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3040 Background: EVEREST-2 is a first-in-human, phase 1/2 trial to assess the safety and efficacy of A2B694, an autologous, logic-gated Tmod CAR T therapy targeted to MSLN, which is normally expressed in the mesothelium and can be upregulated in many solid tumors. A2B694 is designed to overcome challenges of on-target, off-tumor toxicity that have limited other MSLN-targeted approaches by combining a CAR-activating receptor targeting MSLN with a blocker CAR that recognizes HLA-A*02, to distinguish between normal and tumor cells (Tokatlian, et al. J Immunother Cancer. 2022). Methods: Adults with recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression who have progressed after standard-of-care therapy are eligible for EVEREST-2. Enrollment to EVEREST-2 and collection of T-cells occurs through the ongoing prescreening study BASECAMP-1 (NCT04981119). When clinically appropriate, A2B694 is manufactured from cryopreserved T cells, and patients undergo lymphodepletion before A2B694 infusion. The dose-escalation phase is evaluating the safety and tolerability of A2B694 to identify the recommended phase 2 dose (RP2D). Dose escalation was started at 1x10 8 Tmod positive cells (dose level [DL] 1) and will increase up to 14x10 8 in combination with low-dose IL-2 (DL 5). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Results: As of January 15, 2025, 5 participants (median age: 60 years; range, 50-84) have enrolled on EVEREST-2 and received A2B694 at DLs 1-2; participants had ovarian cancer (n = 3), pancreatic cancer (n = 1), and non-small cell lung cancer (n = 1) and had received a median of 4 prior lines of therapy (range, 1-7). Lymphodepleting chemotherapy was well tolerated with no significant cytopenias observed. The most common adverse events were lymphopenia (7 [14.6%]) and decreased appetite (6 [12.5%]). There were no dose-limiting toxicities, cytokine release syndrome, nor related neurotoxicity. One participant was admitted to the hospital for decreased appetite. No long-term toxicities have been noted up to 7.5 months post-infusion. Of the participants who have received A2B694, 5 were efficacy evaluable at DLs 1-2. A2B694 was detected post-infusion in the peripheral blood in all patients. Additionally, A2B694 was detected in an abdominal tumor biopsy from a patient with pancreatic cancer 42 days post-infusion. Conclusions: The logic-gated approach was successful at reducing toxicity seen with prior MSLN-targeted CAR T therapies, and A2B694 showed successful CAR T expansion and tumor infiltration. The maximum tolerated dose has not been reached, and results from the dose-escalation phase continue to determine the RP2D. Clinical trial information: NCT06051695 .

3008 Background: Numerous studies have demonstrated the prognostic value of ctDNA analysis after neoadjuvant chemotherapy for early-stage high-risk breast cancer. Few studies have characterized ctDNA in pts receiving NET for early-stage hormone receptor positive (HR+)/HER2- BC that is predicted to benefit less from chemotherapy. Methods: Cell-free DNA (cfDNA) was isolated from 432 plasma samples from 108 pts enrolled in the I-SPY2 EOP trial. Pts had Stage 2/3 HR+/HER2-, MammaPrint low or high risk 1 BC. Pts were randomized to one of 7 neoadjuvant-based treatment arms including arms containing AI, Z-endoxifen, Lasofoxifene, vepdegestrant (ARV-471), and Abemaciclib. Pts were treated for 6 months prior to surgery. Blood was collected at baseline (T0), 3 weeks (T1), 12 weeks (T2), and 6 months (T3). A personalized ctDNA test (Signatera) was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The chi-square test was used to assess associations between categorical variables, and the Wilcoxon rank-sum test was used to evaluate differences in medians. Results: ctDNA information was available for 101 patients at baseline (T0) (Table 1). At T0, 36 (35.6%) patients were ctDNA-positive. 23/36 (63.9%) became ctDNA-negative and 13/36 (36.1%) remained ctDNA-positive. At T0, 65/101 patients (64.4%) were ctDNA-negative. Of these, 57 (87.7%) remained negative, while 8 (12.3%) became ctDNA-positive at T1 before reverting to ctDNA-negative. A higher percentage of ctDNA-positive patients at T0 were cN+ compared to ctDNA-negative pts (p = 0.036, 64% vs. 40%). Additionally, ctDNA-positivity at T0 was strongly associated with higher Ki67 (p = 0.03) and larger functional tumor volume by MRI at baseline (p = 0.03). T3/T4 and high-grade tumors at baseline were also associated with having ctDNA positivity at baseline, though this was not statistically significant (p = 0.34 and 0.058, respectively). Conclusions: In this study of pts with Stage 2/3 HR+ HER2- BC with largely MammaPrint low risk signatures, over one-third of pts had detectable ctDNA at baseline. Detectable ctDNA at baseline was associated with cN+ disease, larger FTV, and high baseline Ki67. The majority of pts with positive ctDNA at baseline cleared the ctDNA on NET. Clinical trial information: NCT01042379 . Clinicopathologic characteristics of EOP patients. All Patients(N=101) Age at screening 55 (27-80) years* Clinical N Stage Node+ (cN+) 49 (48.5%) Node- (cN-) 52 (51.5%) SET status High 84 (83.2%) Low 14 (13.9%) Missing 3 (2.97%) MammaPrint (MP) risk** High risk 1 (H1) 15 (14.9%) Low risk 86 (85.1%) *Mean(min-max). **H1: MP score between 0 and -0.57; low: MP score between 0 and 0.355.

e16408 Background: A2B530 is a logic-gated CEA-targeting Tmod CAR T therapy being evaluated in the EVEREST-1 (NCT05736731) phase 1/2 study. Tmod CAR T therapy addresses challenges of on-target, off-tumor toxicity that have limited application of CAR T therapy to solid tumors (Tabernero, et al. J Clin Oncol. 2017); through use of a CEA-targeted CAR-activating receptor combined with a blocking receptor recognizing HLA-A*02, A2B530 can distinguish between tumor and normal cells (Sandberg, et al. Sci Transl Med. 2022). Methods: Patients with unresectable locally advanced or metastatic solid tumors expressing CEA and tumor-associated HLA-A*02 LOH are enrolled through the ongoing prescreening study BASECAMP-1 (NCT04981119). Eligible patients undergo leukapheresis and, when clinically appropriate, A2B530 is manufactured for the EVEREST-1 study. Patients undergo lymphodepletion before A2B530 infusion. The phase 1 dose escalation will evaluate safety, tolerability, manufacturing feasibility, and biomarkers starting at 1x10 8 Tmod positive cells (dose level [DL] 1) up to 6x10 8 cells and higher doses of lymphodepleting chemotherapy (LDC; DL 5). After the recommended phase 2 dose has been established, dose expansion will confirm safety and activity. Results: As of January 15, 2025, 14 total participants were enrolled on EVEREST-1 and had received A2B530 infusion at DLs 1-5, 4 (29%) with pancreatic (PANC) and 10 (71%) with colorectal cancer. Median age was 57 years (range, 34-76), with a median of 2 prior lines of therapy (range, 1-6). LDC was well tolerated: neutropenia nadired at days 7-10, with recovery in all patients, and no significant episodes of prolonged cytopenia. There were no dose-limiting toxicities, grade > 3 serious adverse events (AEs), or episodes of related neurotoxicity. Most gastrointestinal AEs occurred early and were grade 1 or 2. One patient in DL 2 (2x10 8 cells) experienced possible grade 2 cytokine release syndrome (CRS), which started on day 15 and resolved with supportive therapy within 2 days; later the CRS diagnosis was confounded by a positive blood culture from the participant’s central line. The low rate of CRS is consistent with the low levels of serum cytokines measured up to 28 days post-infusion. Central response assessment has been completed for the 6 participants in DLs 1-2, with a partial response observed in 1 of 3 (33%) of participants with PANC. Peak expansion shows a possible dose response. Conclusions: Treatment with A2B530 was well tolerated, showing potential clinical efficacy and a potential dose response, although these are initial results. Maximum tolerated dose has not been reached, and dose escalation continues to determine the optimal phase 2 dosing of this treatment regimen. Clinical trial information: NCT05736731 .

4155 Background: The tumor microenvironment (TME) that surrounds pancreatic ductal adenocarcinoma (PDAC) is a multi-faceted and dynamic ecosystem in which stromal fibroblasts communicate with cancer cells to mediate tumor growth, metastasis, and chemotherapy resistance. It is well recognized that both cancer-associated fibroblasts (CAFs) and its non-cellular, fibrotic components within the TME can foster a protumorigenic environment for PDAC. However, we still lack a comprehensive understanding of the precise mechanisms in which this dense, fibrotic matrix can help drive malignant behaviors. Here, we reveal a novel mechanism in which the zinc-finger transcription factor GLI2 regulates type 1 collagen expression within CAFs and how the soluble variant of this collagen promotes irinotecan chemoresistance. Methods: We leveraged transcriptomic data from The Cancer Genome Atlas, International Cancer Genome Consortium, and Clinical Proteomic Tumor Analysis Consortium to evaluate GLI2 expression and stromal content of human PDAC tumors through bulk RNA-sequencing deconvolution. Using single-nucleus RNA sequencing of human PDAC tumors, we validated the association of GLI2 expression and stromal matrix constituents in CAFs. Chromatin immunoprecipitation assays in human CAFs confirmed GLI2 binding at the COL1A1 promoter. Through RNAi-based inactivation of GLI2, we determined how loss of GLI2 impacts regulation of type 1 collagen. Additionally, we conducted MTT assays to assess tumor viability in response to irinotecan treatment. Results: Transcriptomic analysis revealed that GLI2 is highly enriched in CAFs and strongly correlated with stromal fibrosis compared to other non-tumor cell constituents within the TME. We have shown that GLI2 directly binds to the promoter of COL1A1, a key component of type 1 collagen, in CAFs and regulates its transcription in a manner dependent on TGFβ1 signaling. Interestingly, PDAC tumors exposed to type 1 collagen show increased expression of pro-tumorigenic pathways involved in inflammation, EGR signaling, cytokine-receptor interactions, and irinotecan resistance. We further validate that human PDAC cells pre-treated with collagen can confer chemoresistance to irinotecan with viability assays. Conclusions: Taken together, our study demonstrates a novel mechanism in which GLI2 regulates the secretion of collagen within CAFs, which in turn can enable PDAC to acquire resistance to standard-of-care treatments. These findings highlight not only the oncogenic functions for CAFs and their fibrotic secretome, but also open new avenues in which therapeutic targeting of the TME may provide clinical benefit for PDAC patients.

12011 Background: Patients (pts) with high HCT-Comorbidity Index scores (HCT-CI of ≥3), older age (≥65 years), and/or who are frail per gait speed (<0.8 meters/second) have increased morbidity and mortality after allo-HCT compared to younger and healthier counterparts. We report the phase II analysis (PIIA) and interim phase III primary outcome analysis (PIIIA) of a seamless phase II/III prospective, randomized clinical trial conducted at 11 transplant centers to test new approaches to improve quality of life (QOL) in this population. Methods: Phase II compared specialist-administered supportive and palliative care (SPC), patient-administered management of comorbidities (MC, e.g. physical exercise, stress reduction, etc), both (SPC+MC), and usual care (UC) for change in Functional Assessment of Cancer Therapy – Bone Marrow Transplantation (FACT-BMT) QOL scores from baseline to day 90 (D90). Pts deceased prior to D90 were assigned FACT-BMT score=0. The winning phase II arm moved forward versus UC in phase III. Results: PIIA was done after enrolling 35 pts to each of the 4 study arms. Calculating the difference between FACT-BMT scores on D90 minus baseline, excluding missing data, indicated that only SPC resulted in a small improvement in QOL compared to either MC or SPC+MC (Table); hence SPC was the winning phase II arm. The PIIIA was conducted after enrolling 158 SPC pts and 153 UC pts. The SPC and UC arms were well balanced with median age (both 68 years), HCT-CI ≥3 (49% vs 55%), frailty per gait speed (13% vs 12%), female sex (41% vs 34%), non-white race (9.5% vs 11.5%), and Hispanic or unreported ethnicity (7.7% vs 5.7%), respectively. After median follow-up of 362 days, 45 pts had died in each arm. The mean QOL difference between D90 and baseline was 2.83 for SPC and 4.27 for UC (difference of differences, -1.44, 95% CI of difference, -5.03 to 2.14, p=0.43). Fitting a generalized linear model that included baseline, D30, and D90 values and testing the null hypothesis that the slope of scores differs between SPC and UC resulted in p=0.85. Using the Kaplan Meier method, no difference in survival was observed across arms (HR 1.13 [0.75-1.73]). Conclusions: Specialist-administered palliative care showed no meaningful improvement in QOL, nor a survival advantage, compared to usual care in frail, older and comorbid allo-HCT recipients, resulting in the cessation of this Phase II/III trial. Analysis of the whole patient population for primary and secondary outcomes is in progress. Clinical trial information: NCT03870750 . Change in FACT-BMT (D90 value minus baseline value) comparing the 4 arms of phase II. Group Mean difference (sd) Median difference (range) SPC (n=28) -2.93 (28.52) 0.25 (-102 to 38.22) CM (n=18) -18.37 (33.80) -9.50 (-98.33 to 11) SPC+CM (n=27) -15.76 (32.69) -7.67 (-90 to 32)

TPS4616 Background: Osseous metastases (OM) occur in approximately 30% patients with advanced RCC. Despite therapeutic advances, OM are associated with poor survival and risk of symptomatic skeletal events (SSEs). Cabozantinib targets multiple tyrosine kinases, including vascular endothelial growth factor (VEGF) receptors and MET (Mesenchymal-Epithelial Transition factor), which are overexpressed in OM, contributing to cabozantinib’s enhanced bone activity. Radium-223, an alpha-emitting bone-seeking radioisotope, prolongs survival in men with metastatic castration-resistant prostate cancer to the bone. Building on this therapeutic approach targeting OM, our pilot study of radium-223 with VEGF inhibition in RCC with OM has also shown safety, improvement in circulating bone turnover markers, and early efficacy (McKay et al, CCR 2018). To address the unmet need to improve SSE rates and outcomes in RCC and OM, we designed a study investigating cabozantinib with or without radium-223 in patients with RCC with OM (NCT04071223). Methods: This is an open-label, multicenter randomized phase-2 study. Key inclusion criteria include metastatic RCC of any histology with ≥1 OM, at least 1 OM without prior radiation, any number of prior therapies, and Karnofsky performance status ≥ 60%. Use of a bone protecting agent is required unless contraindicated. Patients are randomized 1:1 to cabozantinib with (Arm A) or without (Arm B) radium-223. The starting dose of cabozantinib for Arm A is 40 mg by mouth daily to be escalated to 60 mg daily after cycle 1 (1 cycle = 28 days) if no persistent grade 2 or grade ≥3 toxicity. Radium-223 is administered at a fixed dose of 1.49 microcurie/kg IV every 28 days x 6 doses. The starting dose for cabozantinib in Arm B is 60 mg daily. The primary endpoint is SSE-free survival. Secondary endpoints include safety, progression-free survival, overall survival, time to first SSE, objective response rate, time to subsequent anti-cancer therapies, quality of life (QoL) measures, and correlative analyses including liquid biopsy and tumor tissue analysis. The study is designed to have 85% power to detect an improvement in 6-month SSE-free survival rate from 65% to 78% with one-sided α = 0.05 significance. To ensure 124 evaluable patients, target accrual is 134 (67 per arm). The group-sequential design includes a safety run-in and an interim analysis for futility when 50% of the expected number of events have been observed. The safety run-in, performed in the first 12 patients randomized to combination therapy, did not demonstrate dose limiting toxicities. Final data analysis will occur when 99 events have been observed. The study was activated in July 2020 and accrual is ongoing throughout the National Clinical Trials Network (NCTN). Continued site participation and enrollment are essential to evaluate this therapeutic strategy. Clinical trial information: NCT04071223 .

9578 Background: Anti-PD1 immunotherapy has shown improved clinical outcomes in patients (pts) with advanced cSCC, and recently, in the neoadjuvant setting for resectable disease. Pathological (path) response is predictive of recurrence in melanoma and recent NeoIT trials suggests the same in cSCC; however, an analysis of clinical outcomes in pts with resectable cSCC treated with intended anti-PD1-based NeoIT in larger datasets remains unknown. Methods: Pts with resectable cSCC treated with intended anti-PD1-based NeoIT from 17 cancer centres globally were included. Baseline patient and disease characteristics, treatment regimen, path response and recurrence-free survival (RFS) or progression-free survival (PFS) were collected and examined. Results: 134 pts with resectable cSCC were treated with intended anti-PD1-based NeoIT. Median age was 75 years old (range, 39-97), 72% (n=97) were male. One fifth (22%, n=29) were immunocompromised and 43% (n=58) had ECOG PS of ≥1. Of 125 (93%) pts with known primary cSCC, 82% (n=102) were from the head & neck. Most pts (79%, n=106) were stage III/IV. The majority had anti-PD1 monotherapy (91%, n=122) and 9% (n=12) had anti-PD1+/-investigational agent. Median follow-up from commencement of NeoIT was 10 months (95% CI, 9 - 12). Nearly half of the pts (49%, n=66) underwent surgery; 37 (56%) pts had major pathological response (MPR; ≤10% viable tumour cells at the surgical specimen; 31 [47%] had complete path response [0% of viable tumour cells] and 6 [9%] had near complete path response [1-10% of viable tumour cells]), 6 (9%) had partial path response (pPR; >10% and ≤50% of viable tumour cells), and 23 (35%) had path non-response (pNR; >50% of viable tumour cells). Of the 66 pts who underwent surgery, 11% (n=7) had recurrence (5 loco-regional and 2 distant recurrence), all non-MPR pts (1 pPR and 6 pNR). 12-months RFS was improved with MPR vs non-MPR (100% vs 79%, p=0.004). 52% (n=34) pts had adjuvant treatment (23 anti-PD1 alone, 7 anti-PD1+/-investigational agent, 2 platinum and 2 cetuximab). Within non-MPR pts, 12 had adjuvant treatment (3 recurred; 25%), while 17 did not have adjuvant treatment (4 recurred; 24%). Fifty-one percent (n=68) of pts did not have surgery; 9 (13%) due to progressive disease (PD) and 53 (78%) due to clinical response. Of the 53 pts with a clinical response, 5 (9%) subsequently progressed. Fourteen (10%) pts have died, 6 (4%) related to cSCC; 2 had surgery (non-MPR) and 4 did not have surgery (all due to PD). Conclusions: Anti-PD1-based NeoIT is an active regimen in resectable stage II-IV cSCC and is associated with high clinical response and MPR rates. No pts with MPR from NeoIT has recurred to date, however, 9% of pts who did not have surgery due to clinical response eventually progressed. These findings highlight the importance of further research to investigate the role of surgery in this subgroup of patients.

9503 Background: Neoadjuvant ± adjuvant immunotherapy improves event-free survival relative to adjuvant immunotherapy alone for patients with high-risk resectable stage III melanoma. However, the optimal regimen balancing efficacy and tolerability is not known. T-cell immunoglobulin and ITIM domain (TIGIT) is a promising immune checkpoint but its therapeutic potential in stage III melanoma is underexplored. Methods: In this phase II trial, patients with resectable, macroscopic stage III melanoma received four 21-day neoadjuvant cycles of 1200mg IV atezolizumab (atezo, anti-PD-L1) + 600mg IV tiragolumab (tira, anti-TIGIT), followed by therapeutic lymph node dissection (TLND) and eight 21-day adjuvant cycles of 1200mg IV atezo. Primary endpoints were pathologic response (of all patients initiating neoadjuvant therapy) and recurrence-free survival (RFS) from the time of TLND in patients who were operated on per protocol and received adjuvant therapy. Secondary endpoint was adverse events (AEs); exploratory endpoints included event-free survival (EFS) and distant metastasis-free survival (DMFS). Results: Thirty-four patients, median age 59 years, were accrued and initiated neoadjuvant atezo/tira. 76.5% had >1 metastatic lymph node involved at baseline and 73.5% presented with Stage IIIC disease. All 34 patients were evaluable for AEs, pathologic response and EFS. Four patients were diagnosed with metastatic disease during neoadjuvant treatment, while 30 had TLND per protocol and 28 received adjuvant treatment and were evaluable for RFS and DMFS. Major pathologic responses (MPR, ≤10% viable tumor) were observed in 16/34 patients (47.1%, Table). With 19.9 months median follow-up from registration, 12-month EFS was 72.0% (95% CI 57.9 to 89.5%). With 16 months median follow-up from operation, 12-month RFS was 73.3% (n=28, 95% CI 56.9 to 94.5%), while 12-month DMFS was 86.0% (n=28, 95% CI 72.2 to 100%). In the 16 patients with an MPR, 2 did not receive adjuvant treatment and were followed for 33.3 and 10.8 months without recurrence/death. In the remaining 14 patients, 12-month RFS and 12-month DMFS were both 91.7% (95% CI 77.3 to 100%). 5 patients (14.7%) experienced any grade 3+ AE with 2 (5.9%) at least possibly related to the neoadjuvant regimen. Conclusions: Among patients with high-risk resectable stage III melanoma, neoadjuvant atezo/tira was a promising regimen with a favorable safety profile and warrants further study. Identification of predictive biomarkers will allow for optimization of neoadjuvant therapy for individual patients. Clinical trial information: NCT03554083 . Pathologic response. N=34 Major Pathologic Response 16 (47.1%) Pathologic complete response (no viable tumor) 13 (38.2%) Near-pathologic complete response (0.1−10% viable tumor) 3 (8.8%) Pathologic partial response (>10.0−50% viable tumor) 2 (5.9%) Pathologic non-response (>50% viable tumor) 12 (35.3%) No per protocol operation 4 (11.8%)

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.