Roch Houot

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.

There is an unmet need for effective, off-the-shelf therapies for relapsed or refractory aggressive B cell non-Hodgkin lymphoma (B-NHL). Part 2 of the current study was an open-label, nonrandomized, phase 1 study of escalating doses of the CD19–4-1BBL co-stimulatory molecule, englumafusp alfa, in combination with glofitamab in patients with relapsed or refractory B-NHL. Obinutuzumab pretreatment was administered 7 days before the first glofitamab dose. Glofitamab step-up dosing in cycle 1 was followed by 11 cycles of glofitamab plus englumafusp alfa. Englumafusp alfa was administered at escalating doses, with the initial dose on cycle 2 day 8 (C2D8) or cycle 1 day 10 (C1D10). Primary objectives were to establish the maximum tolerated dose, and safety and tolerability. A total of 134 patients were enrolled, including 109 with aggressive B-NHL and 25 with indolent B-NHL. The maximum tolerated dose of englumafusp alfa was not reached; one dose-limiting toxicity occurred (grade 5 Pneumocystis jirovecii pneumonia). Adverse events were reported in 98.5% of all patients, with grade 3/4 adverse events in 59.0%. Grade 5 adverse events occurred in ten patients. In the subgroup of C2D8 patients with aggressive B-NHL (n = 83), overall response and complete metabolic response rates were 68.7% and 56.6%, respectively; among those without previous exposure to chimeric antigen receptor T cell therapy (n = 41), the corresponding rates were 73.2% and 65.9%. Pharmacodynamic changes following englumafusp alfa administration supported its co-stimulatory mode of action. These data demonstrate that the addition of englumafusp alfa to glofitamab is associated with encouraging efficacy and robust pharmacodynamic modulation, as well as a safety profile consistent with glofitamab monotherapy, in patients with relapsed or refractory B-NHL. CTIS identifier: 2022-502616-37-00; ClinicalTrials.gov identifier: NCT04077723.

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.

In the multinational, phase 3 RELEVANCE trial, 1030 patients with previously untreated follicular lymphoma were randomized to receive rituximab + lenalidomide (R2; n = 513) or rituximab-based immunochemotherapy (R-Chemo; n = 517). In the final analysis, at 120 months of follow-up, median progression-free survival (PFS) was comparable between the treatment groups: 110.6 months with R2 vs 102.8 months with R-Chemo, according to the independent review committee assessment. The 10-year PFS rates were 46.4% for R2 and 46.6% for R-chemo. Median overall survival (OS) and time-to-next lymphoma treatment (TTNLT) were not reached in either arm; 10-year OS rates were 82.4% for R2 and 81.1% for R-chemo, and 10-year TTNLT rates were 62.2% for R2 and 66.3% for R-chemo. Overall, patients with progression of disease within 24 months (POD24) had a poorer prognosis than those without POD24 (hazard ratio, 6.215; P< .0001); however, no difference was observed between the study groups. The incidence of second primary malignancies (SPMs) was 2.11 cases per 100 patient-years (95% confidence interval, 1.80-2.46). Only 9 transformations occurred after 24 months (3 with R2 vs 6 with R-chemo). In each study group, 87 patients died, mainly because of lymphoma progression and SPMs. This long-term follow-up of RELEVANCE confirmed that R2 provides a chemotherapy-free alternative to immunochemotherapy in this patient population. This trial was registered at www.clinicaltrials.gov as NCT01476787 and NCT01650701 and at EudraCT as 2011-002792-42.

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.

Over the past decade, ex vivo autologous chimeric antigen receptor (CAR)‐T‐cell therapies have reshaped the treatment of B‐cell malignancies. Despite their remarkable clinical efficacy, their application remains limited by complex manufacturing processes, demanding logistics, long turnaround times, and substantial costs. In vivo CAR approaches are emerging as a potential solution to address these barriers by enabling direct induction of CAR expression in T cells and other immune cells through in‐patient delivery of genetic constructs. This review provides an overview of the current landscape of in vivo CAR therapies. We describe the major delivery platforms under clinical development, with a focus on lentiviral vectors (LVVs) and lipid nanoparticles (LNPs), and discuss their distinct features in terms of manufacturing, mechanism of action, safety, therapeutic applications, and optimization strategies. We also summarize ongoing clinical trials exploring in vivo CAR approaches for hematologic malignancies, solid tumors, and autoimmune diseases. Finally, we highlight the key scientific and clinical challenges that remain, and examine strategies under investigation to overcome these limitations and advance in vivo CAR therapies toward broader clinical translation.

Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for adults with relapsed/refractory (R/R) mantle cell lymphoma (MCL) based on the ZUMA-2 cohort 1 (ClinicalTrials.gov identifier: NCT02601313) study in which brexu-cel demonstrated a 93% objective response rate (ORR) and 67% complete response (CR) rate in patients with R/R MCL and previous BTKi therapy (N = 60). Here, we report the primary results of ZUMA-2 cohort 3 (brexu-cel in patients with BTKi-naive R/R MCL). Adults received brexu-cel at 2 × 106 anti-CD19 CAR T cells per kilogram. The primary end point was ORR assessed by independent radiology review committee (IRRC). As of 26 November 2023, 95 patients were enrolled, and 86 received brexu-cel; median follow-up was 15.5 months. The primary end point was met, with a 91% ORR (95% confidence interval [CI], 82.5-95.9; P< .0001; N = 86) and a CR rate of 73% (95% CI, 62.6-82.2). Estimated 12-month progression-free survival (PFS), duration of response, and overall survival (OS) rates were 75%, 80%, and 90%, respectively. Among 95 enrolled patients, the ORR was 82%, the CR rate was 66%, and the 12-month PFS and OS rates (95% CI) were 73% (62.1-80.8) and 85% (75.6-90.7), respectively. Most patients (88%) experienced treatment-related grade ≥3 adverse events, including 4 treatment-related grade 5 events. Consistent with cohort 1, brexu-cel demonstrated a high ORR and similar safety profile. These results support the continued use of brexu-cel in patients with R/R MCL, and consideration in some patients without previous BTKi therapy who have high-risk disease. This trial was registered at clinicaltrials.gov as #NCT04880434.

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.

Idecabtagene vicleucel (ide-cel), an adoptive chimeric antigen receptor T-cell therapy directed against B-cell maturation antigen (BCMA), has demonstrated high response rates and improved survival in patients with relapsed/refractory multiple myeloma. However, all patients eventually relapse, and data on salvage therapy outcomes remain limited. We conducted a national, real-world study of 154 patients relapsing after ide-cel, with a median time to progression of 6.0 months (interquartile range, 3.0-9.9). Salvage therapies included anti-BCMA bispecific antibodies (BsAbs) (n = 79), non-BCMA BsAbs targeting GPRC5D or FcRH5 (n = 12), combinations of immunomodulatory agent, proteasome inhibitor, and anti-CD38 monoclonal antibody (n = 40), and others (n = 23). Median overall survival (OS) was 12.12 months (95% confidence interval, 6.6 to not reached), and median progression-free survival (PFS) was 3.48 months (95% CI, 2.6-6.37). The overall response rate (≥ partial response) was higher in patients treated with BsAbs (36%) than others (13%, P = .002). Treatment with non-BCMA BsAbs resulted in significantly higher ORR (67% vs 30%, P = .018), OS (19.48 vs 8.41 months, P = .034) and PFS (9.2 vs 3.81 months, P = .035) compared to anti-BCMA BsAbs. Early relapse after ide-cel (≤6 months) was associated with worse outcomes (OS: 5.95 vs 12.58 months, P = .040), as was extramedullary disease (OS: 13.8 vs 6.28 months, P = .033) and exposure to >3 prior lines of therapy. In summary, anti-BCMA BsAbs offered limited efficacy whereas non-BCMA BsAbs may offer a promising therapeutic approach following ide-cel early relapse. These results underscore the potential benefits of diversifying targets in relapse post-ide-cel treatment strategies. This trial was registered at www.clinicaltrials.gov as #NCT04328298.