: Data on GM is sourced from the MiBioGen consortium, while data on NHL and its subtypes is sourced from the FinnGen consortium R10 version. Inverse variance weighted (IVW) was employed for the primary MR analysis method, with methods such as Bayesian weighted Mendelian randomisation (BWMR) as an adjunct. Sensitivity analyses were conducted using Cochran\'s Q test, MR-Egger regression, MR-PRESSO, and the \"Leave-one-out\" method.
UNASSIGNED: The MR results showed that there is a causality between 27 GMs and NHL. Among them, 20 were negatively associated (OR < 1), and 7 were positively associated (OR > 1) with the corresponding diseases. All 27 MR results passed sensitivity tests, and there was no reverse causal association.
UNASSIGNED: By demonstrating a causal link between GM and NHL, this research offers novel ideas to prevent, monitor, and cure NHL later.

BACKGROUND: RTXM83, a biosimilar of rituximab, was approved after physicochemical, functional, non-clinical, and clinical studies demonstrated their similarity; these studies included RTXM83-AC-01-11, a multicentric double-blind international prospective pivotal study. Long-term data on biosimilars can potentially elucidate their clinical robustness and facilitate their broader adoption.
METHODS: In this retrospective observational study, we analyzed a dataset from a Brazilian cohort previously randomized in the RTXM83-AC-01-11 study followed by the assessment of long-term outcomes in an observational extension phase from randomization in the RTXM83-AC-01-11 study to the last recorded evaluation. Patients with diffuse large B cell lymphoma (DLBCL) received either reference rituximab (R) or RTXM83 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as adjuvant treatment.
RESULTS: The median follow-up period was 77.0 months. Patients with initial DLBCL stages III and IV comprised 50% of the R-CHOP group and 40% of the biosimilar group. Five (18.5%) patients, including two RTXM83-CHOP-treated and three R-CHOP-treated individuals, experienced late adverse events (AEs) of interest. No new safety signs were established. At the final assessment, the progression-free survival (PFS) rates were 93.3% and 50.0% in the RTXM83-CHOP and R-CHOP groups, respectively. Median PFS was not achieved in the RTXM83-CHOP group, which was 40.5 months in the R-CHOP group. The overall survival (OS) rates were 100% and 66.7% in the RTXM83-CHOP and R-CHOP groups, respectively. The median OS was not reached in any group.
CONCLUSIONS: This study demonstrated the long-term safety and effectiveness of RTXM83 in treating DLBCL; outcomes comparable to those of the reference product and potentially improved access to treatment have been indicated. However, further research with more diverse patient groups can validate these findings and advocate the broader adoption of biosimilars in cancer care.
BACKGROUND: ClinicalTrials.gov Identifier: NCT04928573. June 16, 2021, \"retrospectively registered\".

The implications of the genetic component in the initiation and development of chronic lymphoproliferative disorders have been the subject of intense research efforts. Some of the most important genes involved in the occurrence and evolution of these pathologies are the HLA genes. The aim of this study is to analyze, for the first time, possible associations between chronic lymphoproliferative diseases and certain HLA alleles in the Romanian population.
This study included 38 patients with chronic lymphoproliferative disorders, diagnosed between 2021 and 2022 at Fundeni Clinical Institute, Bucharest, Romania, and 50 healthy controls. HLA class I and class II genes (HLA-A/B/C, HLA-DQB1/DPB1/DRB1) were investigated by doing high resolution genotyping using sequence specific primers (SSP).
Several HLA alleles were strongly associated with chronic lymphoproliferative disorders. The most important finding was that the HLA-C*02:02 (p = 0.002, OR = 1.101), and HLA-C*12:02 (p = 0.002, OR = 1.101) have a predisposing role in the development of chronic lymphoproliferative disorders. Moreover, we identified that HLA-A*11:01 (p = 0.01, OR = 0.16), HLA-B*35:02 (p = 0.037, OR = 0.94), HLA-B*81:01 (p = 0.037, OR = 0.94), HLA-C*07:02 (p = 0.036, OR = 0.34), HLA-DRB1*11:01 (p = 0.021, OR = 0.19), and HLA-DRB1*13:02 (p = 0.037, OR = 0.94), alleles have protective roles.
Our study indicates that HLA-C*02:02 and HLA-C*12:02 are positively associated with chronic lymphoproliferative disorders for our Romanian patients while HLA-DRB1*11:01, HLA-DRB1*13:02, and HLA-B*35:02 alleles have a protective role against these diseases.

In this hypothesis-generating analysis, we examined whether longitudinal changes in patient-reported outcomes (PROs), such as symptoms, over time would be prognostic for progression-free survival (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) who were newly treated with obinutuzumab (G) in combination with CHOP (G-CHOP) or rituximab (R) with CHOP (R-CHOP), in the GOYA Phase 3 trial (NCT01287741). Our results show that from the study baseline to cycle 3 day 1, every 1-point increase (worsening) in fever symptoms was associated with a 41% higher risk of death (hazard ratio [HR], 1.41; P = 0.01). Every 1-point increase (worsening) in lumps or swelling symptoms was associated with a 27% higher risk of disease progression or death (PFS events) (HR, 1.27; P = 0.01) and a 29% higher risk of death (OS events) (HR, 1.29; P = 0.02). No significant associations were observed between survival and changes in other symptoms, such as itching. Our study suggests that changes in some PROs are related to survival in DLBCL patients.