Cerhan, James R.

Abstract Monoclonal B-cell lymphocytosis (MBL) is a common hematological premalignant condition that is understudied in screening cohorts. MBL can be classified into low-count (LC) and high-count (HC) types based on the size of the B-cell clone. Using the Mayo Clinic Biobank, we screened for MBL and evaluated its association with future hematologic malignancy and overall survival (OS). We had a two-stage study design including discovery and validation cohorts. We screened for MBL using an eight-color flow-cytometry assay. Medical records were abstracted for hematological cancers and death. We used Cox regression to evaluate associations and estimate hazard ratios and 95% confidence intervals (CIs), adjusting for age and sex. We identified 1712 (17%) individuals with MBL (95% LC-MBL), and the median follow-up time for OS was 34.4 months with 621 individuals who died. We did not observe an association with OS among individuals with LC-MBL (P = .78) but did among HC-MBL (hazard ratio, 1.8; 95% CI, 1.1-3.1; P = .03). Among the discovery cohort with a median of 10.0 years follow-up, 31 individuals developed hematological cancers with two-thirds being lymphoid malignancies. MBL was associated with 3.6-fold risk of hematological cancer compared to controls (95% CI, 1.7-7.7; P < .001) and 7.7-fold increased risk for lymphoid malignancies (95% CI:3.1-19.2; P < .001). LC-MBL was associated with 4.3-fold risk of lymphoid malignancies (95% CI, 1.4-12.7; P = .009); HC-MBL had a 74-fold increased risk (95% CI, 22-246; P < .001). In this large screening cohort, we observed similar survival among individuals with and without LC-MBL, yet individuals with LC-MBL have a fourfold increased risk of lymphoid malignancies. Accumulating evidence indicates that there are clinical consequences to LC-MBL, a condition that affects 8 to 10 million adults in the United States.

Abstract Low-grade B-cell lymphomas other than follicular and small lymphocytic lymphoma (LGBCL) account for 10% of all B-cell non-Hodgkin lymphomas. Despite improvements in survival outcomes for these patients, little is known about cause of death (COD) in the rituximab era. For a better understanding, we studied 822 newly diagnosed patients with marginal zone, lymphoplasmacytic, and unclassifiable low-grade B-cell lymphoma prospectively enrolled in the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource from 2002 to 2015. COD was assigned based on medical record review using a standard protocol. At a median follow-up of 107 months, 219 (27%) patients had died. The incidence of lymphoma-related deaths when pooling across subtypes was lower than non–lymphoma-related deaths (10-year incidence, 8.0%; 95% confidence interval [CI]: 6.2-10.4 vs 13.6%; 95% CI: 11.2-16.6). The incidence of lymphoma-related deaths varied by subtype, ranging from 3.7% at 10 years in extranodal marginal zone lymphoma to 19.3% in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Patients with early progression or retreatment events, defined using event-free survival at 24 months from diagnosis, had significantly higher likelihood of lymphoma-related death compared with patients without early events (10-year estimate: 19.1% vs 5.1%, respectively; P < .001), whereas the rates for non–lymphoma-related death were comparable in patients with or without early events (10-year estimates: 11.0% vs 15.3%, respectively). In conclusion, the most common COD in LGBCLs in the first decade after diagnosis was for causes other than lymphoma. Progression or retreatment within the first 2 years of diagnosis was a strong predictor for risk of lymphoma-related death.

Abstract Cancer clinical trial eligibility criteria may create patient populations studied in trials that do not reflect the patient populations treated in the real-world setting. Follicular lymphoma (FL) is an indolent lymphoma with heterogeneous presentations across a broad range of individuals, resulting in many acceptable management strategies. We evaluated how first-line clinical trial eligibility criteria impacted the demographic makeup and outcomes of patients with FL for whom systemic therapy might be considered. We compared the characteristics of 196 patients with FL from a single institution to eligibility criteria from 10 first-line FL trials on clinicaltrials.gov. Next, we tabulated eligibility criteria from 24 first-line FL protocols and evaluated their impact on 1198 patients with FL with stages II to IV disease from the prospective Molecular Epidemiology Resource (MER) and Lymphoma Epidemiology of Outcomes (LEO) cohort studies. We found that 39.8% and 52.7% of patients with FL might be excluded from clinical trials based on eligibility criteria derived from clinicaltrials.gov and protocol documents, respectively. Patients excluded because of renal function, prior malignancy, and self-reported serious health conditions tended to be older. Expanding stage requirement from III-IV to II-IV, and platelet requirement from ≥150 000 to ≥75 000 increased population size by 21% and 8%, respectively, in MER and by 16% and 13%, respectively, in LEO, without impacting patient demographics or outcomes. These data suggest that management of older individuals with FL may not be fully informed by recent clinical trials. Moreover, liberalizing stage and platelet criteria might expand the eligible population and allow for quicker trial accrual without impacting outcomes.

Abstract Background: DLBCL is the most common non-Hodgkin lymphoma subtype in western countries and is clinically heterogeneous. Gene expression profiling has identified two major biologically distinctive DLBCL subtypes defined by their cell-of-origin (COO): germinal center B-cell (GCB) - characterized by BCL2 rearrangement and C-REL amplification, and activated B-cell (ABC) - characterized by constitutive activation of the NF-kB pathway. We evaluated putative DLBCL risk factors for etiologic heterogeneity as defined by COO. Methods: We used a clinic-based study of newly diagnosed NHL cases and frequency matched controls, enrolled from 2002-2014, with a total of 687 DLBCL cases and 2253 controls for this analysis. Using formalin-fixed, paraffin-embedded tumor tissue, we determined COO by either digital expression profiling (NanoString; classified as GCB, ABC, undetermined) or clinically using the Hans algorithm (immunohistochemical markers; classified as GCB, non-GCB, undetermined). Integrating these two sources of COO data, there were 271 GCB, 170 non-GCB, and 246 undetermined/missing (mainly due to lack of tissue) cases. Risk factor data were collected from self-administered questionnaires and included family history of hematologic malignancy; history of atopy, allergy, asthma, eczema, or autoimmune disease; blood transfusion; vaccination history; regular low-dose aspirin use; body mass index (BMI) 2 years prior diagnosis/enrollment; smoking history; alcohol consumption (never/current/former); leisure-time physical activity; and recreational sun exposure. Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals for COO subtypes, adjusted for age, sex and residence. Results: The median age of cases was 64 years with 55% male; the median age of controls was 64 years and 53% male. The association with BMI (30+ vs. 18.5-24.9 kg/m2) was stronger for non-GCB (OR=2.21; 1.40-3.49) than for GCB (OR=1.70; 1.21-2.40) DLBCL (P-heterogeneity 0.02), while a family history of hematologic malignancy was associated with non-GCB (OR=2.27; 1.47-3.50) but not GCB (OR=1.30; 0.86-1.96) DLBCL, although the P-heterogeneity was not significant (P=0.13). For GCB, there was an inverse association with former (vs. never) alcohol use for GCB (OR=0.57; 0.39-0.83) but not for non-GCB (OR=0.98; 0.61-1.57) DLBCL (P-heterogeneity 0.007), and an inverse association with regular use of low-dose aspirin for GCB (OR=0.64; 0.47-0.87) but not for non-GCB (OR=0.88; 0.61-1.25) DLBCL (P-heterogeneity 0.05). No other risk factors evaluated showed important heterogeneity by COO. Conclusions: These initial results suggest most DLBCL risk factors do not show etiologic heterogeneity by DLBCL COO, although associations with BMI and family history with non-GCB DLBCL and alcohol and low-dose aspirin use with GCB DLBCL warrant follow-up. Citation Format: Geffen Kleinstern, Dennis P. Robinson, Lisa M. Rimsza, Melissa C. Larson, Rebecca L. King, Grzegorz S. Nowakowski, Carrie A. Thompson, Stephen M. Ansell, Matthew J. Maurer, Andrew L. Feldman, Susan L. Slager, Anne J. Novak, Thomas M. Habermann, James R. Cerhan. Evaluation of etiologic heterogeneity for risk of diffuse large B-cell lymphoma (DLBCL) subtype defined by cell-of-origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 741.

Abstract MBL is a common pre-malignant condition characterized by circulating clonal B-cells with an absolute B-cell count <5x109/L and no lymphadenopathy, organomegaly, or cytopenias. MBL is the precursor to CLL. The incidence of cutaneous SCC in CLL is significantly higher compared to controls. The incidence of SCC in MBLs has not yet been determined. Study participants from the Mayo Clinic Biobank who had no prior history of hematologic malignancy, were 40 years or older, and were Olmsted County residents completed a health questionnaire and provided blood samples between 7/2009 and 12/2020. Stored peripheral blood mononuclear cells were screened for MBL using flow cytometry. We defined three MBL immunophenotypes: CLL-like MBL (CD5+, CD20dim), atypical MBL (CD5+, CD20+), and non-CLL-like MBL (CD5-, CD20+). MBL individuals were also classified by cell count into low-count MBL (LC-MBL) and high-count MBL (HC-MBL), with HC-MBL having a percent clonal B-cell count ≥85%. Data on newly diagnosed SCC was abstracted from the medical records, and prior history of skin cancer before sample collection was ascertained from patient questionnaires. Individuals were followed from sample date to the earliest of SCC, death, loss to follow-up, progression, or 12/31/2020. Cumulative SCC incidence was adjusted for competing risk of death. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CIs) adjusted for age and sex. A total of 5,470 participants were screened for MBL and included 949 (17%) with LC-MBL, 63 (1%) with HC-MBL, and 4,458 (81%) controls (negative for MBL). Individuals with HC-MBL (median age 75 years) or LC-MBL (median age 73 years) were significantly older (P<0.001) than controls (median age 66 years). There were 41 (65%) males among HC-MBL, 447 (47%) among LC-MBL, and 1,551 (35%) among controls. Prior skin cancer history was highest among HC-MBLs (N=17, 27%) or LC-MBLs (N=236, 25%) compared to controls (N=767, 17%). After a median follow-up of 18 months (range 0-138), 154 of the 5,470 individuals were identified to have incident SCC following MBL screening. At least one SCC was observed in 3 individuals with HC-MBL, 33 individuals with LC-MBL, and 118 controls. The 5- and 10-year cumulative incidence of SCC in individuals with MBLs was 7% and 16%, respectively; control estimates were 4% and 8%, respectively. However, after adjusting for age and sex, we observed no evidence of an association between MBL and risk of incident SCC (HR=0.95, CI=0.65-1.40, P=0.80), nor when we stratified individuals by age or by sex (all P>0.05). In the largest MBL screening cohort to date, individuals with MBL do not have an increased risk of incident SCC compared to controls. In contrast to individuals with CLL, these individuals with screening MBL do not need increased dermatologic examination for skin cancer, which is important given the high prevalence of MBL (18% of the population above age 40). Citation Format: Ahmed Nadeem Ansari, Sara J. Achenbach, Sameer A. Parikh, Geffen Kleinstern, Aaron D. Norman, Kari G. Rabe, Connie E. Lesnick, Timothy G. Call, Janet E. Olson, James R. Cerhan, Neil E. Kay, Celine M. Vachon, Esteban Braggio, Curtis A. Hanson, Tait D. Shanafelt, Christian L. Baum, Susan L. Slager. Incidence of squamous cell carcinoma (SCC) in a large screening cohort of monoclonal B-cell lymphocytosis (MBL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5256.

Abstract Background: An elevated risk of developing non-Hodgkin's lymphoma (NHL) has been associated with a family history of NHL and several other malignancies, but the magnitude of risks and mechanisms are uncertain. Methods: We used self-reported family history data from a recent multicenter U.S.-based case-control studies of NHL to evaluate familial aggregation of NHL with various hematolymphoproliferative and other cancers. Estimates of familial aggregation were obtained as hazard ratios (HR) that compare incidence of different cancers in first-degree relatives of NHL cases with that in the first-degree relatives of NHL controls. Limitations of the study included low participation rates (76% for cases and 52% for controls) and potential differential accuracy of recall. Results: Risk of NHL was elevated in relatives of NHL cases [HR, 2.9; 95% confidence interval (95% CI), 0.95–8.53]; the aggregation seems to be stronger for siblings (HR, 7.6; 95% CI, 0.98–58.8) and for male relatives (HR, 6.2; 95% CI, 0.77–50.0). Risk of Hodgkin's lymphoma seems to be also elevated among relatives of early-onset (<50 years) NHL cases (HR, 3.2; 95% CI, 0.88–11.6). Evaluation of family history of other cancers provided modest evidence for an increased risk of melanoma of the skin (HR, 2.9; 95% CI, 1.08–7.75), pancreatic cancer (HR, 2.1; 95% CI, 0.96–4.43), stomach cancer (HR, 1.8; 95% CI, 0.91–3.63), and prostate cancer (HR, 1.3; 95% CI, 0.87–1.99). Conclusions: These results are consistent with previous findings of familial aggregation of NHL, Hodgkin's lymphoma, and a few other cancers. The pattern of male-specific and sibling-specific familial aggregation of NHL we observed, if confirmed, may shed new light on the possible mechanisms that underlie familial aggregation of the disease.

Abstract Overweight [body mass index (BMI) 25.0-29.9 kg/m2] and obesity (BMI ≥30 kg/m2) are risk factors for several malignancies. The Iowa Women's Health Study was examined to determine whether increased BMI was associated with leukemia development. Over 40,000 Iowa women (ages 55-69 years) completed a self-administered lifestyle and health questionnaire in 1986 that included current height and weight. Two hundred women developed leukemia during the period 1986 to 2001 including 74 acute myelogenous leukemia (AML) and 88 chronic lymphocytic leukemia. The risk of AML was increased among women who reported being overweight or obese (relative risk, 1.9; 95% confidence interval, 1.0-3.4; relative risk, 2.4; 95% confidence interval, 1.3-4.5; Ptrend = 0.006) compared with women of normal weight. There was little evidence of a positive association for chronic lymphocytic leukemia (Ptrend = 0.6). Given the prevalence of overweight and obesity in the United States, the population attributable risk of AML due to obesity could approach 30%.

Abstract In 1997, the American Institute for Cancer Research (AICR) published 14 recommendations related to diet for individuals to reduce cancer incidence on a global basis; smoking was also discouraged. We operationalized these into nine recommendations that are particularly relevant to western populations in a cohort of 29,564 women ages 55 to 69 years at baseline in 1986 who had no history of cancer or heart disease. The cohort was followed through 1998 for cancer incidence (n = 4,379), cancer mortality (n = 1,434), cardiovascular disease (CVD) mortality (n = 1,124), and total mortality (n = 3,398). The median number (range) of recommendations followed was 4 (0-8), and 33% of the cohort had ever smoked. Women who followed no or one recommendation compared with six to nine recommendations were at an increased risk of cancer incidence [relative risk (RR) 1.35, 95% confidence interval (CI) 1.15-1.58] and cancer mortality (RR 1.43, 95% CI 1.11-1.85), but there was no association with CVD mortality (RR 1.06, 95% CI 0.78-1.43). We calculated the population attributable risk (PAR) to estimate the proportion of cancer incidence, cancer mortality, and CVD mortality that theoretically would have been avoidable if the entire cohort had never smoked, had followed six to nine recommendations, or had done both. The PARs for smoking were 11% (95% CI 10-13) for cancer incidence, 21% (95% CI 17-24) for cancer mortality, and 20% (95% CI 16-23) for CVD mortality. The PARs for not following six to nine recommendations were 22% (95% CI 12-30) for cancer incidence, 11% (95% CI −5 to 24) for cancer mortality, and 4% (95% CI −20 to 19) for CVD mortality. When smoking and the operationalized AICR recommendations were combined together, the PARs were 31% (95% CI 19-37) for cancer incidence, 30% (95% CI 15-40) for cancer mortality, and 22% (95% CI 4-36) for CVD mortality. These data suggest that the adherence to the AICR recommendations, independently and in conjunction with not smoking, is likely to have a substantial public health impact on reducing cancer incidence and, to a lesser degree, cancer mortality at the population level.

7573 Background: While most patients (pts) with follicular lymphoma (FL) usually have favorable outcomes, those with refractory disease after first-line anti-CD20 based immunochemotherapy (IC), or progression within 24 months of diagnosis (POD24) have higher risk of premature death. There are no standard approaches for treating this vulnerable group and studies testing novel agents are ongoing in this setting. We sought to investigate clinical practice treatment choices and efficacy for pts with POD24 that align with eligibility criteria for the randomized SWOG1608 which compares IC with novel agents in this population. Methods: This was a multicenter observational cohort study from the LEO Consortium. Eligible pts had grade 1-3a FL diagnosed between 1/1/2002 and 2/1/2019, and initiated therapy after POD24 to first-line bendamustine or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) based IC. Observation, radiotherapy, or rituximab monotherapy were permitted prior to IC and pts with transformation prior to the subsequent therapy after IC were excluded as per S1608. Outcomes of interest were overall and complete response rate (ORR/CR), progression-free survival (PFS), and overall survival (OS). Results: We identified 196 eligible pts with early progression to IC (39% antiCD20 Benda; 61% antiCD20 CHOP) who received subsequent therapy. Median age at post IC treatment was 57 years, 78% grade 1-2 FL. Treatments for pts with POD24 included CHOP- or Benda-based in 31%, salvage/hematopoietic stem cell transplant (HSCT) in 27%, novel therapies in 10% (including phosphatidylinositol 3-kinase inhibitors), antiCD20 monotherapy in 9%, and lenalidomide-based treatment in 8% (table); 21% of pts were treated on clinical trials. Across all treatments, ORR (CR) was 63% (37%) (95% CI: 55-70). At a median follow up of 6.2 years, 2 year PFS was 22% (95% CI: 17%-29%) and 5 year OS was 71% (95% CI: 65-79). Outcomes by regimen are shown in the table. Conclusions: Pts with FL experiencing POD24 following first-line IC are treated heterogeneously, with many pts still receiving IC as subsequent therapy. Despite modest CR rates and low 2-year PFS, 5-year OS appear to be improving compared to historical outcomes. This supports the ongoing need to investigate novel treatments in this population. [Table: see text]

7562 Background: Lymphoma is the 6th most common cancer and a top 10 cause of cancer deaths. To date, there are no blood test approaches to population screening, and accurate surveillance markers are limited. Methylated DNA markers (MDMs) are broadly informative for early detection of cancer but have not been extensively studied for lymphomas. We sought to discover and validate MDMs in DNA extracted from lymphoma tissue, then test these MDMs in archival blood plasma specimens. Methods: Reduced representation bisulfite sequencing (RRBS) was performed on DNA extracted from a discovery set of frozen tissues of classic Hodgkin lymphoma (CHL, n=24), non-Hodgkin lymphoma (NHL, n=78: T-cell-TCL (8); diffuse large B-cell-DLBCL (18); follicular-FL (12); mantle cell-MCL (20); marginal zone-MZL (15)), and lymphoma cell line samples (27); controls included benign lymph node (n=11) and healthy donor buffy coat (n=30). 30 MDMs were ranked by fold-change and AUC and used to design methylation-specific PCR assays for biological validation on independent DNA samples extracted from FFPE tissue from 13 normal lymph node and 63 lymphoma samples and 36 buffy coats from healthy patients. Target enrichment long-probe quantitative-amplified signal assays were developed for 16 MDMs and then assayed in plasma-extracted, bisulfite-converted DNA samples from 390 independent treatment-naïve lymphoma patients (100 CHL and 290 NHL:100 DLBCL, 73 FL, 41 MCL, 41 MZL, 35 TCL), and 210 controls without cancer. Lymphoma plasma samples and 159 controls were provided by the Lymphoma SPORE (CA97274); 51 controls came from a 7-county population archive. Classification of lymphoma cases vs controls was modeled with random forest method and cross-validated across 500 bootstrap samples of each dataset. Results: For MDMs tested in DNA from independent biological validation samples, cross-validated random forest models identified 60/63 cases (95% sensitivity) and 12/13 normal controls (92% specificity). In plasmas, a panel of 16 MDMs ( ZNF503, VWA5B1, HOXA9_5195, GABRG3, ITGA5, MAX_chr17_793, BNC1_2407, CDK20, MAX_chr4_184, TPBG, DNAH14, SYT2, CACNG8, FAM110B, and NRN1) detected 78% (95% CI, 74-82%) of lymphoma cases at 90% specificity. Excluding MZL and TCL, sensitivity increased to 84% (80-88%) including 26/49 (53% (38-67%)) of stage I and 59/71 (83% (71-90%)) of stage II cases. Conclusions: MDMs show promise to detect lymphoma. These markers could be evaluated as part of multicancer early detection testing and could also be evaluated as response markers to treatment and subsequent surveillance.[Table: see text]