Citations

Abstract Twenty percent of patients with follicular lymphoma relapse early with poor outcomes; however, the molecular mechanisms underlying this aggressive behavior are unknown. Using a multiomic approach, we show that patients with follicular lymphoma with elevated IRF4 expression (IRF4hi) have increased transformation risk, dysregulated immune signaling, and a suppressive tumor microenvironment. Loss- and gain-of-function experiments in IRF4hi lymphoma cells, along with chromatin profiling, demonstrate that IRF4 impairs their interaction with T cells by repressing antigen presentation and co-receptor gene modules while promoting the expression of cytokines that antagonize T-follicular helper cell and regulatory T-cell functions. Additionally, IRF4 rewires tumor metabolism and restricts glucose availability to immune cells. Silencing of IRF4 inhibits tumor cell growth and restores immune surveillance mechanisms, thus representing a promising target for therapy. Our data suggest that IRF4hi lymphoma cells co-opt a developmental mechanism used to exit the germinal center response in promoting a more aggressive cancer via engagement of multiple immune-evasive mechanisms. Significance: We show that IRF4 controls immune and metabolic signaling with functional effects on the cross-talk between B and T cells, resulting in a suppressive immune microenvironment when IRF4 is overexpressed in lymphoma. This underscores the importance of IRF4 as a pivotal therapeutic target to restore antitumor immunosurveillance for IRF4-associated lymphomas.

7073 Background: The Optimized HLH Inflammatory (OHI) index (Zoref-Lorenz et al., Blood , 2022), based on serum soluble CD25 (sCD25) and ferritin, is a prognostic tool identifying inflammation in the hemophagocytic lymphohistiocytosis (HLH) spectrum and early mortality risk. Prior studies were retrospective and enriched with HLH-suspected cases. We hypothesized that the OHI index would predict outcomes in unselected diffuse large B-cell lymphoma (DLBCL). Methods: 670 newly diagnosed DLBCL patients from a prospective cohort (2002–2015) were analyzed: 335 for discovery and 335 for validation. Pre-treatment serum sCD25 and ferritin levels were quantified via ELISA, and we evaluated original thresholds (sCD25 ≥ 3,900 U/mL; ferritin ≥ 1,000 ng/mL) and developed DLBCL-optimized thresholds (using receiver operator curves) for predicting 500-day mortality. We also evaluated event-free survival (EFS), EFS at 24 months (EFS24), and overall survival (OS). Results: The median age was 64, and 51% were male. Using original thresholds, 4.2% (n=14) of patients were OHI+, with a 5.6-fold higher risk of 500-day mortality (95% CI 1.6–17; p<0.001). Optimized thresholds identified 23.6% (n=78) as OHI+ with a 9.2-fold higher 500-day mortality risk (95% CI 4.0–24; p<0.001). Optimized OHI+ also had a higher risk of EFS24 failure and inferior EFS and OS (Table). OHI+ patients had higher rates of B symptoms (35% vs. 20%; p=0.027), elevated LDH (76% vs. 34%; p<0.001), worse performance status (ECOG ≥2: 38% vs. 12%; p<0.001), and advanced-stage disease (Stage IV: 57% vs 38%; p<0.001), though IPI scores (3–5) were not significantly different (44% vs 36%; p=0.28). Adjusting for age and IPI, OHI+ independently predicted 500-day mortality (OR=5.0; CI 1.9–13; p=0.001), EFS24 failure (OR=3.2; CI 1.5–6.5; p=0.0018), and inferior long-term EFS (HR=2.2; CI 1.1–4.3; p=0.030) and OS (HR=2.0; CI 1.0–4.0; p=0.040) at a median follow up of 9.8 years in living patients. In validation, optimized OHI predicted 500-day mortality, EFS24 failure, and long-term OS and EFS (Table). Cytokine profiling revealed elevated inflammatory markers in OHI+ patients, including IL1a (p=0.008), CCL2 (p=0.03), CXCL10 (p<0.001), and CXCL9 (p<0.001), reflecting systemic hyperinflammation. Conclusions: The OHI index is a powerful predictor of early and long-term outcomes in DLBCL patients. Optimized thresholds identify a larger OHI+ group, highlighting hyperinflammation’s critical role in poor outcomes. These findings support its use in routine management and clinical trial design for novel therapies. Odds ratios or hazard ratios and p-values for optimized OHI+ and DLBCL prognosis. Outcome Discovery Validation OR for 500-day mortality 9.2; p<0.001 4.0; p=0.002 OR for EFS24 failure 5.2; p <0.001 6.3; p<0.001 HR for OS 2.3; p<0.001 1.8; p=0.006 HR for EFS 2.4; p<0.001 2.5; p<0.001

7052 Background: Secondary central nervous system lymphoma (SCNSL) is a rare but serious complication that occurs in 2-10% of patients (pts) with diffuse large B-cell lymphoma (DLBCL). The CNS-International Prognostic Index (CNS-IPI) is a validated tool used to assess the risk of CNS relapse. However, with advancements in molecular profiling and treatments, the predictors of SCNSL, including the predictive ability of CNS-IPI combined with other molecular markers and treatment regimens, have become uncertain. This study evaluates new prognostic markers for CNS relapse in DLBCL, focusing on cell-of-origin (COO), gene rearrangements, and treatment types. Methods: DLBCL pts enrolled from 2002-2015 in the Mayo Clinic and University of Iowa Lymphoma Molecular Epidemiology Resource were prospectively followed for incidence of CNS relapse. Pts with primary CNS lymphoma or CNS involvement at diagnosis, and pts treated with high-dose methotrexate containing regimens were excluded. COO classification (GCB vs non-GCB) was determined using Hans algorithm and/or NanoString data. Multivariate Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for predictors of SCNSL. Survival analysis was performed from time of DLBCL diagnosis using Cox proportional hazards model. Results: Among 1278 newly diagnosed DLBCL pts included (median age: 63 years; 43.6% female), SCNSL occurred in 46 (3.6%) pts. Pts with SCNSL were more likely to have intermediate/high CNS-IPI scores (80.4%) than pts without SCNSL (63.9%, p=0.02). The 3 yr SCNSL incidence was 0.016 (0.008-0.0033) in low CNS-IPI vs 0.043 (0.031-0.0060) in high CNS-IPI. Those with SCNSL were significantly more likely at baseline to have non-GCB COO (56.3% vs. 36.5%, p=0.02), and advanced stage (76.1% vs. 59.9%, p=0.03) compared to those without SCNSL. The incidence of SCNSL was not influenced by MYC, BCL2, or BCL6 rearrangements, nor by treatment with R-CHOP, R-EPOCH, or other immunochemotherapy regimens. MVA showed that intermediate CNS-IPI (HR 2.32, 95% CI 1.09-4.92, p=0.029), high CNS-IPI (HR 3.59, 95% CI 1.49-8.62, p=0.004), and non-GCB COO (HR 2.19, 95% CI 1.08-4.42, p=0.0029) were independently associated with increased SCNSL risk. After a median follow-up of 12 years (IQR 9–15), overall survival (OS) was 52.1% for the cohort, with OS significantly worse for SCNSL pts (17.4% vs. 53.4%, p<0.001). Conclusions: This large cohort with extensive follow-up highlights the role of COO as an additional prognostic factor for SCNSL while reinforcing CNS-IPI’s prognostic value. Non-GCB COO pts had a higher risk of SCNSL even when adjusted by CNS-IPI risk. Despite advancements in management, SCNSL pts continue to have poor outcomes. Strategies to reduce the incidence of CNS relapse in high-risk pts require further investigation. MER CNS relapse hazard ratios (95% CI). Characteristics Hazard Ratio 95% CI P-Value CNS-IPI Group 0-1 Low Ref Ref Ref 2-3 Intermediate 2.32 1.09 - 4.92 0.029 4+ High 3.59 1.49 - 8.62 0.004 Cell of Origin* GCB Ref Ref Ref non-GCB 2.19 1.08 - 4.42 0.029 Double Hit* non-DHL Ref Ref Ref DHL 1.08 0.14 - 8.3 0.941 Not Done/Missing 1.38 0.76 - 2.51 0.297 Double Expressor* Negative Ref Ref Ref Positive 2.36 0.71 - 7.85 0.162 Not Done/Missing 1.91 0.89 - 4.08 0.097 IC Group* R-CHOP R-EPOCH Ref 1.63 Ref 0.71 - 3.74 Ref 0.249 Other IC 1.18 0.57 - 2.46 0.660 Any EN Involvement* No Ref Ref Ref Yes 0.98 0.51 - 1.88 0.946 Albumin Group* >=Normal Ref Ref Ref <Normal 1.70 0.75 - 3.85 0.201 Head & Neck Involvement* No Ref Ref Ref Yes 0.35 0.048 - 2.63 0.310 *Adjusted by CNS-IPI risk group.