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Introduction Up to 40% of pts with diffuse large B-cell lymphoma (DLBCL) relapse after first-line chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). CELMoD agents such as GOLCA potently degrade target proteins Ikaros/Aiolos, resulting in antiproliferative, apoptotic, and immunomodulatory activity. GOLCA preferentially distributes to tissues and lymphoid organs. In a phase 1 study, GOLCA demonstrated a manageable safety profile with promising clinical activity as monotherapy in relapsed/refractory non-Hodgkin lymphoma (Michot et al. Blood 2021). CC-220-DLBCL-001 (NCT04884035) is an ongoing open-label, multicenter, dose escalation and expansion trial to assess safety and preliminary efficacy of CELMoD agents + R-CHOP for untreated a-BCL. GOLCA demonstrated a manageable safety profile in the dose escalation phase (Munoz et al. ICML 2023 abstract 438); we report combined results from the GOLCA dose escalation and expansion phases. Methods Eligible pts were ≥ 18 years, had untreated a-BCL with measurable disease (Lugano 2014), ECOG performance status ≤ 2 and International Prognostic Index (IPI) score 0-5 (2-5 in dose expansion). Pts were treated with R-CHOP plus GOLCA in 21-day (D) cycles (C) for up to 6C, or until disease progression/unacceptable toxicity/study withdrawal/physician decision. During dose escalation, pts received GOLCA at dose levels (DL): 0.2 mg D1-7 (DL-1), 0.4 mg D1-7 (DL1), and 0.4 mg D1-10 (DL2). DL2 met the dose-limiting toxicity threshold and was not continued in the expansion phase. During dose expansion, pts were randomized 1:1 to R-CHOP plus GOLCA at DL-1 or DL1. The primary endpoint for the expansion phase was safety of GOLCA at the recommended phase 2 dose (DL1) (based on adverse events [AEs]); secondary endpoints included overall response rate (ORR) and complete metabolic response (CMR) rate (assessed at end of treatment [EoT] by PET-CT [Lugano 2014]). Circulating tumor DNA (ctDNA) was measured at C1D1, C2D1, C3D1, and EoT using the PhasED-Seq assay. Results Across escalation and expansion, 78 pts were treated (DL-1, n = 35; DL1, n = 37; DL2, n = 6). Median age was 63.0 years, 56.4% were male, most had high-intermediate/high IPI (3-5) score at diagnosis (64.1%), Ann Arbor stage III-IV disease (83.3%), and germinal center B cell as cell of origin (51.3%); 83.3% pts had DLBCL histology. At data extraction (May 25, 2023), across escalation and expansion, 38 pts had treatment ongoing, 31 completed treatment, and 35 continued to follow-up. A total of 3 pts discontinued due to AEs, 1 each at DL-1, DL1, and DL2. In the safety population (n = 78), median GOLCA relative dose intensity (RDI) was 99.4%; 82.1% of pts received RDI ≥ 85%. RDI for CHOP components was > 90%. A total of 73 (93.6%) pts had ≥ 1 treatment-emergent AE (TEAE); 70 (89.7%) pts had ≥ 1 TEAE considered related to GOLCA; 65 (83.3%) pts had ≥ 1 grade 3/4 TEAE, 62 (79.5%) pts had ≥ 1 grade 3/4 TEAE considered related to GOLCA. The most frequently occurring grade 3/4 TEAEs were neutropenia (76.9%) and thrombocytopenia (32.1%) ( Table). A total of 30 (38.5%) pts had serious TEAEs, most frequently febrile neutropenia (preferred term: 11 pts, 14.1%); 12 (15.4%) pts had serious TEAEs of infection or infestation (system organ class); 6 pts (7.7%) had venous thromboembolisms considered related to GOLCA (4 deep vein thrombosis, 1 superficial thrombosis, 1 pulmonary embolism). Treatment-related AEs leading to GOLCA dose reduction or discontinuation occurred in 11 (14.1%) pts and 6 (7.7%) pts, respectively. After a median follow-up time of 4.1 months (range 0.3-12.3) and among all treated pts with EoT response available, 21/25 had CMR; together, 14/14 pts who received GOLCA 0.4 mg (DL1 and DL2) achieved CMR at EoT ( Figure). Among efficacy-evaluable pts (n = 56), ORR was 91.1% (95% CI 80.4-97.0). Pts treated with GOLCA at DL-1 and DL1 who were ctDNA high-risk (≥ 2.5 log hGE/mL) responded to study treatment (CMR-PMR) and had early decreases in ctDNA (Kaplan et al. ASH 2023). Conclusions GOLCA demonstrated a manageable safety profile, showed good combinability with R-CHOP, and did not compromise delivery of curative treatment. Efficacy results and substantial ctDNA decrease indicate robust clinical activity in frontline DLBCL, with a high CMR rate at EoT, particularly among patients treated at DL1. Study support Bristol Myers Squibb.

Background: Relapsed DLBCL occurs in up to 40% of patients and has a poor prognosis. Current prognostic tools such as the international prognostic index (IPI) and newer forms (NCCN-IPI) only include baseline clinical features. PET/CT features have not yet been incorporated into prognostic risk models despite being essential for staging and response assessment. Deep learning computer algorithms have consistently demonstrated the ability to analyze imaging data and identify features that are not readily apparent to the human eye. Using a deep learning computer vision model that automatically extracted radiomic features from PET/CTs, we examined the association of changes between baseline PET and interim PET (PET2) radiomic features on survival outcomes and compared the prognostic performance with NCCN-IPI. Methods: Adult patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) between 2005 and 2015 and enrolled in the prospective MER cohort were included. Native DICOM images from FDG PET/CT scans at baseline and interim PET (PET2, after 2-3 cycles of chemotherapy) were preprocessed for regularity and then segmented using the nnU-Net architecture with an external lymphoma-specific model. Feature extraction and standard uptake value (SUV) characterization were accomplished with PyRadiomics and NiBabel. Our computational method included no manual segmentation correction. Individual radiomics features (n=115) and the % change above (Δ High) and below (Δ low) 50 th quartile from baseline to PET2 were evaluated for association with event free survival (EFS) and overall survival (OS) using a univariate Cox regression model and by Kaplan Meier analysis. EFS was defined as time from PET2 to first systemic relapse or death from any cause. OS was defined as time from PET2 to death from any cause. Additionally, Spearman and Pearson correlation matrices were used to guide feature selection while minimizing collinearity. We then assessed the association of the highest scoring radiomics features with EFS in a multivariate cox regression model. Results: A total of 506 patients had baseline and PET2 scans available for radiomic feature extraction. Median age at diagnosis was 61 years (range 18-90), 43% were females. NCCN-IPI composition and outcomes of our cohort was comparable to the previously published NCCN cohort, with patient distribution and 5-year OS as follows: Low (9%, 5-y OS 83%), Low-intermediate (38%, 5-y OS 49%), High-intermediate (41%, 5-y OS 31%), High (11%, 5-y OS 12%). At a median follow up of 81 months,there were 308 events, and272 patients had died.Several radiomics features were associated with EFS including change in tumor surface area (SA Δ) (HR: 1.75, 95% CI 1.36-2.24, p<0.005, median of 26,927 mm 2, Figure 1A) and change in total metabolic tumor volume (TMTV Δ) (HR: 1.64, 95% CI 1.27-2.10, p<0.005, median of 120,473 mm 3, Figure 1B). As a reference, NCCN-IPI univariate Cox regression analysis of EFS produced a Harrell's C-statistic (c) of 0.624. Single radiomics features of SA Δ and TMTV Δ individually produced unadjusted c-statistics of 0.616 and 0.614 respectively. Combinations of radiomics features (SA Δ, TMTV Δ and NCCN-IPI classification) demonstrated cumulative benefit (c=0.652). Conclusion: Automatic PET-CT radiomic feature extraction using deep learning models is feasible among patients with newly diagnosed DLBCL. The change in tumor SA and TMTV appear to be promising radiomic biomarkers. A low decline in either tumor SA or TMTV by PET2 is associated with higher risk of relapse and poor survival outcomes. As individual characteristics, these features are similar prognostic indicators of EFS as the NCCN-IPI. Further investigation into risk stratification when combining radiomics with clinical and genomic variables is warranted. Figure 1. Event free survival for DLBCL patients with A) a change in tumor surface area by PET2 less than 50% percentile (SA_Δ Low) and greater than 50 th percentile (SA_Δ High) and B) a change in TMTV by PET2 less than 50% percentile (TMTV_Δ Low) and greater than 50 th percentile (TMTV_Δ High).

Background: Event-free survival at 24 months (EFS24) after frontline immunochemotherapy (IC) is an important endpoint in diffuse large B-cell lymphoma and follicular lymphoma, and patients who achieve EFS24 have similar survival compared to age- and sex-matched general population. The role of EFS24 in predicting subsequent survival has not been established in mantle cell lymphoma (MCL), possibly due to perceived poor survival historically. In the last decade, the outcomes of MCL are improving in the evolving treatment landscape. In this international multicenter study, we investigated conditional survival and cause of death in patients with MCL who achieved EFS24 after frontline IC in the older and more recent eras. Methods: Outcomes after frontline IC were evaluated in 5 independent cohorts that included over 3000 patients in total: Mayo/Iowa MER prospective cohort, BC Cancer retrospective population-based cohort, US 12-center retrospective cohort, Swedish Lymphoma Registry, and Danish National Lymphoma Registry. For each cohort, 2 treatment eras were defined based on cohort-specific shifts in treatment patterns (Table 1). Overall survival (OS) after diagnosis and after achieving EFS24 were compared to the background age- and sex-matched general population using a standardized mortality ratio (SMR). Cumulative incidences of cause-specific deaths were analyzed using a competing risk model. Results: In the MER cohort, patients treated in Era M1 (2002-2009; n=147) and Era M2 (2010-2015; n=153) both had inferior OS compared to the general US population. A lower SMR in Era M2 vs M1 (2.25 vs 3.46) suggests a narrower gap in OS compared to the general US population. Lymphoma was the leading cause of death in both eras. In Era M1, patients who achieved EFS24 still had inferior OS compared to the general US population (SMR=2.40, 95% CI 1.76-3.19), and lymphoma remained the leading cause of death. For patients in Era M2 who achieved EFS24, the difference in OS compared to the general US population was not statistically significant with current follow-up (SMR=1.43, 95% CI 0.93-2.09), and lymphoma was no longer the leading cause of death (Table 2). In the BC cohort, patients treated in Era B2 (6/2013-2019; n=188) vs Era B1 (2003-5/2013; n=250) had a narrower gap in OS compared to the general British Columbia population (SMR 4.53 vs 6.69). Lymphoma was the leading cause of death in both eras. For patients achieving EFS24, the gap in OS was narrower in Era B2 vs B1 (SMR 3.56 vs 4.99). After achieving EFS24, lymphoma was the single leading cause of death for patients in Era B1 but not in Era B2 (Table 2). In the US 12-center cohort, patients treated in Era U1 (2002-2011; n=312) and Era U2 (2012-2016; n=417) both had inferior OS compared to the general US population (SMR 2.68 and 2.92, respectively). In patients who achieved EFS24, with current follow up, the difference in OS compared to the general US population was statistically significant in Era U1 (SMR=2.01, 95% CI 1.50-2.64) but not in Era U2 (SMR=1.44, 95% CI 0.82-2.34). Lymphoma was not the leading cause of death after achieving EFS24 (Table 2). In the Swedish cohort, the gap in OS compared to the general Swedish population was narrower in Era S2 (2013-2018; n=439) vs S1 (2006-2012; n=442), both after frontline IC (SMR 4.8 vs 5.4) and after achieving EFS24 (SMR 2.6 vs 3.4). After achieving EFS24, lymphoma was the leading cause of death for patients in Era S1 but not in Era S2 (Table 2). In the Danish cohort, patients treated in Era D2 (2014-2020; n=370) vs Era D1 (2004-2013; n=461) had a slightly narrower gap in OS compared to the general Danish population (SMR 1.90 vs 2.10). For patients who achieved EFS24, those in Era D1 still had inferior OS compared to the general Danish population (SMR=1.44, 95% CI 1.22-1.68), but the OS difference compared to the general Danish population in Era D2 was not statistically significant (SMR=1.27, 95% CI 0.92-1.72) with current follow-up (Table 2). Cause of death data were not available in this cohort. Conclusion: Survival in patients with MCL who achieved EFS24 after frontline IC improved in the more recent treatment era and moved closer to the background expected survival. After achieving EFS24, lymphoma-related mortality was no longer the leading cause of death in the more recent era. EFS24 following frontline treatment may become a critical endpoint for predicting subsequent outcomes in patients with MCL in the modern era.

Background: Shorter diagnosis to treatment interval (DTI) has been shown to be associated with more aggressive disease features and inferior outcomes in diffuse large B-cell lymphoma (DLBCL; Maurer et al, JCO 2018). Additional confirmatory studies have also shown that DTI is related to tumor volume (Alig et al, JCO 2021) and molecular phenotype (Aluaij et al, Blood 2023). Here we evaluate DTI in a large multicenter cohort of patients prospectively enrolled and followed as part of the Lymphoma Epidemiology of Outcome (LEO) cohort. Methods: Patients were enrolled within 6 months of diagnosis at one the 8 LEO cohort academic medical centers in the United States between 2015 and 2020. Patients in this analysis had aggressive B-cell lymphoma (BCL) treated with anthracycline-based chemotherapy. DTI was defined as the initial lymphoma biopsy date until the start of initial chemotherapy; patients with DTI between 0-100 days were evaluated. Short DTI was defined as DTI ≤ 14 days (DTI≤14) as previously described in prior publications (e.g. Maurer et al, JCO 2018) and confirmed via examination of functional forms via splines. Event-free survival (EFS) was defined as the time from start of treatment until progression/relapse, retreatment, or death due to any cause. Overall survival (OS) was defined as the time from start of treatment until death due to any cause. Results: 2565 patients with aggressive B-cell lymphoma were evaluated. Median age was 62 years (IQR 51-71) and 1469 (57%) were male. 297 patients (12%) were self-reported non-White race and 314 patients (12%) were self-reported Hispanic or Latino. The majority had DLBCL, NOS subtype (N=1927, 75%), while 227 (9%) had high-grade BCL with MYC and BCL2 and/or BCL6 rearrangements (HG, DH) and 90 (4%) had high-grade BCL NOS (HG, NOS). Clinical characteristics are summarized in the table. At median follow-up of 49 months (IQR 36-68), 800 patients (31%) had an event and 578 patients (23%) died. EFS at 24 months (EFS24) was 76% (95% CI: 74-77). Median DTI across all subtypes was 21 days (IQR 12-33) and 845 patients (33%) had DTI≤14. Patients with DTI≤14 were significantly younger (median age 59 years) but there was no association between DTI and gender, race, or ethnicity. Patients with DTI≤14 were more likely to have HG, DH or HG NOS subtypes, ECOG PS 2-4, advanced stage, elevated LDH, CNS involvement, B symptoms, and bulky disease ( see table). Patients with DTI≤14 were more likely to receive R-EPOCH-based or intensive therapies (41%) and less likely to receive 1L therapy on a clinical trial (3.8%) compared to DTI>14 (26% and 10.1%, respectively). Consistent with previously reported data, DTI≤14 was associated with inferior EFS (HR=1.62, 95% CI: 1.41-1.87, figure), OS (HR=1.73, 95% CI: 1.47-2.04), and EFS24 (OR=1.93, 95% CI: 1.60-2.38). The association between DTI and outcomes remained significant after stratifying for subtype (EFS HR=1.68, 95% CI: 1.46-1.94; OS HR=1.78, 95% CI: 1.50-2.10) and adjustment for IPI (EFS HR=1.43, 95% CI: 1.24-1.65; OS HR=1.47, 95% CI: 1.24-1.74). In subset analysis, DTI≤14 was significantly associated with inferior outcomes within the subtypes of HG, DH (EFS HR=2.70, 95% CI: 1.82-4.01; OS HR=2.97, 95% CI: 1.92-4.60); HG, NOS (EFS HR=2.07, 95% CI: 0.93-4.60; OS HR=2.36, 95% CI: 1.03-5.43); and DLBCL, NOS (EFS HR=1.51, 95% CI: 1.27-1.78; OS HR=1.52, 95% CI: 1.45-1.85). Analysis was limited in other subtypes due to number of events. Notably, within the subset of patients with DTI>14, there was no significant difference in EFS between subtypes for DLBCL, NOS (EFS24=80%, EFS HR=ref), HG, DH (EFS24=73%, EFS HR=1.26, 95% CI: 0.92-1.73) and HG, NOS (EFS24=83%, EFS HR =0.84, 95% CI: 0.40-1.78), logrank p=0.29; similar results were observed for OS (p=0.22). Conclusions: Patients requiring early initiation of therapy for aggressive B-cell lymphoma represent a distinct population of patients with more aggressive clinical features and inferior outcomes. In patients with longer DTI, high grade subtypes had similar outcomes to DLBCL, NOS. Efforts should be made to include patients with anticipated short DTI in clinical trials and translational studies to fully capture the spectrum of patients with aggressive B-cell lymphoma.

Introduction Lymphoid malignancy (LM) is a heterogenous neoplasm with respect to biology, aggressiveness, and treatment with over 100 subtypes, including Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). Genome-wide association studies have identified common variants associated with risk of specific LM subtypes, but less is known about the contribution of rare inherited pathogenic variants (PV) in the genetic architecture of LM risk. Rare PV have been shown to contribute to the genetic architecture of solid tumor cancer risk, many of which have been found in genes that are important to the DNA-damage repair (DDR) pathway (e.g., BRCA1, BRCA1, ATM). Here, we investigated the prevalence of PV in cancer predisposition genes regularly included on multi-gene panel testing based on NCCN guidelines and correlated with risk of LM overall and by common subtypes. Methods In this association study, cases were newly diagnosed lymphomas (excluding chronic lymphocytic leukemia) from Mayo Clinic who were enrolled between 2002 and 2015 in the Lymphoma SPORE Molecular Epidemiology Resource (MER) and MM from Mayo Clinic enrolled primarily between 1998 and 2022 in a clinical registry. Controls were from the Mayo Clinic Biobank who were enrolled between 2009 and 2016, from which we excluded individuals with a history of hematologic malignancy. All participants provided a blood sample for whole exome sequencing, performed by Regeneron on an Illumina NovaSeq panel (mean coverage of 48X). Variants were called using GATK v4 and variant annotation was performed using BioR. All loss-of-function variants (i.e., nonsense, frameshift, and consensus splice sites) and pathogenic missense in 19 cancer predisposition genes with a minor allele frequency < 0.5% were included in the analyses. Logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (CI) for the association between mutation status by gene (burden test) and risk of LM overall, and by subtype that had more than 5 mutation carriers. All analyses were adjusted for age (at diagnosis for cases and at enrollment for controls) and sex. Results A total of 6990 cases and 42432 controls were included. Median age was 63 years for both cases and controls (case range 18-94 years, control range 18-99 years). Males accounted for 58.5% (n=4090) of the cases and 41.7% (n=17762) of the controls. MM accounted for 31% (n=2138) of the cases, followed by diffuse large B-cell lymphoma (DLBCL, n=1146) and follicular lymphoma (FL, n=1132) each accounting for 16% of cases. CHEK2 (1.0%), ATM (0.4%), BRCA2 (0.4%), and BRCA1 (0.3%) had the most PV carriers in controls; these frequencies are in the range of published control populations. A total of 1816 (3.7%) individuals had a PV across the 19 genes, with 4.7% of cases and 3.5% of controls carrying any PV (OR=1.34, 95% CI: 1.18-1.51). ATM (OR=1.86, 95% CI: 1.36-2.49), CHEK2 (OR=1.74, 95% CI: 1.42-2.13) and TP53 (OR=9.07, 95% CI: 4.51-18.87) were all significantly associated with increased risk of LM overall (Figure 1). When investigating subtypes (Table 1), CHEK2 (OR=1.93, 95% CI: 1.23-2.89) and TP53(OR=10.97, 95% CI: 3.06-31.43) were significantly associated with DLBCL. ATM (OR=2.22, 95% CI: 1.13-3.90) was significantly associated with FL. ATM (OR=1.97, 95% CI: 1.16-3.12), CHEK2 (OR=1.75, 95% CI: 1.24-2.41) and TP53 (OR=7.67, 95% CI: 2.43-20.72) were significantly associated with MM and ATM (OR=8.62, 95% CI: 4.47-15.12), NBN (OR=6.94, 95% CI: 2.41-15.76) and TP53 (OR=38.30, 95% CI: 10.27-116.69) were significantly associated with mantle cell lymphoma (MCL). When subset to LM cases overall, there was no evidence of enrichment for young onset (age <60 years), male sex, or family history of hematologic malignancy between PV carriers and non-PV carriers. However, FL cases with an ATM PV tended to be less than 60 years (OR=3.21, P=0.09) compared to non- ATM PV carriers. Similarly, MM cases with a TP53 PV tended to be less than 60 years of age (OR=7.39, P=0.07) compared non-carriers. Discussion In this large case-control study, PV in established cancer predisposition genes were associated with increased risk of LM overall, demonstrating that rare inherited variants may play an important etiologic role. This study also suggests that PV in cancer predisposition genes may be subtype specific. These results will help inform LM risk for individuals who undergo genetic testing of cancer predisposition genes.

Background: Tumor mutational burden (TMB), defined as the number of nonsynonymous mutations per megabase (Mb) in the coding regions of a tumor genome, has been associated with improved response to immune checkpoint blockade treatments and more broadly with overall survival (OS) in many cancers. Limited prior studies have found that TMB is higher in diffuse large B-cell lymphoma (DLBCL) compared to many other cancers. However, only two studies have evaluated TMB and prognosis in newly diagnosed DLBCL patients. The prognostic role of TMB in diffuse large B-cell lymphoma (DLBCL) remains unclear as prior studies have been limited to panel sequencing of cancer genes and/or lacked matched germline-tumor samples for filtering. Methods: We characterized TMB from whole exome sequencing (WES) in newly diagnosed DLBCL patients with matched diagnostic tumor-normal samples prior to treatment with standard immunochemotherapy (IC). Tumor DNA was extracted from formalin-fixed, paraffin embedded tissue sections and germline DNA from peripheral blood. We evaluated the association between TMB and event-free (EFS) and OS using Cox regression adjusted for the international prognostic index (IPI) and other factors including cell of origin (COO), MYC double hit (DH) with BLC2 or BCL6 by FISH, and TP53 mutation status. EFS and OS were defined as time from diagnosis to earliest of treatment failure (EFS only), death, or last follow-up; EFS at 24 months (EFS24) was also modeled as a marker of early aggressive DLBCL. An optimal high/low TMB cutpoint was determined based on EFS using maximally selected rank statistics; sensitivity analyses used an 20/80 percentile to define the threshold. We also evaluated the association of driver tumor mutational load (driverTML) with EFS and OS, defined as the total number of mutations in 292 DLBCL driver genes. Results: In the analysis cohort of 394 DLBCL patients, the median age at diagnosis was 65 years (interquartile range: 56-73), 43% were female, 62.2% had IPI 0-2, and 57.4% germinal center B-cell COO. MYC was DH in 7.5% and TP53 was mutated in 16.2% of patients. Through a median follow-up of 7.5 years, there were 141 events and 122 deaths. EFS24 was achieved in 75.1% of the cohort; 5-year EFS was 69% (95% CI 64-74%) and 5-year OS was 75% (95% CI 71-80%). Median TMB in our cohort of DLBCL patients was 3.6 mutations/Mb, which was the fifth highest compared with 32 cancers in The Cancer Genome Atlas. As a continuous variable, increasing TMB (mutation/Mb) was associated with superior EFS (HR=0.89, 95% CI 0.81-0.98) and OS (HR=0.89, 95% CI 0.81-0.99) after adjustment for IPI. Spline analyses confirmed linear associations of TMB with EFS and OS. The optimal modeled cutpoint based on EFS was 4.5 mutations/Mb, with 31% classified as high TMB (>4.5). No significant ( P >.05) differences were observed between high and low TMB patients with clinical (i.e., age, sex, IPI category) or molecular (cell of origin, MYC DH, TP53 mutated) factors. In Cox regression, high-TMB was significantly protective for EFS and for OS compared to low-TMB after adjustment for each clinical factor ( Figure 1), with simultaneous adjustment for all these factors associated with superior EFS (HR=0.52, 95% CI 0.33-0.84) and OS (HR=0.59, 95% CI 0.36-1.00). TMB (high/low) combined with IPI (0-2, 3-5) was significantly ( P =.001) associated with EFS in Kaplan-Meier analysis ( Figure 2). Among patients with IPI 3-5, high TMB was significantly associated with superior EFS (HR=0.47, 95% CI 0.27-0.81) and OS (HR=0.57, 95% CI 0.33-0.99). Among patients with IPI 0-2, we also observed longer EFS (HR=0.62, 95% CI 0.34-1.11) and OS (HR=0.62, 95% CI 0.32-1.20) in high TMB patients, although the associations were not statistically significant ( P >.05). In sensitivity analyses, a 20/80 percentile TMB threshold found similar results for EFS (HR=0.64, 95% CI 0.41-1.03) and OS (HR=0.69, 95% CI 0.42-1.12) as in our main analyses. TMB and driverTML were significantly correlated ( R=0.65, P <10 -16) and we found similar effect sizes for EFS (HR=0.45, 95% CI 0.22-0.91) and OS (HR=0.55, 95% 0.27-1.13) as in our main analyses. Conclusions: In a large and well-defined cohort of IC treated DLBCL patients, we found DLBCL patients with higher TMB had superior EFS and OS after adjustment for other clinical and molecular prognostic factors, and the prognostic association for TMB was robust to threshold and gene set.

Multiple CD19-directed therapies are available for the treatment of relapsed and refractory (R/R) DLBCL, including CAR T cells, tafasitamab/lenalidomide (TL), and loncastuximab tesirine (lonca-T) (Sermer D., Blood Rev 2023). However, there are few data available on the efficacy of sequential CD19-directed therapies. We performed a retrospective study evaluating all patients with R/R LBCL treated consecutively with TL at 11 institutions from 8/2020 to 8/2022, identifying 178 patients. In this study, we specifically evaluate outcomes in patients who received anti-CD19 therapy prior to or after TL. The primary outcome of interest was progression-free survival (PFS) in TL recipients who previously received CD19-directed CAR T therapy, with overall response rate (ORR), complete response rate (CRR), and overall survival (OS) also evaluated. Outcomes of lonca-T and CAR T after TL therapy were evaluated. Data on CD19 expression was assessed on biopsies after TL; this was determined locally using flow cytometry or immunohistochemistry per institutional protocols. In subgroup analyses, ORR and CRR were compared using Fisher's exact test. PFS and OS were estimated using the Kaplan-Meier method, with differences tested using the log-rank test. Of 178 patients who received TL, 52 had received prior anti-CD19 CAR T therapy, at a median of 7.4 months before TL (Table 1). Median PFS was lower in prior CAR T recipients (1.6 mo, 95% CI 1.1-2.5) vs no prior CAR T (2.1 mo, 95% CI 1.8-3.2), with hazard ratio 1.46 (p = 0.04; Figure 1). Best ORR was lower in patients with prior CAR T exposure (15% vs 33%, p = 0.02) though CRR was not significantly different (15% vs 18%, p = 1.0). We specifically evaluated TL outcomes based on prior response to CAR T, given the previously identified association of refractory disease with poor TL outcomes (Qualls D et al., presented at ASH 2022). Of 19 patients who had progressive disease more than 6 months after CAR T, ORR and CRR to TL therapy were 31.6% (all responses were CRs); in 33 patients with refractory disease (less than CR or relapse within 6 months) after CAR T, ORR and CRR to TL were significantly lower, at 6.1% (p = 0.04). Median PFS after TL was shorter in CAR-refractory than CAR-relapsed disease, at 1.4 vs 3.5 months (HR 2.2, p = 0.02). Of 88 patients who received therapy after TL, 20 (23%) received lonca-T and 14 (16%) received CAR T. Data on survival and initiation of new treatment after CAR T or lonca-T was available, but response and progression data after CAR T or lonca-T therapy is pending. These data allowed an estimate of OS and event-free survival (EFS), defined as survival without initiation of a new treatment after CAR T or lonca-T. With a median 3.9 months' follow-up, median EFS after CAR T administration was 3.7 months (95% CI, 0.9 - 6.5), and median OS was 8.1 months (95% CI, 0.6 - 15.7). In patients who received lonca-T, with median 2.7 months' follow-up from initiation, median EFS was 2.8 months (95% CI, 0.9 - 4.7), and median OS was 3.5 months (95% CI, 1.2 - 5.7). When comparing CAR T and lonca-T to polatuzumab vedotin- or chemotherapy-based therapies after TL, there were no significant differences in OS or EFS. In patients who discontinued TL, 24 had a biopsy a median of 18 days after the last dose of tafasitamab. Of these, 13 (54%) were CD19-positive and 11 (46%) were CD19-negative. All samples obtained more than 21 days after tafasitamab (6/6) were CD19-positive, while 46% obtained within 21 days were CD19-positive. These time-dependent findings may reflect “epitope masking” by tafasitamab rather than CD19 loss, reflecting other recent reports (Fitzgerald K., Leuk Lym 2022; Duell J., Leuk Lym 2022). In patients receiving TL after CAR T, responses and PFS were lower than in patients without prior CAR T therapy; however, with disease that was not refractory to prior CAR T, results were similar to patients who had not had prior CAR T. This may reflect that refractory disease, regardless of prior therapy, is associated with shorter PFS, though the possibility of CD19-mediated mechanisms of resistance remains. Modest EFS and OS were seen in patients receiving CAR T therapy or lonca-T after already receiving TL, though this may also reflect the high-risk disease characteristics of this cohort. Overall, in a high-risk, real-world cohort of TL-treated patients, these data suggest that some patients may benefit from subsequent CD19-directed therapies, but better therapeutic options are needed.

Background: Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma with two-year overall survival (OS) rates of 66-70% reported in prospective clinical trials. Induction therapy with high-dose methotrexate (HD-MTX) followed by consolidation has become the mainstay of treatment, however, there are few contemporary and robust prognostication indices widely available for clinical use. Some of the most used indices were developed prior to the routine use of rituximab and include the International Extranodal Lymphoma Study Group (IELSG; 1980-1999), Memorial Sloan-Kettering Cancer Center (MSKCC; 1983-2003), Nottingham/Barcelona (NB; 1986-2001), and Taipei Score (TS; 2003-2015). Herein, we describe a contemporary comparison of clinical prognostication indices using a single-center cohort of PCNSL patients treated at the Mayo Clinic. Methods: Patients with a diagnosis of PCNSL who received HD-MTX as part of induction therapy at Mayo Clinic between October 2010 and June 2022 were identified and retrospectively reviewed. Patients with prior or concurrent systemic lymphoma were excluded. Primary endpoints were progression-free survival (PFS) defined as time from diagnosis to relapse, progression, or death due to any cause; and OS defined as time from diagnosis to death due to any cause. PFS and OS were evaluated using Kaplan-Meier curves and compared by risk scores using a log-rank test. The association between baseline characteristics and survival outcome were assessed in univariate Cox regression models. Any characteristics showing significant (p-value <0.05) association with outcome were combined using a multivariate Cox regression model. All characteristics that maintained significant association with outcome were combined into a new prognostic model. We compared the performance of each prognostic index model using Harrell's C (HC). Results: A total of 148 patients were identified (50.7% female) with median age at diagnosis of 66 years (range 29-85), with 48 patients (32.4%) age >70 (Table 1). Most had multifocal disease (60.1%) and deep brain involvement (67.6%) at diagnosis with elevated CSF protein (58.1%) but no documented CSF involvement (93.9%). In total, 117 patients (79.1%) received methotrexate, rituximab, and temozolomide (MRT) induction therapy, and the remaining 31 patients (20.9%) received methotrexate and rituximab (MR) induction therapy with various consolidation strategies. The median follow-up for all patients was 4.5 years and the two-year OS was 79% (95% CI: 73-86%). This cohort was stratified using previously published prognostication indices (Table 1). Upon analysis, PFS was not accurately predicted using the IELSG (score 4-5: HR 0.7 (CI 0.3-2.0); HC 0.6), MSKCC (3: 1.3 (0.4-4.0); 0.5), NB (3: 0.9 (0.4-2.5); 0.6), or TS (3: 0.9 (0.1-7.2); 0.5) prognostication indices. Furthermore, OS was not accurately predicted using the IELSG (4-5: 1.5 (0.6-4.0); 0.6), MSKCC (3: 1.2 (0.5-3.2); 0.6), NB (3: 1.2 (0.5-3.2); 0.6), or TS (3: 1.3 (0.2-9.8); 0.6) prognostication indices. Upon multivariate analysis, no variables listed in Table 1 were associated with PFS within this cohort. The two variables predicting a worsened OS were an ECOG performance status of 2 or more (1.9 (1.01-3.6)) and an MR induction regimen instead of MRT (2.1 (1.05-4.3)) (Figure 1). The two-year OS with no risk factors was 86.1% (95% CI: 78.8-94.1%), one risk factor was 75.7% (95% CI: 63.6-90.1%), and two risk factors was 61% (95% CI: 43-86%) (Figure 1). Conclusions: This study reports overall improved outcomes in patients with PCNSL compared to prior prospective and retrospective cohorts, likely in part due to treatment advances and supportive care strategies. This single-center, retrospective cohort of rituximab-exposed patients with PCNSL were not well prognosticated using previously published indices, indicating that further study and more sophisticated approaches to prognostication are warranted. Although multivariate analysis did not demonstrate any variables associated with PFS, it did demonstrate an inferior OS with a performance score of 2 or more and in patients treated with MR rather than MRT.

Background: High Grade B cell Lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements(R) was introduced as an entity in 2016 by the WHO revised 4 th edition. In 2022, both the WHO 5 th edition (beta version) and the International Consensus Classification (ICC) separated DHL- BCL2 (+/- BCL6-R)from DHL- BCL6 given differences in biology . However, while the ICC has maintainedDHL- BCL6 as a provisional entity, the WHO has removed the category, thus removing the requirement to FISH for BCL6-R in this setting. Clinical data on DHL- BCL6 is much more limited, as these cases represent only 10-20% of DHL and have been combined with BCL2-R cases in prior studies. Outcomes are variable in retrospective studies with no consistent data on prognosis or optimal therapeutic strategies. By retaining the category of DHL-BCL6 as a provisional entity, the ICC emphasized the need for further, multicenter, prospective studies evaluating the clinical and biological features of this disease. We herein report a comprehensive comparison of clinical characteristics and outcomes in patients with DHL- BCL6 compared to diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS); DLBCL with MYC rearrangement only; DHL- BCL2; and HGBL, NOS in a large, multicenter, prospective cohort of patients from Lymphoma Epidemiology of Outcomes (LEO). Methods: Adult patients with newly diagnosed large B-cell or HGBL were enrolled within 6 months of diagnosis at one the 8 LEO cohort academic medical centers in the US between 2015 and 2020. Baseline characteristics were abstracted at the time of diagnosis per protocol. Based on FISH data patients were further sub mgrouped into DLBCL, NOS (without MYC rearrangement); MYC-R DLBCL, NOS; HGBL, NOS; DHL- BCL2 and DHL- BCL6. Event-free survival (EFS) was defined as the time from diagnosis until progression/relapse, retreatment, or death. Overall survival (OS) was defined as the time from diagnosis until death due to any cause. Results: A total of 1526 eligible patients were identified during this time period. All FISH data was available at the time of diagnosis and the choice of treatment was based on physician discretion. Median age at diagnosis was 63 years (IQR 53-72), with 148 (10%) patients in the AYA category, and 128 (8%) patients > 80 years. 58% (891) were male, 11% self identified as Hispanic or Latino, and 7% as Black/African American. The median diagnosis to treatment interval (DTI) was 20 days (IQR 12-32), and 33% had DTI < 14 days. The FISH-based subgroups were MYC-negative DLBCL, NOS (N=1146, 75%), MYC-R DLBCL,NOS 227 (N = 96, 6%), DHL- BCL2 (N=154, 10%), DHL- BCL6 (N=38, 3%), and HGBL, NOS (N=92, 6%). When available, COO by Hans algorithm was 92% GCB in DHL- BCL2 and 50% GCB in DHL- BCL6. Clinical characteristics can be found in the table. At a median follow-up of 49 months (IQR 36-67), 490 patients (32%) had an event and 356 patients (23%) died. EFS at 24 months (EFS24) was 75% (95% CI: 73-77). Patients with DHL- BCL6 were younger at diagnosis (median 60 years), had more extranodal site involvement (40%), more often stage III/IV disease (70%), and more often treated with a higher intensity regimen than R-CHOP (69%) compared to DLBCL,NOS and MYC-R DLBCL. DHL- BCL6 also had fewer patients that were males (47%), with DTI <=14 days (33%), NCCN IPI ≥ 4 (45%), elevated LDH (53%) than HGBL, NOS and DHL- BCL2. The 2-year EFS and OS rates were noted to be significantly better in the DHL- BCL6 (EFS 79%, 95% CI: 67-93; OS 92%, 95% CI: 84-100) as compared to DHL- BCL2 (EFS 58%, 95% CI: 50-66; OS 70%, 95% CI 63 - 78) and HGBL, NOS (EFS 74%, 95% CI: 65-84; OS 74%, 95% CI: 65-84 ), (Figure 1) but were comparable to that of DLBCL, NOS (EFS 78%, 95% CI: 76-81; OS 87%, 95% CI: 86-89). Conclusions: Our data support separating DHL- BCL6 from DHL -BCL2 as these patients form a unique subgroup with some clinical characteristics comparable to both DLBCL, NOS as well as HGBL, NOS and DHL- BCL2 subtypes. In this cohort, clinical outcomes are more comparable to DLBCL, NOS than DHL- BCL2 or HGBCL, NOS. More frequent use of intensive chemotherapy in DHL- BCL6 compared with DLBCL may account for this finding, although larger multicenter studies are needed. Our results support continued identification of DHL- BCL6 in the clinical setting to better understand optimal therapy and biology of this cohort.

Background Central nervous system (CNS) involvement is a rare complication (<5% of cases) of mantle cell lymphoma (MCL) and is associated with poor outcomes, highlighting the need for novel treatment approaches. We report the outcomes of a large cohort of patients (pts) with CNS MCL from Mayo Clinic and Memorial Sloan Kettering Cancer Center (MSKCC). Methods MCL pts with CNS involvement seen at Mayo Clinic and MSKCC between 1/2000-1/2021 were included. CNS involvement was defined by histologically confirmed CNS MCL, CSF analysis demonstrating lymphoma cells, and/or neuroimaging findings compatible with CNS lymphoma. Medical records were reviewed for baseline characteristics, treatment, and outcomes. First-line MCL chemotherapy was categorized into higher intensity chemotherapy (i.e., anthracycline-based +/- high-dose cytarabine), moderate intensity chemotherapy (i.e., bendamustine-based regimens or single agent chemotherapy), and other. CNS treatment regimens were categorized as intrathecal (IT) therapy alone, systemic therapy (with CNS penetration such as IV cytarabine or IV methotrexate) with/without IT therapy, regimens with Bruton's tyrosine kinase inhibitors (BTKi), chimeric antigen receptor T cell (CAR-T) therapy, or radiation alone. Kaplan-Meier method was used for time to event analysis. Forest plots were developed using univariable Cox proportional hazards models. Results Seventy patients were included in the cohort, 34 from MSKCC and 36 from Mayo Clinic. Median age at MCL diagnosis was 65 years (range 56-72) and 52 were male (74%). MIPI score was available in 60 pts: low (n=10, 17%), intermediate (n=20, 33%), and high (n=30, 50%) risk. First line therapy included: higher intensity chemotherapy (n=42, 60%), moderate intensity chemotherapy (n=25, 36%) and other (n=3, 4%). Twenty-five (36%) pts underwent autologous hematopoietic cell transplantation in CR1. Median time from initial MCL diagnosis to CNS involvement was 24 months (m) (range 0-167). Four (6%) pts had CNS involvement at initial diagnosis. Abnormal CNS imaging was reported in 53 (76%) pts: leptomeningeal (n=37), leptomeningeal and parenchymal (n=4), parenchymal (n=8), orbital (n=4). The most common regimen following CNS diagnosis was systemic therapy with or without IT therapy (n=34, 54%) followed by treatment including BTKi (n=13, 21%), IT alone (n=10, 16%), radiation alone (n=3, 5%), and treatment including CAR-T (n=3, 5%). Three patients elected hospice care and four patients had missing/unknown CNS treatment. The overall CNS response to therapy was available in 54 patients: CR in 22 (41%) pts, PR in 8 (15%), SD in 11 (20%), and PD in 13 (24%) pts. Of the 70 patients, 63 died. Median follow up was 6.9 years (range: 1.6-11.2) from initial MCL diagnosis and 2.1 years from CNS diagnosis (range: 0.4-7.9). Median OS from MCL diagnosis was 3.4 years (95% CI: 2.4-4.6). In univariable Cox models, sex, stage, performance status, Ki67, or first line systemic chemotherapy type were not significantly associated with OS from MCL diagnosis. Low risk MIPI score (score < 5.7) was associated with favorable OS (HR 0.31, 94% CI: 0.12-0.77; p value 0.01) compared to high risk. First-line treatment and treatment intensity were not associated with a significant difference in OS. Median PFS for the first CNS-directed therapy was 2.4 m (95% CI: 1.7-4.3). Cause of death was disease-related in a majority (n=49, 78%) of pts and therapy-related in 10% (n=6). The remaining 8 deaths had cause of death reported as missing or other (13%). Median OS from CNS involvement was 5.1 m (95% CI: 3.3-10.0) (Figure 1). When assessing OS from time of CNS diagnosis, treatment regimens incorporating BTK inhibitors were associated with a more favorable OS compared to systemic therapy +/- IT therapy (HR=0.37, 95% CI: 0.16-0.89, p value=0.03) (Figure 2). Conclusions Our dual center series confirms patients with CNS involvement by MCL have poor outcomes. When evaluating OS from the time of CNS diagnosis, novel therapies, including BTKi and CAR-T, may be more effective than CNS-penetrant chemotherapy for treatment of CNS relapse suggesting newer therapeutic approaches are required to improve outcomes.