University Hospitals Seidman Cancer Center Research Articles

Abstract A128: A novel approach to understanding disparities in cancer clinical trial enrollment

Abstract Background: Cancer patients who participate in clinical trials have access to novel therapies, increased monitoring, and potentially improved survival. However, this access is not universal. Striking disparities in clinical trial enrollment have been linked to race, sex, and geography. However, studies on this topic are limited due to a lack of patient-specific socioeconomic data. Methods: This analysis used a novel linkage of administrative patient data from University Hospitals Seidman Cancer Center (Cleveland, Ohio) linked to the LexisNexis Socioeconomic Health Attributes, a robust dataset containing 442 patient-specific attributes gathered from public records regarding income, education, housing stability, property ownership and value, social support, and many others. We included cancer patients aged 18-75 years at the time of the latest cancer diagnosis (before trial enrollment if patient was enrolled) during 2007-2022. Because of the substantial differences in the demographic and clinical characteristics between the trial and non-trial patients, we applied the propensity score matching technique to one-to-one match all trial patients to non-trial patients by age, sex, race/ethnicity, cancer type, and year of the latest cancer diagnosis. Next, we applied the classification and regression tree (CART) machine learning algorithm to identify “phenotypes”, or combinations of patient socioeconomic characteristics that predict their trial enrollment status. We additionally performed the random forest algorithm to determine whether our CART model captured the most important variables in predicting trial enrollment. Results: We identified 28,671 cancer patients with a mean and median age of 60 and 62 years. Of those, 2,479 patients were enrolled in trials, and a corresponding 2,479 non-trial patients were matched. We identified 9 phenotypes of trial enrollment from the results of CART. The percentage of patients enrolled in trials ranges from 30% to 80%. Patients belonging to the highest-enrollment phenotype were identified by their estimated annual income exceeding $50,000, higher fraud-risk level, and age under 61 years. Patients falling into the lowest-enrollment phenotype were characterized by an estimated annual income below $30,000, an estimated home value below $243,000, and no college attendance. Variables identified by CART were also among the top-ranked variables in the random forest regarding their variable. Other important variables identified by random forest include, whether the patient ever registered to vote, risk of not being motivated to manage one's own health, and business records. Conclusion: Compared to community-level data, the use of patient-specific socioeconomic data provides a more granular understanding of clinical trial disparities. The use of machine learning methods of CART and random forest offers a promising avenue for future disparities research. This novel approach will deepen our understanding of cancer disparities and improve our ability to intervene and improve care for our most vulnerable patients. Citation Format: Weichuan Dong, Jamie Shoag, Tamila Kindwall-Keller, Ali Kara, John Shanahan, Debora Bruno, Johnie Rose, Siran Koroukian, Richard Hoehn. A novel approach to understanding disparities in cancer clinical trial enrollment [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A128.

Abstract B081: Biological and neighborhood-level social drivers of aggressive prostate disease among Black and White men

Abstract Introduction and study purpose: Prostate cancer (PCa) is the leading type of newly diagnosed cancer and second leading cause of cancer death in American men. Significant racial differences in PCa incidence and mortality have been long-reported in the U.S., with Black men demonstrating a disproportionately higher burden of disease compared to White men. However, some studies conducted in equal access health care settings have revealed equivalent PCa outcomes for White and Black men. Identification of early predictors of prostate disease aggressiveness is essential to avoid over-treatment of clinically favorably disease that is unlikely to progress. This study examines the independent and joint roles of biological and social determinants of health (SDOHs) in predicting prostate disease aggressiveness in a racially diverse cohort of men undergoing biopsy for suspicion of PCa. Methodology: A retrospective cohort study was conducted at the University Hospitals (UH) Seidman Cancer Center in Cleveland, Ohio for the period January 1, 2005-December 2022. A retrospective chart review was conducted to identify eligible men, including White and Black men undergoing transrectal ultrasound-guided biopsy whose biopsy results included the following 3 groups: (i) negative biopsy with a history of 1+ negative biopsy (-ies) and no history of prostate cancer; (ii) biopsy-detected PCa of Gleason sum 6; and (iii) biopsy-detected PCa with metastasis (-es) at initial cancer detection. Detailed clinical and biological specimen data were abstracted and quantitative proteomics analysis of biopsy tissues using mass spectrometry has been conducted at the Pacific Northwest National Laboratory (PNNL). Residential addresses were used to link each man to his census-block group Area Deprivation Index (ADI) score, as a metric of SDoHs. Students t-tests, ANOVAs and Pearson correlation analysis have been performed on the first 60 eligible subjects. Results: This study has generated the entire proteome on the first 60 eligible subjects (“Discovery cohort”) and SDoH metrics have been linked to the first 284 of 300 eligible subjects. Among the first 60 subjects, there was strong separation in proteome profiles for metastatic PCa cases but little separation of Gleason 6 and biopsy negative subjects was observed. Interesting, among the proteins that showed significant correlation with clinical group, few proteins were also significant correlated with subject race. However, several oproteins were strongly associated with SDoHs. Conclusions: Identifying new markers of cancer aggressiveness within and across race has the potential to tailor disease management and identify patients who are likely to benefit from earlier, timely treatment interventions, which will ultimately improve prostate cancer outcomes and quality of life. Upon completion of targeted proteomic analyses, we will perform multi-level modeling to predict prostate disease aggressiveness as a function of protein biomarker candidates in combination with census block group-level SDOHs. Citation Format: Jennifer Cullen, Tao Liu, Karin Rodland, Ranjini Ghosh, Anood Alfahmy, Julia Payne, Sweta Balaji, Holly Hartman, Lee Ponsky, Jonathan Shoag, Gregory MacLennan. Biological and neighborhood-level social drivers of aggressive prostate disease among Black and White men [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B081.

Assessing the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) in Risk-Stratifying Multiple Myeloma Patients for Autologous Stem Cell Transplantation

Background: Hematopoietic stem cell transplant (SCT) is a high-intensity treatment that can cause psychological distress. Pre-transplant psychosocial screening is commonly used to assess mental health, social support, compliance, and health behaviors in HCT centers. However, the optimal standardized approach to psychosocial screening is still being defined. Some studies have shown that pre-transplant psychosocial assessments can predict overall survival (OS) after SCT, while others have found associations with non-relapse mortality (NRM) but not with OS. Single-institution reports consistently indicate that pre-HCT psychosocial assessments are associated with the length of SCT hospitalization and readmission rate. The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is an established tool in the solid organ transplant field that can be used to assess and quantify psychosocial risk, that can help in patient selection and pre-transplant preparation. Objective: This study aimed to validate the SIPAT as a standardized psychological assessment in patients with multiple myeloma (MM) undergoing autologous SCT (ASCT). The primary goal was to analyze the impact of psychosocial risk, as measured by the SIPAT score, on the length of hospital stay and readmission rates within 100 days post-discharge. Secondary outcomes included the risk of infections, progression-free survival (PFS), and overall survival (OS). Methods: This retrospective, single-center study included 87 patients with MM who underwent ASCT between 2019 and 2022 at University Hospitals Seidman Cancer Center. Patient and disease characteristics were collected, and SIPAT scores were recorded for all patients. Patients were grouped based on their SIPAT scores as “Excellent” (score ≤ 6) or “Good” (score > 6). Hospitalization duration during transplant, readmissions, and infections within the first 100 days after ASCT were used as indicators of treatment-related toxicity. Results: 30 patients had an “Excellent” SIPAT score (mean score: 3.47, SD 1.81), while 57 had a “Good” score (mean score: 11.81, SD 5.92). Both groups exhibited similar sex and race distribution, BMI, and KPS scores. The “Excellent” SIPAT group had more patients with HCT-CI scores of 0-2. Both groups had comparable ISS staging and high-risk cytogenetics, along with similar prior lines of treatment and disease status at the time of transplant. Patients in the “Good” SIPAT score group had a higher number of CD34+ cells infused per kg. No significant differences were observed between the groups in terms of engraftment time, hospitalization duration, or rates of hospitalizations and infections within the first 100 days after transplant. Univariate analysis of risk of readmissions showed that BMI had a significant effect (HR 1.09, 95% CI 1.02-1.16, p=0.009) for each unit increase and HCT-CI had a significant effect (HR 5.56, 95% CI 1.39-22.24, p=0.015) for HCT-CI score 3+ compared to 0-2. However, in the multivariable model, these effects did not persist. Conclusions: Although the SIPAT tool is widely used for evaluating different organ transplants, including HCT, a high SIPAT score alone may not be sufficient to risk-stratify candidates for ASCT in MM. Further research and evaluation are warranted to better understand the true predictive value of pre-transplant psychosocial assessments.

OPtimal Treatment by Invoking biologic clusters in renal cell carcinoma (OPTIC RCC)

Abstract Background The first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC) includes immune oncology (IO) based combination therapy. The current standard includes a PD-1 inhibitor plus either an anti-CTLA-4 inhibitor (IO/IO) or an anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGF TKI) (IO/TKI). Currently, there is no evidence to guide a physician’s choice between an IO/IO versus an IO/TKI combination. The phase III IMmotion 151 trial performed RNA-seq from 823 ccRCC tumors and established seven biologically distinct gene expression clusters of ccRCC (Motzer and Rini et al., Cancer Cell 2020). The seven clusters showed differential responses to immune checkpoint inhibitor and may serve as a predictive biomarker to select clusters to assign patients with mccRCC to either an IO/IO (ipilimumab/ nivolumab) or an IO/TKI (nivolumab/cabozantinib) regimen. Methods Patients diagnosed with mccRCC without prior systemic therapy (including in the neoadjuvant or adjuvant setting) and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. RNA-seq will be performed on metastatic tumor specimens and used to assign tumor clusters. Patients with cluster 1/2 tumors will be assigned to the nivolumab/cabozantinib arm. Patients with cluster 4/5 tumors will be assigned to the ipilimumab/nivolumab arm. Cluster 3/6/7 will be excluded. The primary endpoint is overall response rate (ORR) per RECIST 1.1. Key secondary endpoints include progression-free survival, depth of response >80%, and rate of immune-related adverse events (irAEs). The hypothesis is that use of tumor clusters to assign front-line therapy to either nivolumab/cabozantinib or ipilimumab/nivolumab will lead to a 20% greater ORR compared to unselected historical controls in CheckMate 9ER (ORR 55%) or CheckMate 214 (ORR: 40%). This trial adopts Simon’s MiniMax two-stage design (power: 80%, one-sided alpha: 0.1). For the nivolumab/cabozantinib arm, stage I will enroll 12 eligible patients. If there are 7 or more responders in the first 12 patients, stage II will enroll an additional 14 patients (n=26). For the ipilimumab/ nivolumab arm, stage I will enroll 16 eligible patients. If there are 7 or more responders in the first 16, stage II will enroll an additional 12 patients (n=28). The primary endpoint will be met if there are 15 or more responders (ORR>60%). This trial is open and enrolling with 12 patients on study at Vanderbilt University Medical Center and additional sites to open including UT Southwestern, City of Hope, University Hospitals Seidman Cancer Center, and Cleveland Clinic. This trial is funded by the Department of Defense Kidney Cancer Research Program Clinical Trial Award (W81XWH-22-1-1033) (NCT05361720). CDMRP DOD Funding: yes

Abstract C088: Biological and neighborhood-level social determinants of prostate disease aggressiveness among Black and White men undergoing prostate biopsy

Abstract Introduction and study purpose: Prostate cancer (PCa) is the leading type of newly diagnosed cancer and second leading cause of cancer death in American men. Significant racial differences in PCa incidence and mortality have been long-reported in the U.S., with Black men demonstrating a disproportionately higher burden of disease compared to White men. Though some studies conducted in equal access health care settings have revealed equivalent PCa characteristics at diagnosis and comparable PCa outcomes for White and Black men. Identification of early predictors of prostate disease aggressiveness is essential to avoid over-treatment of clinically favorably disease that is unlikely to progress. This study examines the independent and joint roles of biological and social determinants of health (SDOHs) in predicting prostate disease aggressiveness in a racially diverse cohort of men undergoing biopsy for suspicion of PCa. Methodology: A retrospective cohort study was conducted at the University Hospitals Seidman Cancer Center in Cleveland, Ohio for the period January 1, 2005-May 2022. A retrospective chart review was conducted to identify eligible men, including White and Black men undergoing transrectal ultrasound-guided biopsy whose biopsy results included the following 3 groups: (i) negative biopsy with a history of 1+ negative biopsy (-ies) and no history of prostate cancer; (ii) biopsy-detected PCa of Gleason sum 6; and (iii) biopsy-detected PCa with metastases at initial cancer detection. Detailed clinical and biological specimen data were abstracted during retrospective chart review, and quantitative proteomics analysis of biopsy tissues is ongoing, using mass spectrometry, at the Pacific Northwest National Laboratory (PNNL). Multi-level modeling will be conducted to predict prostate disease aggressiveness as a function of protein biomarker candidates in combination with census block group-level SDOHs. Results: This study has achieved its initial goal of assembling a study cohort of 300 eligible men with available biopsy tissue, necessary clinical information, and full street address for assigning census regions. To date, proteomics data have been generated on the first 60 men (“Discovery cohort”) and SDOHs metrics have been linked to the first 180 men. Proteomic profiles and SDOH data will be examined jointly with SDOHs to predict patient clinical phenotype (i.e., metastatic, biopsy Gleason 6, biopsy negative). Conclusions: Identifying new markers of cancer aggressiveness within and across race has the potential to tailor disease management, and identify patients who are likely to benefit from earlier, timely treatment interventions, which will ultimately improve prostate cancer outcomes and quality of life. Predictive modeling that jointly considers biological determinants of cancer disparities in conjunction with neighborhood-level social factors have the potential to elucidate who can be safely spared repeat biopsies, as well as how to optimize cancer care. Citation Format: Jennifer Cullen, Tao Liu, Karin Rodland, Ranjini Ghosh, Anood Alfamy, Julia Payne, Kirsten Eom, Sweta Balaji, Nicole Diaz, Holly Hartman, Annie Liang Zhang, Daniel Spratt, Jonathan Shoag, Erika Trapl, Lee Ponsky, Gregory MacLennan. Biological and neighborhood-level social determinants of prostate disease aggressiveness among Black and White men undergoing prostate biopsy [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C088.

Sex differences in esophageal cancer overall and by histological subtype

Esophageal cancer is the seventh most common type of cancer in the world, the sixth leading cause of cancer-related death and its incidence is expected to rise 140% in the world in a period of 10 years until 2025. The overall incidence is higher in males, while data about prognosis and survival are not well established yet. The goal of this study was to carry out a comprehensive analysis of differences between sexes and other covariates in patients diagnosed with primary esophageal cancer. Data from 2005 to 2020 were obtained from the University Hospitals (UH) Seidman Cancer Center and from 2005 to 2018 from SEER. Patients were categorized according to histological subtype and divided according to sex. Pearson Chi-square test was used to compare variables of interest by sex and the influence of sex on survival was assessed by Kaplan Meier, log rank tests and Cox proportional hazards regression models. A total of 1205 patients were used for analysis. Sex differences in all types were found for age at diagnosis, histology, smoking status and prescriptions of NSAIDs and in SCC for age at diagnosis and alcoholism. Survival analysis didn’t showed differences between males and females on univariable and multivariable models. Males have a higher incidence of Esophageal Cancer and its two main subtypes but none of the comprehensive set of variables analyzed showed to be strongly or unique correlated with this sex difference in incidence nor are they associated with a sex difference in survival.

STEM-17. THE GLIOMA STEM CELL PLATELET INTERACTION DRIVES GBM ONCOGENESIS IDENTIFYING A NOVEL THERAPEUTIC APPROACH

Abstract The effect of platelets on oncogenesis has been studied extensively in cancer metastasis, but not in glioblastoma (GBM), where metastasis is rare. Here we identify the unique crosstalk between glioma stem cells (GSCs) and platelets within GBM solid tumors that enhance disease progression. Targeting GSCs is considered a promising therapeutic approach; however, no clear method has been identified. High platelet counts have been associated with poor clinical outcome in many cancers including ovarian and endometrial cancer. While platelets are known to affect progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Immunofluorescence, qPCR, and western blot were used to evaluate the presence of GSCs and platelets and their colocalization in GBM patient tissue at University Hospitals-Seidman Cancer Center. Functional assays followed by RNA sequencing were conducted to determine the functional effect of healthy and GBM platelets on growth of patient derived, autologous GSCs. Our clinical studies suggest elevated platelet counts positively correlate with GSC proliferation and negatively correlate with overall survival in patients with GBM. Patients with high platelet counts ( >350k/µl) had a median survival time of 9 months compared to 16 months median survival for patients with normal platelet count (150-350/µl) (p<0.05). We demonstrate platelet and GSC co-localization in GBM solid tissue and platelet exposure to patient derived GSCs cell lines results in a ≥ 3-fold increase in GSC proliferation compared to GSCs not exposed to platelets (p<0.0005). Similarly we found that platelets increased the self-renewing capacity by enhancing the average sphere size (p < 0.005), and increasing the GSC “Stem-like” transcriptional pattern (P< 0.05). Conversely, pharmacologic inhibition of platelet activation reversed the effect of platelets on GSC proliferation (p ranging from 0.05-0.005). These studies suggests the platelet-GSC interactions appear to stimulate GBM oncogenesis, identifying a potential therapeutic target for the treatment of GBM.

Development of a Risk Score for Cardiovascular Events in Anthracycline Treated DLBCL Patients

Introduction:There is increased risk of congestive heart failure (CHF) following anthracycline-based chemotherapy in patients with Diffuse Large B-cell lymphoma (DLBCL). Other than increased cumulative anthracycline dose, little is known about risk factors for developing CHF and other cardiovascular events (CVE).Methods:We conducted a retrospective analysis of 539 DLBCL patients diagnosed at University Hospitals Seidman Cancer Center between 2002 - 2016. Baseline patient and disease characteristics, patterns of treatment and outcomes after therapy, including response, survival, relapse, CVE, and causes of death were collected.Time-to-CVE was measured from the date of DLBCL diagnosis to the date of CVE diagnosis and censored at the date of last follow-up for those without CVE, considering death as competing risk. The cumulative incidence of CVE was estimated taking death as competing risk into account. Univariate and multivariable analysis on time-to-CVE was done using Gray's method. Multicollinearity was tested and some of the highly correlated covariables were excluded in the final analysis. CVE risk scores were computed for each patient as a linear combination of the factors included in the multivariable model and their respective coefficients. The optimal cutoff point was identified by searching the spectrum of the risk scores to have the best discrimination of time-to-CVE among patients at low/high risks. All tests were two-sided and p-value ≤ 0.05 were considered statistically significant.Results:We identified 463 patients who received anthracycline to be included in the statistical analysis. Baseline clinical and disease characteristics including comorbidities, clinical risk factors are outlined in Table 1.After a median follow up of 71.1 (range: 0.3 - 216.1) months, 5-year PFS was 59% with median PFS of 82.7 (95% Cl: 71.1 - 115.7) months and 5-year OS was 71% with median OS of 152.6 (95% CI: 127.5 - 162) months.CVE were identified in 92 patients (19.9%), with 128 events identified. The most common CVE was new onset of CHF in 10.4% of patients, followed by atrial fibrillation (4.9%) and asymptomatic heart failure ( 3%) (Table 2).The 3, 6 and 9-year cumulative incidence of CVE for early stage was 13.1%, 15.2% and 18.5%, respectively and 22.2%, 31.4% and 36.5% for advanced stage, respectively (p-value = 0.026). Similarly, the cumulative incidence of CVE was increased in patients with diabetes, with a 3-year cumulative incidence of CVE of 9.4% vs. 17.5% in patients with and without diabetes, respectively.Proportional hazards regression for time-to-CVE identified age >65 years, CD10 expression by IHC, diabetes, and hypertension as significant predictors of time-to-CVE on univariate analysis. On multivariable regression analysis with advanced age at diagnosis, stage, baseline lymphocyte count, and diabetes; stage was still significant in predicting time-to- CVE controlling the effects of advanced age and diabetes, which were also marginally significant.A predictive formula was created to help identify patients at highest risk for cumulative incidence of CVE. Using advanced age (over 65 years of age), baseline lymphocyte count above 800/µL, advanced stage at diagnosis and history of diabetes patients could be stratified into groups with low, intermediate and high risk for CVE (Table 4 and Figure 1).Risk score = Age >65 (3 points) + Lymphocyte count > 800/µL (-1 point) + Stage III/IV(8 points) + Diabetes (3 points) (Table 3)One-year cumulative incidence of CVE was 5.3% for low-risk patients, 7.9% for intermediate risk patients and 13.4% for high risk patients (Figure 1).Conclusions:Our analysis indicates a high risk of CVE in anthracycline treated DLBCL patients, with 19.9% of patients having a CVE in our cohort. The proposed CVE predictive score uses clinical and laboratory parameters routinely collected on all new DLBCL patients and can be easily assessed in the clinical setting. Patients in the high-risk group have a cumulative incidence of CVE of 13.4% at 1 year and would likely benefit from surveillance and interventions. Use of a clinical risk score can aid in the identification of patients at highest CVE risk to conduct studies of surveillance and prevention of this common complication. [Display omitted] DisclosuresBoughan: Beigene: Speakers Bureau. Caimi: Seattle Genetics: Consultancy; Verastem: Consultancy; Amgen Therapeutics.: Consultancy; Kite Pharmaceuticals: Consultancy; TG Therapeutics: Honoraria; ADC Theraputics: Consultancy, Research Funding; Genentech: Research Funding; XaTek: Patents & Royalties: Royalties from patents (wife).

Effect of Histologic Grade on Clinical Outcomes of Follicular Lymphoma: Prolonged Progression Free Survival of Grade 3 Follicular Lymphoma in the Rituximab Era

Introduction: Follicular lymphoma(FL) is a heterogeneous lymphoid malignancy that can be further sub classified into grades 1, 2, 3A and 3B, based on the percentage of centroblasts per high power field. Historically, grade 3A FL has been considered to have a biological and clinical profile akin to grades 1-2 FL whereas grade 3B FL is considered to have a clinical presentation and treatment outcome similar to diffuse large B cell lymphoma (DLBCL). We examine the impact of FL grading and sub classification on initial treatment choice and outcomes in a cohort of FL subjects diagnosed in the rituximab era.Methods: We accessed the Hematological Malignancies database of University Hospitals Seidman Cancer Center to retrieve data on FL patients (pts) diagnosed between 2002 and 2014. Demographic data, laboratory and disease characteristics were recorded. We excluded pts with incomplete follow up data and any unclassified FL cases. Biopsies from all available grade 3 FL cases were reviewed by a hematopathologist for sub classification into grade 3A or 3B FL categories. The outcomes of grade 3 FL patient cohort were separately compared with contemporaneous cohorts of patients diagnosed with grade 1-2 FL and germinal center B cell (GCB) subtype of DLBCL. The Kaplan-Meier method was used to assess overall survival (OS) and progression-free survival (PFS). Two-tailed log-rank test compared OS and PFS curves. All analyses were performed using IBM SPSS Statistics 2015.Results: We identified 227 FL pts with complete clinical information. Approximately one third of pts (n=62, 27%) had grade 3 FL (grade 3A, n = 35, grade 3B, n = 24; unclassified, n = 2). Comparisons between baseline characteristics and initial therapy of grade 1-2 FL and grade 3 FL are presented in Table 1. While baseline demographic characteristics were not different, the rate of transformation was higher in grade 3 FL. Use of cytotoxic chemo-immunotherapy and anthracycline was more common in grade 3 FL.Median OS was not reached for the whole FL cohort. We did not observe a statistically significant difference in OS between grade 1-2 FL and grade 3 FL. Grade 3 FL presented a higher PFS compared with grade 1-2 FL (5-year PFS 61% vs 41%, p=0.016) (Figure 1). To examine the effect of histologic grade on outcomes after therapy, we limited the analysis to subjects treated with chemo-immunotherapy as initial treatment: 5 year PFS was longer for patients diagnosed with grade 3 FL (61% vs 43 %, p=0.015). Limiting the analysis to subjects treated only with first line anthracycline-containing chemo-immunotherapy also demonstrated grade 3 FL presenting with a longer PFS (5-year PFS 61 % vs 31 %, p<0.001). Further subgroup analysis comparing only grade 3A FL (n=35) pts with the anthracycline treated grade 1-2 FL (n=57) demonstrated longer 5-year PFS in the grade 3A cohort (p<0.001). (Figure 2). Consistent with previous reports, there were no differences in baseline clinical features, PFS or OS between the grade 3A and grade 3B FL patient cohorts. Further comparison of outcomes of grade 3A FL in our cohort had a similar PFS to GCB DLBCL (5 year PFS 62% vs 56 %, p=0.188).Conclusion: In this retrospective study of outcomes of follicular lymphoma in the rituximab era, we observed that patients diagnosed with grade 3 FL have better PFS than patients diagnosed with lower grade FL. This improved outcome appears to be independent of the choice of initial therapy, with an apparent plateau in the risk of relapse of patients diagnosed with grade 3A FL, suggesting a subgroup of these subjects can receive front line treatment with curative intent. [Display omitted] DisclosuresMalek:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau. Cooper:Novartis: Research Funding. de Lima:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding. Caimi:Abbvie: Equity Ownership; Seattle Genetics: Equity Ownership; Incyte: Equity Ownership; Celgene: Speakers Bureau.

Central Nervous System Relapse in Diffuse Large B Cell Lymphoma—Predictors at Diagnosis

Background Central nervous system (CNS) relapse of diffuse large B cell lymphoma (DLBCL) is an infrequent outcome with very poor prognosis. Initial studies have identified risk factors for CNS relapse and the CNS international prognostic score ((CNS-IPI) (Schmitz et al, JCO 2016) has been validated in various cohorts. Biologic characteristics of the disease are not included in the derivation of this model. We sought to validate this risk factor model in our single center DLBCL population in search for additional disease - specific factors that could further improve prediction of CNS relapse.Methods The hematologic malignancies database of the University Hospitals Seidman Cancer Center was accessed to identify newly diagnosed DLBCL patients between 2002 and 2014. Patients with extra-nodal CNS involvement at diagnosis were excluded. Through retrospective chart review data, we identified patient and disease characteristics, and outcomes data including response, relapse and death was collected. Patients who underwent therapy and had follow up data were included for final analysis. Univariate Cox proportional hazards analysis was conducted on the risk factors and those reaching statistical significance (p < 0.05) were selected for inclusion in multivariate proportional hazards model to help identify predictors for CNS relapse. CNS IPI score was applied to our population and cumulative incidence (with death as competing risk) was used to estimate the incidence of CNS relapse with the Gray test performed for comparisons between groups.Results: Five hundred and twenty-four patients were included for final analysis. Median age in our cohort was 64 years, with 312 (59.5 %) patients above the age of 60 years. 322 (63 %) patients had stage (III-IV), and 220 patients (37%) had elevated LDH at diagnosis. Two hundred and eighty five patients had extra-nodal disease involvement at the time of diagnosis with 88 patients involving more than one site. Baseline patient and disease characteristics are listed in Table 1. Four hundred (76%) patients received R CHOP as first line therapy, 395 patients achieved complete remission with first line therapy. At a median follow up of 64 months, 187 patients died and 171 patients had relapsed.Twenty-one patients developed CNS relapse in the follow up period, at median of 8.2 months after treatment initiation (95% CI 6.2-9.6) months. Applying the CNS-IPI risk scoring among the evaluable patients, 149 patients (36%) were found to be low risk (0-1 factors), 222 patients (53%) were intermediate risk (2-3 factors) and 47 patients (9%) were high risk (4-6 factors) for CNS relapse. Univariate analysis showed advanced stage (stage III-IV), number of extra-nodal sites involved, liver involvement, non- GCB subtype, translocation t (14; 18) and body mass index were significantly associated with CNS relapse (p<0.05). In multivariate analysis, only non- GCB subtype and translocation t (14; 18) (p = 0.023 and 0.028 respectively) were significant. Table 2 summarizes the results of Cox proportional hazards analysis.We evaluated the cumulative incidence of CNS relapse in the high-risk group, defined as CNS-IPI >1, (n=269, 64%). The 2-year CNS relapse cumulative incidence was at 5.1 % (95% CI: 2.8- 9%) compared to 0% for patients with CNS IPI ≤ 1 (p=0.027) (Figure 1).Median survival after CNS relapse was 3.6 months (0 - 150.2 months). Overall survival from start of initial therapy was 16 months (95% CI 9.5 -81.9 months) for patients with CNS relapse vs 170 months (95% CI 120.3 months - not reached), p<0.001]. (Figure 2)SummaryPrognosis of CNS relapsed of DLBCL is very poor. CNS IPI score helps identify a cohort that may benefit from CNS prophylaxis, and may help avoid unnecessary diagnostic and therapeutic intervention in the low risk cohort, i.e., CNS- IPI score <1. Hepatic involvement at diagnosis may be an additional clinical characteristic associated with high risk of CNS relapse. Biological features including non-GCB subtype and translocation t (14; 18) are novel risk factors that should be considered in the development of future risk models. [Display omitted] DisclosuresMalek:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau. Cooper:Novartis: Research Funding. de Lima:Celgene Corporation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Caimi:Seattle Genetics: Equity Ownership; Abbvie: Equity Ownership; Incyte: Equity Ownership; Celgene: Speakers Bureau.

Early Cardiovascular Toxicity with Treatment of Follicular Lymphoma Is Associated with Shorter Overall Survival

Introduction: The clinical course of follicular lymphoma (FL) is characterized by recurrent relapses and progressively shorter remissions, with many patients surviving beyond one decade from initial diagnosis. During this time, patients will receive several courses of therapy, which can be complicated by significant toxicities, particularly in elderly patients with multiple comorbidities. While the incidence and outcomes of cardiovascular toxicities observed in subjects with aggressive lymphomas treated with anthracycline based chemotherapy are well known, there is limited information regarding the incidence of cardiovascular events (CVE) in FL patients, many of whom have historically received similar antineoplastic regimens. We conducted a retrospective study to observe the incidence of CVE in FL patients from the time of diagnosis and their effect on patient outcomes.Patients and Methods: We accessed the Hematologic Malignancies Database of University Hospitals Seidman Cancer Center to identify patients diagnosed with FL between 2002 and 2014. We collected patient data including baseline demographics and risk factors, disease characteristics, treatments prescribed and outcomes, including response, relapse, and incidence of CVE. Multivariate logistic regression modeling was performed to identify risk factors associated with incidence of CVE. Cumulative incidence (with death as competing risk) was used to estimate the incidence of CVE. The Kaplan-Meier method was used to assess overall survival (OS) and progression-free survival (PFS). Two-tailed log-rank test compared OS and PFS curves. All analyses were performed using IBM SPSS Statistics 2015.Results: Two hundred and twenty-seven FL patients were included for analysis. Median age at diagnosis was 60 years, with 161 patients presenting with advanced stage FL (71%). Approximately two thirds of patients had intermediate or high-risk disease by FLIPI at diagnosis (n= 147, 65%). Decreased ejection fraction at diagnosis was identified in 5 patients (2.2%). Baseline characteristics and initial therapy choice are summarized in Table 1. A total of 143 patients (63%) received chemo-immunotherapy as part of their initial therapy, which included an anthracycline in 99 subjects (44%).After a median follow up of 66 months, 52 patients (23%) have died. Forty-two patients (18.5%) presented with CVE, with 2 and 5 - year cumulative incidence of 6.4 % (95% CI, 3.9-10.6%) and 13.5% (95% CI, 9.5-19.2%) respectively. Twenty- three patients (10%) developed congestive heart failure while 9 (4%) had an acute coronary syndrome or required coronary artery disease revascularization. Multivariate analysis (Table 2) identified age > 60 years, male gender, prior history of coronary artery disease and anthracycline treatment were independent risk factors for CVE.Patients who were prescribed systemic or local therapy after initial diagnosis of FL had a higher cumulative incidence of CVE than patients who were observed initially (5-year cumulative incidence 15.8% vs 9.6 %, respectively) (p=0.043). In addition, subjects who received anthracycline-based therapy at any point in the treatment course presented a higher cumulative incidence of CVE than those never treated with anthracyclines (5-year cumulative incidence 19.1% vs 8.2%, respectively) (p=0.019). The 5-year OS of patients who developed a CVE within 2 years of diagnosis was 56% (95% CI, 27.3-85.6%) versus 85% (95% CI, 80.1-90.3%) in patients who did not develop an early CVE (p=0.048) (Figure 1)Conclusion: Cardiovascular events in patients diagnosed with FL have a significant effect on their OS. Patients who require treatment are at increased risk of developing cardiovascular events, particularly those treated with anthracycline-based chemo-immunotherapy. Continued investigation is necessary to determine whether novel therapies have the same effect in cardiovascular risk. Interventions to identify, monitor and ameliorate cardiovascular risk factors in patients with FL should be investigated to improve survival. [Display omitted] DisclosuresMalek:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau. Cooper:Novartis: Research Funding. de Lima:Celgene Corporation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Caimi:Abbvie: Equity Ownership; Incyte: Equity Ownership; Celgene: Speakers Bureau; Seattle Genetics: Equity Ownership.

Prognostic Impact of Morphological Cellularity in Early Assessment Bone Marrow Biopsy after 7+3 Induction in Patients with Acute Myeloid Leukemia

Background:Blast clearance in early assessment bone marrow biopsy (BMBx) is well studied as a potential prognostic factor for newly diagnosed acute myeloid leukemia (AML) patients (pts). However, prognostic impact of morphological cellularity in early assessment BMBx remains unclear.Methods:We retrospectively identified newly diagnosed AML pts, treated at University Hospitals Seidman Cancer Center between 2003 and 2016, who underwent early assessment BMBx after median of 13 days (range: 12 - 17) from initiation of 7+3 induction chemotherapy. Eventual outcome of induction was defined per Cheson criteria. Risk groups were determined by combining cytogenetic and molecular data based on the National Comprehensive Cancer Network guidelines. Overall survival (OS), calculated from date of diagnosis, and relapse free survival (RFS), calculated from date of first complete remission (CR), were estimated by the Kaplan-Meier method and compared by the log-rank test. Risk factors identified as having statistical significance on univariate Cox proportional hazards analysis (p<0.05) were selected for multivariate analysis.Results: We screened 501 newly diagnosed AML pts and identified 183 AML pts who meet our inclusion criteria for analysis. Median age at diagnosis was 58.3 (range: 25.8 - 76.2). Patient and treatment characteristics are listed in Table 1.After analyzing different cut-off points, ≥10% morphological cellularity in early assessment BM biopsy yielded greatest differential in OS and RFS. Therefore optimal and suboptimal response cohorts were defined as <10% and ≥10% cellularity in early assessment BMBx, respectively. One hundred (55%) pts had optimal and 72 (39%) pts had suboptimal response. Eleven (6%) pts were unclassifiable because cellularity was not mentioned as a numerical value (Figure 1). In the optimal response cohort; 5 (2%) pts underwent second induction after early assessment BMBx and 95 (98%) pts were observed, with CR rate of 80% and 86%, respectively. Among 13 (14%) pts who didn't achieve CR after observation, 12 pts underwent second induction, with CR rate of 25%, and 1 pt died before second induction. In the suboptimal response cohort; 40 (56%) pts underwent second induction after early assessment BMBx and 29 (40%) pts were observed, with CR rate of 70% and 59%, respectively. Twelve (41%) pts who didn't achieve CR after observation underwent second induction, with CR rate of 42%. Overall 50 (69%) pts in the suboptimal response cohort and 88 (88%) pts in the optimal response cohort ultimately achieved CR after either first or second induction.Among observed patients, who did not receive early 2nd induction, ≥10% cellularity in early assessment BMBx was reliable as a predictive tool for CR (specificity 83%, negative predictive value 86%) but it was not reliable as a predictive tool for no-CR (sensitivity 48%, positive predictive value 41%).Median follow-up of pts was 28 months since diagnosis. Two-year OS for pts with optimal and suboptimal response at early assessment BMBx was 59.9% (CI 50.1% - 71.5%) and 33.3% (CI 23.4% - 47.3%), respectively (p= 0.001) (Figure 2A). When we censor pts at their first transplant to remove effect of transplant on survival curves, 2-year OS for pts with optimal and suboptimal response at early assessment BMBx was 77.8% (CI 65.7% - 92.0%) and 44.6% (CI 27.1% - 73.4%), respectively (p= 0.003) (Figure 2B). Two-year RFS for pts with optimal and suboptimal response at early assessment BMBx was 49.5% (CI 39.6% - 61.9%) and 29.9% (CI 19.6% - 45.6%), respectively (p= 0.015) (Figure 2C). On univariate analysis, poor-risk group by cytogenetic and molecular data, hemoglobin (<8.8 g/dL), secondary AML, >5% blast and ≥10% cellularity at early assessment BMBx showed statistically significant correlation with OS (Table 2). On multivariate analysis, only poor-risk group and ≥10% cellularity at early assessment BMBx remained to be statistically significant predictors of OS.Conclusions:In our cohort of pts with AML, ≥10% morphological cellularity in early assessment BMBx provided strong independent predictive value for OS, whereas >5% blast was not an independent risk factor. Our findings indicate that ≥10% cellularity in early assessment BMBx can be part of overall risk stratification tools and the definition of hypoplasia should include <10% cellularity when considering early assessment biopsies. [Display omitted] DisclosuresCooper:Novartis: Research Funding. Caimi:Incyte: Equity Ownership; Celgene: Speakers Bureau; Seattle Genetics: Equity Ownership; Abbvie: Equity Ownership. Malek:Celgene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees. De Lima:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding.

Analysis of Racial Differences in the Incidence of a Targetable Biomarker, t(11;14), in Patients with Multiple Myeloma

Introduction Compared with Caucasian Americans (CA), African Americans (AA) have an increased incidence of multiple myeloma (MM), earlier age at diagnosis, and overall better prognosis [1]. The molecular mechanisms underlying such racial disparity are not well understood. Using targeted next generation sequencing assay or traditional fluorescence in situ hybridization (FISH) methods, previous studies reported that t(11;14) is more common in AA compared with CA with MM and monoclonal gammopathies [2,3]. However, the number of AA cases studied were small and conflicting data exists. Clinical trials in relapsed or refractory MM indicate that t(11;14) is a biomarker which may be used to predict response to a therapeutic agent (venetoclax) which targets BCL-2 [4,5]. Identifying racial differences in molecular biomarkers would be helpful in our understanding of the known racial disparities of incidence in MM and in the development of therapeutic trials. Methods 737 patients with newly diagnosed MM or smoldering myeloma (SM) at University Hospitals Seidman Cancer Center between 2009 and 2020 were identified. All had myeloma FISH panel sent at diagnosis, which included trisomy of chromosomes 3, 7, or 11, deletion 13q14.3 or loss of chromosome 13, deletion 17p13.1, 1q21 (CKS1B) amplification, and 14q32.3 rearrangements. IGH/CCND1 [t(11;14)(q13;q32)] dual fusion probe was used prior to 2018. Extra signal would trigger reflex test for IGH/FGFR3 [t(4;14)(p16.3;q32)] and IGH/MAF [t(14;16)(q32;q23)]. IGH break apart probe was used since 2018. IGH rearrangement would trigger reflex testing for translocation partners as listed above. Between-group differences were assessed with T-test for continuous variables, and Chi-square / Fisher's exact test for categorical variables. Results Of the 737 patients (661 MM, 76 SM), 502 (68.1%) were self-reported as CA, 213 (28.9%) were AA, and 22 (3.0%) were of other races or listed as unknown. Median age was 71 among CA and 70 among AA (p=0.67). The male-female ratio was 291/211 (58% male) among CA and 101/112 (47% male) among AA (p=0.0095). Overall t(11;14) was detected in 4.5% of cases, 5.2% CA and 2.8% AA (p=0.165); among 661 MM, t(11;14) was tested positive in 30/656 (4.57%), including 23 (5.1%) CAs, 6 (3.1%) AAs, and 1 others (p= 0.80); among 76 SM, t(11;14) was tested positive in 3/76 (3.95%), all were CAs. The percentages of patients who tested positive for other cytogenetic abnormalities were as follows: trisomy 3,7, or 11 was detected in 35.6% CA and 32.4% AA (p=0.42); 1q21 amplification was detected in 25.5% CA and 23.9% AA (p=0.72); deletion 13q14.3 or loss of chromosome 13 was detected in 16.5% CA and 10.7% AA (p=0.08); deletion 17p13.1 was detected in 6.4% CA and 5.2% AA (p=0.54); t(4;14) was detected in 2.8% CA and 1.4% AA (p=0.27); t(14;16) was detected in 0.4% CA and 0.5% AA (p=0.89) Conclusions This retrospective series of 737 MM and SM patients did not find an increased incidence of the targetable biomarker t(11;14) in AA patients. The overall percentage of t(11;14) cases was lower than expected. The lack of our finding a racial difference differs from some other reports, perhaps due to a fairly enriched AA population. There were also no significant racial differences found in other cytogenetic abnormalities. Further investigation at the molecular level should be performed to elucidate the mechanisms of racial disparity in MM.

Use of simulation for training family caregivers of patients receiving radiation therapy.

TPS12129 Background: Positive treatment outcomes and avoidance of complications are dependent to a large extent on the care provided by family members. However, family caregivers report feeling unprepared to assume the multiple, complex tasks of caregiving, including tracheostomy care, tube feedings, wound and colostomy care, pain management, and emotional support. Despite being a critical extension of the oncology healthcare team, training of caregivers to manage symptoms, deal with communication issues with the care recipients, and take care of their own physical and emotional health as caregivers, is not integrated into clinical practice. The purpose of this clinical trial is to measure the effect of a psychoeducational caregiver intervention that incorporates simulation techniques focused on skill development to improve caregiver and patient outcomes. Simulation, commonly used in training healthcare professionals, is a form of experiential learning that creates events or situations to mimic clinical situations. Use of simulation for skills training in family caregivers of patients with cancer is rarely studied. Methods: This two-group, randomized clinical trial, which opened to accrual in December 2019, will recruit 180 caregivers from University Hospitals Seidman Cancer Center. Patients must be receiving radiation therapy for a diagnosis of stage I - III cancers of the rectum, anus, and esophagus; stage III NSCLC; or stage I – IV A/B head/neck cancer. Adult caregivers must be identified by the patient as their primary caregiver, who is providing daily assistance and/or emotional support. The intervention involves three in-person, one-on-one sessions during radiation treatments. The control group is usual care. Data will be collected at baseline, at the end of radiation treatment, and 4 and 20 weeks post-radiation treatment. The primary outcome is caregiver anxiety at 20 weeks postradiation treatment. Other caregiver outcomes include depression, health-related quality of life [HRQOL], and fatigue. Patient outcomes (HRQOL and interrupted treatment course) and healthcare utilization outcomes (unplanned hospital admission, emergency room visits, and use of intravenous fluids) will be measured. The analysis will consist of linear mixed model repeated measures, mediation and moderation tests, and Poisson regression methods. Clinical trial information: NCT04055948 .

Lymphoma-Specific Venous Thromboembolism Score (LyV-Score): Use of Lymphoma Subtype to Refine Risk Prediction

Background: Patients (pts) diagnosed with non-Hodgkin lymphoma (NHL) have increased risk of venous thromboembolic event (VTE). Retrospective studies have observed the risk of VTE is not the same across lymphoma subtypes, with aggressive subtypes having higher risk than indolent lymphomas. Current VTE prediction models such as the Khorana score (K-Score) consider all lymphomas as having equal risk of VTE. We conducted retrospective time - based analyses to develop a VTE prediction model that includes lymphoma subtype as a risk factor. Methods: We accessed the Hematologic Malignancies Database at University Hospitals Seidman Cancer Center and collected records of pts diagnosed with diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL) between 2000 and 2016. Pts with CNS involvement or active anticoagulation were excluded. FL grade 3B pts were included in the DLBCL cohort. Information retrieved included demographic characteristics, baseline disease and laboratory parameters, as well as comorbidities and diagnosis of VTE, including radiographic confirmation. Time to VTE was measured from the date of NHL diagnosis to the date of VTE incidence or censored at the date of last follow-up for those without VTE. Cumulative incidence of VTE was estimated using Kaplan-Meier method and its difference among groups was examined by log-rank test. Cumulative incidence of VTE was also calculated considering death as competing risk and comparisons done using the Gray test. Cox proportional hazards model was used to evaluate the effect of continuous and categorical covariates on cumulative incidence of VTE and to identify prognostic factors of VTE. Fifty percent of the study participants were randomly assigned to training cohort or reserved as an independent validation cohort. Performance of multivariate models was evaluated using the Akaike Information Criterion (AIC) and Concordance Index (C-Index). The final models built using the training dataset were further validated using the validation cohort. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. Results: We identified 627 pts with DLBCL (n=421) or FL (n=206) with available baseline characteristics, (Table 1). After a median follow up of 48 months (range 1-191), 77 pts experienced a VTE after NHL diagnosis. The cumulative incidence of VTE at 4 years for the whole cohort was 10.5% (95% CI 8.3-13.2). DLBCL pts had a significantly higher 4 - year cumulative incidence of VTE: 13.7% (95% CI 10.8-17.5) vs. 4.0% (95% CI 2.0 - 7.9) in FL pts (p &lt;0.0001)(Figure 1). Univariate analysis on the training cohort showed that lymphoma subtype (DLBCL vs. FL) was associated with incidence of VTE (p = 0.02); other baseline variables associated with VTE include ECOG performance status, bulky disease, history of VTE, and serum albumin, calcium, WBC count and WBC subtypes (Table 2). Analysis of overall performance of multivariate models, including the K-Score as well as the variables identified in univariate analysis, demonstrated that the addition of lymphoma subtype and albumin to the K-Score improved the C-Index and the AIC (Table 3). The Lymphoma-specific VTE Score (LyV-Score) including lymphoma subtype, presence of bulky disease, baseline WBC and serum albumin resulted in improved performance, with C-Index of 0.775 and AIC of 234.913. To further evaluate the performance of the LyV-Score model, we performed time - dependent ROC and calibration analyses. When applied to the training cohort, 2 and 4-year AUC for the LyV-Score were 0.7767 and 0.7463, respectively, whereas for the K-Score 2 and 4-year AUC were 0.6215 and 0.6032 (Figure 2). Time - based ROC analyses in the validation cohort confirmed the higher AUC achieved by the LyV-Score. Cumulative incidence analyses show the LyV-Score and the K-Score identified groups with statistically significant differences in VTE risk (Figure 3), these differences were more marked between groups identified by the LyV-Score. Conclusions: VTE risk models have considered all lymphoma subtypes as risk factor for VTE. We show this risk is not equivalent for all lymphoma subjects, with aggressive lymphoma patients presenting higher VTE risk. We have developed the LyV-Score as a VTE prediction model that incorporates NHL histologic subtype. This model shows improved performance over historic VTE risk models and can help identify lymphoma patients that may benefit from interventions to prevent VTE. Disclosures Malek: Celgene: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Medpacto: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Adaptive: Consultancy. Metheny:Takeda: Speakers Bureau; Incyte: Speakers Bureau. Caimi:Genentech: Research Funding; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau.

Venous Thromboembolism (VTE) in Sickle Cell Disease (SCD) Is Associated with Neutrophilia

Introduction Venous thromboembolic events (VTE) are a frequent complication of patients with sickle cell disease (SCD). The estimated incidence of thrombosis is 25% and is associated with increased morbidity and mortality. Recent studies have implicated leukocytes and their subsets in development and propagation of VTE in malignancies and inflammatory diseases. However the role of leukocytes have not been elucidated in SCD. We conducted a retrospective study to precisely study the association of leukocytes and their subsets in VTE. Methods We accessed the medical records of patients with SCD who presented to University Hospitals Seidman Cancer Center from 2004 to 2018. Information collected included demographic characteristics, comorbidities, laboratory parameters as well as treatment details. Patient records were reviewed for VTE with radiographic confirmation. Cases were defined as patients with SCD with diagnosed VTE and controls were SCD patients without VTE. Cases and controls were matched for age, gender, red blood cell (RBC) genotype and treatment. We included twice as many controls as cases for the study. Inclusion criteria were age greater than 18 years and were followed up at the outpatient sickle cell clinic. Patients were excluded if they had infection, thrombophilia, neoplasm, pregnancy or arterial thrombosis. For cases, lab parameters at the time of the VTE were recorded. Since most patients with VTE were diagnosed during an admission, lab parameters for controls were also recorded during an admission for pain crises. For both cases and controls, steady state lab data 3 months prior to their admission was also recorded and compared. Data was analyzed using STATA SE 15 version. Mann-Whitney U test was used to analyze continuous variables and Fischer's exact test was used to analyze discrete variables. P-values less than 0.05 were considered significant. Results A total of 263 records were reviewed of which 97 patients were eligible for the study. There were 35 patients with VTE and 62 patients without VTE. Baseline characteristics are presented in Table 1. Compared to controls, patients with VTE had more comorbidities such as avascular necrosis (AVN; p = 0.0038), pulmonary hypertension or albuminuria (pHTN; p= 0.032), higher body mass index (BMI) (p = 0.038) and had more hospitalizations (p &amp;lt; 0.001). Due to small number of patients, the comorbidities were analyzed as a group across all genotypes. A complete list of comparison of comorbidities is summarized in Table 2. When compared to controls, patients with VTE as a group had higher total white blood cell count (WBC) and neutrophil count (p=0.0032 and p = 0.0006 respectively) at the time of event. When RBC genotype was taken into account, patients with SC and SS genotype had a significantly elevated neutrophil count whereas only patients with SS genotype had a higher WBC count compared to controls (Please refer to Table 3). When compared to controls, cases as a group also had WBC and neutrophil count 3 months prior to the event (p=0.025 and p=0.020 respectively). Patients with SS and SC patients had a significantly higher WBC count 3 months prior compared to their non VTE counterparts (Please refer to Table 4) No other comorbidity or lab parameter was found to be significantly different between cases and controls. A multivariate analysis could not be performed due to small study numbers. Conclusion Our study is the first to show that VTE in SCD was associated with higher neutrophil counts 3 months prior to the event suggesting that patients with baseline or steady state leukocytosis and neutrophilia are at increased risk of thrombosis. Larger studies are needed to confirm this association. In addition, patients with VTE also had higher incidence of comorbidities such as AVN, pHTN or albuminuria and increased hospitalizations. Given the small number of patient, a multivariate analysis was not possible. While the association between pHTN and VTE is well documented; the association of AVN and higher BMI with VTE described here is novel and needs further exploration with larger studies. Disclosures Little: Hemex Health, Inc.: Patents &amp; Royalties; GBT: Research Funding.

Building Family Caregiver Skills Using a Simulation-Based Intervention: A Randomized Pilot Trial.

To evaluate the feasibility, acceptability, safety, and fidelity of a psychoeducational intervention to improve family caregiver technical and communication skills using structured simulations. 18 family caregivers of adult patients receiving radiation therapy for head and neck cancer at University Hospitals Seidman Cancer Center in Cleveland, Ohio. A two-group, randomized pilot trial design was used. The intervention consisted of four one-on-one sessions between the caregiver and nurse interventionist during the patient's first, second, fourth, and sixth week of radiation treatment. Participants completed measures of self-efficacy for caregiving, anxiety, depression, and health-related quality of life at baseline, during the fifth week of radiation therapy, and four weeks after radiation therapy. 4 of the 9 caregiver participants completed the intervention. Improvements in scores for the intervention group were noted for self-efficacy, global mental health, anxiety, and depression. Refinement of the intervention is needed to improve feasibility. Although a caregiver intervention that incorporates simulation for skills training is acceptable and safe, flexibility in protocol is needed.

Patterns of Care of Diffuse Large B Cell Lymphoma Patients 80 Years and Older: Worse Outcomes after Treatment without Increased Relapse

Introduction: Very advanced age (≥80 years) DLBCL patients have worse prognosis. These unfavorable outcomes are largely considered to be a result of the combined effects of increased comorbidities, frailty, diminished tolerance and access to effective chemoimmunotherapy. It is not clear yet whether DLBCL patients of very advanced age have disease that is intrinsically more aggressive.Methods: We accessed the Stem Cell Transplant and Hematologic Malignancies database of University Hospitals Seidman Cancer Center for DLBCL patients diagnosed between 2000 and 2016. Information collected included demographic characteristics, baseline laboratory and disease information, as well as treatment details. Progression free survival and overall survival were calculated from time of diagnosis using Kaplan Meier methodology, comparisons were done with log rank. Cumulative incidence of relapse with death as competing risk was calculated for patients who underwent treatment, comparisons between age groups were done with the Gray test.Results: A total of 542 DLBCL patients were identified, 85 (16%) were older than 80 years. Table 1 shows the baseline demographic and disease characteristics. Older patients had a higher incidence of comorbidities, specifically cardiovascular comorbidities, prior renal insufficiency, and hyperlipidemia. Expectedly, very elderly patients had higher R-IPI, with a trend towards worse performance status that did not reach statistical difference. The proportion of patients diagnosed with non - germinal center DLBCL was not different than younger DLBCL patients, and there was no statistical difference in the incidence of double expressor or double hit lymphomas, possibly secondary to the small number of patients tested.A smaller proportion of patients ≥ 80 years received antineoplastic therapy (89% vs. 98%, p = 0.001), and use of less intense therapy was more common (table 2). Sixty one percent of patients, however, were still treated with R-CHOP (38.8%) or R-miniCHOP (22.2%). The overall response rate (ORR) for any therapy was 68.2%, lower than the ORR for younger patients (85.9%, p = 0.007). When only patients treated with RCHOP/R-miniCHOP were included, the difference in ORR was smaller, though still statistically significant (77.5% vs. 89.8%, p = 0.021). Median number of cycles was similar (5 vs. 6 cycles, respectively). Patients of all ages treated with single agent rituximab presented an ORR of 43%.After a median of 40 months follow up, estimated 4-year overall survival was 42% (95% CI 31-54%) for patients ≥ 80 years, 67% for patients aged between 60 and 79 years (95% CI 61-74%) and 78% for patients < 60 years (95% CI 73-84%) (Figure 1). Four - year survival for patients ≥80 years treated with R-CHOP or R-miniCHOP chemoimmunotherapy was 50% (95% CI 36-65%) vs. 75% for younger patients (95% CI 70-79%) (p<0.001), with 4-year PFS of 48% vs. 63% (95% CI 58-68%) (p = 0.04). Cumulative incidence of relapse (with death in remission as competing risk) for chemoimmunotherapy - treated patients at 1 and 4 years was 10% (95% CI 4-22%) and 20% (95% CI 11-37%), respectively for patients older than 80 years and 20% (95% CI 11-36%) and 29% (95% CI 25-35%), respectively for younger patients (p = 0.12) (Figure 2). There was no observed difference in the rates of disease - related mortality (53% vs. 61%, p = 0.5).Conclusions: Very elderly (≥80 years of age) DLBCL patients have significantly worse overall survival, progression free survival, and treatment response rates than younger patients. However, when chemoimmunotherapy is feasible, disease relapse rates are comparable to those of younger patients, and increased mortality does not appear to be a result of increased disease relapse. Additional research is needed to establish more widely applicable, better tolerated effective treatment regimens for this patient population. DisclosuresLazarus:Pluristem Ltd.: Consultancy. Malek:Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Tomlinson:Foundation Medicine: Consultancy. Caimi:Genentech: Other: Advisory Board PArticipation, Research Funding; Kite Pharma: Other: Advisory Board Participation; Celgene: Speakers Bureau; Kite Pharma: Other: Advisory Board Participation.

Hypoxia Enhanced Red Cell Adhesion in Vitro May Identify Patients at Risk for Vasculopathy

Background:Priapism is a serious complication associated with Sickle Cell Disease (SCD) that may be a manifestation of underlying vasculopathy. The Centers for the Study of Complex Diseases of Childhood (CSCCD), comprising independent Comprehensive Sickle Cell Centers, demonstrated an association of priapism with hemolysis.1 Previously, we identified two groups of people with SCD based on red blood cell (RBC) adhesion under hypoxic conditions: those patients whose RBCs showed hypoxia-enhanced adhesion (HEA) and those whose did not (non-HEA).2 Patients with HEA had evidence for more hemolysis in vivo. Here, we aimed to examine (1) the association of HEA with hypoxia in vivo, and (2) RBC adhesion in normoxic and hypoxic conditions in male patients with or without a history of priapism.Methods:This retrospective study was conducted at the Adult Sickle Cell Disease Clinic at the University Hospitals Seidman Cancer Center, in Cleveland, OH between 2015 to 2018. Blood samples were obtained from 26 male subjects (29 samples, 25 HbSS and 1 HbSS HPFH). Adhesion experiments were performed as previously reported by passing surplus whole blood through LN-immobilized microchannels at physiological conditions under both normoxic and hypoxic conditions.2,3 Adherent RBCs were then quantified with microscope after a wash step. The median value was used for data analyses from multiple samples obtained from an individual. Chart review was conducted to examine results of hypoxia testing obtained in vivo as part of routine clinical care.Results:Male subjects with HbSS and a history of priapism had higher HEA in comparison to subjects without a history of priapism (3268 ± 5647 vs. 122 ± 1218, p=0.016). However, there was no significant difference between RBC adhesion of the two groups under normoxic conditions (529 ± 1528 vs. 402 ± 280). More male subjects with priapism had hypoxia in vivo (10 out of 14) than subjects without priapism (5 out of 12). Compared to male subjects with a history of priapism, those without a history of priapism had lower lactate dehydrogenase levels (474 ± 267 vs. 290 ± 215, p=0.008).Conclusions: Our data showed that subjects with a history of priapism had a higher HEA and tended to have more evidence for hypoxia in vivo than did subjects without a history of priapism. Further, male subjects with hypoxia in vivo had more HEA than did those without hypoxia in vivo (not shown). Hypoxia in vivo may cause increased RBC damage (reflected by HEA), hemolysis, nitric oxide depletion, and consequent vasculopathy, resulting in priapism. Hypoxia may be treatable, when identified in subjects with a history priapism in vivo or possibly with HEA in vitro. This could plausibly modify disease severity in some cases.

The Direction of KIR Ligand Incompatibility Is Associated with Graft Failure and May Predict the Dominant Donor Following Double Umbilical Cord Blood Transplantation

While there is plausible evidence suggesting the benefit of natural killer (NK) cell alloreactivity in post-transplantation outcomes, there is no consensus on how such alloreactivity can be best predicted when selecting unrelated graft donors. Epitopes of HLA Class I molecules HLA-B and HLA-C are the ligands for inhibitory killer immunoglobulin-like receptors (KIRs) that regulate NK cell cytotoxicity. Based on the hypothesis that NK cell licensing in the bone marrow selects for circulating NK cells with corresponding inhibitory KIRs for self KIR ligands (KIR-L), these ligands, as determined by HLA-B/C antigens have been used as surrogates to predict NK cell alloreactivity in mismatched transplants. There is also the potential for alloreactivity by NK cells in the host versus graft (HvG) direction particularly in cord blood transplantation where reduced intensity conditioning is common. We examined cord blood transplantations at our institution to determine the impact of donor/recipient KIR ligand mismatch, and its direction, on graft failure.Methods: We analyzed the Stem Cell Transplant database of all cord blood transplants (CBT) performed at University Hospitals Seidman Cancer Center between December 2010 and April 2018. Data extracted from electronic medical record review included demographics, indication for transplant, disease status at time of transplant, conditioning regimen, graft versus host disease (GVHD) prophylaxis including the use of antithymocyte globulin (ATG) and post transplantation outcomes. For the cohort we computed KIR ligands for transplant recipients and cord blood unit(s), then predicted direction of alloreactivity using the KIR ligand calculator available online (https://www.ebi.ac.uk/ipd/kir/ligand.html). We determined the relative risk of developing graft failure as well as summary statistics of time to neutrophil engraftment and achieving a stable lymphocyte count of 500/ul or more in those that engrafted.Results: We identified 67 patients that received cord blood transplants for which donor and recipient KIR-L could be adequately computed. Three of these patients required a second cord blood transplant for graft failure, resulting in a total of 70 CBTs. Demographics, disease characteristics and treatment regimens are outlined in Table 1. There were KIR-L mismatches (MM) in the HvG and GvH direction in 32 and 31 recipient-cord blood unit pairs respectively. While there were no KIR-L MM in 26 transplants, 7 transplants had KIR-L mismatches in both GvH and HvG directions. There was an increased risk of graft failure in recipients of HvG-directed KIR-L MM transplants (R.R 2.15; p=0.063) with this trend most significant when the mismatch was in HLA-C ligand (R.R 2.46; p=0.027); Table 2. Out of 8 double CBTs where 1 cord unit had HvG-directed KIR-L MM, the non-mismatched unit fully engrafted in 7 (75%) cases. In 1 case the non-mismatched unit shared donor chimerism with the KIR-L MM unit at 85% and 15% respectively till 10 months post-transplant. In 6 double CBTs where there was KIR-L MM from only 1 cord unit in the GvH-direction, 4 (67%) of such units became the dominant graft. Of 8 double CBTs in which both cord units had KIR-L MM in the HvG direction there was graft failure in 3 (37.5%). The time to neutrophil engraftment and lymphocyte recovery in the patients that engrafted was not significantly impacted by KIR-L incompatibility (Table 3).Conclusions: From this study we see an increased likelihood of graft failure when KIR-ligand incompatibility exists in the host versus graft direction for CBT. There is also a trend in favor of engrafting the cord unit that is KIR-L mismatched in the graft versus host direction against the second cord in double CBT. These factors should be considered when selecting cord units for double CBT as well as in making single cord decisions where multiple options are available. [Display omitted] DisclosuresLittle:Hemex: Patents & Royalties: Patent, no honoraria; Doris Duke Charitable Foundations: Research Funding; PCORI: Research Funding; NHLBI: Research Funding. Malek:Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.