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Background: Chronic lymphocytic leukemia (CLL) is one of the most common leukemias in the United States (US), with an estimated incidence of 20,700 cases in 2024. Population-based studies conducted in Olmsted County (OC), Minnesota, reported an increase in CLL incidence over a 55-year period (1935 through 1989), which was attributed to increased detection of early-stage cases in individuals over age 50. In an updated study from 2000 to 2010 in OC, we reported no further increase in the incidence of CLL using the 2008 International Workshop on CLL (IWCLL 2008) guidelines. Additionally, when we compared the 1996 National Cancer Institute Working Group (NCI-WG 96) criteria with the IWCLL 2008 guidelines incorporating the monoclonal B-cell lymphocytosis designation, we found that the use of the IWCLL 2008 guidelines reduced the overt CLL incidence, modified the distribution of Rai Stages at diagnosis, and shortened the median time to first treatment (TTFT). Over the last two decades, 5-year survival for CLL has increased due to new therapies and improved supportive care. Herein we provide updated data on the incidence, prevalence, and natural progression of CLL in OC and studied similar features in an expanded 6-county region around Mayo Clinic, Rochester. Methods: We utilized the Rochester Epidemiology Project (REP), a population-based medical records linkage system, to identify CLL cases from 2000 to 2020 using International Classification of Diseases codes. We included individuals residing in OC and the expanded 7-county region (REP-7, including OC), for which data became available starting in 2010. CLL cases were included if they met the IWCLL 2008 criteria. All CLL diagnoses were confirmed by manual review of medical records and data on CLL-related factors were collected, including treatment status, prior history of other cancers, and overall survival (OS). Age- and sex-specific incidence rates were derived from REP census data and adjusted to the 2020 US white population. OS analyses were conducted using the Kaplan-Meier method. TTFT was calculated with death as a competing risk. Cox regression was used to evaluate the effect of decade on TTFT and OS among patients in OC. Results: From 2010-2020, 242 patients were diagnosed with CLL in REP-7, and between 2000-2020, 174 patients were diagnosed in OC. Among the 242 CLL patients in REP-7, the median age at diagnosis was 71 years (range 30-96),158 (65%) were male, 236 (99%) were white, and 74 (31%) had a history of other cancer, with non-melanoma skin cancer being the most common. After age and sex adjustment to the 2020 US white population, the CLL incidence in REP-7 and OC from 2010 to 2020 was 7.8 and 8.1 per 100,000 individuals, respectively. In OC, the age- and sex-adjusted CLL incidence from 2000 to 2020 was 7.5 per 100,000 individuals, showing no significant trend changes over time. Among the 242 patients diagnosed with CLL in REP-7 between 2010 and 2020, 102 received treatment with a median TTFT of 9.8 years. In OC from 2000 to 2020, 79 out of 174 patients received treatment with a median TTFT of 9.4 years. When comparing across two decades in OC, the median TTFT was 12.8 years for the period from 2000 to 2009, decreasing to 5.9 years between 2010 and 2020, but was not significantly different after accounting for age and sex. The median OS for patients diagnosed with CLL in REP-7 from 2010 to 2020 was 11 years. The median OS for patients in OC between 2000 to 2020 was 12.6 years. When comparing across decades in OC, the median OS was 8.9 years for the period from 2000 to 2009, increasing to 13.6 years for those diagnosed between 2010 and 2020, but this trend was not significantly different after accounting for age and sex. Prevalence data for REP-7 and OC were analyzed as of 01/01/2020. Additionally, prevalence data for OC were available for 01/01/2010. In REP-7, the prevalence of CLL was 97 per 100,000 individuals on 01/01/2020. In OC, the CLL prevalence was 86 per 100,000 individuals on 01/01/2010, and 100 per 100,000 individuals on 01/01/2020. Conclusions: We observed no substantial increase in the incidence rates of CLL in REP-7 from 2010 to 2020, nor in the 20 years of available data from OC. However, the prevalence of CLL in OC increased by 16% from 2010 to 2020. Additionally, evidence indicated a longer OS among newly diagnosed CLL cases in OC compared to previous decades, suggesting a potential impact of improved therapeutic approaches on OS.

Background: Due to recent advances, patients with follicular lymphoma (FL) have multiple treatment options with high response rates and durability. However, there is a gap in understanding how patient preferences influence treatment selection. To close this gap, we conducted a qualitative study using focus groups of adults with FL to understand their knowledge of treatment options, priorities, and decision-making process. We designed this study to inform the content of a planned discrete choice experiment in a larger population of patients with FL to better understand patient preferences and trade-offs around treatment delivery, side effects, outcomes, and quality of life. Methods: We conducted focus groups lasting 60-90 minutes, each with 3-5 participants recruited from the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study. The LEO Cohort Study is a multi-institutional prospective cohort study of newly diagnosed adults with non-Hodgkin lymphoma from July 2015 to present. Each focus group was co-led by two investigators (U.D. and M.T.) and conducted using Zoom video technology. Participants were asked to comment on their understanding about FL and available treatments, their ideal treatment, their decision-making process about prior therapies, and quality of life and side effects associated with treatment. We performed exploratory content analysis of participant understanding of FL and their treatment preferences. We will continue to conduct focus groups until we reach thematic saturation, which we anticipate will occur with one additional focus group. Themes from all focus groups were identified and agreed upon by both investigators (U.D. and M.T.) and were verified by additional investigators (J.D., M.L, M.H., B.K.L, C.C., M.M.). Results: To date, we conducted five focus groups with a total of N=21 participants (median age 60 [range 41-88], 66.7% female, 71.4% non-Hispanic White, 14.3% Hispanic, 9.5% Asian, 4.8% Black/Hispanic). We identified the following themes and representative quotes: 1) Holistic approach:Participants wanted their oncologists to view their care from a holistic perspective, discussing their individual priorities and options that would accommodate their fitness routine and ability to work. “[I wish] if doctors can consider not just the physical choices, but also the mental and emotional choices as well, the holistic person.” - Participant 13 “There's zero chance I can go back to working in the type of career where other people rely on me for things. I can't keep things straight.” - Participant 16 2) Ideal treatment:An ideal treatment would limit impact on fatigue, cognitive function, and have minimal toxicity to preserve quality of life and an active lifestyle. “I would say something that has minimal impact on daily life would be ideal and something that would make you feel better.” - Participant 6 3) Shared decision-making: Participants wanted to be better informed about available treatment options and often utilized second opinions to inform their decisions. “It helped to get the second opinion versus not. It would've been a completely different set of events.” - Participant 17 4) Treatment burden:Financial impact and effort required by patients to receive care (e.g., travel, number of office visits, and duration of therapy) were key factors in patient decision-making. “Part of my quality of life went down because I had to fight with my insurance company consistently, and we pay a lot of money.” - Participant 11 “Really explain the time options and calendarize the treatment and be more specific about the amount of time that you're going to spend at the hospital and the process.” - Participant 20 5) Representation: Minority participants raised concerns about not knowing if the available treatment data pertained to them. “[My end-goal would be] having an understanding of how the treatment is going to be for minority people. Many times the treatments are tested, they are not tested for minorities.” - Participant 21 Conclusions: The patient perspective is critical for treatment decision-making and education. People living with FL expressed a desire for a holistic and individualized approach to treatment decision-making that incorporated their lifestyle, minimized side effects, and limited overall treatment burden. These focus groups identified emerging themes that warrant further investigation for survivors with FL.

ABSTRACTDiffuse large B‐cell lymphoma (DLBCL) patients that fail to achieve a complete metabolic response with frontline immunochemotherapy have a poor prognosis. Genomic profiling has led to a broader understanding of the molecular drivers in DLBCL, but it is unknown how well current classifiers identify patients that will experience primary treatment resistance (PTR). Using whole exome and RNA sequencing data from newly diagnosed DLBCL patients, we evaluated the genomic landscape of PTR and compared it to that of non‐PTR DLBCL. We found a significant increase in the frequency of TP53 (34% vs. 15%, p = 0.005) and ARID1A mutations (21% vs. 7%, p = 0.007) in PTR cases, with pathway analysis further demonstrating a downregulation of TP53 and an increase in chromatin modifying pathways. These results suggest that TP53 and ARID1A may be key mediators of PTR and important pathways contributing to the poor outcomes. We found that the current molecular classifiers were unable to identify PTR cases at diagnosis. However, our newly identified high‐risk signature identified 46% of PTR cases at diagnosis. Overall, these results contribute to our understanding of the genomic landscape of patients with primary treatment resistance.

Abstract Progression of disease within 24 months of initial immunochemotherapy (POD24) is a negative prognostic factor for patients with follicular lymphoma (FL). There is no standard treatment after POD24. Assembling an academic-based cohort from the Lymphoma Epidemiology of Outcomes Consortium for Real World Evidence, we evaluated patterns of care and outcomes for 220 patients with FL with POD24 and retained FL histology. Therapy after POD24 was heterogeneous, with no treatment category accounting for >25% of the total. Among patients initially treated with bendamustine-rituximab, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) was the predominant second-line choice (48%). Among patients initially treated with R-CHOP, aggressive salvage therapy was the predominant second-line choice (38%). Overall response rate to therapy after POD24 was 64% (95% confidence interval [CI], 56-70); complete response rate was 39% (95% CI, 32-46). The median event-free survival for therapy after POD24 was 9.8 months (95% CI, 7.3-12.1); 5-year overall survival (OS) was 71% (95% CI, 65-78). OS was inferior for patients aged >70 years (hazard ratio [HR], 2.31; 95% CI, 1.27-4.20) and those with high-risk FL International Prognostic Index scores at diagnosis (HR, 2.10; 95% CI, 1.23-3.60). No treatment category stood out with more favorable results. Cause of death was predominantly lymphoma related. Patients with follicular histology at their POD24 event had a low cumulative incidence of transformation (1.1% at 5 years). Our study is among the largest cohorts describing contemporary patterns of care for patients with POD24, providing a focused data set useful for interpreting and designing prospective clinical trials in this population.

ABSTRACT Lymphoma is one of the leading causes of cancer and cancer deaths and yet has not been amenable to population screening. The role of methylated DNA markers (MDMs) in the detection of lymphoma has not been extensively studied. We aimed to discover, validate, and test tissue–derived MDMs of lymphoma in archival plasma specimens. Reduced representation bisulfite sequencing (RRBS) was performed on a discovery set of frozen tissues. MDMs identified were converted to methylation–specific PCR assays and validated on independent formalin–fixed, paraffin‐embedded (FFPE) tissues. Target enrichment long–probe quantitative‐amplified signal (TELQAS) assays were developed and assayed in plasma–extracted, bisulfite‐converted DNA from independent treatment‐naïve lymphoma patients and healthy controls. Prediction of cancer status was modeled using random forest model with in silico cross‐validation. After discovery and validation in tissue, 16 TELQAS assays ( ZNF503 , VWA5B1 , HOXA9 , GABRG3 , ITGA5 , MAX.chr17.7190 , BNC1 , CDK20 , MAX.chr4.4069 , TPBG , DNAH14 , SYT6 , CACNG8 , FAM110B , ADRA1D , and NRN1 ) were selected for testing in plasma. These detected 78% (95% CI, 74%–82%) of lymphoma cases at 90% specificity. Excluding marginal zone and T‐cell lymphomas, sensitivity increased to 84% (80%–88%). MDMs in plasma show promise to detect lymphoma and are candidates for inclusion in multi‐cancer detection studies.

Background: Major adverse cardiovascular events (MACE), including myocardial infarction, acute coronary syndrome, ischemic heart disease requiring revascularization, stroke, and heart failure, have been documented as significant contributors to mortality in cancer survivors. Coronary artery calcium (CAC) can predict MACE in non-cancer populations, while calcium in the aorta (CA) has not been evaluated as a prognostic marker. Every patient diagnosed with cancer undergoes a standard-of-care Positron Emission Tomography-Computed Tomography (PET-CT) or a chest CT before the initiation of chemotherapy. Hypothesis: To determine whether the CAC or CA of patients with Hodgkin's or non-Hodgkin's lymphoma, derived from standard-of-care PET-CT/chest CT, can predict the incidence of MACE. Methods: Patients treated with anthracycline-based chemotherapy, diagnosed and followed from January 1, 2013, through June 30, 2023, were included. Patients who did not undergo a PET-CT or CT, and/or developed MACE before treatment initiation were excluded. Univariate and multivariate adjusted Cox regression models were employed to assess whether the presence of CAC, CA, or CAC-CA was associated with the development of MACE. Calcium was retrospectively quantified using TeraRecon software (Durham NC) and categorized as: 0, 1-99, and >100. Outcome analyses was estimated using the Kaplan-Meier method. Results: 326 patients were included, mean age of 55 years (range: 52-60), predominantly male 201 (61%) and white 314 (96%), CAC was found in 89 patients and CA in 140. In the univariate regression model, a statistically significant association was found with values >100 for CA, CAC and CAC-CA with the risk of MACE. (Fig 1a/b/c). CAC equal to 0 demonstrated a significant protective effect against MACE. (Fig 1a). In the multivariable analysis, these associations persisted even after adjusting for comorbidities. (Table 1). Conclusion: CAC, CA and CAC/CA >100 in the standard-of-care CT/PET CT are predictors of MACE in lymphoma patients undergoing anthracycline treatment, a CAC equal to 0 has protective effect, these relationships remained statistically significant after adjusting for comorbidities.

Abstract Introduction Anthracyclines (ACs) have been identified as cardiotoxic drugs. They are associated with contractile dysfunction of the heart, which can manifest as heart failure. However, differentiating between HFrEF (left ventricular ejection fractions [LVEF] ≤40%) or HFpEF (LVEF >40%) has been overlooked. Purpose Using a retrospective cohort of patients with breast cancer (BC), Hodgkin (HL) or non-Hodgkin lymphoma (NHL) and controls from the Rochester Epidemiology Project, we evaluated the association of ACs use with risk of HFrEF and/or HFpEF. Methods 797 subjects with BC, HL or NHL diagnosed from 1988 to 2010 were identified, 658 treated with ACs (ACs group) and 139 not treated with ACs (no-ACs group). Controls (n=1526) were subjects without cancer. The median (Q1, Q3) follow up was 11.5 years (7.4, 16.7). Cox proportional hazards regression was used to compare the risk of HFpEF and HFrEF in the three cohorts, adjustment for sex, CV comorbidities (type 2 diabetes [T2D], hypertension [HTN] and dyslipidemia), radiotherapy (RT), and ACs cumulative dose was performed. Results Baseline characteristics are shown in table 1. HFpEF occurred in 29/1526 subjects in the control group, 3/139 in the no-ACs group and in 14/658 in the ACs group. Compared to the control group, there was not an increased risk of developing HFpEF in the no-ACs group (HR 1.67, CI 95%: 0.5 – 5.53, p = 0.39) or in the ACs group (HR 1.83, CI 95%: 0.95 – 3.52, p = 0.06) (Figure 1). Compared with no-ACs group, the ACs group had a similar risk of developing HFpEF (HR 1.09, CI 95%: 0.3 – 3.87, p = 0.88). RT was associated with a lower risk of HFpEF (HR 0.21, CI 95%: 0.06 – 0.75, p = 0.01). In the multivariable analysis, T2D (HR 6.91, CI 95%: 3.07-15.56, p = <0.0001) was associated with higher risk of HFpEF. A cumulative dose of ACs > 250 mg/m2 was not associated with increased risk of HFpEF. HFrEF occurred in 25/1526 subjects in the control group, in 4/139 in the no-ACs group and in 31/658 in the ACs group. Compared to the control group, the ACs group had a significant increase in the risk of HFrEF (HR 4.77, CI 95%: 2.76 – 8.22, p < 0.0001), the no-ACs group did not (HR 2.81, CI 95%: 0.97 – 8.12, p = 0.055) (figure 2). RT was associated with lower risk of HFrEF (HR 0.29, CI 95%: 0.13 – 0.65, p = 0.002). In the multivariable analysis, ACs (HR 4.23, CI 95%: 2.4-7.47, p = < 0.0001) being male (HR 2.45, CI 95%: 1.43 – 4.15, p < 0.0001), smoking history (HR 2, CI 95%: 1.16 – 3.44, p < 0.01), and HTN (HR 3.23, CI 95%: 1.9 – 5.61, p < 0.0001), were associated with higher risk of HFrEF. A cumulative dose of ACs > 250 mg/m2 was not associated with increased risk of HFrEF. Conclusion To our knowledge this is the first study to differentiate between HFpEF and HFrEF in this cohort. ACs were not associated with increased risk of HFpEF. However, ACs were associated with increased risk of HFrEF, but not with a specific dose. These results should be validated in other population cohorts.

Abstract Background Major adverse cardiovascular events (MACE), commonly defined as acute myocardial infarction, acute coronary syndrome/ischemic heart disease requiring revascularization, stroke, and heart failure, represent a significant cause of mortality among patients with cancer. With increased rates of both cancer and cancer survivorship, the identification of new predictive markers for the development of MACE in this population is crucial for implementing effective preventive and risk-mitigation strategies. Purpose To determine whether the presence of calcifications in the coronary arteries (CAC) or aorta (CA) of lymphoma patients, as reported in standard-of-care PET-CT (Positron Emission Tomography-Computed Tomography) or chest CT (Computed Tomography) scan, can predict the occurrence of MACE. Methods A Retrospective analysis was conducted on a cohort of patients diagnosed with Hodgkin or non-Hodgkin lymphoma and treated with anthracycline-based chemotherapy. Patients were diagnosed from January 1, 2013, and followed through to June 30, 2023. The reference point for the study was the radiologist’s report of the PET-CT or chest CT conducted before the initiation of anthracycline therapy. Patients who did not undergo a PET-CT or CT before the start of treatment, and/or developed MACE before treatment initiation were excluded. Univariate and multivariate adjusted Cox regression models were employed to assess whether the presence of CA and CAC was associated with the development of MACE. Associations with outcomes were evaluated using the Kaplan-Meier method and Cox regression. Results 326 patients were included with a mean age of 55 years (range: 52-60), predominantly male 201 (61%) and white 314 (96%), CAC was reported in 75 patients (23%) and CA in 18 (6%). In the univariate regression model, a statistically significant association was found between the presence of both CA and CAC with the risk of MACE. CAC showed a stronger association with the development of MACE than CA (HR: 3.7 [1-7.9], p=0.0005 vs HR: 2.9 [1- 8.5], p=0.050). In multivariable analysis CAC emerged as the strongest predictor of MACE (HR: 2.9 [1.3 – 6.4], p=0.01), after accounting for hypertension, diabetes, dyslipidemia, and GFR <60 (Table 1), while the association with CA attenuated (HR: 2.01 [0.7-6.5], p=0.2010) and was no longer significant (Table 2). Conclusion CAC in the standard-of-care PET/-CT scans was a predictor of MACE in lymphoma patients treated with anthracyclines, while the association with CA weakened in multivariable analyses and was likely underpowered given the small number of patients with CA. If replicated, this finding warrants closer surveillance of this group of patients and can be considered as a non-invasive cardiovascular risk marker.

Abstract Marginal zone lymphoma (MZL) includes extranodal MZL (EMZL), splenic MZL (SMZL), and nodal MZL (NMZL) subtypes. Histologic transformation (HT) to large B-cell lymphomas is well documented but with a large variability in published cumulative incidence rates. We report results from the Molecular Epidemiology Resource (MER) cohort on the cumulative incidence of HT (with death as competing risk) and the associated risk factors and outcomes. We also conducted a meta-analysis of available studies on the cumulative incidence of HT. From 2002 to 2015, 529 patients with MZL were enrolled in the MER study (69% EMZL, 16% SMZL, and 15% NMZL). The 10-year overall survival (OS) from diagnosis was 66%. HT occurred in 21 patients with a 5-year and 10-year cumulative incidence of 2.7% (95% confidence interval [CI], 0.02-0.05) and 3.6% (95% CI, 0.02-0.06), respectively. HT was associated with an increased risk for death (subdistribution hazard ratio [HR], 3.95; 95% CI, 2.06-7.55). Predictors of HT were ≥2 extranodal sites and mucosa-associated lymphoid tissue International Prognostic Index score ≥2. The OS was 79% at 5 years and 55% at 10 years after HT. In the meta-analysis of 12 studies (6161 patients), the 5- and 10-year cumulative incidence of HT across all subtypes were 5% (95% CI, 0.05-0.06) and 8% (95% CI, 0.07-0.09), respectively. These rates were lower in EMZL (3% and 5%) than in SMZL (7% and 13%) and NMZL (9% and 13%). Although HT is relatively uncommon in the first decade after MZL diagnosis, it is associated with an inferior outcome and needs new approaches for prevention and management.