High-risk Diffuse Large B-cell Lymphoma Research Articles

Specific mortality in patients with diffuse large B-cell lymphoma: a retrospective analysis based on the surveillance, epidemiology, and end results database.

The full potential of competing risk modeling approaches in the context of diffuse large B-cell lymphoma (DLBCL) patients has yet to be fully harnessed. This study aims to address this gap by developing a sophisticated competing risk model specifically designed to predict specific mortality in DLBCL patients. We extracted DLBCL patients' data from the SEER (Surveillance, Epidemiology, and End Results) database. To identify relevant variables, we conducted a two-step screening process using univariate and multivariate Fine and Gray regression analyses. Subsequently, a nomogram was constructed based on the results. The model's consistency index (C-index) was calculated to assess its performance. Additionally, calibration curves and receiver operator characteristic (ROC) curves were generated to validate the model's effectiveness. This study enrolled a total of 24,402 patients. The feature selection analysis identified 13 variables that were statistically significant and therefore included in the model. The model validation results demonstrated that the area under the receiver operating characteristic (ROC) curve (AUC) for predicting 6-month, 1-year, and 3-year DLBCL-specific mortality was 0.748, 0.718, and 0.698, respectively, in the training cohort. In the validation cohort, the AUC values were 0.747, 0.721, and 0.697. The calibration curves indicated good consistency between the training and validation cohorts. The most significant predictor of DLBCL-specific mortality is the age of the patient, followed by the Ann Arbor stage and the administration of chemotherapy. This predictive model has the potential to facilitate the identification of high-risk DLBCL patients by clinicians, ultimately leading to improved prognosis.

Prognosis Prediction of Diffuse Large B-cell Lymphoma in 18F-FDG PET images Based on Multi-Deep-Learning Models.

Diffuse large B-cell lymphoma (DLBCL), a cancer of B cells, has been one of the most challenging and complicated diseases because of its considerable variation in clinical behavior, response to therapy, and prognosis. Radiomic features from medical images, such as PET images, have become one of the most valuable features for disease classification or prognosis prediction using learning-based methods. In this paper, a new flexible ensemble deep learning model is proposed for the prognosis prediction of the DLBCL in 18F-FDG PET images. This study proposes the multi-R-signature construction through selected pre-trained deep learning models for predicting progression-free survival (PFS) and overall survival (OS). The proposed method is trained and validated on two datasets from different imaging centers. Through analyzing and comparing the results, the prediction models, including Age, Ann abor stage, Bulky disease, SUVmax, TMTV, and multi-R-signature, achieve the almost best PFS prediction performance (C-index: 0.770, 95% CI: 0.705-0.834, with feature adding fusion method and C-index: 0.764, 95% CI: 0.695-0.832, with feature concatenate fusion method) and OS prediction (C-index: 0.770 (0.692-0.848) and 0.771 (0.694-0.849)) on the validation dataset. The developed multiparametric model could achieve accurate survival risk stratification of DLBCL patients. The outcomes of this study will be helpful for the early identification of high-risk DLBCL patients with refractory relapses and for guiding individualized treatment strategies.

Abstract CT245: Circulating tumor DNA and nivolumab maintenance: A pilot study in diffuse large B cell lymphoma

Abstract Introduction: Molecular minimal residual disease (MRD) status correlates with disease relapse in patients (pts) with diffuse large B cell lymphoma (DLBCL). However, the clinical impact of early treatment intervention a time of detectable MRD (dMRD) prior to clinical relapse is unknown. Checkpoint inhibitor (CPI) therapy has activity in some pts with DLBCL. We hypothesized that early CPI therapy in patients with dMRD without clinical relapse may lower relapse rate. We conducted a pilot study in high risk pts in remission after most recent line of therapy (LOT) in whom maintenance nivolumab (MN) was offered at time of dMRD to assess effect on MRD clearance and relapse rate. Methods: Pts >18 years (yrs) with high-risk DLBCL (ABC-subtype, high grade B cell lymphoma (HGBCL), MYC translocation, relapsed/refractory disease, or Ki67 >90%) who had achieved CR on most recent LOT were eligible. Patients were monitored for detectable MRD (dMRD) based on the clonoSEQ assay for circulating tumor DNA (ctDNA). Pts had monthly MRD assessment and every 4 month imaging for 2 yrs. If conversion from uMRD to dMRD without clinical relapse, pts received MN (240 mg IV q2 weeks) for up 2 yrs. Pts with overt relapse at time of dMRD or dMRD at initial MRD assessment were ineligible for MN. The primary endpoint was rate of conversion from dMRD to undetectable MRD (uMRD). Results: 20 pts were screened and 15 pts enrolled between June 2018 and March 2022. 4 had transformed DLBCL (2 from FL, 1 from MZL, and 1 Richter’s transformation from CLL), 2 pts had HGBCL (one of which was also transformed). All pts with dMRD had radiographic relapse within 4 months of molecular relapse. No pts with uMRD by ctDNA had clinical relapse on study during 2 yrs follow up. Of the 8 pts who enrolled after first LOT, none had molecular or clinical relapse. Of the 7 pts with 2+ prior LOT, 3 had dMRD: two had clinical relapse at same time as dMRD and were taken off study (one had dMRD at baseline MRD assessment and the other 135 days post enrollment after initial period of uMRD). In the single patient eligible for MN, dMRD preceded radiographic relapse by 105 days, 410 days after enrollment. The pt received 2 cycles of MN before clinical progression and was taken off study. This pt failed to achieve conversion of dMRD to uMRD. Conclusion: Due to small sample size and lower than expected relapse, we were unable to demonstrate conversion of dMRD to uMRD using MN. However, this pilot study did confirm high correlation of uMRD and dMRD status with disease free survival and clinical relapse within 4 months, respectively. If strong negative predictive value is confirmed in a larger study, ctDNA MRD testing may be used to spare pts from imaging or to guide additional work up in pts with inconclusive findings on scans. Citation Format: Shazia Nakhoda, Tamarrah Sklarz, Cheyenne Pagan, Matthew Matasar, Zachary A. Frosch, Marcus Messmer, Asya Varshavsky Yanovsky, Rashmi Khanal, Carlyn Tan, Eli Mikkelsen, Henry Fung, Eric Ross, Mark Roschewski, Allison Jacob, Nadia Khan. Circulating tumor DNA and nivolumab maintenance: A pilot study in diffuse large B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT245.

Circulating-tumor DNA Assessment in Diffuse Large B-cell Lymphoma to Determine Up-front Stem Cell Transplantation: A Pilot Study.

This study evaluated the possibility of clinical use of circulating-tumor DNA (ctDNA) as a biomarker to determine up-front autologous stem cell transplantation (auto-SCT) for patients with high-risk diffuse large B-cell lymphoma (DLBCL) in practice. To explore the dynamics of ctDNA in DLBCL, blood samples were collected sequentially before and after treatment from patients with newly diagnosed DLBCL who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. To conduct ctDNA genotyping and ctDNA monitoring simultaneously, targeted sequencing by cancer personalized profiling using deep sequencing was used. Ten patients between the ages of 50 and 60 years were enrolled. Based on the international prognostic index (IPI), seven patients were classified as high-IPI-risk group, and three patients were classified as low-IPI-risk group. The IPI risk group correlated with total metabolic tumor volume. All patients completed six cycles of R-CHOP chemotherapy, and seven patients achieved complete response. Changes in ctDNA mutation numbers did not correlate with changes in PET scan images and treatment response. In most high-risk patients, new mutations appeared in ctDNA after completion of chemotherapy that conceivably marked resistant clones. Notably, disease relapse did not occur in high-risk patients with poor prognostic mutations who underwent autologous SCT. ctDNA monitoring was meaningful in high-risk patients. Moreover, ctDNA and well-known prognostic factors should be considered in the decision making for auto-SCT. If a new genetic mutation in ctDNA with a negative prognosis would emerge during treatment, high-risk patients should consider auto-SCT.

Second-Line Chimeric Antigen Receptor T-Cell Therapy in Diffuse Large B-Cell Lymphoma : A Cost-Effectiveness Analysis.

First-line treatment of diffuse large B-cell lymphoma (DLBCL) achieves durable remission in approximately 60% of patients. In relapsed or refractory disease, only about 20% achieve durable remission with salvage chemoimmunotherapy and consolidative autologous stem cell transplantation (ASCT). The ZUMA-7 (axicabtagene ciloleucel [axi-cel]) and TRANSFORM (lisocabtagene maraleucel [liso-cel]) trials demonstrated superior event-free survival (and, in ZUMA-7, overall survival) in primary-refractory or early-relapsed (high-risk) DLBCL with chimeric antigen receptor T-cell therapy (CAR-T) compared with salvage chemoimmunotherapy and consolidative ASCT; however, list prices for CAR-T exceed $400 000 per infusion. To determine the cost-effectiveness of second-line CAR-T versus salvage chemoimmunotherapy and consolidative ASCT. State-transition microsimulation model. ZUMA-7, TRANSFORM, other trials, and observational data. "High-risk" patients with DLBCL. Lifetime. Health care sector. Axi-cel or liso-cel versus ASCT. Incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (iNMB) in 2022 U.S. dollars per quality-adjusted life-year (QALY) for a willingness-to-pay (WTP) threshold of $200 000 per QALY. The increase in median overall survival was 4 months for axi-cel and 1 month for liso-cel. For axi-cel, the ICER was $684 225 per QALY and the iNMB was -$107 642. For liso-cel, the ICER was $1 171 909 per QALY and the iNMB was -$102 477. To be cost-effective with a WTP of $200 000, the cost of CAR-T would have to be reduced to $321 123 for axi-cel and $313 730 for liso-cel. Implementation in high-risk patients would increase U.S. health care spending by approximately $6.8 billion over a 5-year period. Differences in preinfusion bridging therapies precluded cross-trial comparisons. Neither second-line axi-cel nor liso-cel was cost-effective at a WTP of $200 000 per QALY. Clinical outcomes improved incrementally, but costs of CAR-T must be lowered substantially to enable cost-effectiveness. No research-specific funding.

Phase II Clinical Trial of R-CHOP Combined with Lenalidomide in the First-Line Treatment for Patients with High Risk Diffuse Large B Cell Lymphoma

Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (NHL). Currently, R-CHOP (Rituximab-Cyclophosphamide, Epirubicin, Vincristine and Prednisone) is world-widely used in the first-line treatment for DLBCL, producing a long-term survival rate of approximately 60%. The unmet need is focused on high-risk DLBCL patients, having high International Prognostic Index (IPI) scores, non-germinal center-like B cell (non-GCB) origin, double expression of MYC and BCL2 protein, or TP53 aberrations. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of DLBCL by increasing interferon-stimulated gene transcription and activation of immunomodulatory mechanisms. At present, it has been approved for the treatment of multiple myeloma with good efficacy and safety. This is a prospective single arm, multi-center, phase II clinical trial and the goal of our trial is to assess the efficacy and safety of R-CHOP combined with lenalidomide in the first-line treatment for patients with high risk diffuse large B cell lymphoma. Methods: We did an investigator-initiated, open-label, phase 2 trial at the Affiliated Cancer Hospital of Zhengzhou University in China. Patients were eligible if they were aged over 18 years, had histologically confirmed DLBCL. The key inclusion criteria included untreated and medium to high /high risk DLBCL (International Prognostic Index (IPI) score 3-5, aaIPI score 2-3 or NCCN-IPI score≥ 4/ Immunohistochemical staining of double expression (BCL2 ≥ 50% and C-MYC ≥ 40%) or P53 protein mutation positive ≥ 50%). Participants in RL-CHOP cohort were given Lenalidomide orally 25 mg per day on days 1 through 10 of each cycle and delivered concomitantly with standard dose R-CHOP-21 chemotherapy. We also set another group treated with conventional R-CHOP-21 used as a matched contemporary cohort. The primary clinical endpoint was 2-year progression-free survival (PFS). The secondary efficacy endpoints were objective response rate (ORR), 2-year overall survival (OS) and safety. This trial is registered with ClinicalTrials.gov, number NCT04214626. Results: Between December 2019 and January 2023, 63 patients with untreated DLBCL enrolled and were evaluable in the investigator-initiated phase II study. The median age was 59 years (range: 25-76 years); 49.2% of patients were older than age 60 years. 46 of 63 patients (73.02%) had a ECOG score of 0-1; 43 of 63 patients (68.25%) had stage III-IV disease, and 33 of 63 patients (52.38%) had ≥2 extranodal localizations. The IPI score was high-intermediate and high in 73.02% (46/63) of patients. 51 of 63 patients (80.95%) were non-GCB subtype; 25 of 63 patients (39.68%) were double expressor. The TP53 protein was positive in 34.55% (19/55) of patients. In RL-CHOP cohort, the complete response rate was 80.95%, with overall response rate achieving 100%. The median follow-up time was 18.25 (3.73-42) months, median PFS and OS were not reached, and 2-year PFS and OS was 71.1% (+-6.7) and 87.4% (+-4.5), respectively. Comparing with historical matched contemporary cohort, the 2-year PFS and OS rates were improved for medium to high /high risk DLBCL. The most common adverse events of treatment were hematologic toxicities. Grade 3/4 AEs occurred in ≥20% patients were neutropenia, leukopenia, anemia, thrombocytopenia and decreased serum potassium, without bleeding complications. No grade 4 non-hematological adverse event was reported. Conclusion: RL-CHOP is effective and safe in patients with newly diagnosed DLBCL with high risk. Relevance of molecular biomarkers on RL-CHOP response warrants further investigation in DLBCL.

A Phase Ib Study to Evaluate the Safety and Efficacy of Nivolumab in Combination with R-CHOP in High-Risk DLBCL

Introduction Chemoimmunotherapy with R-CHOP is an established standard of care for diffuse large B-cell lymphoma (DLBCL) but is not curative in all patients (pts). Approximately 20% of DLBCL have aberrations involving the PD-L1/PD-L2 locus. This justifies the investigation of PD-1 checkpoint inhibitors in pts with DLBCL. This Phase 1b study was conducted to determine the maximum tolerated dose (MTD) for nivolumab in combination with R-CHOP in pts with DLBCL and to evaluate the preliminary efficacy of the regimen. Methods Patients with newly diagnosed de novo DLBCL or transformed low-grade lymphoma (tLL) were enrolled from 2019-2022. Treatment comprised a lead-in phase (LIP) with nivolumab 240 mg x 1 followed 2 weeks later by combination nivolumab-R-CHOP given every 3 weeks for 6 cycles. For combination therapy, nivolumab was administered on Day 1 followed by R-CHOP on Days 1-5 (Days 2-6 for Cycle 1). To establish MTD with Phase 1, nivolumab dosing followed a modified 3+3 dose escalation, starting with 1 mg/kg (dose level 1), escalating to 240 mg (dose level 2). MTD was administered for the Phase Ib portion of the study. Primary endpoints were determination of MTD and rate of complete metabolic response (CMR) by PET/CT using Lugano 2014 as best response by completion of 6 cycles of combination therapy (EOT). Correlations of immune subsets with durability of response and toxicity were exploratory. Results Thirty-three patients were enrolled, of which 25 and 22 pts were evaluable for toxicity and efficacy, respectively. The majority were men (n=21, 64%), White (n=26, 79%) with ECOG performance status of 0-1 (n=30, 91%). Twenty-seven (82%) had advanced stage and/or intermediate/high risk IPI score and 20 (65%) had germinal center subtype. Fifteen (45%) and 16 (48.5%) had tLL (2 with prior therapy for LL prior to transformation) and MYC aberrancy (13 with gains; 2 with single-hit and 1 with double-hit rearrangements), respectively. A dose of 240 mg of nivolumab was established as MTD. Twenty of 22 (91%) achieved CMR and 2 partial metabolic response (PMR) by EOT with overall response in 100%. One pt died from COVID-19 after 4 cycles but was in CMR on interim imaging. With median follow-up of 12 months (mo), 4 pts had progression. Both pts with PMR by EOT have not relapsed. Estimated 18-mo OS & PFS were 95.4% & 71.6%, respectively. Correlation of PFS with PD-L1 expression is underway. Most common therapy-related adverse events (TRAEs) attributed to nivolumab-R-CHOP were fatigue in 22 (88%), HTN in 21 (84%), lymphopenia in 21 (84%), and neutropenia in 18 (72%). High-grade (grade 3/4) neutropenia occurred in 15 (60%) with growth factor use per discretion of treating physician. Fifteen (60%) pts had infections, 47% high-grade. Immunotoxicities (IT) were the most common TRAEs attributed to nivolumab in 18 pts (72%), including thyroiditis (n=5, 20%), dermatitis (n=4, 16%), hepatitis (n=3, 12%), and infusion reactions (n=3, 12%). Most common high-grade IT: 1 case each of colitis, hepatitis, myocarditis (discontinued nivolumab), and dermatitis (discontinued nivolumab). For biologic correlates (Figures 1 & 2): non-progressors (NP) were enriched for T regulatory cell (e.g., IFN-γ producing CD4+Foxp3+ phenotype) fragility while progressors (PD) were enriched for exhausted T cell immunophenotype (CD4+PD-1+CD39+) prior to both LIP and initiation of combination therapy (C1D1). Furthermore, exhausted-like T cell levels were significantly reduced at C1D1 in comparison to LIP in NP but not PD. Toxicities correlated to less exhausted-like effector T cell phenotype, decreased CD4+ naïve and central memory T cells, and increased circulating B cells and myeloid-derived suppressor cells. Conclusions This study demonstrates promising efficacy of frontline combination nivolumab-R-CHOP for high-risk DLBCL including pts with intermediate/high risk IPI, tLL, and MYC aberrancy. While limited by small sample size, this regimen resulted in response, PFS, and OS rates above historical rates reported in high-risk pts and provides basis for further evaluation of nivolumab-based therapies in such pts. We found correlations between progression, toxicity and specific immune subset populations. Attention to these biologic correlates as predictors of durable response and toxicity may allow for better patient selection to optimize benefits of therapeutic effect and risks of increased toxicity with nivolumab-based therapies in DLBCL.

Phase II, Single-Center, Prospective Study of Intrathecal Thiotepa for the Prophylaxis of Secondary Central Nervous System Involvement in Highly Aggressive B-Cell Lymphoma

Background Central nervous system (CNS) recurrence of systemic diffuse large B cell lymphoma (DLBCL) is a well-recognized and almost uniformly fatal complication that tends to occur within 2 years of initiating treatment. The probability of CNS relapse in DLBCL ranges from 4 to 7% overall but is increased to 20% in certain subgroups. Evidence supporting the use of intravenous methotrexate (MTX) or arabinoside (AraC) in high-risk patients is growing, however, the use of other agents remains to be defined. Thiotepa (TT) is a polyfunctional alkylating agent first developed in the 1950s. Both thiotepa and its metabolite tepa demonstrate good CNS bioavailability, making thiotepa a useful adjunctive chemotherapy for primary and secondary CNS lymphoma, particularly in the context of hematopoietic stem cell transplant (HSCT). Herein, we conduct this prospective trial to evaluate the efficacy and safety of prophylactic intrathecal thiotepa for the prevention of secondary CNS involvement in patients with DLBCL. Methods Patients The primary end point is 2-year cumulative incidence of CNS. The secondary end points are 2-year progression free survival (PFS), 2-year overall survival (OS), and safety. The main inclusion criteria include: adults patients ≥18 years old; histopathological confirmed DLBCL without previous antitumor therapy; high-risk CNS involvement (one of the following): primary breast or testicular lymphoma, involvement of any of the following organs: testis, breast, kidney, adrenal gland, paranasal sinus, epidural space or uterus; CNS International Prognostic Index (CNS-IPI)≥4; dual protein expression (DE) or double/triple hit (DH/TH) lymphoma. The main exclusion criteria include: Burkitt lymphoma, primary CNS lymphoma, or large B cell lymphoma transformed from indolent lymphoma; the presence of parenchymal or meningeal lymphoma; history of whole brain radiotherapy or craniospinal cord irradiation; obstructive hydrocephalus patients requiring neurosurgical intervention. Treatment protocol The systemic chemotherapy regimen is determined by investigator. All patients are need to receive IT thiotepa 10 mg and dexamethasone 5 mg on day 1 of each cycle of chemotherapy for at least 4 cycles. All patients are asked to lie flat for 4 to 6 hours after the lumbar puncture. Follow-up Routine biochemical and cytological analysis of cerebrospinal fluid is performed for each cycle. Imaging examination, such as brain magnetic resonance imaging (MRI) and body computed tomography (CT), is repeated every 2 cycles of chemotherapy, then every 3 months during follow-up. Results From February 2022 to June, 2023, 27 patients (female 14, male 13) received IT thiotepa. The clinical characteristics are shown in Table 1. The median age was 66 years old (range: 46-74). As first-line chemotherapy, 15 (55.6%) patients received rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (RCHOP), 5 (18.5%) patients received RCHOP+BTK inhibitor, 3 (11.1%) patients received BTK inhibitor, lenalidomide with rituximab (ZR2) followed by RCHOP, and 4 (14.8%) patients received RCHOP with intravenous MTX. Thirteen (48.1%) patients had IPI score 4-6 and 17 (63%) patients had DE of c-myc and bcl-2. All patients received fluorescence in situ hybridization (FISH) cytogenetic testing for C-MYC, BCL-2, BCL-6 and TP53. Four (14.8%) patients had TP53 deletion, and 11 (40.7%) patients had sole rearrangement of C-MYC or BCL-2 or BCL-6, but no one were diagnosed with DH/TH lymphoma. All patient have received IT thiotepa for at least once, and 12 (44.4%) patients completed 4-6 cycles of IT, 84 cycles totally. IT thiotepa was a safe measure, for no one experienced post-LP headache, local infection, bleeding, or cerebral herniation. But there were 4 patients had five times of inability to identify direction and slow speech response. They could recover normally the next day without any treatment. Although the follow-up period was short, no patient developed CNS involvement. Conclusion Prophylactic intrathecal thiotepa is an effective and side-effects manageable measure for preventing secondary central nervous system involvement in high-risk DLBCL. Longer follow-up and larger-scale prospective trial is needed to testify this measure.

Epcoritamab SC + R-Mini-CHOP Leads to High Complete Metabolic Response Rates in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma Ineligible for Full-Dose R-CHOP: First Disclosure from Arm 8 of the Epcore NHL-2 Trial

Background: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a standard of care for previously untreated (1L) diffuse large B-cell lymphoma (DLBCL); however, some patients are not candidates for full-dose R-CHOP due to advanced age, frailty, or underlying comorbidities. For these patients, various attenuated treatment regimens have been evaluated, with low-dose R-CHOP (R-mini-CHOP) being widely adopted as a standard 1L regimen. However, outcomes are suboptimal, with overall response rates (ORRs) and complete metabolic response (CMR) rates around 70% and 40-60%, respectively, and a 2-y progression-free survival rate of only 47%, leaving substantial room for improvement. Epcoritamab, a subcutaneous (SC) CD3xCD20 bispecific antibody, was approved by the US FDA for the treatment of adults with relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic therapy. In the 1L setting in patients with high-risk DLBCL, epcoritamab SC with full-dose R-CHOP had a favorable safety profile and showed promising efficacy, including an ORR of 100% (Falchi et al, ASCO 2023). Here we report initial data from arm 8 of the EPCORE™ NHL-2 study (NCT04663347; phase 1/2) evaluating epcoritamab SC + R-mini-CHOP in 1L DLBCL. Methods: Adults with 1L CD20 + DLBCL who were not considered candidates for full-dose R-CHOP due to age ≥75 y or age ≥65 y with comorbidities (reduced left ventricular ejection fraction, history of myocardial infarction [>6 mo prior to enrollment], exertional chest pain, arrhythmia [grade ≤2], hypertension requiring treatment, or diabetes) were enrolled. Patients received epcoritamab SC (QW, cycles 1-2 [21 d each]; Q3W, cycles 3-6 [21 d each]; Q4W, cycles 7-8 [28 d each]) with R-mini-CHOP in cycles 1-6 (Q3W). A safety run-in was conducted to confirm acceptability of the safety profile. The primary endpoint of arm 8 was ORR as assessed by PET-CT per Lugano criteria. Results: As of April 24, 2023, 28 patients had received epcoritamab SC 48 mg + R-mini-CHOP. The median age was 81 y, 14 patients (50%) had IPI 3-5, 10 patients (36%) had bulky disease (>6 cm), and 15 patients (54%) had stage IV disease. At the data cutoff, median follow-up was 6.2 mo (range, 2.5+ to 11.7), with 9 patients (32%) having completed treatment and 15 patients (54%) still on treatment. R-mini-CHOP median relative dose intensity was ≥94%. There were no dose-limiting toxicities. The most common treatment-emergent AEs (TEAEs) of any grade were cytokine release syndrome (CRS; 43%), neutropenia (32%), fatigue (25%), anemia (21%), constipation (21%), and hypokalemia (21%). TEAEs decreased over time; 3 patients (11%) discontinued epcoritamab SC due to TEAEs. One grade 5 TEAE (cytomegalovirus infection reactivation) was recorded. CRS events were primarily low grade (grade 1-2: 39%, grade 3: 4%, grade ≥4: 0%), timing was predictable, and a majority of events were observed after the first full dose (cycle 1, day 15); all events resolved, with a median time to resolution of 3 d (range, 1-7). No ICANS events were reported. All 20 efficacy-evaluable patients had a response (ORR, 100%), with 17 patients (85%) achieving CMR. Median time to response was 1.4 mo ( Figure). At both month 6 and month 9, most patients who achieved CMR remained in CMR, suggesting durability of response. The study is ongoing and updated results will be presented. Conclusions: Epcoritamab SC + R-mini-CHOP showed encouraging efficacy with high response rates in patients with 1L DLBCL who cannot tolerate full-dose R-CHOP, including elderly, frail, and high-risk patients. There were no new safety signals, and findings were consistent with previously reported data, supporting the feasibility of the combination. These results warrant further investigation of epcoritamab-based therapies in 1L DLBCL.

Molecular Monitoring with Tumor DNA and Nivolumab Maintenance: A Pilot Study in Diffuse Large B-Cell Lymphoma

Introduction Molecular minimal residual disease (MRD) has been shown to correlate with disease relapse in patients (pts) with Diffuse Large B cell Lymphoma (DLBCL)[1-4]. However, the clinical impact of detectable MRD (dMRD) prior to clinical relapse is unknown. Checkpoint inhibitor (CPI) therapy has some activity in certain pts with DLBCL, particularly after CAR-T therapy attributed to effects on T cell activity [5-8]. We hypothesized that early intervention with CPI may lower relapse rate in pts with molecular recurrence only. Patients were monitored for detectable MRD (dMRD) by circulating tumor DNA (ctDNA) using the clonoSEQ assay monthly. We conducted a pilot study in high risk pts in remission after most recent line of therapy (LOT) in which maintenance nivolumab (MN) was offered at time of dMRD to assess effect on MRD clearance and relapse rate. Methods Pts >18 years with high-risk DLBCL (ABC-subtype, high grade B cell lymphoma (HGBCL), MYC translocation, relapsed/refractory disease, or Ki67 >90%) who had achieved CR on most recent LOT. Pts had monthly MRD and every 4 month CT or PET/CT and exam for 2 years. If conversion to dMRD without clinical relapse, pts received MN (240 mg IV q2 weeks) until clinical relapse or toxicity for up to 2 years (26 cycles). Pts with overt relapse at time of dMRD were ineligible for MN and taken off trial. The primary endpoint was rate of conversion from +MRD to undetectable MRD (uMRD) in pts receiving . Results 20 pts were screened and 15 pts were enrolled between June 2018 and March 2022. 5 pts had non-GCB subtype, 2 had GCB subtype, and two had unknown cell of origin. 4 had transformed DLBCL (2 from FL, 1 from MZL, and 1 Richter's), 2 pts had HGBCL (one of which was also transformed). Of the 8 pts who enrolled after 1 prior LOT, none had molecular or clinical relapse (Figure). In 7 pts who enrolled after 2+ prior LOT, 3 had dMRD. 2/3 had clinical relapse at same time as dMRD and were taken off study– one at initial enrollment with dMRD at first ctDNA screening and one converting from uMRD to dMRD after 135 days post enrollment. In the single patient who was eligible for MN, dMRD preceded radiographic relapse by 105 days, 410 days after enrollment. The pt went on to receive 2 cycles of MN before clinical progression and was taken off study. This pt failed to achieve conversion of dMRD to uMRD. Conclusions Due to small sample size and lower than expected relapse rates, we were unable to demonstrate conversion of dMRD to uMRD using MN. Of the 3 pts with dMRD, 2 were not eligible for MN due to clinical relapse at same time as dMRD and both died due to lymphoma progression. In the single pt who received MN, this intervention did not achieve uMRD or prevent relapse. However, this pt went on to achieve CR to subsequent CAR-T and remains in prolonged remission despite multiple relapsed/refractory disease. It is unknown if this patient's positive outcome was impacted by the effect of nivolumab on T cells and/or related to slower disease kinetics as this pt had a 3 month period between dMRD and radiographic detection and long duration of response to prior lines. A larger study is needed to adequately assess impact of early intervention MN using MRD kinetics, particularly in patients receiving CAR-T. All pts with dMRD had radiographic relapse within 4 months of molecular relapse. No pts with uMRD by ctDNA had clinical relapse on study during 2 year follow up, confirming uMRD correlates with disease free survival. If a strong negative predictive value is confirmed in a larger study, ctDNA MRD testing may be used to spare pts from imaging or to guide additional work up in pts with inconclusive findings on scans.

Retrospective Analysis of Clinical Outcomes of Utilizing R-CHOP Plus Zanubrutinib for High-Risk Diffuse Large B Cell Lymphoma Patients with Extranodal Involvement or MYC/BCL2 Double Expression

Background: Diffuse large B-cell lymphoma (DLBCL) patients with extranodal involvement and double expression of MYC and BCL2 often have a poorer prognosis when treated with the standard first-line R-CHOP regimen. The 5-year progression-free survival (PFS) and overall survival (OS) rates are both below 40% for these high-risk DLBCL cases. In this study, we perform a retrospective analysis of the clinical outcomes and adverse events of the high-risk DLBCL patients with extranodal involvement and double expression, who were admitted to our center and used Bruton's tyrosine kinase inhibitor (BTKi) zanubrutinib on the basis of R-CHOP regimen. Methods: We conducted a retrospective analysis of 26 DLBCL patients with extranodal involvement or MYC/BCL2 double expression who were admitted to our center and used R-CHOP regimen in combination with zanubrutinib between 1 st January 2021 and 30 th April 2023 (Figure A). Of these patients, 19 had extranodal involvement, and 7 were identified as double expression cases. The patients had a median age of 70 years, ranging from 34 to 87. Among them, 20 cases (77%) were aged over 60, and 8 cases (30%) were aged over 75. Moreover, 20 cases (76.9%) exhibited an Eastern Cooperative Oncology Group (ECOG) performance status score higher than 2 points. All the patients received an induction regimen consisting of zanubrutinib in combination with R-CHOP for a total of 4 cycles. After the fourth cycle, treatment efficacy was assessed using 18FDG-PET/CT scans. Patients achieving partial response (PR) or better continued with rituximab in combination with zanubrutinib for consolidation maintenance therapy, lasting for 1 year. For patients at risk of central nervous system involvement, oral administration of zanubrutinib continued for 2 years. During the treatment period, imaging evaluations were performed every 3 months to assess treatment response (Figure B). Results: After the induction therapy, a mid-term PET/CT evaluation showed that all patients achieved PR or above, resulting in an overall response rate (ORR) of 100%. Among them, 19 patients (73.1%) achieved complete response (CR), while 7 patients (26.9%) achieved PR. During the consolidation and maintenance therapy, 7 patients who were initially in PR converted to CR. As of the latest follow-up, with a median follow-up duration of 11 months (ranging from 4.1 to 30.0 months), 2 patients (7.7%) were lost to follow-up, and 2 patients (7.7%) experienced disease progression. The median PFS and OS were not reached. The 2-year PFS was 69.7±13.4% (Figure C), and the 2-year OS was 77.4±12.2% (Figure D). Non-hematological adverse events included fatigue (38.5%), hypertension (15.38%), neurological symptoms (7.7%), and infections (100%). Among the infections, 3 cases (11.5%) were of >3-grade and led to treatment discontinuation. Additionally, one patient experienced immune encephalitis and went into a coma. Hematological adverse events included granulocytopenia (55%), anemia (26%), thrombocytopenia (42.3%), and bleeding (38.5%). Among them, >3-grade granulocytopenia occurred in 4.5% of the patients. Five patients who were on long-term anticoagulant therapy due to concurrent cardiovascular diseases experienced a reduction in zanubrutinib dosage during the follow-up period, resulting in an improvement in bleeding symptoms. Conclusions: The combination of 4 cycles of R-CHOP regimen with zanubrutinib in the induction treatment of DLBCL patients with high-risk factors, such as extranodal involvement or MYC/BCL2 double expression, has shown promising clinical outcomes especially in older or unfit/frail patients. This approach allows for a reduction in the number of cytotoxic drug cycles, thereby improving the patients' tolerance to the treatment. Moreover, the efficacy of this regimen is superior to the traditional 6-8 cycles of R-CHOP induction therapy. Furthermore, the consolidation and maintenance therapy with rituximab in combination with zanubrutinib has demonstrated good safety and manageable adverse effects. This approach exhibits hope for further enhancing the prognosis of high-risk DLBCL patients.

CNS Prophylaxis in Diffuse Large B-Cell Lymphoma: A Common Toxic Clinical Practice Based on Abundant Opinion, Despite Evidence Suggesting Futility

Introduction: The history of medicine is replete with clinical practices, some clearly dangerous that have not been supported by what we would now consider to be mandatory data. Likewise, the field of hematology has not been immune from such practices as, for example, routine laparotomy and splenectomy in Hodgkin disease. Despite such history, and a push for evidence-based medicine, contemporary patient care still includes practices that have mainstream support despite a dearth of supporting evidence. CNS prophylaxis for diffuse large B-cell lymphoma(DLBCL) is one glaring example. Current Practice: In patients with high CNS-IPI score (≥4), multiple extra-nodal (EN) sites (≥3) and high-risk extra-nodal site, brain imaging is obtained (usually MRI) and cerebro-spinal fluid (CSF) is analyzed. If CNS involvement at diagnosis is ruled out, systemic chemotherapy followed by high-dose methotrexate (HD-MTX) is typically offered to fit patients. Intra-thecal (IT) therapy or no prophylaxis is the usual practice for unfit patients. These therapies, modelled on the CNS prophylaxis in adults with acute lymphoblastic leukemia (ALL), are not free of side effects and include mucositis, myelosuppression, hepatic, renal, neurological, and gastro-intestinal toxicities. Expert Opinion: Multiple national guidelines support the use of CNS prophylaxis for high-risk DLBCL. For example, the updated NCCN guidelines state that “CNS prophylaxis should be considered for patients with risk factors for CNS disease, but the optimal method is controversial”( NCCN Guidelines®, B cell lymphomas, version 5.2023). The British Society of Haematology recommend HD MTX administration for “high risk patients that are considered fit for such treatment”(McKay et al. British Journal of Haematology 2020). The European Society for Medical Oncology (ESMO) states that “HD-MTX is an option, even though the level of supporting evidence is low”(Tilly et al. Annals of Oncology 2015) ; the Canadian Lymphoma group recommends that ' Patients at high risk 'could consider' prophylaxis with high dose methotrexate“( Shafey et al. 2021) ; the Spanish Lymphoma Group recommends that 'CNS-directed prophylaxis should be offered to patients at high risk of CNS relapse'(Peñalver et al. Haematologica 2017). Similarly , multiple 'How I Treat' or guideline articles in top journals( Melchardt et al. ESMO Open 2023; Peñalver et al. Haematologica 2017; Bobillo et al. Haematologica 2023) support such use. Published data: There are no randomized controlled studies assessing CNS prophylaxis compared to none. There are, however, multiple reports in the past two decades of the use of some form of CNS prophylaxis. Without any controls, the value of such therapy is impossible to assess. At the same time, there are several comparative reports, based only on historic controls and compounded by heterogeneity of treatments and comorbidities, that suggested a benefit for CNS prophylaxis (Table 1). More recently, a large body of retrospective studies, with controls, were published (Table 2). These included a cohort that received HD-MTX versus those who did not receive HD-MTX or those who did not receive any CNS prophylaxis. In virtually all these reports there was no evidence of reduction in CNS relapse. Widespread use: Currently, the use of CNS prophylaxis is prevalent among fit and young patients with high-risk features ( Bobillo et al. Haematologica 2023; Demirci et al. Blood Research 2023). The concern for CNS relapse is the driving force behind this practice with a muted assurance that such may indeed prevent disease recurrence. Among older or unfit patients, CNS prophylaxis is most often withheld, with no evidence of a higher rate of CNS relapse ( Boehme et al. Blood, 2009; Eyre et al. Haematologica 2019). Conclusion: Relapse in the CNS after treatment of DLBCL has long been recognized as a serious clinical problem. It was assumed by many that, as in ALL, simple prophylaxis would be an effective remedy. This hope was never convincingly shown to be effective. Several phase II studies, with biased controls, suggested a benefit which, nevertheless, could not be confirmed in large retrospective controlled studies. Perhaps a different mold of CNS prophylaxis is needed, but the current approach appears marginally effective at best or unnecessarily harmful, at worst. Is it not time to step forward and resolve this issue, before it becomes religiously entrenched as standard of care?

Loncastuximab Tesirine Demonstrated Substantial Single-Agent Efficacy and Manageable Safety Profile in Heavily Pretreated Chinese Patients with Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Introduction: Patients with R/R DLBCL who failed multi-agent chemoimmunotherapies usually have a poor prognosis, leaving a significant unmet medical need. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate, composed of a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer toxin that showed clinical efficacy and manageable safety in heavily pretreated DLBCL patients in a global phase 2 study of Lonca monotherapy (NCT03075696). Here we present results from a phase 2 study (ChiCTR2300072058) of Lonca monotherapy in Chinese patients with R/R DLBCL for the first time, including analyses of responses in high-risk DLBCL subgroups. Methods: This open-label, single-arm, phase 2 study was designed to confirm the safety, efficacy and PK profiles of Lonca monotherapy in Chinese patients with R/R DLBCL who had failed ≥ 2 lines of systemic therapies. The primary endpoint was overall response rate (ORR) as assessed by IRC according to the Lugano 2014 criteria. Secondary efficacy endpoints include complete response rate (CRR), DOR, RFS, PFS, and OS. Treatment-emergent adverse events (TEAEs) were reported by CTCAE v4.0. Results: As of data cutoff (11-Jan-2023), 64 Chinese patients with DLBCL were enrolled and received at least one dose of Lonca (median: 4.0 cycles [range: 1-17]) and were evaluable for safety and efficacy analyses. The median number of prior lines of therapies was 3.0 (range: 2-12), with 67.2% of patients having ≥ 3 lines of prior therapies. Four patients (6.3%) had received prior CD19 CAR-T therapy. Forty-three patients (67.2%) were refractory to the first-line therapy (primary refractory), 56 patients (87.5%) were refractory to the most recent line of therapy and 40 patients (62.5%) were refractory to all prior lines of therapies. At data cutoff, the median follow-up was 8.5 months. The ORR by IRC was 51.6% (95% CI: 38.7% to 64.2%), and CRR was 23.4%. The median DOR (mDOR) was 6.37 months as assessed either by IRC or by investigator. For patients with a CR, the mDOR was 10.22 months (6.08 months for patients with PR). The median time to first response was 41.0 days. The median PFS and median OS were 4.96 and 9.33 months, respectively. Responses, including CRs, were observed in several high-risk subgroups (Fig. 1): ORR was 54.7% in patients with advanced stage disease (Stage III/IV) and 50.0% in patients with transformed disease. Patients who were refractory to first-line therapy, to the most recent therapy, or to all prior therapies had ORRs of 44.2%, 51.8% and 42.5%, respectively. Three patients who had received a prior SCT had an ORR of 100%. Lonca was also effective in elderly patients ≥ 65 years (ORR of 45.8%, mDOR of 6.37 months) and in patients who had received prior CD19 CAR-T therapy (ORR of 50%). Overall, 64 (100%) patients had at least one TEAE and 61 (95.3%) patients had at least one TEAE ≥ Grade 3. The most common (≥30%) all-grade TEAEs were GGT increased (71.9%), followed by anaemia (70.3%), platelet count decreased (65.6%), AST increased (64.1%), WBC count decreased (64.1%), neutrophil count decreased (60.9%), ALT increased (51.6%), hypokalaemia (37.5%), and blood ALP increased (32.8%). The most common (≥15%) TEAEs of Grade ≥3 were platelet count decreased (34.4%), neutrophil count decreased (28.1%), WBC count decreased (28.1%), GGT increased (25.0%), anaemia (18.8%), hypokalaemia (18.8%), neutropenia (17.2%), and lymphocyte count decreased (15.6%). The rate of febrile neutropenia was low (3.1%). The majority of Grade ≥ 3 TEAEs were abnormalities of clinical laboratory values as opposed to clinical symptoms and were generally reversible. Treatment-related TEAEs leading to treatment discontinuation occurred in 10 patients (15.6%), most commonly GGT increased (3 patients; 4.7%). No increase in toxicity was seen in patients aged ≥65 years compared with younger patients. Conclusions: Lonca demonstrated substantial and clinically meaningful single-agent efficacy and was well-tolerated in heavily pretreated Chinese patients with R/R DLBCL. Toxicities were generally manageable and reversible in most patients by routine clinical practice and/or with dose modifications, with neither unexpected safety concerns nor different toxicity profile in patients aged ≥65 years. Encouraging and durable responses were also observed in high-risk patient groups, including patients with advanced stage, transformed or refractory DLBCL.

Early Identification of Very High Risk Patients with Diffuse Large B Cell Lymphoma (DLBCL) By PET-CT

TITLE Early identification of very high risk patients with Diffuse Large B Cell Lymphoma (DLBCL) by PET-CT. INTRODUCTION Early identification of high risk DLBCL after the start of treatment continues to be a challenge that has not been fully resolved. The main aim of this study was to analyze the prognostic impact on progression free survival (PFS) of some PET-CT parameters at diagnosis (PET0) and after two cycles of first-line treatment (PET2). METHODS Patients diagnosed with DLBCL eligible for immunochemotherapy were prospectively included. A PET-CT was done at diagnosis, after two cycles of treatment and at the end of treatment. Metabolic tumoral volume (MTV), total lesion glycolysis (TLG) and maximum standardized uptake value (SUVmax) were the main initial parameters analyzed whereas Deauville score (Dv), the difference between PET0-PET2 SUVmax (deltaSUV) and MTV2 were the parameters analyzed after two cycles. The MTV was defined as the volume of hypermetabolic tissue with a SUV greater than a threshold value of 3 using volume viewer software (Lyfex). All PET/CT studies were performed at the same hospital and with the same equipment and analyzed by 3 Nuclear Medicine experts. The primary endpoint was PFS. RESULTS 153 patients diagnosed with DLBCL from 8 hospitals in Castilla y León were included. All of them received first line treatment with R-CHOP or similar immunochemotherapy regimens. Median age was 64 (24-86) years, and 51% were male; 70% had III-IV Ann-Arbor stage. The revised International Prognostic Index (R-IPI) distribution was low risk (0), 7,2%, intermediate risk (1-2), 51%, and high risk (3-5), 41,8%. Median MTV0 was 478,6 cm 3. ROC analysis identified as the optimal cut-off points 700 cm 3 for MTV0, 6430 cm 3 for TLG0, 25 for SUVmax and 1,85 cm 3 for MTV2. The cut-off of 66% was used for deltaSUV, as described in previous publications. Overall response rate (ORR) after treatment was 87,6% (71,2% complete response). With a median follow up of 39 months, estimated PFS at 3 years was 74,8%. In addition to R-IPI, all PET0 and PET2 parameters analyzed, with the exception of SUVmax at PET0, showed significant influence on PFS, as shown in table 1. In multivariate analysis, MTV0 and deltaSUV maintain independent influence. Based on these two factors, 3 groups with different PFS were obtained, as shown in figures 1 including a high-risk group (MTV0 >700 cm 3 and deltaSUV <66%) that comprised 24% of the series, with PFS at 3 years of 30,5%. CONCLUSIONS The combination of different PET parameters at diagnosis and after two cycles of treatment give us the possibility of identify, independently of IPI, a subgroup of patients with very poor PFS. It could serve as a basis for risk-adapted treatments, although further prospective studies with larger population are required in order to confirm our results.

Do the Control Cohorts of Phase III Randomized Trials Reflect the Real-World Results of DLBCL Patients?

Do the Control Cohorts of Phase III Randomized Trials Reflect the Real-World Results of DLBCL Patients?

The Efficacy and Safety of Decitabine Combined with Fludarabine and Cyclophosphamide As Conditioning Regimen in Second CD19 CAR-T Infusion

Background Chimeric antigen receptor (CAR) T therapy is widely accept for the first line treatment of refractory/relapsed diffuse large B cell lymphoma(DLBCL). However, insufficient remission and short duration of response are the barrier of current CART therapy. More and more patients meet the failure of CD19 CART therapy. Pre-CART condition treatment is an important factor in durable responses. Decitabine, the hypomethylating agent, has been found that it can reduce T cell exhaustion, enhance T cell cytotoxicity and overcome tumor immune escape in the tumor microenvironment. We initiated this study to evaluate the efficacy and safety of decitabine combined with fludarabine and cyclophosphamide as conditioning regimen in 2nd CD19 CART therapy. Methods Patients are enrolled in the clinical trail (NCT02537977), inclusion and exclusion criteria are described. Pre-CART conditioning regimen is decitabine 10mg/m2 D-7~-3, fludarabine 25mg/m2 D-5~-3 and cyclophosphamide 300mg/m2 D-5~-3. The dose of second CD19 CART infusion is 5*10^6/kg. Primary outcome is the safety and secondary outcome is the efficacy. Results 6 patients are enrolled in this trail and all patients are failure of CD19 CART. The media age is 57 year old and median line of treatment is 4. 4 patients(67%) are female. 5 patients(83%) have TP53 mutation/deletion and double expression, 4 patients(67%) have IPI ≥3.4 patients(67%) got complete remission(CR) after the first CD19 CART therapy and 2 patients(33%) got partial remission(PR). The median time of relapse/progression after first CD19 CART is 9 months. The objective response rate is 50%, 2 patients(33%) got CR and 1 patient(17%) got PR. With median 13 months followup, the 3 patients(50%) maintain remission more than 1 year and are still under follow up. 2 patients(33%) got stable disease for 3 months and undergo salvage therapy. 1 patient(17%) had no response in 1 month and died due to disease progression. Of all 6 patients, only 1 patient(17%) received 2nd CART infusion in 3 months after 1st infusion and had detecable CART cell in peripheral blood. 2 patients(33%) got grade 1-2 cytokines release syndrome(CRS). No sever CRS and Immune effector cell-associated neurotoxicity syndrome(ICANS) were observed. Grade 3-4 adverse events are hematologic toxicity. Conclusion Decitabine combined with fludarabine and cyclophosphamide maybe an alternative conditioning regimen in CD19 CART therapy in high risk DLBCL patients. More patients are needed for further study and the trail is undergoing.

Second-line treatment of diffuse large B‐cell lymphoma: Evolution of options

In the era of immunochemotherapy, approximately 60%-70% of diffuse large B-cell lymphoma (DLBCL) patients achieve remission with first-line rituximab-based chemoimmunotherapy. However, 30%-40% relapse after initial response to first-line therapy and, out of them, 20%-50% are refractory or experience early relapse. The second-line therapy algorithm for DLBCL has recently evolved, thanks to the recent approval of new therapeutic agents or their combinations. The new guidelines suggest a stratification of relapsed/refractory (R/R) DLBCL based on the time to relapse. For transplant-eligible patients, autologous stem cell transplant remains the preferred option when the patient relapses after 12 months from diagnosis, while anti-CD19 CART-cell therapy is the current preferred choice for high-risk DLBCL, defined as primary refractory or relapse ≤12 months. For transplant-ineligible or CAR T-cell therapy-ineligible patients, the therapeutic arsenal historically lacked effective options. However, new therapeutic options, including polatuzumab vedotin combined with bendamustine-rituximab and tafasitamab with lenalidomide, have been recently approved, and novel agents such as loncastuximab tesirine, selinexor, anti-CD19 CAR T-cell therapy, and bispecific antibodies have shown promising efficacy and manageable safety in this setting offering new hope to patients in this challenging scenario.

Genotyping on circulating tumor DNA improves mutation detection rate in high-risk diffuse large B-cell lymphoma

Genotyping on circulating tumor DNA improves mutation detection rate in high-risk diffuse large B-cell lymphoma

Identification of lactate regulation pattern on tumor immune infiltration, therapy response, and DNA methylation in diffuse large B-cell lymphoma.

Lactate, produced through glycolytic metabolism in the tumor microenvironment (TME), is implicated in tumorigenesis and progression in diverse cancers. However, the impact of lactate on the remodeling of the TME in diffuse large B-cell lymphoma (DLBCL) and its implications for therapy options remain unclear. A lactate-related (LAR) scoring model was constructed in DLBCL patients using bioinformatic methods. CIBERSORT, XCELL, and ssGSEA algorithms were used to determine the correlation between LAR score and immune cell infiltration. Tumor Immune Dysfunction and Exclusion (TIDE), rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) cohorts, and Genomics of Drug Sensitivity in Cancer (GDSC) were utilized to predict the therapeutic response of DLBCL patients. The impact of the hub gene STAT4 on tumor biological behavior and DNA methylation was experimentally validated or accessed by the TSIDE database. The LAR scoring model was developed based on 20 prognosis-related lactate genes, which enabled the division of DLBCL patients into high- and low-risk groups based on the median LAR score. Patients with high-risk DLBCL exhibited significantly worse survival outcomes in both the training cohorts (GSE181063) and the validation cohorts (GSE10846, GSE32918, and GSE69053), as indicated by statistically significant differences (all P<0.05) and area under the curve (AUC) values exceeding 0.6. Immune analyses revealed that low-risk DLBCL patients had higher levels of immune cell infiltration and antitumor immune activation compared to high-risk DLBCL patients. Furthermore, DLBCL patients with high LAR scores were associated with a lower TIDE value and poor therapeutic efficacy of the R-CHOP regimen. GDSC analysis identified 18 drugs that exhibited significant response sensitivity in low-risk DLBCL patients. Moreover, in vitro experiments demonstrated that overexpression of the lactate key gene STAT4 could suppress proliferation and migration, induce cell cycle arrest, and promote cell apoptosis in DLBCL cells. Transcriptional expression and methylation of the STAT4 gene were found to be associated with immunomodulators and chemokines. The lactate-based gene signature effectively predicts the prognosis and regulates TME in DLBCL. Our study underscores the role of lactate gene, STAT4, as an important tumor suppressor in DLBCL. Modulating STAT4 could be a promising strategy for DLBCL in clinical practice.

POSTER: ABCL-429 Epcoritamab + R-CHOP in Patients With Previously Untreated (1L) High-Risk Diffuse Large B-Cell Lymphoma, Including Double-Hit/Triple-Hit Lymphoma: Updated EPCORE NHL-2 Data

POSTER: ABCL-429 Epcoritamab + R-CHOP in Patients With Previously Untreated (1L) High-Risk Diffuse Large B-Cell Lymphoma, Including Double-Hit/Triple-Hit Lymphoma: Updated EPCORE NHL-2 Data