Lucie Oberic

Summary: Using LYmphoma Study Association clinical trials combining 438 first‐line large B‐cell lymphomas (LBCL) patients >80 years old, we defined SENIOR‐IPI, an easily applicable prognostic index for this elderly population treated with an anti‐CD20‐miniCHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)‐based regimen. SENIOR‐International Prognostic Index (SENIOR‐IPI) takes into account accessible variables (number of aaIPI predictors, lactate dehydrogenase > 3x Upper Limit of Normal (LDH >3× ULN), albumin 80 years old fit for age‐adapted immunochemotherapy than IPI, aaIPI and NCCN‐IPI.

Although clinical trials showed outcomes improvement in MCL, their applicability to real‐world practice remains limited. Using the prospective REALYSA registry (NCT03869619), we evaluated contemporary management, highlighting evolving practices and differences by age. Among 295 patients, 63% were ≥ 65 years, 48% had a high‐risk MIPI score with Ki‐67 ≥ 30% in 53% and aggressive morphology in 11%. Younger patients received high‐dose cytarabine (93%) and ASCT (78%). Older patients were treated with bendamustine‐rituximab (28%), R‐CHOP (18%), and low‐dose cytarabine (20%). Two‐year event‐free (EFS‐2y) and overall (OS‐2y) survivals were 80% and 89% in < 65y; 60% and 77% in ≥ 65y. Among 238 patients responders after induction, rituximab maintenance (RM) use was frequent but lower in older patients (88% vs. 76%). In time‐dependent Cox models adjusted for age (< 65 vs. ≥ 65) and MIPI, RM was associated with a lower hazard of EFS events (HR 0.48; 95% CI: 0.25–0.92), although residual confounding related to treatment selection may remain. In the second‐line setting ( n = 72), most patients were POD24 (89%) and 56% received ibrutinib, yet outcomes remained poor (CR 24%, ORR 35%, median EFS and OS of 6.3 and 25.6 months, respectively). These findings underscore the need for improved strategies for older and high‐risk patients. Retrospective landmark analyses suggest a potential association between RM and improved EFS but are limited by baseline differences between groups.

Primary mediastinal large B-cell lymphoma (PMBL) achieves excellent outcomes with dose-dense immunochemotherapy, yet response assessment by positron emission tomography (PET) remains limited. In this prospective multicenter observational study, we evaluated the clinical relevance of circulating tumor DNA (ctDNA) minimal residual disease (MRD) in patients with newly diagnosed PMBL and assessed whether MRD enhances outcome discrimination beyond PET. Plasma and PET images were collected at baseline and after 2 and 4 cycles. ctDNA and tumor biopsy were analyzed by high-depth, error-corrected sequencing (limit of detection ∼10−3). Associations between MRD, PET response, and progression-free survival (PFS) were evaluated. Among 84 patients, baseline ctDNA was detected in 98%. After 4 cycles of treatment with R-CHOP14 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, administered every 14 days) or R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone), 87.7% had undetectable MRD. Persistence of minimal residual disease after 4 cycles of therapy (MRD4) was associated with shorter PFS (hazard ratio [HR], 78.1; 95% confidence interval [CI], 9.5-641.8). The 1-year PFS was 98.4% (95% CI, 95.4%-100%) for patients with undetectable MRD4 vs 33.3% (95% CI, 13.2%-84.0%) for patients with detectable MRD4 (P < 10^-4). MRD4 showed a higher positive predictive value (89% vs 50%) for disease progression than PET4, (PET after 4 cycles of chemotherapy) maintaining a similar negative predictive value (100% vs 93%). In multivariate analysis, only PET4−/MRD4− remained associated with PFS (adjusted HR, 0.07; 95% CI, 0.01-0.90). Plasma ctDNA represents a highly abundant source of genetic markers for tumor fingerprinting and disease monitoring. MRD detection after frontline therapy strongly complements PET response criteria in predicting outcome. These findings support the use of ctDNA monitoring as a valuable tool for future risk-adapted strategies in PMBL. This trial was registered at www.clinicaltrials.gov as NCT04980222.

The treatment efficacy, acute toxicity, and neurocognitive sequelae of older patients with primary central nervous system lymphoma (PCNSL) remain therapeutic challenges. The standard first‐line therapy consisted of high‐dose methotrexate and cytarabine (AraC) and led to a complete response (CR) in half of the patients. To improve the response rate, we proposed intensifying the standard rituximab, methotrexate, procarbazine, vincristine, and cytarabine (R‐MPVA) regimen by sequentially adding etoposide (100 mg/m ² D2) to R‐MPV (R‐MPV‐E) and ifosfamide (1.5 g/m ² Days 1–3) to R‐AraC (R‐AraC‐I) for patients aged between 60 and 70 years. The primary objective of this retrospective study was to determine the CR rates after three and two planned cycles of R‐MPV‐E and R‐AraC‐I, respectively. Thirty‐two consecutive patients received this regimen between 2013 and 2021 in Lyon University Hospitals. After the R‐MPV‐E and R‐AraC‐I sequences, 11 (34.4%) and 26 (81.3%) patients achieved CR or unconfirmed CR (CRu), respectively, with favorable safety profiles (19% and 38%, of ≥ Grade 3 hematological toxicity; 19% and 27%, of ≥ Grade 3 infection during the induction and consolidation, respectively). With a median follow‐up of 42.4 months, the 3‐year event‐free survival (EFS) and overall survival (OS) rates were 40.2% and 63.2%, respectively. Historical comparisons with a subset of patients from the LOC network database revealed an improvement in CR rates of 81% after R‐MPV‐E/R‐AraC‐I versus 42.9% and 60.5% after MPVA and R‐MPVA, respectively, mainly owing to the addition of ifosfamide to the R‐AraC sequence. Similar results were observed in an independent retrospective cohort of 20 patients treated at Toulouse University‐Hospital, with a 70% CR rate after R‐MPV‐E/R‐AraC‐I. In addition, 7/26 (27%) CR/CRu patients in the main cohort could then be referred for autograft consolidation. In conclusion, this study revealed that ifosfamide combined with R‐AraC could increase the CR/CRu rate at the end of induction in 60–70‐year‐old PCNSL 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.

The phase 2 ALYCANTE trial aimed to evaluate the investigator-assessed complete metabolic response at 3 months from the axicabtagene ciloleucel (axi-cel) infusion as a primary end point in patients with high-risk relapsed/refractory large B-cell lymphoma who are ineligible for autologous stem cell transplantation (ASCT). This study showed a significant improvement in complete metabolic response rate at 3 months based on historical controls. This study reports the health-related quality of life (HRQoL) results as a secondary end point. HRQoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) cancer-specific questionnaire, the Quality of Life Questionnaire high-grade non-Hodgkin lymphoma 29 (QLQ-NHL-HG29) , and the EuroQol Quality of Life Scale-5 dimensions-5 levels of severity (EQ-5D-5L) generic questionnaire at baseline and 1, 3, 6, and 12 months after axi-cel infusion. Among the 62 patients included, 60 (97%) completed a baseline and at least 1 postbaseline HRQoL assessment. At 1 month infusion, adjusted mean change in HRQoL scores from baseline showed a clinically significant deterioration (greater than the clinical threshold) in physical, role, social functioning, and fatigue. However, all HRQoL dimensions recovered by 3 months after infusion and remained stable or continued to improve by 12 months. In an exploratory analysis, adjusted mean change in HRQoL score from baseline in ALYCANTE was similar to or better than in ASCT-eligible patients who received axi-cel in the phase 3 ZUMA-7 trial. Finally, the global health status and fatigue scores of the ALYCANTE population improved to levels comparable to the general French population of similar age by 3 months after infusion. These findings indicate that axi-cel improves HRQoL regardless of transplant eligibility, supporting its use across a broad patient population. This trial was registered at www.clinicaltrials.gov as #NCT04531046.

Early detection of ultrahigh-risk diffuse large B-cell lymphoma (DLBCL) is an unmet medical need to aid patient stratification for alternative treatment approaches. Metabolomics applied to biofluids of patients with cancer has emerged as a novel omics that could provide important information to better stratify these patients. In this work, the authors performed a retrospective study by nuclear magnetic resonance (NMR)–based metabolomics using plasma samples at diagnosis from 154 randomized patients with DLBCL treated by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) (from the phase 3 REMARC [Reduced-intensity Maintenance therapy with Rituximab After R-CHOP in elderly patients with DLBCL] trial). Remarkably, a combination of 3 circulating metabolites was linked to lipid metabolism (named the “NMR score”) that significantly affected overall survival (OS) (P< .0001) and progression-free survival (PFS) (P = .0003). The optimal cutoff for each metabolite was determined using X-Tile and confirmed by a training validation method. Combining 2-amino-butyrate, 3-hydroxy-butyrate, and LDL-1 lipoprotein yielded 3 risk groups with low- (0-1), intermediate- (2-3), and high-risk (4-5) patients. Germinal center B-cell (GCB)/non-GCB profile along with Bcl2 and Myc expression did not correlate with NMR score survival. In conclusion, the combination of 3 circulating metabolites linked to lipid metabolism is revealed as a feature that captures heterogeneity among patients with DLBCL. This NMR score seemed promising for DLBCL risk stratification, even among responder patients after R-CHOP treatment. This trial was registered at www.ClinicalTrials.gov as #NCT01122472.

Prolonged and refractory hematotoxicity is a severe complication of anti‐BCMA CAR‐T cell therapy, associated with substantial morbidity. When conventional supportive measures (transfusions and hematopoietic growth factors) fail, alternative strategies are urgently needed. We report the case of a 55‐year‐old man who developed persistent cytopenias after idecabtagene vicleucel. Reinfusion of cryopreserved autologous stem cells (stem cell boost), administered without conditioning chemotherapy, resulted in rapid and complete hematopoietic recovery after 14 days. This case highlights the potential of stem cell boost as a salvage approach for prolonged post‐CAR‐T hematotoxicity and underscores the need for prospective multicenter studies to standardize indications, timing, and procedures for this intervention.

In the POLARIX study (ClinicalTrials.gov identifier: NCT03274492 ), polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) showed a significant progression-free survival (PFS) benefit versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated intermediate- or high-risk diffuse large B-cell lymphoma (DLBCL; median follow-up: 28 months). In this 5-year update, sustained PFS benefits favoring Pola-R-CHP were observed. In the global intention-to-treat population (N = 879; median follow-up: 64.1 months), Pola-R-CHP demonstrated a significant PFS benefit over R-CHOP (hazard ratio [HR], 0.77 [95% CI, 0.62 to 0.97]), with 5-year PFS rates of 64.9% (95% CI, 59.8 to 70.0) and 59.1% (95% CI, 53.9 to 64.3), respectively. Although not statistically significant, overall survival analysis showed a HR of 0.85 (95% CI, 0.63 to 1.15) at the 5-year data cut compared with 0.94 (95% CI, 0.67 to 1.33) at the 2-year data cut. In the expanded population, 46 and 62 patients had lymphoma-related deaths in the Pola-R-CHP and R-CHOP arms, respectively. Exploratory analyses showed favorable 5-year survival rates with Pola-R-CHP in high-risk subgroups, including activated B-cell DLBCL and International Prognostic Index score 3-5. Long-term tolerability was similar between treatment arms. Findings confirm Pola-R-CHP represents a standard of care for frontline treatment of DLBCL.