The prognostic significance of impaired renal function in Waldenström macroglobulinaemia (WM) remains poorly defined. We conducted a nationwide multicentre study to evaluate its clinical characteristics and prognostic impact in symptomatic patients. We analysed 402 symptomatic WM patients, stratified according to renal function at diagnosis (creatinine clearance <60 mL/min/1.73 m2). Renal dysfunction was identified in 119 patients (29.6%). Renal biopsy was performed in 33 cases. Patients with reduced renal function were older (median age 76 vs. 67 years, p < 0.0001), had lower haemoglobin levels (10.8 vs. 11.8 g/dL, p = 0.008) and higher 24-h proteinuria (0.29 vs. 0.20 g, p = 0.04). Comorbidities of renal interest were similarly distributed between groups. Renal dysfunction was associated with inferior median overall survival (139 vs. 203 months, p < 0.001) and progression-free survival (PFS) (80 vs. 106 months, p = 0.002). Among patients aged <70 years, renal dysfunction remained associated with shorter PFS (77 vs. 121 months, p = 0.005). Importantly, worsening renal function did not correlate with increasing age. In this setting, first-line chemoimmunotherapy was associated with improved median PFS. Thus, renal dysfunction at diagnosis may represent an underrecognized, independent adverse prognostic factor in symptomatic WM.

BACKGROUND:Effective treatments with deep and durable responses for relapsed or refractory marginal zone lymphoma (MZL) are lacking. The objective of the primary analysis from the MZL cohort of TRANSCEND FL was to evaluate the efficacy and safety of the CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel. METHODS:In this phase 2, single-arm, multicohort study, patients from 30 sites in the USA, Canada, Europe, and Japan with relapsed or refractory MZL who had at least two previous lines of systemic therapy were eligible to receive lisocabtagene maraleucel (100 × 106 CAR+ T cells). Bridging therapy was allowed. The primary endpoint was overall response rate per independent review committee by CT by use of Lugano 2014 criteria (null hypothesis ≤50%). This study is registered with ClinicalTrials.gov, NCT04245839, and is ongoing. FINDINGS:Of 77 leukapheresed patients recruited between November 11, 2020, and August 24, 2023, 67 received lisocabtagene maraleucel and 66 were efficacy evaluable. MZL subtypes included nodal (n=32 [48%]), splenic (n=18 [27%]), and extranodal-mucosa-associated lymphoid tissue (n=17 [25%]). Median (IQR) previous lines of systemic therapy was 3 (2-4). Median on-study follow-up was 24·1 months. The primary endpoint was met, with an overall response rate of 95% (n=63; 95% CI, 87·3-99·1; one-sided p<0·0001). All patients experienced a treatment-related adverse event. Grade 3 cytokine release syndrome or neurological events occurred in three (4%) patients each (no grade 4-5 events). 11 (16%) patients had grade ≥3 infections: six (9%) patients during the 90-day treatment-emergent period and seven (10%) during the post-treatment-emergent period. INTERPRETATION:In patients with relapsed or refractory MZL, lisocabtagene maraleucel showed high rates of durable responses. The safety profile was manageable, with no new safety signals. These results support lisocabtagene maraleucel as a new treatment option for patients with relapsed or refractory MZL. FUNDING:Celgene, a Bristol-Myers Squibb Company.

BACKGROUND:Chimeric antigen receptor (CAR)-T cell therapy has revolutionized outcomes in relapsed/refractory lymphomas, yet nonrelapse mortality (NRM) has emerged as a notable concern, with older age and infections identified as major determinants of NRM in real-life studies. OBJECTIVE:The aim of the present study was to describe the rate and causes of NRM after CAR-T cells and identify risk factors. STUDY DESIGN:Within the framework of the prospective, multicenter, observational CART‑SIE study, we analyzed causes and determinants of NRM in a large real-world cohort of lymphoma patients receiving CAR‑T cells from 2019 to 2025. Associations between NRM and clinical or biological factors were assessed using Fine and Gray subdistribution hazard models. RESULTS:From 2019 to 2025, 1132 patients were enrolled in the CART-SIE Study; among those, 932 were evaluable for outcomes, with a median follow-up of 17.8 months (IQR 6.3-25.4). In this cohort, 305 deaths were observed, mainly occurring after disease progression (n = 258); overall, 47 deaths were solely attributable to NRM (5%), either early (≤28 days, 40.4%), late (29-90 days, 23.4%) or very late (>90 days, 36.2%). The 1- and 2-year cumulative incidence of NRM were 5.5% and 8.8%. Infections were the leading cause (51%), followed by CAR-T acute toxicities (CRS, ICANS, and HLH/MAS; 30%), and secondary malignancies (11%). In univariable analysis, age > 60 gt; 60 years, diabetes, atrial fibrillation, high CAR-HEMATOTOX score, elevated ferritin, baseline cytopenias, CRS grade ≥3, any-grade or grade ≥3 ICANS and infectious events were risk factors for NRM. Multivariable models revealed that, among pre-infusion factors, only high ferritin levels (HR 3.23, 95% CI: 1.37-7.62, P = .007) and diabetes (HR 3.93, 95% CI: 1.28-12.1, P = .017) independently predicted NRM, while only severe CRS, ICANS, and infections remained strong post-infusion predictors. CONCLUSIONS:These findings emphasize the role of host-related factors and inflammation in shaping CAR-T outcomes. Optimized patient selection, rigorous management of acute toxicities, tailored infectious prophylaxis and long-term oncologic surveillance are essential components of long-term survivorship care, aiming to mitigate NRM and sustain long-term benefits of CAR-T cells. Clinical trial registration ClinicalTrials.gov ID: NCT06339255.

BACKGROUND:Transformed indolent non-Hodgkin lymphoma (TiNHL) generally has poorer outcomes than de novo diffuse large B-cell lymphoma (dnDLBCL). Although anti-CD19 CAR T-cell therapy is standard for relapsed/refractory (R/R) large B-cell lymphoma (LBCL), its prognostic role across histologies remains unclear. METHODS:We conducted a multicenter, retrospective/prospective observational study comparing R/R TiNHL and R/R dnDLBCL patients treated with commercial CAR T-cell therapy and enrolled in the Italian CART-SIE study. FINDINGS:Among 438 patients, 107 had TiNHL (96 transformed follicular lymphoma [tFL], 11 transformed marginal zone lymphoma [tMZL]) and 331 had dnDLBCL. Baseline characteristics were comparable. TiNHL patients showed superior overall (83% vs 69%) and complete response rates (62% vs 53%) (both p < 0·01), with better 2-year progression-free survival (PFS: 44% vs 31%) and overall survival (OS: 61% vs 48%) (both p < 0·01). CAR-HEMATOTOX score predicted worse outcomes (PFS HR=2·10; OS HR=3·57). No significant differences were found between tFL and tMZL. Two-year relapse/progression incidence was lower in TiNHL (28% vs 47%, p < 0·01), with similar non-relapse mortality (11% vs 4%, p = 0·12). Safety profiles, including cytokine release syndrome and ICANS rates, were comparable. CONCLUSION:TiNHL patients receiving CAR T-cell therapy achieved better outcomes than dnDLBCL patients, with comparable safety, supporting its use as a standard treatment in TiNHL.

Treatment of relapsed/refractory primary mediastinal B-cell lymphoma (R/R PMBCL) patients has been revolutionized by the advent of checkpoint inhibitors (CPIs) and CAR T-cells therapy. Most patients receiving CAR T-cells have been treated with CPIs, either as part of salvage treatment, as bridging treatment or after CAR T-cells failure. This study aims to evaluate whether exposure to CPIs influences efficacy and toxicity profile of CAR T cells therapy. CAR-T SIE is a prospective multicenter observational study enrolling patients treated with antiCD19 CAR T-cells in 23 Italian centers. Among the 1309 patients (pts) enrolled in the study, 93 with R/R PMBCL who received axicel (n=90) or lisocel (n=3) were eligible for this analysis. All pts provided written informed consent for the study. Fifty-five pts received CPIs either as part of salvage therapy (n=20), as bridging therapy (n=26) or both (n=9). An additional 11 pts received CPIs following CAR T-cell failure, whereas 38 pts never received CPIs. No significant differences in clinical characteristics were observed between CPI exposed and CPI-naïve pts: median age was 37 and 34 years, respectively; 49% and 45% of patients were female; 29% and 39% presented stage III or IV; 31% and 40% had extranodal disease, and 29% and 40% had received more than two prior lines of therapy. After a median follow-up of 23.7 months (range, 12.2 – 39), 2-years OS and PFS for the entire cohort were 81.9% and 61.8%, respectively. 2-years PFS was similar between patients never exposed to CPIs (62.3%) and those who received CPIs as salvage or bridging (61.3%) (HR1.12, 95%CI 0.56-2.26). Similarly, no significant differences in 2-years OS were observed, with rates of 89% and 77.5% in pts never exposed and exposed to CPIs, respectively (HR 1.96, 95%CI 0.62 – 6.16). No significant differences in PFS were observed between pts who received CPIs exclusively as bridging therapy and those pts treated with CPI both during salvage and bridging therapy (HR 0.33; 95%CI 0.11-1-02). PFS was similar between pts who received CPI in second line versus third and further line (HR 0.44, 95%CI 0.11-1.79). The type of CPI used, Nivolumab or Pembrolizumab, had no impact on either OS or PFS. Overall response rate at 30 days after CAR T infusion was comparable between CPI exposed and CPI-naive pts (87% and 81%, respectively); the proportion of patients achieving a metabolic CR at 30 days was similar between the two groups (47% and 52% respectively). Following CAR T-cell failure, 11 patients received CPIs, achieving an ORR of 60%, with 1 partial response (PR) and 5 complete responses (CR). In comparison, 8 patients were treated with alternative therapies, resulting in an ORR of 40% (1 PR and 1 CR). No significant difference in ORR and OS was observed between patients rescued with CPI and those receiving other treatments, but numbers are very small and no conclusion can be drawn. Regarding safety, CRS was observed in 85% of CPI-exposed patients and 95% of CPI-naïve patients (p = ns), predominantly of grade1-2 (87% and 91% of pts respectively). Immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 38% CPI-exposed patients and 35% CPI-naïve patients, severe ICANS (grade > 3) occurred in 48% patients treated with CPIs and in 38% of patients who were not (p=ns). In this large real-world cohort of patients with R/R PMBCL treated with CAR T-cell therapy, prior exposure to CPI did not appear to impact CAR T-cell outcomes, including response rates, PET scan results, and survival. Moreover, CPI exposure was not associated with an increased risk of CRS or ICANS. Findings of this study suggest that the use of CPI is safe and may be beneficial as part of salvage therapy to improve disease control before infusion or to rescue patients following CAR T-cell failure. Due to the limited number of patients experiencing CAR T-cell failure, the optimal salvage strategy in this setting remains undetermined.

ABSTRACT:High-grade B-cell lymphomas (HGBL, including double-hit/triple-hit [HGBL-DH/TH], and HGBL not otherwise specified) have a poor prognosis upon failure of first-line therapy. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for third-line aggressive large B-cell lymphomas (LBCL) resulted in long-term remission in ≤40% of patients. This study evaluated factors that can predict outcomes in HGBL compared to diffuse LBCL (DLBCL). We assessed the predictive value of the subtype (HGBL vs DLBCL) using weighted log-rank tests and weighted Cox models, and overall survival (OS) following CAR T-cell therapy failure. The prospective study cohort comprised 432 patients (HGBL, n = 78; DLBCL, n = 354), median follow-up of 22.8 months for HGBL and 18 months for DLBCL. Interestingly, there was no statistically significant difference in progression-free survival and OS between patients with HGBL-DH/TH lymphomas vs other high-grade histotypes. CAR T-cell therapy expansion in HGBL did not correlate with response. Before weighting, a significant difference in OS was observed between HGBL vs DLBCL (24-month OS: 37% vs 49%, P = .0036). After weighting, the difference in 2-year OS remained significant (37% vs 44%, P = .0343), and it was related to inferior survival following CAR T-cell therapy failure. The 2-year nonrelapse mortality and incidence of secondary malignancies were similar in patients with HGBL and DLBCL (11% vs 11%, P = .830; 6.4% vs 11.4%, P = .844). Among patients in whom CAR T-cell therapy failed, the 1-year OS after failure was significantly higher in transformed than de novo DLBCL and HGBL (59% vs 32% vs 11%, <0.0004). Earlier use of CAR T-cell therapy may improve the outcome of HGBL. This trial was registered at www.clinicaltrials.gov as #NCT06339255.

Background: Post-transplant lymphoproliferative disorders (PTLDs) are rare lymphomas that arise as complications of solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT), with a cumulative incidence of approximately 1% at 10 years. The Fondazione Italiana Linfomi (FIL) initiated the multicenter, observational, retrospective FIL_PTLD cohort study to assess PTLD management across Italian hematology centers. Primary objectives include the characterization of clinical features and survival outcomes, as well as the identification of prognostic factors affecting disease progression and mortality. Methods: Adult patients diagnosed with PTLD between January 2011 and December 2021 were retrospectively included. As of this preliminary analysis, 217 patients have been enrolled across 15 centers. Overall survival (OS) was measured from PTLD diagnosis, estimated using Kaplan-Meier method, and compared across groups with Cox model. Results: The median time from transplantation (SOT or HSCT) to PTLD diagnosis was 7.7 years, with shorter latency (p<0.001) observed in EBV-positive cases (2.0 years, range 0.58-11.58) compared to EBV-negative cases (8.25 years, range 5.08-14.75). Early-onset PTLD (within 2 years post-transplant) occurred in 24.0% of patients, while 76.0% had late-onset disease. Most cases followed SOT (92.1%), including kidney (37.5%), liver (36.0%), heart (19.0%), and lung (5.0%) transplants. Only 7.8% occurred after HSCT and 2.5% after combined transplants. The predominant histological subtype was monomorphic PTLD (90.8%), with diffuse large B-cell lymphoma in 68.2%, Burkitt lymphoma in 8.3%, lymphoplasmacytic lymphoma in 2.3%, marginal zone lymphoma in 4.6%, and classical Hodgkin lymphoma in 2.8%. Serum LDH was elevated in 58.6% of cases. Ann Arbor stage at diagnosis was advanced (stage III–IV) in 63.9% of patients. EBV-encoded RNA (EBER) status was available for 147 patients: 44.2% were EBV-positive, with 41.5% diagnosed early and 58.5% late post-transplant. Extranodal involvement was observed in 58.1% of cases, including central nervous system disease in 6.3%. Treatment consisted of immunosuppression reduction alone (11.4%), rituximab monotherapy (44.0%), chemoimmunotherapy (32.0%), chemotherapy alone (6.3%), other approaches (2.2%; surgery or steroids), or no treatment (3.4%). Overall response rates included complete response in 52.1%, partial response in 17.9%, stable disease in 11.4%, and progressive disease in 18.6%. With a median follow-up of 86 months (interquartile range: 52–128), 5-year and 10-year overall survival (OS) rates were 58% (95% CI, 50–66) and 51% (95% CI, 42–59), respectively. Multivariable analysis with Cox model identified age (HR per 1-y 1.02; p = .018), advanced stage (HR 2.61; p = .004), and ECOG performance status ≥2 (HR 2.23; p = .005) as independent predictors of inferior OS. EBER positivity (HR 1.65; p = .105), elevated LDH (HR 1.50; p = .157), and extranodal localization (HR 1.46; p = .277) were not significantly associated with survival. Conclusion: PTLD in adults predominantly arises after SOT and frequently presents in the late-onset form. Treatment approaches were heterogeneous across centers. Advanced age, poor performance status, and advanced stage at diagnosis were associated with worse overall survival.

Introduction Chimeric Antigen Receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed or refractory large B-cell lymphoma (LBCL), yet predicting long term remissions remains a significant clinical challenge. This study aimed to develop machine learning (ML) models trained on real-world data (RWD) that predict progression-free survival (PFS) based solely on clinical and inflammatory factors available at leukapheresis. The goal is to assist clinicians in optimizing CAR T-outcome to reduce the risk of ineffective treatments, also mitigating the costs associated with this therapy. Methods We analyzed prospectively collected RWD from 1309 LBCL patients treated with anti-CD19 CAR T therapy across 23 institutions since 2019, enrolled in the Italian multicenter prospective CART-SIE study. Of the 1309 patients, 779 were included in the analysis after excluding those diagnosed with Mantle Cell Lymphoma (MCL), those receiving lisocabtagene maraleucel, or treated with CAR T in second line, and those for whom PFS could not be computed. Eligible patients had Diffuse Large B-cell Lymphoma (DLBCL, n=508), Primary Mediastinal B-cell Lymphoma (PMBCL, n=85), High-Grade B-cell Lymphoma (HGBCL, n=126), or transformed Follicular Lymphoma (tFL, n=50), and received tisagenlecleucel (n=345) or axicabtagene ciloleucel (n=431) as third-line therapy or beyond. A small subset (~8%) from a single center was used for external validation. The remaining cohort was split into training and test sets (80–20%) using stratification based on PFS status. Five ML survival models, with continuous PFS as the outcome, were trained using 22 pre-leukapheresis clinical and inflammatory variables. Feature selection, hyperparameter tuning, and stratified cross-validation (CV) were conducted on the training set. Explainability was assessed using SHapley Additive exPlanations (SHAP), enabling interpretation of both global and patient-specific predictions. Results All models consistently identified LDH, bulky disease, hemoglobin (Hb), and prior autologous stem cell transplant (ASCT) as key predictors. The Extra Survival Trees model, trained on univariately selected features, achieved a concordance index (C-index) of 0.68, 0.67 (±0.05), and 0.68 on the training, CV, and test sets, respectively and was selected as the best-performing model. SHAP analysis on test set predictions confirmed known prognostic factors, including elevated LDH, bulky disease, low Hb and platelet count, high ferritin, and absence of ASCT, as associated with poorer outcomes. Although external validation performance was lower (C-index = 0.55), likely due to differences in follow-up (median follow-up 6 vs. 19 and 17 months in train and test sets, respectively) and censoring, the model showed stable results on internal test data, providing support for its generalizability. Conclusion An ML model based on a limited set of routinely available pre-leukapheresis variables (bulky disease, LDH, ASCT, Hb, ferritin levels, platelet count) can predict PFS in LBCL patients undergoing CAR T therapy. While further validation is needed, especially across heterogeneous centers, the model's simplicity and interpretability make it promising for clinical integration. A clinician-facing ML tool derived from this work will be presented and could allow real-time risk prediction using six key inputs, with transparent SHAP-based visual explanations to support personalized treatment planning.

Surgical excision biopsy of lymph nodes stands as the gold standard for histological characterization of lymphoproliferative disorders (LD). However, contemporary clinical practice increasingly leans toward core needle biopsy (CNB). This study seeks to explore the factors influencing the diagnostic yield of CNB in LD. This unicentric retrospective study presents data from patients referred for suspicion of new or relapsing LD. All patients underwent image-guided CNB of the target lesion based on PET/CT findings. The primary endpoint was the diagnostic outcome, comparing the ability to achieve a definitive diagnosis according to international guidelines with CNB versus the necessity for subsequent excisional biopsy. We enrolled 478 consecutive patients undergoing CNB, categorized into two cohorts. Cohort A comprised patients who underwent CNB using 18-20G full-core Menghini needles, with a median macroscopic fragment dimension of 1 cm. Cohort B included patients who underwent CNB with 16-18G semiautomatic guillotine needles, with a median macroscopic fragment dimension of 1.5 cm. In cohort A, the rates of diagnostic and non-diagnostic (or non-sufficiently detailed) CNBs were 95 (73

Background: Anti-CD19 CAR T-cells have revolutionized outcomes in relapsed/refractory large B-cell lymphomas. Long-term follow-up underscored the role of hematological toxicity in nonrelapse mortality, largely driven by infections, leading to the development of the CAR-HEMATOTOX (HT) score for predicting neutropenia. The European scientific community (EHA/EBMT) later reached a consensus, defining a new entity: immune effector cell-associated hematotoxicity (ICAHT). Aims: To validate the ability of the HT score to predict ICAHT and survival. Methods: The CART-SIE is an ongoing multicenter prospective observational study collecting data on patients affected by B-cell lymphoma treated with commercial anti-CD19 CAR T-cells (ClinicalTrials.gov ID: NCT06339255). Results: Since 2019 to 2024, 1002 consecutive patients were enrolled. Out of 746 patients infused, the HT score at infusion was evaluable in 389. Median age was 59 years (48-66). Patients with high HT score had greater disease burden and a greater need for bridge therapy. Patients with a HTHIGH score had a 4-fold higher risk of experiencing late ICAHT of grade >= 3 (OR = 3.99, 95% CI = 1.16-13.77, P = .03). Patients with a HTHIGH score also showed lower overall response rates (ORR) and complete response rates (CRR) at 90 days (CRR at 90 days: 59% HTLOW versus 38% HTHIGH, OR = 0.42, 95% CI = 0.27-0.66, P = .0002; ORR at 90 days: 67% HTLOW versus 49% HTHIGH, OR = 0.47, 95% CI = 0.29-0.74, P = .001). Adjusted logistic models confirmed that the effect of HT score was independent from baseline characteristics. With a median follow-up of 18 months, patients with a HTHIGH score have lower OS and PFS (1-year OS: 78% HTLOW versus 62% HTHIGH, P = .0002; 1-year PFS: 49% versus 39%, P = .003). Adjusted Cox models confirmed that HT was an independent prognostic factor for OS. A high HT-score was found to be associated with higher risk of secondary primary malignancy (HR=2.8, 95% CI = 1.03-7.8, P = .04). A simplified version of HT (simpleHT), based solely on the platelet count and C-reactive protein at infusion, was calculated for 560 patients and proved significant in predicting both OS and PFS (1-year was 72% simpleHT(LOW) versus 37% simpleHT(HIGH), P < .0001, 1-year PFS was 48% simpleHT(LOW) versus 22% simpleHT(HIGH), P < .0001). Conclusion: In our prospective real-world study, we validated the ability of the HT score to predict ICAHT and survival. SimpleHT identified a population at very high risk with an impaired progression free and overall survival. (c) 2025 The Authors. Published by Elsevier Inc. on behalf of The American Society for Transplantation and Cellular Therapy. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

CD5-positive diffuse large B-cell lymphomas (DLBCL) represent 5-10% of all DLBCLs. This rare entity exhibits distinct clinical and biological features, including common extranodal disease involvement, leading to unfavorable prognosis with shorter progression free and overall survival and central nervous system (CNS) relapses frequently reported after conventional immune-chemotherapy. Data on efficacy and safety of anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy in this subgroup of DLBCL patients are lacking. Here we report an analysis on outcome of CD5-positive DLBCL after CAR T-cell therapy from the CAR-T SIE observational prospective multicenter study. We evaluated patients with DLBCL for which complete clinical data and assessment of CD5 status on immunohistochemistry were available. Patients with high-grade B cell lymphoma (with/without MYC and BCL-2 gene rearrangements), DLBCL transformed from indolent lymphomas or primary mediastinal B cell lymphomas were excluded. Primary endpoints included response rates (overall [ORR] and complete response [CR] at 90 days), progression-free survival (PFS), overall survival (OS), and safety, focusing on cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). One hundred eighty-three patients were eligible for the analysis and were stratified into CD5-positive (CD5+, n=36) and CD5-negative (CD5-, n=147). Median age was 60 years [interquartile range (IQR): 52-66], with CD5+ patients found to be slightly older (median 62.5 vs. 59 years, p=0.026) than CD5- patients. No other significant demographic or clinical differences were observed between the two groups including: ECOG performance status, Ann Arbor stage, bulky disease, extranodal involvement including bone marrow infiltration assessment, disease status at leukapheresis (relapsed vs. refractory), international prognostic index (IPI), prior lines of therapy, response to bridging therapy or CAR T-cell product [tisagenlecleucel (tisa-cel) vs. axicabtagene ciloleucel (axi-cel)]. CRS incidence was lower in CD5+ (81%) vs. CD5- (92%) patients, although this difference did not reach statistical significance (p=0.065), while ICANS rates were significantly lower in CD5+ patients (11% vs. 28%, p=0.025). However, no differences were seen in grade ≥3 CRS (3.4% vs. 6.9%, p 0.083) and grade ≥3 ICANS rates (25% vs. 29.3%, p 0.386). The median follow-up was 15.5 months (IQR: 6.71-24.64). At 90 days, 166/183 patients were evaluable for response. ORR was 57% in the overall population and was similar between CD5+ (53%) and CD5- (58%) patients (p=0.691). CR rate was also comparable (53% overall; CD5-positive 50%, CD5-negative 54%, p=0.844). Only 3 CNS disease relapses were reported, all of which occurred in CD5- patients. No statistically significant difference emerged in PFS between CD5+ and CD5- patients [median PFS 3.88 months (95% confidence interval, CI) 3.03-NA vs. 6.09 months (95% CI 3.72-11.97), p=0.812], with a 2-year PFS rate of 36.1% (95% CI 22.2-58.6%) vs. 34.9% (95% CI 27.1-45%) for CD5+ and CD5- patients, respectively. Accordingly, median OS was similar between the two groups [median OS 23.88 months (95% CI 11.7-NA) in CD5+ patients vs. 29.01 months (95% CI 14.7-NA) in CD5-, p=0.925], with 2-year OS rates of 47.0% (95% CI 28.7-77.1%) and 51.5% (95% CI 42.2-62.9) in CD5+ and CD5- patients, respectively. A multivariable analysis assessing risk factors for lower PFS and OS rates identified CAR T-cell product (tisa-cel vs. axi-cel, HR=2.05, 95% CI 1.37-3.07, p<0.001) and bulky disease (HR=2.10, 95% CI 1.37-3.22, p=0.001) as significant predictors of worse PFS, independent of CD5 status (p=0.795). Similarly, bulky disease and CAR T-cell product significantly predicted worse OS [HR=3.15 (95% CI 1.90-5.24) p<0.001, and HR=1.75 (95% CI 1.04-2.93) p=0.035 for tisa-cel vs. axi-cel], while CD5 status was not prognostic (p=0.926). Non-relapse mortality at 12 months was low in both groups (2.9% in CD5+ vs. 4.5% in CD5-, p=0.931). Our report shows that anti-CD19 CAR T-cell therapy might overcome the prognostic impact of CD5-positivity in patients with DLBCL, demonstrating comparable outcomes in CD5+ and CD5- patients, with no significant differences in ORR, CR rate, PFS, OS and severe toxicities.

Background TRANSCEND FL primary analysis (NCT04245839) demonstrated high response rates and consistent safety profile as previously reported with liso-cel in 2L+ FL, including high-risk 2L FL. Here, we report outcomes by BT status and safety in outpatients. Methods Consented patients with 2L+ FL received liso-cel; patients with 2L FL had progression of disease ≤24 months from diagnosis after treatment with anti-CD20+alkylator ≤6 months of FL diagnosis and/or met mGELF criteria. Optional BT per investigator was allowed during liso-cel manufacturing with reconfirmation of PET/CT-positive FL before liso-cel infusion. Primary endpoint was ORR per independent review committee; secondary endpoints included CR rate, duration of response (DOR), PFS, OS, and safety. Comparisons between BT and non-BT subgroups are descriptive. Outpatient monitoring occurred per investigator's discretion. Participating study sites had a multidisciplinary CAR T-cell therapy team and SOPs for cytokine release syndrome (CRS)/neurological event (NE) management. Results Of 139 patients having leukapheresis (BT/non-BT, n=54/85), 130 received liso-cel (BT/non-BT, n=49/81) and 124 were efficacy evaluable (BT/non-BT, n=45/79). Fifteen patients were monitored as outpatients. BT subgroup had higher baseline (screening and pre-lymphodepletion) disease burden versus non-BT. ORR/CR rates were high and similar across subgroups (BT, 93%/93%; non-BT, 99%/95%), with all responders in the BT subgroup achieving CR. With 18.9-month median follow-up, 12-month DOR/PFS/OS rates were high (BT, 88%/82%/87%; non-BT, 81%/83%/96%); medians were not reached. Grade ≥3 laboratory-based cytopenia for BT/non-BT at Day 29 was 37%/14%; most recovered to grade ≤2 by Day 90. Grade 3 CRS/NEs/infections were low across subgroups (BT, 0%/6%/2%; non-BT, 1%/0%/7%), with no grade 4/5 events. Of 15 outpatients, 6/2 experienced CRS/NEs (grade 1/2 events only). Seven outpatients were hospitalized; median (range) time to initial hospitalization was 7 days (4-16) and duration was 5 days (3-8) (no ICU stays). Conclusions Liso-cel showed similar efficacy and safety (low rates of severe CRS/NEs/infections) in both subgroups, suggesting BT may slow disease progression (despite higher baseline disease burden), potentially improving outcomes in this high-risk population. Safety in the outpatient setting was consistent with the overall population and with liso-cel in OUTREACH (NCT03744676; LBCL outpatient setting), with no new safety signals.

Background High-grade B-cell lymphomas (HGBCL) represent a group of aggressive lymphoid malignancies characterized by rapid progression and unfavorable clinical behavior. Despite advancements in treatment modalities, first-line treatment of HGBL represents a significant clinical challenge, without a consensus on the current standard of care. Current treatment approaches for HGBL include intensified chemotherapy programs such as CODOX-M-IVAC or R-DA EPOCH or the Berlin-Frankfurt-Munster (BFM) protocol. All these programs are commonly used also for Burkitt Lymphoma. Patients and Methods The German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia protocol GMALL B ALL/NHL 2002 is an intensive chemotherapy regimen derived from the Berlin-Frankfurt-Munster (BFM) protocol that was used for other aggressive lymphoid malignancies, including Burkitt Lymphoma, yielding high complete response rates and durable responses as previously reported by other studies. 1. 2 From February 2011 to December 2023 we adopted the (GMALL B-ALL/NHL2002), (Clinical trial.gov NCT03131531) for the treatment of 53 adult (>18y) consecutive patients with HGBCL. The median age at diagnosis was 56 years (range: 21-75). Nineteen patients (35,8%) were classified as double-hit lymphoma (DHL) according to WHO 2022, harboring BCL2 and MYC rearrangement. Five patients were HIV positive (9,3%). Results The overall response rate (ORR) was 92,4% (n=49). By PET-CT scan, a complete metabolic response (CR) was documented in 42 patients (79,2%) at the end of treatment (EOT evaluation). Thirty patients (56.6%) achieved a complete metabolic response after the first 2 cycles (interim PET-CT). One patient showed progressive disease at interim PET-CT evaluation and 4 patients (7,5%) at the EOT imaging evaluation. Overall, the 6-year PFS among HGBCL patients was 72%. According to histology, the 6-year PFS was 83% among HGBCL patients and 49% among DHL patients. The 6-year PFS for patients over 55 years old was 61% compared to 82% for those younger than 55 years. Patients achieving CR at the EOT evaluation showed a 6-year PFS of 82% compared to 57% for partial responders (p=0.036). Interim TC/PET evaluation had an impact on PFS, with patients in PR having shorter PFS when confronted with patients in CR (p=0.04). The 6-year overall survival in the HGBCL cohort was 76%. According to histology, 6-year OS was 86% among HGBCL patients and 56% among DHL patients. Patients achieving CR at the EOT evaluation had a significantly longer median OS compared to PR patients, underscoring the importance of achieving deep responses in this setting (p=0.006). Overall, 11 patients died during the follow-up, in most cases as a consequence of progressive or relapsed disease (n=9). During treatment, adverse events were closely monitored. Nearly 50% of patients (n=25) experienced adverse reactions to therapy. Febrile neutropenia was the most common hematologic toxicity, occurring in 22,6% of patients (n=12). Sepsis occurred in 7,5% of cases (n=4), requiring admission to the hospital Emergency Room. Mucositis was observed in 16,9% of patients (n=9). Hepatic toxicity was common after the first cycle, with 5,6% of patients (n=3) experiencing elevated liver enzymes, which resolved with treatment delay and supportive care. No patient died during the treatment due to protocol adverse events. One patient (1,8%) developed secondary myelodysplasia and died for this reason. Conclusions The GMALL B ALL/NHL 2002 protocol induced a high complete response rate with durable response and overall survival in HGBCL patients. Patients failing to achieve an EOT complete response have dismal prognosis and should be rapidly selected for CAR-T cell therapy or other experimental treatment options.