Lurie Comprehensive Cancer Center Research Articles

Advancing survivorship at a comprehensive cancer center: integrating clinical care, education and research initiativesat NorthwesternMedicine and the Robert H. Lurie Comprehensive Cancer Center.

The unprecedented and growing number of cancer survivors requires comprehensive quality care that includes cancer surveillance, symptom management, and health promotion to reduce morbidity and mortality and improve quality of life. However, coordinated and sustainable survivorship care has been challenged by barriers at multiple levels. We outline the survivorship programs at Northwestern Medicine and the Robert H. Lurie Comprehensive Cancer Center that have evolved over two decades. Our current survivorship clinics comprise STAR (Survivors Taking Action and Responsibility) for adult survivors of childhood cancers; Adult Specialty Survivorship for survivors of breast, colorectal and testicular cancers, lymphomas, and leukemias; and Gynecologic Oncology Survivorship. Care provision models align with general, disease/treatment-specific, and integrated survivorship models, respectively. Reimbursement for survivorship services has been bolstered by institutional budget allocations. We have standardized survivor education, counseling, and referrals through electronic health record (EHR)-integrated survivorship care plan (SCP) templates that incorporate partial auto-population. We developed EHR-integrated data collection tools (e.g., dashboards; SmartForm, and registry) to facilitate data analytics, personalized patient referrals, and reports to the Commission on Cancer (CoC). We report to the CoC on SCP delivery, dietitian encounters, and DEXA scans. For the last decade, our Cancer Survivorship Institute has aligned the efforts of clinicians, researchers, and educators. The institute promotes evidence-based care, high-impact research, and state-of-the-science educational programs for professionals, survivors, and the community. Future plans include expansion of clinical services and funding for applied research centered on the unique needs of post-treatment cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: The survivorship programs at Northwestern Medicine and the Robert H. Lurie Comprehensive Cancer Centerunderscore the imperative for comprehensive, coordinated, and sustainable survivorship care to address the needsof increasing numbers of cancer survivors, with a focus on evidence-based clinical practices, associated research,and educational initiatives.

0855 Patient-reported sleep symptoms across four cycles of chemotherapy among adults with lymphoma: A pilot study

Abstract Introduction Sleep disturbance is one of the primary symptoms reported by cancer survivors before, during, and after treatment. To better understand trajectories of sleep disturbance over the course of chemotherapy, we evaluated patient-reported symptoms among adults being treated for lymphoma. Methods Participants were 18-74 years old, English-speaking, and scheduled to be treated with a full course of anthracycline-based chemotherapy. Among other assessments, participants completed a battery of patient-reported outcome measures prior to the first cycle of chemotherapy (T1) and on the final days of the second (T2) and fourth (T3) cycles. Sleep symptoms were assessed with the Insomnia Severity Index (ISI), PROMIS Sleep Disturbance (PROMIS-SD), and PROMIS Sleep-Related Impairment (PROMIS-SRI) measures. Given the small sample size, descriptives and effect sizes were calculated rather than conducting inferential analyses. Results Participants were 9 adults with Hodgkin’s (n=5) or Non-Hodgkin’s (n=4) lymphoma, mean age 41 years (SD=13.9), mostly male (89%), White (78%), and non-Hispanic (89%). The majority had higher scores on the ISI (85.7%), PROMIS-SD (71.4%), and PROMIS-SRI (71.4%) at T2 than T1, demonstrating more sleep disturbance mid-chemotherapy than prior to chemotherapy. Conversely, the majority had lower scores at T3 than T2 (ISI: 80.0%, PROMIS-SD: 80.0%, PROMIS-SRI: 100.0%), demonstrating less sleep disturbance at late-chemotherapy than mid-chemotherapy. For most participants scores remained higher at T3 than T1 (all 3 measures: 75.0%), indicating more sleep disturbance at late-chemotherapy than pre-chemotherapy. Averaged across participants, differences in scores from T1 to T2 were small-to-medium (ISI: Hedges’ g=0.42, PROMIS-SD: g=0.44, PROMIS-SRI: g=0.62), from T1 to T3 were small (ISI: g=0.26, PROMIS-SD: g=0.26, PROMIS-SRI: g=0.23), and from T2 to T3 were medium-to-large (ISI: g=0.98, PROMIS-SD: g=0.73, PROMIS-SRI: g=0.53). Conclusion Patient-reported sleep symptoms worsened over the first two cycles of anthracycline-based chemotherapy. Symptoms improved over the subsequent two cycles; however, for most participants they remained worse than baseline levels. Pending replication in a larger sample, intervening before initiating chemotherapy or during the early cycles thereof may be beneficial to diminish sleep disturbance among patients with lymphoma. Support (if any) The project described was supported by the Robert H. Lurie Comprehensive Cancer Center. RSF was supported by NCI grant #K08CA247973. EH was supported by NHLBI grant #K01HL152009.

Abstract CT051: Double lung transplant registry aimed for lung-limited malignancies (DREAM) - a prospective registry study of bilateral lung transplantation for medically refractory cancers confined to the lungs

Abstract Background: According to a consensus document from the International Society for Heart and Lung Transplantation (ISHLT), adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are listed as ‘special circumstances’ for lung transplantation (Weill D et al., 2015). There have been five reported studies of lung transplantation in carefully selected subsets of patients with multifocal lung adenocarcinoma (Raemdonck DV et al., 2016; Glanville AR et al., 2018). The 5-year survival rate of bilateral sequential lung transplantation was estimated at over 50% in patients with multifocal BAC, invasive adenocarcinoma, and NSCLC (Ahmad U et al., 2012; Paloyan EB et al., 2000; Zorn GL et al., 2003; de Perrot M et al., 2004). In 1999, a case series reported a post-transplant recurrence-free survival of 23 to 56 months in three patients (Garver RI et al., 1999). There is also an unmet need for patients who have lung-limited metastasis after successful treatment for primary tumors such as sarcomas or colorectal cancer (CRC). As with liver transplantation for CRC patients who have liver-confined metastases (Dueland S et at., 2020; Hernandez-Alejandro R et al., 2022), the applicability of lung transplantation in lung-limited metastasis patients should be explored. Methods: This is a prospective registration trial to evaluate outcomes of patients who undergo lung transplantation for the treatment of the select groups of medically refractory cancers (primary lung cancers or metastatic cancers in lungs). Overall survival (OS), disease-free survival (DFS), allograft rejection (AR) and allograft survival (AS) will be monitored as well as molecular and genetic biomarkers to investigate the correlation with prognosis. The study duration will be 10 years including surveillance. Recruitment to occur during the first 5 years of the study. The goal is to enroll 175 participants through the Lurie Comprehensive Cancer Center of Northwestern University. Essential Criteria: The tumor should be without any involvement of mediastinal lymph nodes involvement confirmed by endobronchial ultrasound (EBUS) or mediastinoscopy. The patient who are resistant or refractory to or without available standard of care treatment options or experimental treatment options that are known to increase survival outcome. Study cohorts: • Cohort A: Primary lung cancers - Examples include, but not limited to, invasive mucinous/non-mucinous non-small cell lung cancers and multifocal carcinomas. • Cohort B: Metastatic cancers to the lung only - Examples include, but not limited to, germ cell tumors, head & neck tumors, colorectal tumors, renal cell tumors, testicular cancers. Clinical trial registry number: NCT05671887. Enrollment began November 16, 2022. Trial is open and recruiting as of January 12, 2023. Citation Format: Young Chae, Liam Il-Young Chung, Rade Tomic, Ankit Bharat. Double lung transplant registry aimed for lung-limited malignancies (DREAM) - a prospective registry study of bilateral lung transplantation for medically refractory cancers confined to the lungs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT051.

Abstract P2-20-15: Proteolytic regulation of CD73 by TRIM2 orchestrates tumor immunogenicity

Abstract Proteolytic regulation of CD73 by TRIM2 orchestrates tumor immunogenicity Ziyi Fu1,2, Siqi Chen3, Yueming Zhu4, Donghong Zhang4, Ping Xie3, Qiao Jiao4, Shipeng Xu1, Yifan Xue6, Xinhua Lu6, Xinxin Song7, Massimo Cristofanilli8, William J Gradishar3, Kevin Kalinsky5, Yongmei Yin2, Bin Zhang3 and Yong Wan4,5* 1Department of Obstetrics and Gynecology, Department of Pharmacology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, USA. 2Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, China 3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, USA. 4Department of Pharmacology and Chemical Biology, Winship Cancer Institute, Emory University School of Medicine, USA. 5Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, USA. 6Department of Biomedical Informatics, University of Pittsburgh School of Medicine, USA. 7Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA. 8Department of Medicine, Weill Cornell Medicine, USA. ABSTRACT Despite the rapid utilization of immunotherapy, emerging challenges to the current immune checkpoint blockade need to be resolved. Here, we report that uncontrolled elevation of CD73 levels due to its aberrant turnover is tightly correlated with poor prognosis in immune-cold triple negative breast cancers (TNBCs), which impedes the efficacy for chemotherapy and immunotherapy. We have identified TRIM21 as a E3 ligase that governs CD73 destruction. Disruption of TRIM21 stabilizes CD73 that in turn enhances CD73-catalyzed production of adenosine, resulting in the suppression of CD8+ T cell function. The immunostaining demonstrated the cytosolic colocalization between TRIM21 and CD73. Molecular mapping further identified the amino acid stretches from 340-476 on TRIM21 and residues from 176–224 on CD73 mediated the interaction between TRIM21 and CD73. Replacement of lysine 133, 208, 262 and 321 by arginine on CD73 attenuated CD73 ubiquitylation and degradation. Moreover, TRIM21 is upregulated but CD73 is downregulated in response to IFN- secreted from activated CD8+ T cells in a feedback manner. Importantly, in preclinical animal models, diminishing of CD73 ubiquitylation remarkably promotes tumor growth and impedes antitumor immunity. In addition, a TRIM2hight/CD73low signature in a subgroup of human breast malignancies was associated with a favorable immune profile. Collectively, our findings uncover a novel mechanism that governs CD73 proteolysis and point to a new therapeutic strategy by modulating CD73 ubiquitylation. Citation Format: Ziyi Fu, Yueming Zhu, Kevin Kalinsky, Yong Wan. Proteolytic regulation of CD73 by TRIM2 orchestrates tumor immunogenicity [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-20-15.

CLL-211 Humoral Immune Response Following COVID-19 Vaccination in Patients With Chronic Lymphocytic Leukemia (CLL) and Indolent Non-Hodgkin Lymphoma (NHL): Results From a Large, Single-Center Observational Study

Context: CLL and indolent NHL are hematologic malignancies that typically result in immune dysfunction. Infection represents a major cause of morbidity and mortality in these patients. Patients with CLL and NHL are at higher risk of hospitalization and death from COVID-19.3 Data is lacking regarding the effectiveness of COVID-19 vaccination in this patient population. Objective: Determine antibody (Ab) response rate (RR) to the COVID-19 vaccination in patients with CLL and indolent NHL. Design: A retrospective, observational study of patients seen between January and October 2021. Updated data was collected until May 27, 2022. Setting: Patients followed in a lymphoma clinic at the Robert H. Lurie Comprehensive Cancer Center. Participants: 398 patients were screened for eligibility. Inclusion criteria were confirmed diagnosis of CLL or indolent NHL, completion of a full vaccination series with either Johnson & Johnson, Moderna, or Pfizer, and Ab testing within 6 months of the initial vaccination series. Main Outcome Measures: SARS-CoV-2 Ab titers were obtained after completion of a full vaccination series and, if applicable, after a third vaccine dose. Ab response was considered positive if either total Ab titer or IgG spike protein Ab was positive. Comparisons were performed using chi-square tests. Results: 240 patients were included in the final analysis. Ab response to the initial vaccination series was 50% (91/181) in CLL and 69% (41/59) in other indolent NHLs. For CLL patients, there was a higher Ab RR in patients receiving the Moderna compared to the Pfizer vaccine (61% vs 44%, p=0.028). Current or prior cancer therapy correlated with a lower Ab RR (36% vs 68%, p<0.0001). Use of anti-CD20 agents in the year prior to vaccination resulted in a lower Ab RR (12% vs 53%, p<0.0001). Of the 71 patients with negative Ab response who subsequently received a third vaccine dose, 38% (27/71) developed a measurable Ab response. Conclusions: Ab RR to COVID-19 vaccination is suboptimal in patients with CLL and indolent NHL, and continued infection precautions should be employed. The Moderna vaccine may provide superior humoral immunity to COVID-19 in patients with CLL. A third vaccine dose increases Ab RR in this patient population.

Central nervous system immune interactome is a function of cancer lineage, tumor microenvironment, and STAT3 expression.

BACKGROUNDImmune cell profiling of primary and metastatic CNS tumors has been focused on the tumor, not the tumor microenvironment (TME), or has been analyzed via biopsies.METHODSEn bloc resections of gliomas (n = 10) and lung metastases (n = 10) were analyzed via tissue segmentation and high-dimension Opal 7-color multiplex imaging. Single-cell RNA analyses were used to infer immune cell functionality.RESULTSWithin gliomas, T cells were localized in the infiltrating edge and perivascular space of tumors, while residing mostly in the stroma of metastatic tumors. CD163+ macrophages were evident throughout the TME of metastatic tumors, whereas in gliomas, CD68+, CD11c+CD68+, and CD11c+CD68+CD163+ cell subtypes were commonly observed. In lung metastases, T cells interacted with CD163+ macrophages as dyads and clusters at the brain-tumor interface and within the tumor itself and as clusters within the necrotic core. In contrast, gliomas typically lacked dyad and cluster interactions, except for T cell CD68+ cell dyads within the tumor. Analysis of transcriptomic data in glioblastomas revealed that innate immune cells expressed both proinflammatory and immunosuppressive gene signatures.CONCLUSIONOur results show that immunosuppressive macrophages are abundant within the TME and that the immune cell interactome between cancer lineages is distinct. Further, these data provide information for evaluating the role of different immune cell populations in brain tumor growth and therapeutic responses.FUNDINGThis study was supported by the NIH (NS120547), a Developmental research project award (P50CA221747), ReMission Alliance, institutional funding from Northwestern University and the Lurie Comprehensive Cancer Center, and gifts from the Mosky family and Perry McKay. Performed in the Flow Cytometry & Cellular Imaging Core Facility at MD Anderson Cancer Center, this study received support in part from the NIH (CA016672) and the National Cancer Institute (NCI) Research Specialist award 1 (R50 CA243707). Additional support was provided by CCSG Bioinformatics Shared Resource 5 (P30 CA046592), a gift from Agilent Technologies, a Research Scholar Grant from the American Cancer Society (RSG-16-005-01), a Precision Health Investigator Award from University of Michigan (U-M) Precision Health, the NCI (R37-CA214955), startup institutional research funds from U-M, and a Biomedical Informatics & Data Science Training Grant (T32GM141746).

Abstract P2-02-05: Dynamic circulating tumor cell changes in enumeration and HER2 expression during systemic therapy for metastatic breast cancer

Abstract Introduction: CTCs are tumor cells that circulate in the blood of patient with primary and MBC and, are responsible for seeing of metastasis. The monitoring of CTCs in MBC emerged as strong prognostic and possible predictive biomarker in oncology over the past couple of decades. Meanwhile, overexpression of HER2 protein has been associated with rapid cell division and worse prognosis of MBC. Here we report a significant correlation between dynamic CTCs enumeration and CTCs-HER2 expression during the systemic therapies, with potential implication to understand treatment resistance. Methods: A total of 298 whole blood samples (7.5ml/each) were collected from 149 patients with stage IV breast cancer (2016-2020) at the Northwestern University Robert H Lurie Comprehensive Cancer Center, before (Baseline) and 3 months after (Time point 2) initiation of systemic treatment. CTC enumerations were performed using the FDA approved CellSearch™ system (Menarini) which is specific for the intracellular protein cytokeratin (CK) in epithelial cells, DAPI stains the cell nucleus, anti-CD45-APC is specific for leukocytes, and anti-HER-2/neu-FLU is specific for HER-2/neu antigen. The CTCs were classified as CK+, EpCAM+, DAPI+ and CD45-. We developed a criteria for evaluation of HER2 expression by 4 different categories (0,1+,2+,3+) based on expression intensity in our lab (present in 2021 ASCO). In this study we included CTCs with all intensities of HER2 expression (1+ to 3+) which was standardized in our lab. Mann-Whitney U test was used for statistics. Results: Of the 149 baseline samples, CTC≥1 were found in 101 patients (67.8%). A change in CTCs between baseline and time point 2 for these 101 patients: Three groups were identified: Group 1: 33patients (33%) with increase CTCs; Group 2: 64 patients (63%) with decreased CTC; Group 3: 4 patients (4%) with no change The median increase of total CTCs and HER2+ CTCs in Group 1 were 7.0 and 2.0, respectively; the median decrease of total CTCs and HER2+ CTCs in Group 2 were 9.5 and 2.0, respectively. The change of HER2+ CTCs was significantly correlated with the change of total CTCs after systemic therapy, with the correlation coefficient as rs=0.662 (p&amp;lt;0.001) for these 101 patients. A significant positive correlation between HER2+ CTCs and total CTCs were found in both Group 1 and Group 2, rs=0.717 (p&amp;lt;0.001) and rs=0.604 (p&amp;lt;0.001) respectively. Furthermore, the ratio of HER2+ CTCs (HER2+ CTCs/total CTCs) in both Group 1 and Group 2 was also significantly correlated with total CTCs after therapy with the corresponding correlation coefficient as rs=0.536 (p&amp;lt;0.001) and rs=0.388 (p&amp;lt;0.001) in Group 1 and Group 2, respectively. Conclusion: Our study demonstrated that dynamic changes of CTCs after systemic therapies, are positively correlated with the HER2 expression in CTCs in different levels of baseline CTCs amounts. Observation of HER2 expression and ratio in CTCs during the course of systemic therapy is useful in monitoring therapy efficacy and potential disease progress. Citation Format: Qiang Zhang, Weijun Qin, Paolo D'Amico, Andrew A. Davis, Jianhua Jiao, Lorenzo Gerratana, Saya L. Jacob, Youbin Zhang, Jeannine Donahue, Wenan Qiang, Ami N Shah, Amir Behdad, Lisa Flaum, William Gradishar, Leonidas C Platanias, Massimo Cristofanilli. Dynamic circulating tumor cell changes in enumeration and HER2 expression during systemic therapy for metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-02-05.

Abstract PO-037: Connecting cancer research and communities: Assessing barriers and facilitators to the implementation of a community scientist program

Abstract Introduction: Community Scientist (CS) programs — often referred to as Citizen Scientist programs — that facilitate direct engagement between scientific researchers and community members have emerged as effective strategies for building community trust in scientists and better informing research design and dissemination to address true community needs. While population health research has increasingly incorporated community stakeholders into the research continuum, basic and translational sciences struggle to do the same and may contribute to cancer disparities. We designed and implemented a virtual CS program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (LCC). We report barriers, facilitators, and lessons learned. Methods: Translational scientists (TSs) were recruited from among LCC investigators, and CSs were identified for participation from among LCC community networks. We sought to recruit a CS cohort representing LCC's catchment area and a TS cohort whose research focuses on cancers most impacting LCC catchment. CS program interactions included monthly meetings between two CSs and one TS wherein the CS-TS triad discuss TS research in lay terms and work together to co-create educational infographics suitable for dissemination to the catchment and LCC scientists. Virtual attendance was tracked and meeting recordings retroactively reviewed to identify and create product development. Results: Six CSs and three TSs agreed to participate in the CS program. The CS cohort includes cancer survivors, patient advocates, community organization leaders, a nurse, and an educator, while the TS cohort includes breast, prostate, and lung cancer researchers. Currently, 11 of 18 triad meetings have been completed, with attendance averaging 97%. Barriers to program implementation have included technological difficulties, restrictions on in-person meeting, scheduling conflicts, time limitation, and language barriers, while facilitators have included small group meetings to promote comfortable group-member contribution, presence of a trained facilitator, articulation of achievable meeting goals and mission for product creation, and clear assignment of team roles. Conclusion: The COVID-19 pandemic has illuminated pre-existing needs for improved connectivity between communities impacted by cancer disparities and cancer researchers. By identifying current barriers and facilitators to successful virtual CS program implementation, our findings can be used to guide development and implementation of similar programs at LCC and other cancer centers that are aimed at mitigating cancer health disparities. Citation Format: Will Dunne, Kai Holder, Kevin Wamala, Magdalena Nava, Laura Tom, Catherine O'Brian, Sharon Post, Carmen Velasquez, Candace Henley, Rosemarie Rogers, Joanne Glenn, Jose Lopez, Jorge Girotti, Qi Cao, Yanis Boumber, Deyu Fang, Tarneka Manning, Adam B. Murphy, Melissa A. Simon. Connecting cancer research and communities: Assessing barriers and facilitators to the implementation of a community scientist program [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-037.

Improving Hematology Clinic Access for Patients with Cancer-Associated Thrombosis

Background :Venous thromboembolism (VTE) is a common consequence for patients with malignancy, and adversely impacts quality of life, morbidity and mortality. While historically low-molecular weight heparin (LMWH) was considered standard of care for treatment of cancer-associated thrombosis (CAT), more recent data support the safety and efficacy of direct oral anticoagulants (DOACs). However, management of CAT remains complex, and a national shortage of non-malignant hematologists limits access to thrombosis experts. Our non-malignant hematology group developed a pilot program to expedite referrals for oncology patients with CAT to aid in management and selection of appropriate therapies.Methods:With guidance from the Process Improvement team at Northwestern Medicine, the Cancer-Associated Thrombosis clinic was established in April 2020. Information about the clinic was disseminated via administrative meetings and e-mails from the clinical practice director. Patients were referred from the Robert H. Lurie Comprehensive Cancer Center for either: (1) newly diagnosed (“acute”) venous thromboembolic event (VTE) that could be managed in an outpatient setting, or (2) “ongoing management” of an established VTE diagnosis. We aimed to see acute referrals within 24 business hours and ongoing management referrals within 2 weeks. Patients were seen initially by an advanced practice provider, with case discussion with an attending non-malignant hematologist and pharmacist review for anticoagulant eligibility and teaching. Patients were to be scheduled for follow-up with an attending hematologist within 3 months. Decision-making regarding anticoagulant choice was based on perceived bleeding risk, tumor type, drug interactions, and patient preferences. Herein we report our experience during the first year (April 2020-April 2021) of the CAT clinic.ResultsSixty-three patients were seen in the first year, of whom 59% were women, with a median age of 63 years (range 30-90 years). 20.6% of patients had a prior history of VTE, and 6.3% had a prior history of bleeding. Tumor types from nine oncology sites were represented, of which gastrointestinal (33.3%); gynecological (22.2%); hematological malignancies (14.2%), and breast (7.9%) were the most common. Among 18 patients (28.5%) referred for acute VTE, the median time to appointment was 0 days, and among 45 patients (71.4%) referred for ongoing VTE management, the median time to appointment was 10 days. The most common VTE was pulmonary embolism (PE) (25.4%), followed by proximal deep vein thrombosis (DVT) (20.6%), concurrent PE and DVT (14.3%) and upper extremity DVT (11.1%). Additionally, 7.9% of thrombotic events involved splanchnic vein and 4.8% cerebral veins (1 isolated, 2 together with DVT and/or PE).DOACs were recommended in 29 (46%) of patients (19 apixaban, 9 rivaroxaban, 1 edoxaban), whereas enoxaparin was advised in 28 patients (44.4%). Four patients were advised to discontinue anticoagulation and 1 was advised to continue warfarin given prior DOAC failure and preference for an oral anticoagulant. Of 28 patients advised to use enoxaparin over a DOAC, the most common reasons included perceived bleeding risk/tumor type (50%), DOAC failure (21.4%), and drug-drug interactions (17.8%). Thirteen patients (21%) switched to a different anticoagulant (7 to a DOAC) in follow-up after the initial recommendation.Thirty-seven patients (59.7%) had a follow-up visit in the CAT clinic. During follow-up, 5 patients (7.9%) experienced recurrent or progressive VTE, and 7 (11.1%) patients had bleeding events. Fifteen patients (24.2%) died during follow-up.ConclusionsThe aim of this process improvement project was to improve access and assist with anticoagulant choice and management of CAT. Compared to a historical 3 month wait time for non-malignant hematology appointments at our institution, most acute CAT patients were scheduled within 24 hours, and patients requiring ongoing management were seen within 10 days. While DOACs are increasingly prescribed for treatment of CAT, we found that DOACs were not our recommended anticoagulant in over half of patients referred to our clinic, largely due to perceived risk of bleeding/tumor type. This highlights the complexity of management of CAT, and demonstrates the benefit of dedicated thrombosis expertise to aid in management of CAT. DisclosuresMartin: Janssen: Research Funding; Penumbra: Other: Scientific Advisory Board. Kalhagen: Harborside: Other: Consulting; Incyte: Speakers Bureau. Zakarija: Bayer: Other: Consultancy Advisory Board. Stein: Pharmassentia: Other: Advisory Board and Steering Committee; Constellation Pharmaceuticals: Other: Advisory Board x 1.

Outcomes and Predictors of Relapse with Use of Hypomethylating Agents in Combination with Venetoclax Prior to Allogeneic Transplant in Acute Myeloid Leukemia

IntroductionThe treatment of acute myeloid leukemia (AML) has evolved tremendously. Recently, venetoclax with hypomethylating agents (HMA/ven) demonstrated durable responses in the frontline and relapsed/refractory (R/R) settings. This regimen is now standard of care for older adults or those unfit for intensive induction chemotherapy (DiNardo CD, N Engl J Med, 2020). Our institution also often uses HMA/ven to treat fit patients (pts) with high risk disease characteristics. Because HMA/ven was studied in transplant-ineligible pts, outcomes following potentially curative allogeneic hematopoietic stem cell transplantation (HSCT) remain unknown. This retrospective study aims to describe characteristics and outcomes of pts treated with HMA/ven who proceeded to HSCT.MethodsAdult pts diagnosed with AML and treated with HMA/ven either in the frontline or R/R setting between 1/2010 and 2/2020 at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University were identified. Hypomethylating agents included either azacitadine or decitabine. Data were collected and analyzed based on demographics, laboratory and clinical characteristics, and disease and toxicity outcomes. Efficacy endpoints included complete remission (CR), CR with incomplete hematologic recovery (CRi), and CR with incomplete platelet recovery (CRp). Survival curves for overall survival (OS) and leukemia-free survival (LFS) were calculated using the Kaplan-Meier method. Univariate analyses were performed to determine impact of clinical variables on outcomes (significance defined as p≤0.05). Cohorts were compared using χ 2 or Fisher's exact test for categorical variables and the unpaired t-test for continuous variables.ResultsClinical and demographic features at time of diagnosis are listed in Table 1. In total, 257 pts received HMA/ven. Of these, 36 pts received a HSCT, which was the population analyzed in this study. In the front-line setting 11 (31%) pts received HMA/ven and 25 (69%) pts received HMA/ven for R/R disease. 25 (69%) pts received azacitadine and 11 (31%) pts received decitabine (5 days, n=5, 14%; 10 days, n=6, 17%). Based on ELN guidelines, 23 (64%) pts had adverse risk disease at diagnosis. Response to HMA/ven in the pre-transplant setting is shown in Table 2. Of 35 evaluable pts, 34 achieved remission (CR, n=32, 91%; CRi, n=1, 3%; CRp, n=1, 3%).Table 3 shows outcomes following HSCT. 14 (39%) pts relapsed post HSCT and 13 (36%) pts received treatment for relapse. With a median follow-up of 11.6 months, median LFS from time of transplantation was 11.2 months. Median OS was not reached over follow up period but estimated to be 25.4 months. There was a significant difference in rates of relapse based on ELN classification at diagnosis (p=0.0296). In comparison, presence of complex/monosomal karyotypes (p=0.593), blast percentage at diagnosis (p=0.456), donor type (p=0.484), and number of previous lines of therapy (p=0.822) did not predict for relapse. Median LFS in adverse and favorable/intermediate risk ELN groups was 5.8 and 19.8 months, respectively. Median OS in adverse and favorable/intermediate risk ELN groups was 25.4 and 29.5 months, respectively.Following transplant, 10 (28%) pts received maintenance therapy with a median of 5 cycles (range 1-14); 8 pts (22%) received HMA/ven maintenance following HSCT. There was no significant difference in relapse rates between those who received maintenance therapy (n=6, 43%) and those who did not (n=8, 57%) (p = 0.107). Median time to relapse from HSCT was 4.42 months in those who received maintenance therapy compared to 2.98 months in those who did not receive maintenance therapy (p=0.370).Following relapse, 10 (28%) pts were retreated with HMA/ven, but less than half (n=4, 40%) had a response. To date, 22 (61%) pts are alive with the majority (n=19, 86%) in remission. 14 (39%) pts died with half in remission at the time of death.ConclusionsOur study showed that HMA/ven can feasibly be used not only to bridge to transplant, but to achieve durable remissions post HSCT. For those pts that relapsed post HSCT, duration of remission was very short. ELN classification was the only factor that informed relapse risk. Prospective studies must be done to understand which cytogenetic and molecular subgroups benefit the most from HMA/ven prior to transplant. [Display omitted] DisclosuresAbaza: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Altman: Biosight: Consultancy, Other: Travel fees, Research Funding; Fujifilm: Research Funding; Kura: Research Funding; Immunogen: Research Funding; Kartos: Research Funding; Daiichi Sankyo: Consultancy; ALZ Oncology: Research Funding; Theradex: Consultancy, Other: Advisory boards; Syros: Consultancy; Amgen: Research Funding; Aprea: Research Funding; Boehringer Ingelheim: Research Funding; Astellas: Consultancy, Other: Advisory Board, Research Funding; GlycoMimetics: Other: Participation on an advisory board; AbbVie: Consultancy, Other: Advisory Board, Research Funding; BMS: Research Funding; Kura Oncology: Consultancy. Dinner: Pfizer: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria.

Editorial introductions.

Editorial introductions.

An Open Letter: COVID-19 and Cancer.

Among the many affected by the devastating impact of the COVID-19 pandemic in our society, patients with cancer have paid a very high toll. Increasing evidence suggests that COVID-19 causes higher morbidity and mortality among some types of patients with cancer, especially those receiving intensely immunosuppressive treatments. Prevention, early detection, and early intervention efforts have been delayed for many. In some hospitals, significant treatment delays have resulted as COVID-19 cases have overwhelmed patient wards and intensive care units. Consequently, patients who have cancer have presented with more advanced disease, which is more difficult to treat, much less to cure. A year after the first case of COVID-19 was reported in the United States, we finally have effective vaccines available, and this raises hopes that the pandemic can eventually be controlled. Unfortunately, vaccine distribution at the state level has been relatively slow and most states have not prioritized the distribution of currently available vaccines for patients with cancer. We strongly recommend that this policy be changed. The Biden administration and the new leadership of the CDC have shown a refreshing respect for science and are developing strong initiatives to control the pandemic. We believe that consideration should be given at the national level to prioritizing patients with cancer, or at least those who appear to be at particularly increased risk, for vaccine distribution and administration. A cancer diagnosis and cancer therapy are always stressful, but dealing with cancer during a pandemic is extraordinarily difficult. Prioritizing vaccine administration to these patients is simply the right thing to do. Leonidas C. Platanias, MD, PhD Director, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois Benjamin G. Neel, MD, PhD Director, Laura and Isaac Perlmutter Cancer Center at New York University, New York, New York

Venetoclax in Combination with Decitabine or Azacitidine in Relapsed or Refractory Acute Myeloid Leukemia Is Comparable to Alternative Regimens

Venetoclax in Combination with Decitabine or Azacitidine in Relapsed or Refractory Acute Myeloid Leukemia Is Comparable to Alternative Regimens

Editorial introductions

Editorial introductions

Leveraging Patient Reported Outcomes Measurement via the Electronic Health Record to Connect Patients with Cancer to Smoking Cessation Treatment.

Tobacco use negatively impacts cancer treatment outcomes, yet too few providers actively support their patients in quitting. Barriers to consistently addressing tobacco use and referring to treatment include time constraints and lack of knowledge surrounding treatment options. Patient Reported Outcomes (PRO) measurement is best practice in cancer care and has potential to help address these barriers to tobacco cessation treatment. This descriptive program evaluation study reports preliminary results following implementation of a novel automated PRO tobacco use screener and referral system via the electronic health record (EHR) patient portal (MyChart) that was developed and implemented as a part of a population-based tobacco treatment program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Between 25 June 2019 and 6 April 2020, 4589 unique patients completed the screener and 164 (3.6%) unique patients screened positive for recent (past month) cigarette smoking. All patients who screened positive were automatically referred to a smoking cessation treatment program integrated within the Lurie Cancer Center, and 71 (49.7%) patients engaged in treatment, as defined by completing at least one behavioral counseling session. Preliminary results indicate that the PRO/MyChart system may improve smoker identification and increase offering of treatment and, despite the “cold call” following a positive screen, may result in a treatment engagement rate that is higher than rates of treatment engagement previously documented in oncology settings. Longer term evaluation with formal statistical testing is needed before drawing conclusions regarding effectiveness, but PRO measurement via the EHR patient portal may serve a potentially important role in a multi-component approach to reaching and engaging cancer patients in comprehensive tobacco cessation treatment.

Neutrophil‐induced genomic instability impedes resolution of inflammation and wound healing

Neutrophil (PMN) infiltration of the intestinal mucosa is a hallmark of tissue injury associated with inflammatory bowel diseases (IBD). The pathological effects of PMNs are largely attributed to the release of soluble mediators and reactive oxygen species (ROS). We identified a new, ROS‐independent mechanism, whereby activated, tissue‐infiltrating PMNs release microparticles armed with pro‐inflammatory microRNAs (miR‐23a and miR‐155). Using IBD clinical samples, in vitro and in vivo injury models, we show that PMN‐derived miR‐23a/155 promote accumulation of double‐strand breaks (DSBs) by inducing Lamin B1‐dependent replication fork collapse, and inhibition of homologous recombination (HR) by targeting HR‐regulator RAD51. DSB accumulation in injured epithelium led to impaired colonic healing and genomic instability. Targeted inhibition of miR‐23a/155 in cultured intestinal epithelial cells and in acutely injured mucosa decreased the detrimental effects of PMNs and enhanced tissue healing responses, suggesting that this approach can be used in therapies aimed at resolution of inflammation, wound healing and potentially prevent neoplasia.Support or Funding InformationThis work was supported by grants from the National Institutes of Health (NIH) DK101675, Digestive Health Foundation, Chicago and by the Robert H. Lurie Comprehensive Cancer Center(Eisenberg Scholar grant).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

PMNs promote Non‐Homologous End‐Joining (NHEJ)‐mediated survival of colorectal cancer cells in inflammatory setting

Exacerbated Inflammation that can be driven by neutrophil (PMN) infiltration is one of the major risk factors for development and progression of colorectal cancer (CRC). Using a biopsy‐based acute‐injury model, we previously showed that miRNAs derived from PMN‐microparticles (MPs) inhibit Homologous Recombination (HR), leading to accumulation of Double‐Strand Breaks (DSBs). These observations led us to investigate the effects of long‐term exposure of intestinal epithelial cancer cells HCT116 to PMNs and PMN‐MPs. Consistent with the acute‐injury model, long‐term PMN‐MP treatment led to HR suppression with concomitant accumulation of DSBs, increased aneuploidy and apoptosis within 7 population doublings (PD7). With continued HR inhibition by PMN‐MPs, by PD12 we observed an upregulation of Non‐Homologous End‐Joining (NHEJ) activity. Importantly, DSBs and cell apoptosis were also significantly decreased at PD12, despite elevated aneuploidy, suggesting that PMN‐induced NHEJ activation promotes tumor cell survival and aneuploidy.To test this in vivo, we employed a tumor xenograft model in conjunction with an antibody‐based PMN depletion strategy. Consistent with in vitro observations, HR inhibition, NHEJ upregulation, decreased apoptosis, and increased aneuploidy were confirmed in PMN‐infiltrated (PMN+) tumors as compared to PMN‐depleted (PMN−) tumors. To examine whether PMNs indeed provide survival advantage to tumor cells and help them overcome DSB accumulation, we performed ex vivo clonogenicity assay, where cells were challenged with DSB‐inducing agents Camptothecin (CMPT). PMN+ tumor cells were resistant to CMPT treatment and were able to more efficiently re‐propagate compared to parental HCT116 cells and PMN‐ tumor cells, which underwent apoptosis in response to CMPT‐induced genotoxic stress. Consistently, in PMN‐ tumor cells, upregulation of H2AX and cell cycle regulatory genes (p16INK4a, p27Kip1, TP53, p21Cip1) was observed, indicating inefficient DNA Damage repair. As such, our findings define a new regulatory role of PMNs in promoting CRC survival during carcinogenesis.Support or Funding InformationThis work was supported by grants from the National Institutes of Health (NIH) DK101675, Digestive Health Foundation, Chicago and by the Robert H. Lurie Comprehensive Cancer Center (Eisenberg Scholar grant) and by American Cancer Society to Ronen Sumagin.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract C25: Bridging the gap through a targeted research fellowship: Introduction and recruitment of under-represented minority students to the cancer research physician scientist pipeline

Abstract Introduction: The Chicago Cancer Health Equity Collaborative (ChicagoCHEC) is a National Cancer Institute comprehensive cancer partnership led by the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northeastern Illinois University, and the University of Illinois at Chicago. The mission of ChicagoCHEC is to advance cancer health equity through meaningful scientific discovery, education, training, and community engagement. The current number of individuals in research and cancer health equity-related careers does not mirror the nation's demographics. While there are several gains in health status among racial and ethnic minority groups, disparities in health status have widened for certain indicators. At the culmination of the eight weeks, Research Fellows learned fundamental research practices and methodologies, pertinent research content topics (e.g., cancer inequity and recruitment of underserved minorities in clinical trials), social contexts for health inequity across the cancer continuum, and critical professional development practices and networks. Methods: Eligible participants were all undergraduate and post-baccalaureate students without graduate education from Northwestern University, Northeastern Illinois University, the University of Illinois at Chicago, and City Colleges of Chicago. Quantitative and qualitative data were collected and entered into RedCap via responses to module evaluations and a baseline survey with questions on self-efficacy in cancer disparity research. We applied modules around overarching core competencies envisioned by the ChicagoCHEC Research Education Core: (1) research practices, (2) research content, (3) social context/ interaction and personal development, and (4) professionalization. We recruited an intentional selected sample of underrepresented minorities to achieve representation across various definitions of “underrepresented” not limited to race/ethnicity, citizenship status, gender identification, sexual orientation, first-generation college student, and more. To achieve a high number of competitive candidates, the Research Education Core, one of four cores of the overarching U54 ChicagoCHEC, utilized existing cross-institutional inventories of student programs and groups, and corresponding recruitment strategies. This included Research Education Core staff collaborative presentations at career fairs, with student organizations, and in classes. The program leveraged the expertise of leading scholars and cancer researchers, health professionals, institutional leadership, and community leaders across Chicago taking part as guest lecturers, project mentors, and site visit hosts. The program served as an opportunity to move the needle on health by expanding opportunities to the next generation in a way that also changes the architecture of collaboration, community engagement, and the culture of research education to address health inequities. Core components of the intervention include individual and personal reflection, group exercises, didactic lecture, and classroom-based, and immersion and hands on experiences. These learning vehicles aimed to advance core values and competencies. Core values include teamwork, mentorship, critical thinking, value alignment, professionalism, intellectual curiosity, social justice, and reflective dialogue. Citation Format: Shaneah Taylor, Melinda Monge. Bridging the gap through a targeted research fellowship: Introduction and recruitment of under-represented minority students to the cancer research physician scientist pipeline [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C25.

Nuclear localization of immunosuppressive IDO1 in cancer: a paradigm‐shift to the tryptophan depletion theory

ObjectiveIndoleamine 2,3 dioxygenase 1 (IDO1) is canonically‐described as a rate‐limiting cytoplasmic enzyme that catabolizes L‐tryptophan into L‐kynurenine. Previous work has demonstrated that, syngeneic, subcutaneously‐engrafted mouse breast cancer expressing IDO1 cDNA, suppresses immune cell control of tumor outgrowth. Previously, IDO1 expression by tumor cells was thought to suppress immune cell effector function(s) through enzymatic activity. This was based on in vitro work showing that, IDO1‐mediated tryptophan depletion and kynurenine accumulation was commensurate with anergy and/or death of cultured cytolytic CD8+ T cells. Co‐incidentally, our laboratory's previous work demonstrated that, shRNA knockdown of IDO1 in syngeneic, intracranially‐engrafted mouse glioblastoma (GBM) reverses suppression of tumor immunity and increases survival in animal subjects. Paradoxically, pharmacologic inhibition of IDO1 activity has no effect on immune response or survival. Here we present novel data showing nuclear IDO1 localization in many types of aggressive cancer and the novel hypothesis that enzyme activity is dispensable for IDO1‐mediated suppression of anti‐tumor immune effects.MethodsPatient‐resected cancers including GBM, ovarian, pancreatic, prostate, and endometrial, melanoma, and lung, either at primary sites or in brain metastases (n=10/cancer) were investigated. Additionally, brain tumors from NOD‐scid mice intracranially‐engrafted a novel human GBM cell line that expresses HA‐tagged human IDO1 were also characterized. Intracranial tumor growth was monitored by bioluminescence imaging. For immunohistochemistry (IHC) and confocal microscopy (CM), human IDO1 mAb, HA mAb, and/or human vimentin mAb was utilized. Distribution and intensity of cytoplasmic and nuclear staining was scored under blinded conditions and confirmed by a board‐certified neuropathologist.ResultsIHC and CM imaging confirmed IDO1 co‐localization, both in the cytoplasm and nucleus of cancer cells, in situ. IDO1 immunoreactivity was highest in gynecologic and pancreatic carcinomas (P&lt;0.01). Interestingly, the in vitro analysis of our novel HA‐IDO1 cDNA expressing human GBM cells showed cytoplasmic localization when cultured alone, but demonstrated nuclear translocation after co‐culture with parenchymal cells isolated from normal mouse brain, suggesting that IDO1 requires non‐cell autonomous signals for anatomical localization in the nucleus.ConclusionsThis work describes the noncanonical observation of IDO1 localization in the nucleus of aggressive cancer cells, in situ. It also introduces the novel observation demonstrating non‐cell autonomous‐driven nuclear IDO1 translocation in human glioblastoma cells. The existing hypothesis that, IDO1‐mediated enzymatic activity leads to immunotolerance in cancer, fails to explain the lack of antitumor effects in recent Phase I clinical trials testing monotherapeutic IDO1 enzyme inhibition in cancer patients. Our novel data suggest an alternative hypothesis that, nuclear IDO1 promotes immunosuppression, independent of enzyme activity.Support or Funding InformationD.A. Wainwright is supported by PHS grant numbers R00NS082381 and R01NS097851, awarded by the NIH/NINDS, U.S. Department of Health and Human Services; a Robert H. Lurie Comprehensive Cancer Center – Zell Scholar Program of the Zell Family Foundation Gift; and the Northwestern Brain Tumor Institute.

Hepatotoxicity with Vismodegib: An MD Anderson Cancer Center and Research on Adverse Drug Events and Reports Project.

BackgroundOn 30 January 2012, the US FDA approved vismodegib (Erivedge®, Genentech, CA, USA) for the management of both metastatic and locally advanced basal cell carcinoma.ObjectiveOur objective was to identify evidence of hepatotoxicity with vismodegib in the FDA Adverse Event Reporting System (FAERS) in treated patients in two National Cancer Institute Comprehensive Cancer Centers.MethodsFAERS was searched for reports dated 1 January 2009 through 31 December 2015 using terms including hedgehog pathway and vismodegib and hepatic-related terms such as liver, jaundice, and hepatitis, among others. Disproportionality analyses with estimates of proportional reporting ratio and empirical Bayesian geometric mean were conducted. A comprehensive literature review was conducted, and the clinical databases at the University of Texas MD Anderson Cancer Center and Robert H. Lurie Comprehensive Cancer Center of Northwestern University were searched.ResultsTwo cases of severe liver dysfunction were published (Common Terminology Criteria for Adverse Events [CTCAE] class III), and 94 reports of adverse events (AEs) were detected in FAERS, 35 of which were serious AEs. Safety notifications related to hepatotoxicity have not been issued by the manufacturer or the FDA, although vismodegib is listed in LiverTox and the European Medicines Agency website.ConclusionWe identified a detectable safety signal for hepatotoxicity for vismodegib within 4 years of FDA approval. Vismodegib should be used in patients with severe liver disease only after careful consideration, and concomitant hepatotoxic medications should be avoided. Rapid dissemination of such safety concerns is expected to result in fewer serious hepatotoxic AEs and more optimal outcomes for patients with cancer receiving vismodegib.Electronic supplementary materialThe online version of this article (doi:10.1007/s40268-016-0168-2) contains supplementary material, which is available to authorized users.