ABSTRACT: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.

BackgroundBody composition has a significant impact on the prognosis of cancer patients. However, little is known about its impact on the efficacy and safety of antibody–drug conjugates (ADCs), despite the need for accurate patient profiling to ensure reliable safety data and early signals of activity.MethodsAll patients treated with ADCs in early-phase clinical trials between March 2015 and March 2023 in our institution were retrospectively included in the analysis. Pre-treatment injected CT scans were acquired for all patients. A deep learning software, Anthropometer3DNet, automatically quantified anthropometric parameters in three dimensions (3D) on the acquired CT scans: skeletal muscle mass (SMM), total adipose tissue (TAT), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and lean body mass (LBM). The effect of these anthropometric parameters on progression-free survival (PFS), overall survival (OS), and time in protocol (TIP) was analyzed.ResultsA total of 136 patients were included. The median age, Eastern Cooperative Oncology Group Performance Status (ECOG PS), albumin, and number of previous lines of treatment were respectively 60.8 years (30 to 85), 1 (0–2), 42 g/L [interquartile range (IQR): 39–44], and 3 (IQR: 0–2). The median PFS and OS were 2.6 and 7.9 months, respectively; 90 (66%) patients had experienced toxicity (of which 46 were grade 3–5). Univariate analyses showed that higher SAT [hazard ratio (HR) = 0.67, p = 0.03] and TAT (HR = 0.60, p = 0.01) were significantly associated with longer PFS [median PFS (mPFS) = 2.76 vs. 2.3 and 2.76 vs. 1.9, respectively]. Higher SAT (HR = 0.66, p = 0.04) and higher VAT (HR = 0.65, p = 0.04) were significantly associated with longer OS [median OS (mOS) = 9.34 vs. 7.43 months and 9.27 vs. 6.08 months, respectively]. Higher TAT was associated with longer TIP in both univariate and multivariate analyses (HR = 0.56, p = 0.006). A Royal Marsden Hospital (RMH) prognostic score of 2 or more was associated with PFS, OS, and TIP in both univariate and multivariate analyses (HR = 1.78, 1.89, and 1.74, respectively). All anthropometric parameters were significantly associated with all-grade toxicity in the univariate analysis but not in the multivariate analysis.ConclusionsAutomatic extraction of body composition parameters using artificial intelligence (AI) may help in anticipating the benefits of ADCs in patients included in early-phase clinical trials. Combining anthropomorphic data with clinical and biological data may lead to more refined patient selection.

7003 Background: The epigenetic enzyme protein arginine methyltransferase 5 (PRMT5) plays a critical role in cell proliferation and differentiation; PRMT5 dysregulation is associated with cancer development. Methylthioadenosine (MTA) is an endogenous partial inhibitor of PRMT5 that accumulates in cancer cells deficient in MTA phosphorylase (MTAP). In classic Hodgkin lymphoma (cHL), we previously reported that >80% of primary patient (pt) tumor samples are MTAP deficient (Urosevic J, ASH 2023). The MTA-cooperative PRMT5 inhibitor AZD3470 preferentially binds to the MTA-bound state of PRMT5, increasing its target engagement to MTAP-deficient cancer cells. Here, we present safety and preliminary efficacy of AZD3470 from a first-in-human Phase 1 study in relapsed/refractory (r/r) cHL (NCT06137144). Methods: Eligible pts were ≥18 years with r/r cHL after ≥3 prior lines of therapy (including brentuximab vedotin (BV) and anti-PD-1). In dose escalation, pts received oral AZD3470 monotherapy QD in ascending dose levels (DLs) using an mTPI-2 design. Primary endpoints were incidence and severity of treatment-emergent adverse events (TEAEs) and dose-limiting toxicity (DLT). Secondary endpoints were overall response rate (ORR) and complete response rate (CRR) per Lugano 2014 criteria. Results: As of Nov 25, 2025, 39 pts had received AZD3470 at DLs ranging from 1 to 8. Most pts were male (62%) with stage IV disease (77%) and a median age of 42 (range 25–78) years. Pts had received a median of 6 prior lines of anticancer therapy (range 3–14); all had had prior BV and anti-PD1 treatments, and 20 (51%) and 5 (13%) pts had had prior autologous and allogeneic hematopoietic stem cell transplantation, respectively. All patients evaluable for MTAP protein expression were MTAP deficient. Median duration of exposure was 15 weeks (range 0.1–45.1), with treatment ongoing in 16 pts (41%). TEAEs occurred in 85% of pts, predominantly grades 1 or 2. The most common TEAEs (any grade) were anemia (28%) and nausea (15%), followed by asthenia, constipation, fatigue, and neutropenia (13% each). Grade ≥3 TEAEs occurred in 28% of pts, most commonly neutropenia (related) and hypokalemia (n=2 each). Serious TEAEs occurred in 5 (13%) pts. Two pts had dose reductions due to TEAEs (grade 4 hypertriglyceridemia and grade 3 esophagitis). No DLTs, treatment discontinuations nor deaths due to TEAEs were reported. Of the 31 pts evaluable for efficacy, 14 had an objective response, with responses at doses ≥DL4. The highest response rate was observed at doses ≥DL7 (n=10) with an ORR of 80% and CRR of 50%. Conclusions: AZD3470 monotherapy was well tolerated up to DL8, with no DLTs and mainly low-grade AEs. Incidences of grade ≥3 AEs and SAEs were low. Importantly, both the ORR and CRR were dose-dependent and notably high in this heavily pretreated cHL population. Dose optimization is ongoing and further safety and efficacy will be reported. Clinical trial information: NCT06137144 .

PURPOSE:An unmet treatment need remains for relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL), including the follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL) subtypes. The PI3K/AKT/mTOR pathway is dysregulated and associated with poor prognosis in NHL. The AKT inhibitor capivasertib has preclinical activity in hematologic malignancy models. PATIENTS AND METHODS:NCT05008055 was a modular, open-label, multicenter phase II study that examined oral capivasertib monotherapy in patients with R/R B-cell NHL who had received ≥2 prior lines of therapy. Patients had R/R FL (cohort 1A), MZL (cohort 1B), or MCL (cohort 1C). Capivasertib 480 mg twice daily was administered orally 4 days on/3 days off. The primary objective was to determine the objective response rate (ORR) by blinded independent central review. RESULTS:Thirty patients were enrolled (of 272 planned). The ORR for patients with R/R FL, MZL, and MCL were 18.8% (three of 16), 33.3% (one of three), and 30% (three of 10), respectively; 62.5% (10 of 16) of patients with R/R FL had stable disease. Baseline tumor PTEN expression was deficient/undetectable in the two patients who had a complete response and three of five patients who had a partial response. The most common capivasertib-related adverse events (AE) were diarrhea (63.3%), nausea (20%), vomiting (13.3%), and hyperglycemia (10%). Capivasertib-related grade ≥3 AE or serious AE were observed in nine and three patients, respectively. CONCLUSIONS:The study was terminated early with a small sample size, limiting interpretation, although antitumor activity was limited. Future studies of capivasertib in hematologic malignancies would likely require biomarker-directed patient selection and/or combination therapy.

ABSTRACT: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.

Supplementary figure 1: Bar graphs showing IHC quantification of PTEN and FOXO3a/1 protein expression in baseline tumors (n=11 participants). PTENpositive, >10% of tumor cells stain positive for PTEN; PTENnegative, ≤10% of tumor cells stain positive for PTEN.

The prognosis of elderly patients with Hodgkin lymphoma (HL) unfit for conventional chemotherapy remains poor. We report the results of the LYSA phase II NIVINIHO trial in treatment-naive HL patients aged ≥ 61 years with comorbidities contraindicating standard chemotherapy. Treatment included an induction phase with nivolumab alone, followed by a consolidation phase: either nivolumab monotherapy for patients with early complete metabolic response or nivolumab plus vinblastine for patients with stable disease or partial response. The primary objective of the study was the complete metabolic response (CMR) rate at the end of treatment. From August 2018 to April 2020, 64 patients were enrolled. Median age was 75.0 (range, 62 to 91) years, Ann Arbor stage was advanced (stage III-IV) in 75.0% of patients. At end of nivolumab induction, 11 patients (17.2%) achieved CMR and were consolidated with nivolumab alone, 23 (35.9%) patients obtained PMR or SD and received vinblastine plus nivolumab. Among the 56 evaluable patients, 16 (28.6%) achieved CMR at the end of treatment. With a median follow-up of 24.4 months (range, 0.9 to 35.2), median progression-free survival (PFS) was 9.8 months (95% confidence interval [CI], 4.2 to 12) while the 2-year overall survival (OS) rate was 74.1% (95%CI, 58.9% to 84.4%). Thirtytwo patients (50%) experienced grade ≥ 3 adverse events (AEs). Nivolumab-related adverse events led to treatment discontinuation in 19 patients (29.7%). Our results show that nivolumab can be administrated to elderly, frail patients unfit for classical chemotherapy; however, the objective response rate with monotherapy remains low. Trial registration number: NCT03580408.

ABSTRACT Mantle cell lymphoma (MCL) is defined by the t(11;14)(q13;q32) translocation, which drives constitutive CCND1 expression, yet the broader regulatory consequences of this rearrangement remain incompletely understood. Here, we combined transcriptomic, epigenomic, Hi-C, and 3D-FISH analyses in primary MCL samples and cell lines to investigate the genome-wide impact of t(11;14) on chromatin organization and gene regulation beyond the rearranged chromosomes. We show that MCL cells exhibit widespread enhancer activation, accompanied by expansion of super-enhancer regions. The translocated CCND1 locus repositions toward the nuclear interior and acquires enhancer-like features. Genome-wide analysis highlighted chromosome 19 as a hotspot of transcriptional upregulation. Notably, Hi-C and 3D-FISH revealed recurrent interchromosomal contacts between chromosome 19 and the CCND1 locus, preferentially involving the derivative chromosome. These contacts colocalize with active RNA polymerase II and are associated with increased expression of nearby chr19 genes, suggesting an association between spatial proximity and transcriptional activation in trans. Minnelide treatment reduced chromatin accessibility at the CCND1 locus, decreased the frequency of chr19-der14 interactions, and partially reversed the MCL transcriptional program, while exerting strong anti-tumor effects in vitro and in vivo . Together, these findings identify a recurrent interchromosomal interaction associated with coordinated gene activation in MCL and suggest that spatial genome reorganization contributes to disease-specific transcriptional programs.

Introduction: Immunochemotherapy remains the cornerstone of treatment for Mantle Cell Lymphoma (MCL). However, 25% of patients experience early progression, with survival rates of less than two years. Current prognostic tools, such as the MCL International Prognostic Index (MIPI), and poor prognostic histological and genetic features are insufficient for stratifying patients into individualized therapeutic strategies. This study aimed to identify biomarkers for high-risk MCL patients using an integrated analysis of clinical and biological factors. Methods: We analyzed data from 299 patients enrolled in the LyMa phase 3 trial, with a focus on high-risk patients, defined by refractoriness to immunochemotherapy or relapse within 12 months post-autologous stem cell transplantation. We used optical genome mapping (OGM) on frozen samples, alongside whole-exome sequencing (WES), RNA sequencing, and DNA methylation arrays analyses on FFPE tumor biopsies to identify genetic, transcriptomic and epigenetic alterations. Machine learning models, including random forest analysis and Partial Least-Squares Discriminant Analysis (PLS-DA), were employed to predict high-risk MCL status. Results: Among the 299 patients, 31 (10.4%) were identified as high-risk (HR) with a median overall survival of 8.5 months after relapse. HR patients exhibited significantly higher levels of LDH, higher-risk MIPI scores (45% vs. 16%, p<0.001), Ki-67 >30% (71% vs. 31%, p<0.001) and blastoid/pleomorphic histology (32% vs. 9%, p<0.001). In multivariate analysis, only high-risk MIPI score, and Ki-67 >30% were associated with HR MCL. These factors were insufficient to specifically capture HR patients, as one-third of long-term responders would have been misidentified as high-risk. The high-risk (HR) subgroup displayed a greater burden of complex genetic alterations, with significantly increased frequencies of TP53 alterations (OR 25.4, p < 0.001), CDKN2A deletions (OR 4.5, p = 0.015), RB1 deletions (OR 4.9, p = 0.024), MYC gains (OR 5.8, p = 0.047), and MIR17HG gains (OR 11.8, p = 0.013). To improve predictive accuracy, an integrative analysis combining well-established prognostic markers with gene alterations assessed by WES, was performed. Random forest analysis achieved a test accuracy of 91% when predicting HR MCL status, with a ROC AUC of 96%. The sensitivity was 84% and the specificity was 96%, with a misclassification rate of 14%. The most influential features included the Ki-67 index, histological subtype, TP53 alterations, MIPI score, and gains of MYC and MIR17HG. Unsupervised Uniform Manifold Approximation and Projection (UMAP) analysis of gene expression profiling on 49 FFPE samples, including 15 HR MCLs, showed that HR MCLs tended to cluster together, but the distinction was not perfect. Supervised analyses, using PLS-DA, indicated potential overfitting, suggesting that transcriptomic signals alone are insufficient for perfect discrimination. In contrast, DNA methylation analysis of 29 FFPE samples, including 12 HR MCLs, revealed a distinct epigenetic signature that robustly discriminated HR MCLs from control cases. Supervised approaches (PLS-DA) identified differentially methylated probes (DMPs, n=225) that perfectly discriminated HR MCL from controls. Importantly, this epigenetic signature was validated in an independent cohort (Barcelona cohort, n=64). To explore the genome-wide impact of DNA methylation on gene expression, we performed correlation analyses between promoter methylation and transcriptomic data across all protein-coding genes. A subset of genes showed significant correlations, with a predominant inverse relationship in HR cases, absent in controls, indicating that promoter hypermethylation may drive transcriptional deregulation in this subgroup. Notably, CHL1, a tumor suppressor, and KLHL6, associated with chemoresistance, demonstrated strong inverse correlations between methylation and expression, supporting their involvement in HR MCL pathogenesis. Conclusion: This study provides an integrated characterization of high-risk MCL, identifying a novel epigenetic signature that outperform traditional prognostic markers. Our baseline epigenetic approach may enhance patient stratification and support the development of personalized therapies. These results support the combined analysis of genetic and epigenetic features to capture MCL's full biological complexity.

Abstract Purpose: Patients with relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) generally have poor prognoses and limited treatment options. This study evaluated the efficacy of a novel CD30/CD16A bispecific innate cell engager, acimtamig (AFM13), in patients with R/R PTCL. Patients and Methods: Patients included those with CD30 expression in ≥1% of tumor cells and who were R/R following ≥1 prior line of systemic therapy. Acimtamig (200 mg) was administered once weekly in 8-week cycles. The primary endpoint was the overall response rate by fluorodeoxyglucose-PET per independent review committee; secondary and exploratory endpoints included duration of response, safety, progression-free survival, and overall survival. Results: The overall response rate in 108 patients was 32.4% [95% confidence interval (CI), 23.7, 42.1] with a complete response rate of 10.2% (95% CI, 5.2, 17.5); the median duration of response was 2.3 months (95% CI, 1.9, 6.5). Patients with R/R angioimmunoblastic T-cell lymphoma exhibited the greatest number of responses [53.3% (95% CI, 34.3, 71.7)]. Responses were independent of CD30 expression level, prior brentuximab vedotin treatment, or steroid premedication. Acimtamig exhibited a tolerable safety profile; the most common treatment-related adverse events were infusion-related reactions in 27 patients (25.0%) and neutropenia in 11 patients (10.2%). No cases of cytokine release syndrome or acimtamig-related deaths were reported. Despite exhibiting promising clinical activity and tolerable safety in a heavily pretreated PTCL population, the study did not meet the criteria for the primary endpoint. Conclusions: The promising clinical efficacy observed warrants further investigation, and development of acimtamig for patients with R/R CD30+ lymphomas continues in combination with allogeneic NK cells.

INTRODUCTION:Mantle cell lymphoma is still a lymphoma subtype with productive clinical research. Recent published data on Bruton kinase inhibitors have changed the management of patients. AREAS COVERED:This review summarizes the most important trials evaluating the different treatment options in mantle cell lymphoma in the frontline and the relapsed/refractory setting in young and older patients, focusing on the role of Bruton kinase inhibitors in improving disease outcome and omitting consolidative autologous stem cell transplantation. EXPERT OPINION:Following the results of the TRIANGLE trial, the addition of ibrutinib to the induction and maintenance treatment should be considered and the omission of autologous stem cell transplantation is questionable in all patients. Minimal residual disease is a promising biomarker that would dictate our decision making especially in the maintenance setting. CAR-T cells remain the best option in the relapsed/refractory patients after Brutonkinase inhibitors.

e24081 Background: Infectious complications were recently reported in patients (pts) receiving T-cell engager (TCE) therapy and require further investigations. Infections may result of depleting tumor-associated antigens, mobilizing immune T-cell compartment, or employing comedications like corticosteroids and/or anti-cytokine to manage cytokine release syndrome (CRS). This study aims to assess infectious events in patients undergoing TCE and to identify risk factors. Methods: Study design is a cohort study observational, nested in the French academic pharmacovigilance register, Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC, CNIL number 2098694v0). All pts treated at Gustave Roussy (Villejuif, France), for all tumor indications except acute leukemia, were included. The primary objective was to report on infectious events and risk factors during TCE treatment. A competing-risk approach identify factors predisposing pts to infections with end of treatment as the competing event. Comedications with corticosteroids and anti-cytokine therapies associated with TCE were evaluated as a potential risk factor for infections. Results: Overall, 181 pts treated with TCE, median [range] age 62 [5-83] years, 64.1% male, median of 4 [1–11] prior lines of therapy (LOT), 118 (65.2%) with solid tumors and 63 (34.8%) with hematological (hem.) cancers, were included. CRS and neurological events (all grades), occurred in 111 (61,3%) and 11 (6,1%) of pts, respectively. The cumulative incidence of infections (all grades) was 29.8% (95% CI (22.1-38.0)) and 16.9% (95% CI (9.8-25.8)) for severe infections. Patients with hem. cancers, as compared with those with solid tumors, had significantly higher cumulative incidence of severe infections (35.3% vs. 7.6%.; p = 0.001). Six fatal infections (3.3%) occurred, all in pts with hem. cancers. The multivariable model found hem. cancer indications and > 3 prior LOT were associated with an increased risk of severe infections (HR = 3.11 [95% CI: 1.32–7.33], p = 0.009, and HR = 3.11 [95% CI: 1.19–8.06], p = 0.02, respectively). Comedications with corticosteroids or anti-cytokine therapies did not enhance the risk of infections. Microbiological distribution of pathogens unraveled hem. cancers pts were more infected by gram-negative bacteria, resistant gram-positive bacteria, and viral infections, as compared to solid tumors pts (p = 0.03; p = 0.08; and p = 0.02, respectively). Comprehensive microbiological map and sites of infections will be disclosed at the conference. Conclusions: Infectious events with TCE were primarily observed and severe in patients with hem. cancer. Comedications with corticosteroids or anti-cytokines did not enhance the risk of infections. Supportive care and preventive anti-infectious measures should be prioritized in patients at higher risk of infections.

3102 Background: EZH2 inhibition antitumor activity occurs through various mechanistic pathways in multiple tumor types, including via synthetic lethality in advanced ARID1A -mutated ovarian clear cell carcinoma (OCCC) and endometrial carcinoma (EC). Oral, next-generation, dual EZH2/EZH1 inhibitor tulmimetostat is in Phase II evaluation in multiple disease cohorts (NCT04104776; Oaknin et al. ASCO 2024, ESMO 2024). We report updated efficacy and safety data from the ARID1A -mutated OCCC/EC cohorts, including dose optimization and expansion arms. Methods: Phase II Stage 1 evaluated tulmimetostat 350 mg once daily (QD). Stage 2 dose-optimization design randomizes further patients with OCCC (M2) or EC (M3) to 200 mg or 300 mg tulmimetostat QD in Stage 2a, with an efficacy gateway for each arm to open Stage 2b. Primary endpoint is objective response rate (complete response [CR] + partial response [PR]), and secondary objectives include safety. Results: As of October 15, 2024, enrollment into the M2/M3 200 mg, 300 mg, and 350 mg arms included 20/10, 21/21 and 14/11 patients, respectively. A total of 56.4% M2 and 61.9% M3 patients received ≥3 prior lines of therapy. Most responses were seen in the M2 200 mg arm and in the M3 350 mg arm (n=4 each; Table). The safety profile across arms was consistent with the EZH1/2 drug class. In M2/M3 cohorts, treatment-emergent adverse events (TEAEs) leading to dose modifications were reported in 55.0%/60.0%, 71.4%/85.7%, and 92.9%/90.9% of patients at 200 mg, 300 mg, and 350 mg, respectively. TEAEs leading to treatment discontinuation were reported in 5.0%/20.0%, 4.8%/4.8%, and 14.3%/9.1%, respectively. Serious TEAEs considered at least possibly related (TRAEs) to tulmimetostat treatment were reported in 5.0%/0%, 9.5%/14.3%, and 21.4%/27.3%, respectively. Grade ≥3 TRAEs were mainly hematologic (Table); no TRAEs leading to death were reported. Conclusions: Tulmimetostat showed an improved and acceptable safety profile in OCCC and EC at 200 mg and 300 mg doses (versus 350 mg) with promising antitumor activity, supporting further clinical investigation. Clinical trial information: NCT04104776 . Best confirmed responses and most common grade ≥3 related TEAEs. Cohort M2: OCCC M3: EC Dose, mg 200 300 350 200 300 350 Efficacy evaluable*, N 20 20 14 10 15 11 Best confirmed response † , n CRPRStable disease 0410 0210 0 17 008 115 042 Progressive diseaseNo post-baseline response assessment 51 71 60 11 71 41 Safety evaluable, N 20 21 14 10 21 11 Grade ≥3 related TEAEs ‡ , n (%) Thrombocytopenia 1 (5) 3 (14) 4 (29) 0 4 (19) 2 (18) Anemia 3 (15) 0 7 (50) 0 5 (24) 1 (9) Neutropenia 0 0 2 (14) 0 0 4 (36) Diarrhea 0 4 (19) 0 0 0 2 (18) Data cut off: October 15, 2024. *Patients who received ≥1 dose, had ≥1 post-baseline response assessment, or discontinued treatment prior to first post-baseline assessment for any reason. † RECIST 1.1. ‡ >10% in any M2/M3 arm.

Although chimeric antigen receptor (CAR) T cells have shown excellent results in treating hematological malignancies, they also cause side effects. Patients treated with CAR T cells experience persistent cytopenia or hematotox. Here, using a fully immunocompetent mouse model, we recapitulated hematotox and demonstrated that a lymphodepleting regimen alone was insufficient to induce hematotox and required CAR T cell injection. Analysis of bone marrow (BM) samples from patients experiencing hematotox revealed a correlation between BM CAR T cells and hematotox severity. CAR T cells exhibited an activated program, leading to intense inflammation. In addition, we observed a high rate of clonal hematopoiesis in our patient cohort and the emergence of distinct hematopoietic clones in the months after CAR T cell injection. Our study provides insights into the pathophysiology of hematotox and highlights the need for long-term follow-up studies to determine the relevance of this intense BM inflammation in clonal selection.

Background:In the phase I Epi-RCHOP study (NCT02889523), we reported that R-CHOP-tazemetostat was well tolerated with the recommended phase II dose, consistent with monotherapy. Methods:Phase II included newly diagnosed diffuse large B cell lymphoma patients aged 60-80 years who received six cycles of rituximab-CHOP (R-CHOP) with continuous tazemetostat (800 mg BID), plus two cycles of tazemetostat and rituximab (cycles 7 and 8), from July 31, 2020 to July 18, 2022. Primary endpoint was positron emission tomography complete metabolic response (CMR). Sample size was calculated with H0 of 70% and H1 assumption of 80%. Findings:The trial enrolled 122 patients: median age 70 (60-80), 90.2% with stage III-IV, and 73.8% with International Prognostic Index 3-5. Overall, 100 patients (82%) received eight cycles, while 22 had premature treatment discontinuation (PTD), including 12 during the first two cycles. Reasons for PTD were consent withdrawal (N = 10), adverse events (N = 6), death (N = 2), protocol deviation (N = 2), progressive disease (N = 1), and physician decision (N = 1). The median percentage of relative dose intensity of tazemetostat and R-CHOP exceeded 90%, but required a protocol amendment and reduction in vincristine dosage at 1 mg full dose. At the end of treatment or PTD, 92/122 patients (75.4%) achieved CMR, eight (6.6%) partial metabolic response, five (4.1%) progressive disease, two (1.6%) died (septic shock), and 15 (12.3%) were not evaluated. Sensitivity analysis, excluding ten non-evaluated patients who withdrew consent, showed CMR in 82.1%. After a median follow-up of 18.5 months (IQR: 15.4-21), estimated progression-free and overall survival at 18 months were 77.7% (95% CI: 67.5-85.1%) and 88.8% (95% CI: 79.9-93.9%), respectively. Interpretation:R-CHOP plus tazemetostat is feasible with a promising CMR in elderly DLBCL patients. Complementary biomarker studies are needed for a more personalized approach. Funding:This study was sponsored under a grant from Ipsen.