Loïc Renaud

PURPOSE: In large B-cell lymphoma (LBCL), use of high-dose methotrexate (HD-MTX) to prevent CNS relapse (so-called CNS prophylaxis) remains controversial. International guidelines continue to recommend HD-MTX in patients deemed ultra high risk (UHR) because of a lack of robust data specific to these subgroups. This study was designed to examine the impact of HD-MTX specifically in UHR patients. METHODS: Data from two previous retrospective analyses were combined to produce a cohort of UHR patients (≥1 of the following criteria: CNS international prognostic index score 5-6; testicular, renal/adrenal, or breast involvement; ≥3 extranodal sites), treated with or without HD-MTX. The primary outcome was CNS relapse rate (isolated or concurrent with systemic relapse) measured from diagnosis with additional landmark analysis of all responding patients with no progression event at 6 months. RESULTS: Analyses were performed on 1,923 patients meeting UHR criteria. No significant difference in 3-year CNS relapse rate was observed between no HD-MTX (n = 1,051) versus HD-MTX patients (n = 872), including in multivariable analyses adjusting for baseline characteristics (3-year rate, 9.3% v 8.1%; adjusted hazard ratio [HR], 1.13 [95% CI, 0.82 to 1.57]). Analyses restricted to isolated CNS relapse also confirmed no difference (5.9% v 5.7%; adjusted HR, 1.03 [95% CI, 0.69 to 1.53]). In the landmark analysis (no HD-MTX n = 782, HD-MTX n = 773), no difference in 3-year CNS relapse was observed (6.7% v 6.6%, adjusted HR, 0.95 [95% CI, 0.62 to 1.44]). CONCLUSION: To our knowledge, this is the largest international comparative data set of patients with LBCL with UHR features showing no significant reduction in CNS relapse with HD-MTX in all UHR or in any individual subgroup. Despite inherent limitations of retrospective analyses, the data strongly support previous studies in suggesting HD-MTX prophylaxis has no meaningful benefit for most patients.

Primary mediastinal B-cell lymphoma (PMBL) is an uncommon aggressive lymphoma with generally favorable outcomes; however, 15-20% of patients develop refractory disease. Reliable baseline prognostic biomarkers remain lacking. We evaluated the prognostic value of radiomic parameters derived from baseline 18F-FDG PET/CT in newly diagnosed PMBL. This post-hoc analysis included 180 treatment-naïve patients from the multicenter LYSA cohort (2007-2017) treated with rituximab plus ACVBP, R-CHOP14, or R-CHOP21. Twelve 3D PET-derived radiomic features were extracted using Oncometer3D. Inter-parameter correlations were assessed using Spearman coefficients. Receiver operating characteristic (ROC) analyses determined optimal cut-offs. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier estimates and Cox regression models. Four clusters of correlated features were identified: activity, tumor burden, massiveness/fragmentation, and dispersion. Among these, total metabolic tumor volume (TMTV), maximal inter-lesion distance (Dmax), and median peripheral centroid distance (medPCD) demonstrated the strongest prognostic associations. TMTV and Dmax were significantly associated with shorter PFS and OS, while medPCD predicted OS. In multivariable analysis adjusted for IPI, bulky disease, B symptoms, and treatment regimen, a composite radiomic score (2-3 high-risk features vs 0-1) independently predicted OS (HR 7.76, 95% CI 1.59-37.74) and showed a strong trend for PFS. The composite score outperformed conventional clinical risk factors. Baseline PET-derived radiomic features capturing tumor burden, spatial dispersion, and compactness provide independent prognostic information in PMBL. A three-parameter radiomic score outperformed conventional risk factors and identified a high-risk subgroup at diagnosis, warranting prospective and external validation before clinical implementation.

Primary mediastinal large B‐cell lymphoma (PMBL) is a rare entity that predominantly affects young female patients and typically presents as a large and compressive anterior mediastinal mass. Accumulating evidence suggests relationships among PMBL patient body composition (BC), cancer outcomes, and treatment‐related toxicities. The aim of this study was to evaluate the impact of BC on PMBL patients using PET‐CT images acquired pretreatment. Two hundred nineteen patients were included in an ancillary analysis of a multicenter retrospective LYSA cohort of treatment‐naïve adult PMBL patients who received first‐line treatment with ACVBP, CHOP14 or CHOP21 plus anti‐CD20. Anthropometric parameters were assessed from the baseline PET‐CT image using two methods: (i) manual segmentation at the L3 level and (ii) automatic software‐based multislice measurements with Anthropometer3DNet. The median age was 35.4 years (range 18–88 years), and the median body mass index was 23.8 kg/m² (15.6; 40.8). Overall, 137 patients were treated with R‐ACVBP, 44 received R‐CHOP14, and 38 were treated with R‐CHOP21. Patients with low lean body mass had a higher incidence of febrile neutropenia, both in the overall cohort (25% vs. 12.6%, p = 0.02) and in the R‐ACVBP subgroup (35.7% vs. 19.4%, p = 0.03). Univariate analysis showed that in patients treated with R‐ACVBP, subcutaneous low adiposity, determined by 3D measurements, was associated with overall survival (OS) (p = 0.04). At 3 years, the OS (95% CI) was 96% (93–100) in above‐median adiposity patients and 86% (78–95) in below‐median adiposity patients. Low lean body mass (LBM), assessed from the pretreatment PET‐CT images using automatic Anthropometer3DNet software, may serve as a predictive marker for acute treatment‐related toxicity in PMBL patients, particularly those receiving the dose‐intensive R‐ACVBP regimen. Additionally, depletion of the subcutaneous fat mass was correlated with an increased risk of mortality, highlighting the importance of a comprehensive BC assessment in this patient population.

Objectives: Diffuse large B‐cell lymphoma (DLBCL) constitutes 30–40% of non‐Hodgkin lymphoma cases. Despite therapeutic advances, persistence of relapsed cases has been linked to the complex tumor microenvironment (TME) and its interactions with lymphoma cells. In particular, characterising T‐cell subsets, including rare cell types, and their interplay with the remaining TME is crucial for unravelling DLBCL pathogenesis and refining therapeutic strategies. Methods: Using flow and spectral cytometry with unsupervised analysis, we investigated T‐cell subpopulations across DLBCL biopsies and control lymph nodes (LN). We also inferred communication pathways between T cells and other immune cells in the TME based on the correlation of ligand–receptor expression. Results: Our analysis revealed a higher frequency of CD8 ⁺ follicular regulatory T (Tfr) cells in DLBCL biopsies compared to control LN. These cells exhibited an effector‐memory phenotype (CD45RA ⁻ CCR7 ⁻ ), expressed follicular markers (PD‐1 ⁺ CXCR5 ⁺ ) and had a regulatory profile (CD127 ⁻ CD25 ⁺ ) along with an activation/co‐stimulatory signature (HLA‐DR ⁺ , ICOS ⁺ , CD95 ⁺ ). Correlation analysis highlighted a co‐stimulatory interaction between lymphoma B cells and CD8 ⁺ Tfr cells through the ICOS/ICOSL pathway, which may contribute to a protumor effect. Validation in independent scRNAseq and flow cytometry datasets confirmed the notable prevalence of CD8 ⁺ Tfr cells in DLBCL biopsies. Conclusions: Our study highlights the utility of high‐dimensional computational cytometry in elucidating T‐cell subpopulations, including an increased frequency of CD8 ⁺ follicular regulatory T cells and their communication patterns within the DLBCL TME. This unbiased approach sheds light on novel cellular mechanisms in DLBCL, uncovering potential targets and biomarkers for immunotherapy.

There is a scarcity of data on the tumor B-cell receptor (BCR) repertoire and lymphoid microenvironment in primary mediastinal B-cell lymphoma (PMBL). We applied 5ʹ rapid amplification of complimentary DNA ends (5′RACE) to tumor RNA samples from 137 patients with PMBL with available gene expression profiling and next-generation sequencing data. We obtained 5′RACE results for 75 of the 137 (54.7%) patients with the following clinical characteristics: median age (range), 33 years (18-64); female, 53.3%; performance status score 0 to 1, 86.7%; stage I to II, 57.3%; first-line treatment with anti-CD20 plus doxorubicin-based chemotherapy, 100%. Among the 60 biopsies that expressed a productive BCR, we highlighted a strong somatic hypermutation profile, defined as 81.1% and >78.6% of all complementarity-determining region 3 sequences for IgVH and IgVL, respectively. When compared with other patients, this subgroup had similar clinical characteristics but a greater median allele frequency for all somatic variants, a decreased BCR diversity, and greater expression of PDL1/PDL2 and MS4A1 genes, suggesting greater tumoral infiltration. We confirmed this poorer prognosis in a multivariate model and in an independent validation cohort in which 6 of 37 (16%) PMBL patients exhibited HCD (PFS: HR, 12; OS: HR, 17).

Brentuximab vedotin (BV)‐bendamustine (90 or 120 mg/m2 day 1 and 2) every 28 days is an effective treatment for relapsed/refractory Hodgkin lymphoma (R/R HL) but associated to high toxicity especially for elderly patients. We conducted in St Louis Hospital, Paris, between 2015 and 2021 a retrospective single‐center analysis of 44 patients with R/R HL treated with one‐day BV‐bendamustine (120 mg/m2) every 21 days. Sixteen percent of patients were ≥ 60 years old (yo). Seventy‐three percent of patients received total number of cycles without interruption nor adaptation. No patient ≥ 70 yo required treatment interruption. Dose adjustment was necessary for 18% of patients. Infusion‐related reaction (36%) occurred always at cycle 2 and was the only cause of treatment interruption. One febrile neutropenia, one non‐documented septic shock, one pyelonephritis on transplanted kidney and one COVID complicated by cytopenias were reported. Sixteen percent patients presented a peripheral sensory neuropathy, 7% and 4% respectively grade 3–4 neutropenia and thrombocytopenia. Overall response was 84%, with 73% of complete remission. Median progression‐free survival was of 19.8 months (95% CI 13.1‐NR) and median overall survival was not reached with a median follow‐up of 31 months. We suggest that one‐day BV‐bendamustine (120 mg/m2) ever 21 days is a safe and feasible treatment for R/R HL especially for elderly patients.

Progression or relapse in the central nervous system (CNS) remains a rare but mostly fatal event for patients with diffuse large B-cell lymphoma (DLBCL). In a retrospective analysis of 5189 patients treated within 19 prospective German and French phase 2/3 trials, we identified 159 patients experiencing a CNS event (relapse: 62%, progression: 38%). Intracerebral, meningeal, intraspinal, or combined involvement was reported in 44%, 31%, 3%, and 22% of patients, respectively. 62 of 155 evaluable patients (40%) showed concurrent systemic progression/ relapse. 82% of all CNS events occurred within two years after study inclusion or randomization. 87% of patients showed extranodal involvement outside the CNS. Patients generally had poor outcomes with a median overall survival (OS) of 3.4 months (95% CI 2.9–4.2) and a 2-year OS of 15% (10–22%). Outcomes did not differ depending on the site or time point of CNS events. Patients with isolated CNS events demonstrated significantly better OS (p = 0.023). Twenty-five patients were consolidated with autologous or allogeneic stem cell transplantation and achieved a 3-year OS of 36% (20–66%). This large study including more than 5000 DLBCL patients highlights the unmet medical need to improve the outcome of DLBCL patients suffering from CNS relapse.