ABSTRACT: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.

BACKGROUND:Tetraspanin CD37, highly expressed in mature B-cells, represents an opportunity for therapeutic targeting in B-cell malignancies. GEN3009 (DuoHexaBody-CD37), a humanized biparatopic IgG1 antibody with an E430G hexamerization-enhancing mutation targeting two non-overlapping CD37 epitopes, was shown to induce potent tumor cell killing through enhanced complement-dependent cytotoxicity (CDC) and other fragment crystallizable-mediated effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), in vitro and in vivo. GEN3009 was assessed in non-clinical studies and a phase 1 dose-escalation study of B-cell non-Hodgkin's lymphoma (B-NHL). METHODS:After a non-clinical toxicity study was conducted in cynomolgus monkeys, a phase 1, first-in-human, open-label, multicenter dose-escalation trial of GEN3009 monotherapy enrolled adults with relapsed/refractory (R/R) B-NHL (NCT04358458). A modified Bayesian optimal interval design informed dose escalation and de-escalation with dose levels ranging from 6 mg to 2000 mg. Primary endpoints were the rate of dose-limiting toxicities (DLTs) to determine the recommended phase 2 dose (RP2D) and safety and tolerability. RESULTS:In the toxicity study, 10 mg/kg GEN3009 weekly was identified as the highest non-severely toxic dose. In the phase 1 study, from March 13, 2020, to July 28, 2023, 46 patients with R/R B-NHL received intravenous GEN3009 infusions. Median duration of treatment was 1.2 months (range, 0.0-14.5). No DLTs were observed up to 1600 mg. The most common treatment-emergent adverse events were neutropenia (n=41 (89.1%)), infusion-related reactions (n=39 (84.8%)), and thrombocytopenia (n=18 (39.1%)). Plasma GEN3009 concentrations increased over time with increasing GEN3009 doses, with no apparent accumulation of GEN3009 observed over the course of treatment. Antitumor activity was observed at dose levels of ≥180 mg in both aggressive and indolent NHL. GEN3009 treatment reduced total hemolytic complement activity (CH50) levels in serum, and peak changes in CH50 levels were significantly correlated with clinical response (p=0.008 by Wilcoxon rank-sum test). CONCLUSIONS:Based on safety, efficacy, and pharmacokinetics, the RP2D of GEN3009 was determined to be 1200 mg. Preliminary data suggest that GEN3009 monotherapy demonstrated an acceptable safety profile at the RP2D of 1200 mg, with modest clinical activity. These findings provide the first clinical proof-of-concept for hexamerization-potentiated molecules that induce antitumor activity through enhanced CDC.

This case report describes the rare coexistence of pulmonary tuberculosis and pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma in a 68-year-old woman. The initial diagnosis of tuberculosis was supported by clinical, radiological, and microbiological findings, and the patient started on standard tuberculostatic therapy. However, the persistence of radiological abnormalities after several months of appropriate treatment, despite improvement in pleural effusion, raised suspicion for an underlying malignancy. Subsequent imaging and histopathological evaluation confirmed the diagnosis of primary pulmonary MALT lymphoma. The patient was successfully treated with immunochemotherapy, achieving complete remission. This case underscores the importance of maintaining a high index of suspicion for alternative or concomitant diagnoses, particularly malignancies, when tuberculosis exhibits an atypical clinical course or when radiological findings fail to resolve as expected. Furthermore, it highlights the need for thorough diagnostic evaluation in patients with persistent pulmonary abnormalities to ensure timely and accurate diagnosis and management.

Abstract Varnimcabtagene autoleucel (var‐cel) is an autologous CD19‐directed chimeric antigen receptor (CAR) T‐cell therapy administered using an adaptive, fractionated dosing strategy. We conducted a multicenter retrospective study to evaluate the safety and efficacy of var‐cel in patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) treated at four Spanish centers, including patients enrolled in the CART19‐BE‐01 trial and a subsequent compassionate use program. Thirty patients underwent leukapheresis; 27 received var‐cel following lymphodepletion and fractionated infusion in three escalating doses (0.1 to 5 × 106 CAR T cells/kg). Any‐grade cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS) occurred in 93% and 4%, respectively, with Grade ≥3 CRS and/or ICANS observed in a single patient (4%). The overall response rate among infused patients was 89% (95% CI, 71–98), including 78% complete responses (95% CI, 58–91). Median duration of response and progression‐free survival were 17.1 and 15.4 months, respectively. With a median follow‐up of 21.7 months, median overall survival was 35.2 months. In this multicenter academic experience, var‐cel demonstrated high antitumor activity with low rates of severe CRS and ICANS, supporting its use within a coordinated national network.

BACKGROUND:Adding ibrutinib to standard, first-line immunochemotherapy improves failure-free survival in adult patients aged 18-65 years with mantle cell lymphoma, according to the first results from the TRIANGLE trial. With prolonged follow-up, we investigated whether the addition of autologous stem-cell transplantation (ASCT) to an ibrutinib-containing regimen improves failure-free survival, and evaluated effects on overall survival. METHODS:We conducted a three-arm, randomised, open-label, phase 3 superiority trial (TRIANGLE) in 165 secondary or tertiary clinical centres, with experience in mantle cell lymphoma treatment and the capability to perform ASCT or an association with such a centre, in 13 European countries and Israel. Patients aged 18-65 years with untreated, stage II-IV mantle cell lymphoma and suitable for ASCT were randomly assigned (1:1:1) to control group A or experimental groups A + I or I. Randomisation was done using computer-generated random numbers and stratified by study groups and Mantle Cell Lymphoma International Prognostic Index risk groups. Treatment in group A consisted of six alternating, 21-day cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, vincristine 1·4 mg/m2 on day 1 [up to a maximum of 2 mg], and oral prednisone 100 mg on days 1-5) and R-DHAP or R-DHAOx (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, high-dose intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, plus either intravenous cisplatin 100 mg/m2 over 24 h on day 1 [R-DHAP] or intravenous oxaliplatin 130 mg/m2 on day 1 [R-DHAOx]), followed by ASCT. In group A + I, oral ibrutinib (560 mg daily) was added on days 1-19 of R-CHOP cycles and as 2-year maintenance after ASCT. In group I, ibrutinib was given the same way, but ASCT was omitted. Rituximab maintenance was allowed in all treatment groups according to national guidelines. Three pairwise, one-sided, log-rank tests for the primary outcome (failure-free survival) were statistically monitored. The primary analysis was by intention to treat and included all randomly assigned patients, ignoring protocol deviations. Safety was assessed in randomly assigned patients who started any trial treatment component of the respective treatment phase. The trial is registered with ClinicalTrials.gov (NCT02858258) and is complete. FINDINGS:Between July 29, 2016, and Dec 28, 2020, 870 patients (662 [76%] were male, 208 [24%] were female) were randomly assigned to group A (n=288), group A + I (n=292), or group I (n=290). After median follow-up of 54·9 months (95% CI 54·4-56·0), group A + I did not show superiority over group I, with 4-year failure-free survival of 82% (95% CI 78-87) versus 81% (76-86; hazard ratio [HR] 0·86 [one-sided 98·33% CI 0·00-1·27]; one-sided p=0·21). Group A + I remained superior to group A (82% [78-87] vs 70% [65-76]; HR 0·63 [one-sided 98·33% CI 0·00-0·89]; one-sided p=0·0026) and, as before, group A did not show superiority over group I (70% [65-76] vs 81% [76-86]; HR 1·45 [one-sided 98·33% CI 0·00-2·02]; one-sided p=0·99). 4-year overall survival was 88% (95% CI 84-92) in group A + I versus 81% (76-85) in group A (HR 0·59 [95% CI 0·38-0·92], p=0·0036) and 90% (87-94) in group I versus 81% (76-85) in group A (0·57 [0·36-0·90], p=0·0019). During maintenance or follow-up, the most common grade 3-5 adverse events were haematological disorders, reported in 127 (54%) of 234 patients in group A + I versus 74 (28%) of 269 in group I and 56 (23%) of 240 patients in group A, and infections, reported in 80 (34%) of 234 patients in group A + I versus 71 (26%) of 269 in group I and 37 (15%) of 240 patients in group A. Infections and infestations were the most common fatal adverse events during maintenance or follow-up, occurring in four (2%) of 234 patients in group A + I and five (2%) of 269 patients in group I. INTERPRETATION:After a prolonged follow-up of 55 months, both ibrutinib-containing groups showed relevant improvements not only in failure-free survival-a modified form of progression-free survival-but also in overall survival. In contrast, the addition of ASCT to an ibrutinib-containing regimen had no supplementary benefit but increased toxicity. Induction treatment with ibrutinib and R-CHOP plus R-DHAP (or R-DHAOx), followed by 2 years of maintenance treatment with ibrutinib, should be considered as a new standard of care for younger patients with mantle cell lymphoma. FUNDING:Janssen.

Brexucabtagene-autoleucel (brexu-cel) is an anti-CD19 chimeric antigen receptor T-cell (CAR-T) product approved for relapsed/refractory Mantle Cell Lymphoma (MCL) after two prior treatment lines, including Bruton tyrosine kinase inhibitors (BTKi). Patients with high-risk (hr) disease—defined by high-intermediate or high-risk MIPI-c, p53 overexpression, or TP53 alterations—have a poor prognosis, underscoring the need for improved first-line strategies. The European Mantle Cell Lymphoma Network therefore designed a phase II trial to investigate the incorporation of brexu-cel into first-line therapy for hr MCL. CARMAN is a randomized controlled, international, multicenter, open-label phase II trial evaluating efficacy, safety, and tolerability of an abbreviated induction followed by first-line brexu-cel and 6 months Ibrutinib maintenance (Arm A) as compared to standard of care induction and maintenance (Arm B). In Arm A, induction consists of two cycles of ibrutinib plus rituximab (I + R) followed by two cycles of R-CHOP plus ibrutinib (I). R-CHOP + I may be omitted in patients achieving complete or partial remission after two cycles of I + R, who then receive one additional I + R cycle before brexu-cel infusion and I maintenance. Arm B comprises a TRIANGLE-like regimen based on age, fitness, and investigator choice (alternating R-CHOP plus ibrutinib/R-DHAP or IR-bendamustine), followed by IR maintenance. Overall, 150 patients from five European countries are randomized 1:1. The primary endpoint is failure-free survival from randomization, with failure event defined as the earliest of stable disease at the end of induction (Arm B, or Arm A if brexu-cel is not infused) or within 12 weeks from CAR-T-cell infusion (Arm A), disease progression after induction, or death from any cause. Secondary endpoints include efficacy (overall and complete response rates and PET-negative CR rate 6 months from randomization as assessed according to Lugano criteria, molecular remission rate as measured by MRD), safety and tolerability (adverse events graded according to CTCAE), and patient-reported quality of life as measured by the EORTC-QLQ-C30 and EORTC-QLQ-NHL-HG29 questionnaires. When complete, CARMAN will provide important information on efficacy and safety in first-line CAR-T cell therapy in hr MCL and has the potential to prepare a practice changing confirmatory trial for these difficult-to-treat patients. Recruitment is ongoing. EU clinical trial number: 2022-502405-15-00.

The TRIANGLE trial established an ibrutinib-containing therapy without autologous stem-cell transplantation (ASCT) as the new standard for younger, treatment-naïve patients with mantle cell lymphoma (MCL). However, the benefit of rituximab maintenance (RM) within this novel standard is unclear. We investigated whether RM improves progression-free survival (PFS) and overall survival (OS) with acceptable toxicity when added to the experimental arms of TRIANGLE. This secondary analysis of TRIANGLE included patients randomly assigned to ibrutinib-containing therapy without (I) or with (A + I) ASCT who responded to induction/ASCT. RM was given per national and center practice. PFS and OS of patients with and without RM were compared with inverse probability of treatment weighted Kaplan-Meier curves and log-rank tests. Among responders after induction/ASCT (I: 274; A + I: 237), RM was given to 61% (I) and 64% (A + I). RM prolonged PFS in ibrutinib-containing treatment arms (I: log-rank test: P = .003, 4-year PFS probability RM v no RM, 85% v 73%; A + I: P < .001, 90% v 75%). There were trends toward prolonged OS in RM groups. RM groups were at higher risk of grade 3 to 5 infectious toxicity (I: 34% v 11%; A + I: 41% v 18%). Our findings support adding RM to BTK inhibitor treatments in younger, untreated patients with MCL to achieve prolonged remission.

MALAT1 is a long non-coding RNA (lncRNA) with altered expression in many cancers but poorly studied in B-cell neoplasms like mantle cell lymphoma (MCL), a very aggressive B-cell lymphoma. To elucidate the role of MALAT1 in MCL we have investigated its expression in 219 primary tumors using microarray data. We also analyzed the expression of its natural antisense transcript (TALAM1), which is key for the processing of MALAT1 RNA to its active isoform. High expression of MALAT1/TALAM1 lncRNAs was consistently linked to favorable clinical behavior in MCL, independently of other alterations previously described to influence MCL prognosis. In concordance with the observed clinical association, we found that the increased expression of these lncRNAs was inversely associated with gene signatures related to a proliferative and activation phenotype (MCL35-proliferation/BCR signaling signatures) in MCL samples from lymph nodes as peripheral blood. Finally, functional studies of MALAT1 in MCL primary samples showed that its levels were downregulated by microenvironmental stimuli and EZH2 activity, a known epigenetic factor induced by pro-proliferative stimuli and previously related with poor MCL prognosis. Altogether, these data support the favorable prognostic value of MALAT1 expression in MCL, and the MALAT1 dual role as oncogene or tumor suppressor in different neoplasms.

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma characterized by a profoundly immunosuppressive tumor microenvironment. PD-L1 overexpression by tumor cells is a recognized immune escape mechanism and may underlie resistance to cellular therapies, including CAR T-cell therapy. We report a case of a 29-year-old woman with refractory stage IV-B THRLBCL treated with anti-CD19 CAR T-cell therapy (varnimcabtagene autoleucel), who achieved an initial response (day +28) but experienced disease progression by day +100 despite robust CAR T-cell expansion. Peripheral blood analysis revealed persistent absolute B-cell aplasia, while bone marrow biopsy confirmed CD19-positive disease. Comparative immunohistochemistry demonstrated markedly increased PD-L1 expression in post-CAR T-cell samples, suggesting adaptive immune resistance via PD-1/PD-L1-mediated CAR T-cell inhibition. Nivolumab was initiated at month +4 to overcome this checkpoint-mediated resistance. Notably, a complete metabolic response was documented on PET/CT after four doses of nivolumab (month +6). The patient remains in sustained remission, with persistent B-cell aplasia, four years post-intervention. This case provides clinical and pathological evidence supporting the use of immune checkpoint blockade to rescue CAR T-cell efficacy, highlighting the potential of this synergistic approach in THRLBCL and possibly other B-cell malignancies exhibiting similar immune evasion.

Indolent MCL (iMCL) is an infrequent presentation of the disease with variable incidence across different studies, and there is neither a formal definition nor a standard clinical management. Active observation (AO), deferring the start of first-line treatment (1L) until clinical progression occurs, is currently an accepted strategy in most guidelines.The aim of this study was to describe the characteristics and outcomes of patients with iMCL in clinical practice in Spain. The GELTAMO-MCL-2022 study retrospectively included 1162 MCL patients between 2000 and 2023 in 34 Spanish centers. Indolent MCL were identified by AO ≥ 3 months. We excluded from the analysis 12 non-evaluable patients (early deaths and lost to follow-up) and 34 iMCL patients treated in the IMCL2015 clinical trial under the study's specific criteria.Early and late progression/relapse (E-POD, L-POD) in iMCL treated after AO were calculated from the start of 1L. Kaplan-Meier was used to analyze survival and the COX model for HR (CI95%) and p value of factors associated with PFS and OS. Out of 1150 evaluable patients, 161 patients (14%) were considered iMCL and 989 (86%) conventional MCL (cMCL). After the first diagnosis, cMCL patients received 1L upfront and iMCL patients started AO, as indicated per local protocols. Median time on AO (M) was 24m (3-300) for 127 evaluable iMCL: 17 (13.5%) were lost after M=19m (3-106) (including 3 cases dying from MCL without treatment), 84 (66%) progressed and received 1L after M=20m (3-156) and 26 (20.5%) remained alive in AO after M= 61m (4-300) at data cut-off. At diagnosis, iMCL patients were older than cMCL [M age 69 yrs (39-93) vs. 67 yrs (29-93), p=.019] and their disease biologically less aggressive (Ki67≥30% 15% vs. 55%; blastoid histology 1.9% vs. 20%, p<.001). Gender, MIPI, stage and extranodal involvement were similar, except for 23 cMCL with CNS involvement and none in iMCL. We did not observe significant differences between iMCL requiring treatment and iMCL in ongoing AO. Between treated patients (84 iMCL and 989 cMCL), iMCL received more non-HiDAC regimens in 1L (71% iMCL vs. 55% cMCL, p<.001), HiDAC was used in 23% vs. 39%, respectively, and BTKi in 1L was 6% in both groups (in CTs other than IMCL2015). More cMCL received ASCT (30% vs. 15.5%, p=.002) while the use of Rituximab Maintenance was similar (43% vs. 40.3%). After 1L, L-POD was more frequent than E-POD in both groups (69% and 31% in iMCL vs. 62% and 38% in cMCL, p=.3)). Regarding the number of lines received, most iMCL patients had received only 1 (66% vs. 43% cMCL, p<.001) and only 13% required ≥3 (vs. 32% cMCL). Management in 2L was comparable between iMCL and cMCL. With median FU=90.2m (83.5-99.3), 58.4% iMCL patients were alive (vs. 45.7% cMCL) and 37.8% iMCL had died (vs. 51% cMCL), being MCL the main cause of death (51% vs. 55.2%). Median OS (mOS) was longer in iMCL vs. cMCL (8.58 yrs vs. 6.82 yrs, HR=0.71, p=.014), with no differences between iMCL receiving 1L and iMCL in ongoing AO. In the MVA, age>65 and HR-MIPI had a negative impact (HR=2.16, p<.001) whereas being eligible for AO and the use of BTKi in 1L were independent factors for longer OS (HR=0.64, p=.006; HR=0.49, p=.009). Median PFS was only numerically longer in treated iMCL vs. cMCL (HR=0.88, p=.409), being BTKi in 1L (HR=0.37, p<.001) and HiDAC (HR=0.81, p=05) independent factors for longer PFS.Regarding POD24, E-POD had a strong negative impact on OS in both iMCL and cMCL, with no OS advantage observed for iMCL (1.58 and 1.36 yrs, HR=1.12, p=.682). Similarly, the OS difference in L-POD between iMCL and cMCL was not statistically significant: 14.95 and 10.7 yrs for iMCL and cMCL, respectively; HR=0.74, p=.260). In Spain, only 14% of the patients diagnosed with MCL are deemed eligible for AO, with 66% of them progressing and requiring treatment within less than 24 months.Their disease is biologically less aggressive at diagnosis (lower Ki67, rarely blastoid or pleomorphic) with a significant 29% OS advantage over cMCL, which remains even when the disease progresses and 1L is required, thus suggesting that the previous time on AO did not have a negative impact on OS in iMCL.However, this survival advantage for iMCL is no longer observed when E-POD occurs, with mOS dropping below 24m in both groups, which reinforces the need for more effective treatments from the 1L for all patients with MCL.

Adding ibrutinib to first-line immunochemotherapy (Ibru-R-chemo) showed superiority in younger mantle cell lymphoma (MCL) patients in the TRIANGLE trial (NCT02858258). To investigate response mechanisms and kinetics across treatment arms, we genotyped 57 patients from cell-free (cf)DNA using targeted-capture sequencing and investigated measurable residual disease (MRD) in cfDNA and peripheral blood by targeted-sequencing and qPCR. Pre-treatment cfDNA and circulating tumor (ct)DNA levels predicted outcomes, and precisely genotyped all patients. Circulating tumor cell (CTC)-clearance was more frequent and rapid than ctDNA-clearance across arms. At interim staging (IS), 55% of patients were ctDNA-positive while 35% and 41% were CTC-positive by qPCR and immunoglobulin gene (IG)-NGS. At end of induction, 43% were ctDNA-positive, while 15% (qPCR) and 25% (IG-NGS) were CTC-positive. MRD by qPCR was most predictive for outcomes. Ibru-R-chemo seemed to overcome TP53mut-mediated risk (hazard ratio 1.9 vs. 10) and induce early MRD response, represented by enhanced CTC (71% vs. 57%) and ctDNA clearance (59% vs. 24%) at IS. Flow-cytometry-based immunomonitoring showed ibrutinib’s influence on inhibitory T-cell phenotypes, showing ≥25% reduction in PD1+ and PD1+ KLRG1+ CD4+-T-cells in four patients. Taken together, besides direct anti-B-cell efficacy, ibrutinib improves chemotherapy efficiency by reconstituting an effective immune system and enhancing immune cell control.

Mantle cell lymphoma (MCL) is a relatively rare B-cell lymphoma subtype, with a higher incidence among males and a median age of 70 years at diagnosis. MCL is characterized by clinically diverse behavior, from indolent disease to extremely aggressive, related to the presence of biological risk factors such as proliferation rate and TP53 mutations. Most often, patients present with disseminated disease, necessitating systemic treatment. Immunochemotherapy has historically been the mainstay of treatment, but recent data indicate that addition of novel agents, especially covalent Bruton tyrosine kinase inhibitors (cBTKi), may substantially improve outcome in younger and older patients, although a curative approach remains to be shown. In elderly patients, the standard of care is still immuno-chemotherapy such as rituximab-bendamustine, although this may be challenged by non-chemotherapeutic options, such as rituximab plus cBTKi. For patients with relapsed or refractory disease, treatment options are developing rapidly, including CAR-T cell therapy, novel BTK targeting agents, BCL2 inhibitors, and T-cell engagers. In this clinical practice guideline, we present current evidence-based recommendations for diagnosis, staging, treatment, and follow-up of MCL.

We report the outcome of patients with relapsed/refractory (R/R) follicular lymphoma (FL) treated with varnimcabtagene autoleucel (var-cel), an academic anti-CD19 chimeric antigen receptor (CAR) T-cell product. Patients were included in the CART19-BE-01 clinical trial and a compassionate use program. Twenty-seven patients with FL were treated. Cytokine release syndrome (any grade) occurred in 55% of patients (4% Grade ≥3). Only 1 case (4%) of Grade 1 neurotoxicity was documented. The objective response rate was 100% at Day +100 (93% complete response rate), and the 3-year duration of response was 78%. The 3-year progression-free survival and overall survival were 78% and 81%, respectively. All patients developed B-cell aplasia, and the 3-year incidence of B-cell recovery was 17%. In conclusion, patients with R/R FL treated with var-cel obtained excellent disease control, with prolonged CAR T-cell survival and manageable toxicity. This trial was registered as NCT03144583.

Central nervous system (CNS) involvement in mantle cell lymphoma (MCL) is an uncommon but clinically significant event, often associated with poor prognosis. Prior studies have offered important insights, yet data from large, unselected real-world populations remain scarce. We report findings from one of the largest multicenter cohorts of MCL patients in Spain, aimed at characterizing CNS involvement and comparing clinical outcomes—including treatment response, progression-free survival (PFS), and overall survival (OS)—between patients with and without CNS infiltration. This retrospective multicenter study included 1,162 MCL patients diagnosed in Spain (GELTAMO-MCL-2022). Among them, 60 patients (5.2%) had CNS involvement, either at diagnosis or during the course of the disease, while 1,102 had no evidence of CNS infiltration. Data from participating centers encompassed baseline characteristics, treatment approaches, response rates, and survival outcomes. PFS and OS were analyzed and compared between groups. The crude incidence of CNS involvement was 5.2%, with 1.4% at the time of diagnosis. For patients who developed CNS relapse later (not at diagnosis), the median time from initial diagnosis to CNS involvement was 15.10 months (IQR 7.47–34.14). CNS localization was leptomeningeal in 70%, parenchymal in 16%, and both in 14%. Baseline characteristics, including established high-risk features, were compared between patients with and without CNS involvement. Sex distribution (male 73% in both; p=0.9), age >65 years (47% vs. 53%; p=0.2), and extranodal disease (p=0.3) were similar between groups. In contrast, high-risk baseline features such as high-risk MIPI (77% vs. 44%; p=0.001), blastoid/pleomorphic variant (45% vs. 16%; p=0.001), and Ki-67 >30% (80% vs. 49%; p=0.001) were significantly more frequent in patients with CNS involvement. First-line intensive regimens including high-dose cytarabine (HIDAC) were given to 48% with CNS involvement versus 36% without (p=ns). BTK inhibitors were used as a frontline treatment in 8% overall, but none of the CNS patients. Early progression of disease (ePOD) was more frequent with CNS involvement (72% vs. 51%; p=0.003). In multivariate analysis, CNS involvement at diagnosis was an independent adverse factor for OS (HR 3.25; 95% CI: 1.62–6.52; p<0.001) and PFS (HR 2.09; 95% CI: 1.45–3.01; p=0.001). Other independent predictors of OS were age >65 (HR 2.04; p<0.001), high-risk MIPI (HR 1.72; p=0.003), and Ki-67 >30% (HR 1.63; p=0.001). For PFS, age (HR 1.39; p=0.016), high-risk MIPI (HR 1.45; p=0.014), and Ki-67 >30% (HR 1.39; p=0.007) were significant; blastoid morphology showed a trend toward significance (HR 1.30; p=0.056). Treatment with HIDAC was not an independent predictor of survival, neither for OS nor for PFS. Median OS from diagnosis was 1.41 years (95% CI: 1.19–NA) for patients with CNS involvement at diagnosis (n=16) versus 7.5 years (95% CI: 6.92–8.4) for those without (p=0.001). Median PFS was 11.3 months (95% CI: 2.89–NA) versus 42.1 months (95% CI: 36.6–47.0), respectively (p=0.012). In patients with CNS involvement at diagnosis, high-dose cytarabine (HIDAC) did not significantly improve OS or PFS. Median OS was 1.41 years with HIDAC and 1.30 years without it (HR 2.08; p=0.277), while median PFS was 16.4 vs 9.6 months, respectively (HR 1.51; p=0.504). Similarly, first-line consolidation with autologous stem cell transplantation had no significant impact on survival. When calculated from the time of CNS involvement, patients with CNS disease at diagnosis had significantly worse outcomes compared to those with CNS relapse, with a median PFS of 3.5 vs 18.0 months (HR 3.00; 95% CI: 1.36–6.59; p=0.006) and median OS of 1.5 vs 0.19 years (HR 3.02; 95% CI: 1.36–6.69; p=0.006). In this large Spanish multicenter cohort, CNS involvement in MCL—although a rare complication both at diagnosis and at relapse—was associated with markedly poorer PFS and OS. It remained an independent adverse prognostic factor alongside age, high-risk MIPI, and Ki-67. CNS infiltration at diagnosis was the strongest predictor of poor outcome, while occurrence during disease evolution conferred an even worse prognosis. These findings highlight the need for early identification and tailored therapeutic approaches for high-risk patients.

Mantle cell lymphoma (MCL) remains a challenging and generally incurable disease. We aimed to evaluate survival trends in advanced-stage MCL over the past three decades, focusing on the impact of evolving first-line therapies. We pooled six randomized phase III trials of treatment-naïve, advanced-stage MCL patients enrolled between 1996 and 2020. Patients were grouped into four eras by enrollment period. Failure-free survival (FFS) and overall survival (OS) were compared across eras using Kaplan-Meier methods and Cox regression adjusted for the Mantle Cell Lymphoma International Prognostic Index (MIPI) and treatment. Dynamic survival trends were analyzed using penalized splines. Among 2,541 MCL patients, survival outcomes have improved steadily since 1996. In younger and transplant-eligible patients (≤ 65 years), there was a strong increase in median OS from 4.9 years (5-year OS: 49%) in the period 1996-2000 to 13.8 years (73%) in 2004-2014 and was not reached (84%) in 2016-2020. In older and transplant-ineligible patients, median OS improved from 3.8 to 4.8 years (5-year OS: 40-49%) between 1996 and 2014. Dynamic trends revealed a sharp decline in treatment failure and mortality risk between 2000 and 2005, followed by sustained improvements. Patients receiving the same treatment regimens had comparable FFS and OS across eras. Adjusting for treatment eliminated most survival trends, underscoring the impact of rituximab, ASCT, high-dose cytarabine, and ibrutinib on survival improvements. In conclusion, OS in MCL has substantially improved over the past three decades, especially in younger patients, driven largely by improvements in first-line treatment. In older patients, despite significantly improved OS in recent decades, there remains an urgent need for further improvements.

Introduction: Brexu-cel is an autologous anti-CD19 CAR T-cell therapy approved for adults with R/R MCL in the US and after ≥2 prior lines of therapy (LoT) including a BTKi in the EU. In the pivotal ZUMA-2 Cohort 1 study, brexu-cel induced durable responses in pts with 1-5 prior LoT (median of 3) including a BTKi, with a median duration of response (DOR) and overall survival (OS) of 36.5 and 46.5 mo, respectively (median follow-up: 67.8 mo; Wang M. et al, ASH 2024). ZUMA-2 Cohort 3 is a Phase 2 study designed to assess the safety and efficacy of brexu-cel in pts with BTKi-naive R/R MCL (NCT04880434). In the primary analysis (PA), brexu-cel demonstrated a 91% objective response rate (ORR; P<.0001) and a 73% complete response (CR) rate after 15.5 mo of median follow-up in 86 pts with R/R MCL who were BTKi-naive (Meerten T. et al, ASH 2024). Here we report the 2-y update of ZUMA-2, Cohort 3. Methods: Pts (≥18 y) underwent leukapheresis, optional bridging therapy, lymphodepleting chemotherapy, and infusion of brexu-cel (2×106anti-CD19 CAR T cells/kg). Pts had 1-5 prior LoT including chemotherapy and an anti-CD20 monoclonal antibody (excluding BTKi). The primary endpoint was ORR (CR + partial response) per Lugano Classification (Cheson et al. J Clin Oncol. 2014) by independent radiology review committee (IRRC). Key secondary endpoints were ORR per investigator review, DOR, progression-free survival (PFS), OS, and safety. Results: As of November 26, 2024, median follow-up in 86 treated pts was 26.4 mo (range, 1.4-39.0). As reported in the PA, median age was 64 y (range, 40-82), 78% were male, and 91% were white. High-risk disease features were common: 73% had high or intermediate s-MIPI score, 65% had Ki-67 positivity ≥30%, and 65% had Stage IV disease. Most pts (79%) had 1 prior LoT with anthracycline and bendamustine received by 79% and 27% of pts, respectively; 48% had prior autologous stem cell transplantation (SCT), and 36% received bridging therapy. The ORR per IRRC remained 91% (n=78; 95% CI, 82.5-95.9) with an updated CR rate of 79% (95% CI, 69.0-87.1). Per investigator, ORR and CR rates were 97% and 85% (94% and 87% concordance), respectively. Median DOR, PFS, and OS were not reached (NR). The 24-mo (95% CI) DOR, PFS, and OS rates were 75% (63.6-83.2; 81% for CR), 69% (58.0-77.8), and 84% (74.0-90.0), respectively. Of the 78 responders included in the DOR assessment, at data cutoff, 54 (69%) pts were censored for ongoing response without subsequent therapy or SCT, and 4 were censored for starting a new anti-cancer therapy; there were 14 (18%) progressive disease (PD) events and 6 (8%) death events. Ongoing response rates were similar across key subgroups including pts with high or intermediate s-MIPI scores, pts with Ki-67 IHC positivity ≥30%, and pts with advanced disease; however, notable differences were observed by prior LoT (69% for 1 vs 41% for 2-3) and prior bendamustine (43% for yes vs 70% for no). At data cutoff, 69 pts (80%) were alive and 17 (20%) had died, 4 deaths occurred since the PA (all due to PD). Of the 17 deaths on study, 9 were due to PD and 8 were due to other reasons as previously reported (9% non-PD mortality rate). Since the PA, the proportion of pts with Grade (Gr) ≥3 brexu-cel–related adverse events (AEs) increased from 88% to 90% and increased from 23% to 30% for Gr ≥3 infections. Rates remained the same for Gr 5 AEs (9%), Gr ≥3 cytokine release syndrome (6%), and Gr≥3 neurological events (27%). Rates of any Gr and Gr ≥3 early (≤30 days of infusion) immune effector cell-associated hematotoxicity (ICAHT) were 90% and 14% and rates of any Gr and Gr ≥3 late (>30 days of infusion) ICAHT were 31% and 5%, respectively. Medians for peak and area under the curve CAR T-cells were numerically higher in pts who had DOR of CR ≥6 mo (n=66) vs pts who had DOR of CR <6 mo (n=11), though not statistically significant. Conclusions: After 2-y of median follow-up, IRRC-assessed ORR and CR rates were 91% and 79% with medians for DOR, PFS, and OS NR. Most responders were still in response with consistent ongoing response rates across most prespecified subgroups. Late onset toxicities were rare with no new Gr 5 events since the PA. These results suggest that brexu-cel may benefit pts in earlier LoT including some pts who are BTKi-naive with high-risk disease features, though the risk/benefit for each pt should be carefully assessed before determining salvage treatment.

Introduction: Follicular lymphoma (FL) is an indolent lymphoma characterized by a chronic course with remissions and relapses. While immunochemotherapy has significantly improved overall survival (OS), FL is still considered incurable. Nevertheless, a small subset of patients achieves long-term progression-free survival beyond 15 years (PFS15), suggesting the possibility of a functional cure (FC), a concept that remains poorly defined. This study aimed to (1) compare baseline clinical features, treatment strategies, survival and causes of death between PFS15 and non-PFS15 patients, and (2) develop a predictive model to identify patients most likely to achieve FC. Methods: From an initial cohort of 626 pts diagnosed with FL between 2000 and 2021 at Hospital Clínic of Barcelona, we excluded those with primary cutaneous FL (n=33), grade 3B (n=21), composite lymphomas (FL/DLBCL) (n=46), and pts either untreated, treated without rituximab or with less than 15 years of follow-up without relapse (n=275), yielding a final cohort of 251 pts. PFS15 was defined as absence of relapse or death for at least 15 years after first-line treatment. Baseline clinical and biological characteristics were compared between PFS15 and non-PFS15 pts. Chi-squared and Wilcoxon tests were used for categorical and continuous variables, respectively. Candidate predictors, including diagnostic and treatment-related variables, were included if missingness was ≤30% and imputed with multiple imputation by chained equations (MICE) when necessary. LASSO logistic regression with 10-fold cross-validation selecting the lambda at 1 SE was used for variable selection, and the selected predictors were then included in a multivariable logistic regression model. Internal validation was performed using bootstrap resampling to correct for optimism. Model performance was evaluated in terms of discrimination, calibration, and stratification in survival analysis. Results: Among the 251 pts [130 (52%) male; median age of 58 yrs] included in the analysis, 62 (25%) were PFS15. PFS15 pts were younger (median years: 55 vs. 60; p=0.004) and more frequently presented with localized stages (46% vs. 18%; p<0.001), low ß2m (71% vs 40%; p<0.001) or low-risk FLIPI (92% vs. 71%; p<0.001). Eighty-nine percent of PFS15 pts received first-line immunochemotherapy, achieving complete remission in all but five cases. After a median follow-up of 18.7 years (95%CI: 17.9–19.2), median OS for the PFS15 group was not reached; the 20-year OS was 84% (95% CI: 71–100), with only four relapses after 15 years. Five PFS15 pts died, only one due to lymphoma progression. LASSO regression selected eight predictors of PFS15: age, disease stage, β2m levels, FLIPI score, ECOG performance status, treatment category, platelet count, and bone marrow infiltration at diagnosis. The model showed good discrimination (AUC = 0.82; optimism-corrected AUC = 0.78) and excellent calibration (slope = 1.00, 95% CI: 0.69–1.31), with the smoothed calibration curve indicating strong agreement between predicted and observed probabilities. Based on predicted risk, pts were stratified into three groups: very low (<0.20, n = 141), intermediate (0.20–0.65, n = 89), and high (≥0.65, n = 21) probability of achieving FC. The accuracy between the two extreme groups was 0.88, with a precision of 0.76, recall of 0.53 and with a specificity of 0.96. Pts classified as high-PFS15 demonstrated significantly better PFS compared to intermediate- (HR=3.2, 95% CI: 1.4-7.3, p=0.007) and low-probability groups (HR=7.6. 95% CI: 3.3-17.2, p<0.001), with corresponding PFS rates at 5 years (85.7% vs. 56.2%, vs. 29.1%), 10 y (85.7% vs. 40.4% vs. 10.6%), and 15 y (76.2% vs. 36% vs. 9.9%). In terms of OS, low-probability group had significantly worse outcomes compared to others (HR = 6.8, 95% CI: 2.1–21.6, p < 0.001)(5y: 100% vs. 91% vs. 67.6%; 10y: 95.2% vs. 84% vs. 54.1% and 15y: 90.5% vs. 82.6% vs. 43.4%). Conclusion: A substantial proportion of FL patients achieve remission lasting over 15 years without the need for further intervention, supporting the concept of a potential functional cure (PFS15). These patients exhibited distinctive baseline features. Furthermore, we developed and internally validated the first predictive model capable of identifying patients more likely to achieve PFS15 and predicting an accurate probability of functional cure. External validation is warranted to confirm its clinical utility.