Citations

Abstract Introduction: Patients with coronavirus disease 2019 (COVID-19) have an increased risk for venous thromboembolic events. Thrombotic events contribute to the morbidity and mortality associated with COVID-19 infection, and have prompted investigation into strategies for mitigating thrombosis risk in patients hospitalized with COVID-19 infection. Our team reviewed the charts of patients hospitalized with COVID-19 pneumonia at a tertiary hospital in metropolitan Phoenix Arizona between 2020-2021, to assess frequency and efficacy of utilizing a VTE prophylaxis algorithm designed to prevent thrombosis in patients infected with COVID-19. Methods: A total of 846 patients were retrospectively evaluated to determine if they were treated with guideline-appropriate anticoagulation while hospitalized with COVID-19, as well as if they developed venous or arterial thrombotic events, or major or minor bleeds. 317 patients were excluded for taking therapeutic anticoagulation prior to admission, or for having a COVID-19 diagnosis >7 days after admission. Appropriate anticoagulation was determined by an institutionally designed COVID-19 thromboprophylaxis algorithm, based on platelet count, d-dimer, bleeding risk, and level of medical care required. Regimen options included: no anticoagulation, prophylactic enoxaparin (40 mg SQ daily) or heparin in the setting of kidney dysfunction, weight-based dosing of enoxaparin (40 mg SQ BID if BMI>40), intermediate intensity enoxaparin without thrombus (30 mg BID if BMI<40, or 40 mg BID if BMI>40), and therapeutic anticoagulation (for example enoxaparin 1 mg/kg BID) with thrombus. Demographics: Demographic data and clinical characteristics were collected for 529 patients. Average age was 59 years old, and the majority were men (58.4%). Most patients were White (58.3%), followed by Hispanic (17.8%), or Native American (15.7%). Fewer patients had a normal BMI (21.3%; BMI 18.5 - 24.9) compared to those who were overweight (31.2%; BMI 25-29.9) or obese (43.1% BMI > 30). Other comorbidities included Type 1 or Type 2 diabetes mellitus (N= 172, 32.5%), hypertension (N = 271, 51.2%), and hyperlipidemia (N = 176, 33.3%). Results: A total of 42 patients (8%), were diagnosed with a venous thrombosis during hospitalization. Patients admitted to the ICU were significantly more likely to have a thrombotic event of any type compared to non-ICU patients (21.6% to 5.7%; p < 0.001). Specifically, critically ill patients had higher incidences of deep vein thrombosis (9.5% to 0.7%), pulmonary emboli (8.1% to 4.8%), and superficial thrombi (2.7% to 0.2%). Only 1.1% of patients (6/529) experienced any bleeding, of which 3 were classified as a major bleed. Discussion: Among patients hospitalized at our institution with COVID-19, the majority were anticoagulated appropriately according to the COVID-19 thromboprophylaxis algorithm. Overall incidence of thrombosis in the study population was 8%. A significantly higher percent of critically ill patients had thrombi, supporting reports of correlation between severity of illness and thrombosis risk. The two regimens of anticoagulation least adhered to were weight-based and intermediate-based dosing, likely reflecting a departure from the hospital's thromboprophylaxis regimens prior to COVID-19 pandemic. Further studies are needed to characterize whether identifiable risk factors correlate with the incidence of thrombosis, and whether treatment with lower than recommended doses of anticoagulation, based on the COVID-19 thromboprophylaxis algorithm, were associated with thrombosis. Disclosures No relevant conflicts of interest to declare.

Abstract Interferon-alpha (IFN), the first approved immunotherapy for cancer, remains an effective therapy for patients with myeloproliferative neoplasms (MPN). The mechanisms of action of IFN on MPN cells are poorly understood, particularly in patients with CALR mutated (MUT) MPNs, who often exhibit clinical but not molecular responses. Previously, by developing Genotyping of Transcriptomes (GoT) that captures mutation status and single-cell RNA-seq (scRNA-seq) in high-throughput, we observed that CALR mutations led to cell identity-dependent effects on CD34 + cells, including a strong megakaryocytic progenitor (MkP) differentiation bias and fitness. We hypothesized that the IFN effects may be cell identity and mutation status dependent; thus we applied GoT to serial bone marrow aspirates (BM) from 5 patients with CALRmutated ET treated with pegylated-IFN-alfa2a who participated in MPD-RC-111/112 clinical trials. To capture the transcriptional impact of IFN, we removed experimental batch effects with Cell Hashing, in which CD34 + cells from serial BM were uniquely labeled and combined for the same GoT experiment (Fig. 1A). Cell clustering based on transcriptomic data alone revealed that the cells on active treatment clustered based on cell identity and IFN effects (Fig. 1B). When off therapy for 3 weeks, the strong transcriptional effects of IFN were largely lost (Fig. 1B). Next, we batch corrected and integrated across time points for each BM sample (Fig. 1C). We observed that IFN caused large shifts in the composition of wildtype (WT) and MUT cell subsets (Fig. 1D). IFN resulted in a dramatic expansion of WT lymphoid progenitors with a corresponding diminution of other progenitors (Fig. 1E). MUT cells at baseline were enriched for MkPs, compared to WT cells; after treatment, we observed an expansion of the immature myeloid (IMP) and neutrophil progenitors, with a less striking expansion of lymphoid progenitors (Fig. 1E). As IFN has been reported to induce cell cycling of murine hematopoietic progenitor cells, we examined whether a differential increase in proliferation by IFN underlies the differentiation shifts in WT and MUT cells. Cell cycle gene expression of ProB cells increased after treatment similarly in MUT and WT cells, while cell cycle expression of IMPs was increased to a greater extent in MUT cells (Fig. 1F), consistent with the differential shifts in populations. Next, we performed differential expression analysis between baseline and treated WT and MUT cells, respectively. We observed enrichment of the IFN pathways post-therapy, whereas TNF-a signaling was downregulated (Fig. 1G). Uniquely in the MUT cells, TGF-b signaling was downregulated, which may underlie improvements in marrow fibrosis following IFN therapy (Fig. 1G). Finally, as the differentiation biases of IFN persisted after discontinuation, we hypothesized that IFN results in chromatin remodeling of the earliest hematopoietic stem progenitor cells (HSPCs), with respect to transcription factor (TF) accessibility. We leveraged single nuclei chromatin accessibility (snATAC-seq) as a powerful measure of TF regulatory activities. We developed GoT-ATAC, an adaptation of the Multiome platform (10x Genomics), to capture snRNA-seq, snATAC-seq and somatic genotyping within the same cells in high-throughput (Fig. 1H). We applied GoT-ATAC to CD34 + cells from the same clinical trial cohorts (Fig. 1I, n = 3 patients: 3 baseline, 2 treated) and identified the expected enrichment of IRFs and STAT2 in treated HSPCs (Fig. 1J). Accessibility of BCL11A, critical for early lymphoid development, was increased in treated MUT and WT HSPCs. We also identified enhanced motif accessibility of PU.1 which can associate with IRF and is essential for myeloid and lymphoid differentiation. Uniquely within the treated MUT cells, we observed enhanced CEBPA motif enrichment, which regulates myeloid differentiation, together with PU.1. In conclusion, GoT revealed that IFN reshapes the differentiation landscape by promoting early lymphoid development and, uniquely in MUT cells, myeloid differentiation, providing a novel mechanism of actions underlying the effects of IFN in MPN patients. Downregulations of TNF-a and TGF-b signaling were other key molecular consequences of IFN. Lastly, GoT-ATAC demonstrated that IFN governs master regulators of hematopoietic differentiation as a function of the underlying mutational status. Figure 1 Figure 1. Disclosures Mimitou: Immunai: Current Employment. Smibert: Immunai: Current Employment. Hoffman: AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding; Novartis: Other: Data Safety Monitoring Board, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Kartos Therapeutics, Inc.: Research Funding.

132 Background: Enhancing equitable oncologic care is an increasingly emphasized priority. Our study aims to identify aspects of breast cancer (BC) care in which differences exist based on insurance coverage. Methods: We performed a retrospective, case control study, (from 2014-2020); 39 Hispanic ethnicity uninsured patients (UP) from underserved communities with newly diagnosed BC and 119 insured patients (IP) diagnosed at Mayo Clinic Arizona (MCA). Patients were matched 3:1 for age, stage, year of diagnosis, estrogen receptors and HER-2 status. Demographic information, clinical variables, and zip code level specific socioeconomic information were compared. Continuous variables were compared by Wilcoxon rank-sum test and categorical variables by chi-square test. All patients were treated at MCA. Results: Similar treatment patterns with radiotherapy, chemotherapy and surgery were observed between groups. Primary language was Spanish for 94% of UP and English for 97.5% of IP. The majority of UP were of Hispanic ethnicity (97.4%); IP were 83.2% non-Hispanic White, 9.2% Hispanic, 3.4% African American. Zip code level information reflected more unemployment with a median of 10.6% versus 6.9% p < 0.001, percent of high school or lower (53.0 % v 23.2 %, p < 0.001), and lower income for UP (33733.5 v 64728.0 p values < 0.001).BMI was significantly higher for UP (30.6 V 24.7, p = 0.005), with presence of more co-morbidities; diabetes (28.2% v 5.0%, p < 0.001), hypertension (35.9 % v 20.2%, p = 0.046), dyslipidemia (28.2% v 12.6%, p = 0.023), metabolic syndrome (p 23.7% v 8.5, p = 0.013), and tobacco use (17.9% v 2.5%, p < 0.001). Genetics consultation was performed for 62.2% IP versus 35.9% UP (p = 0.004), lower acceptance of nutrition consultation for UP (29.4% vs 7.4%, p = 0.024). Median time from mammogram to biopsy (25.5 days vs. 14 days, p = 0.056), and interval from diagnosis to treatment (62 days vs. 39 days) (p = 0.001) were less favorable for UP compared to IP. Conclusions: In comparing the status of UP and IP with newly diagnosed BC, we identified greater prevalence of co-morbidities and adverse social determinants of health in the former group. We identified access to genetic counseling, nutrition consultation, and timeliness of diagnostic biopsy and initiation of treatment as disparate features in the care pathway. These observations allowed development of tailored interventions to achieve greater equity in delivery of BC care at Mayo Clinic.

AbstractBackground and ObjectivesThe prognostic significance of regression in predicting melanoma recurrences is unknown. We present a large multicenter study correlating regression with recurrence.MethodsThe Sentinel Lymph Node Working Group database was queried from 1993 to 2018 for cases with regression data. Clinicopathologic factors were correlated with overall and first‐site of recurrence and with recurrence‐free survival (RFS).ResultsThere were 4790 patients and the median follow‐up was 39.6 months. Regression and recurrences were seen in 1081 (22.6%) and 773 (16.1%) cases, respectively. First‐site locoregional and distant recurrences were seen in 412 (8.6%) and 352 (7.3%) patients, respectively. Regression was seen in 15.8% and 24.7% of all cases with and without recurrences (p < 0.0001), respectively, while regression was seen in 14.3% and 17.9% of first‐site locoregional and distant recurrent cases, respectively, compared with 23.3% and 22.9% of patients with regression and without first‐site locoregional and distant recurrences, respectively (p = 0.29). On multivariable analysis, after controlling for age, gender, thickness, ulceration, lymphovascular invasion, and sentinel lymph node status, regression significantly predicted improved RFS (p = 0.004) and fewer first‐site regional recurrences (p = 0.017).ConclusionOur data suggest that regression is a favorable prognostic marker in melanoma and predicts significantly better RFS and decreased first‐site regional recurrences.

Abstract Background and aims Biliary tract cancers (BTCs) are uncommon, but highly lethal, gastrointestinal malignancies. Gemcitabine/cisplatin is a standard‐of‐care systemic therapy, but has a modest impact on survival and harbors toxicities, including myelosuppression, nephropathy, neuropathy, and ototoxicity. Whereas BTCs are characterized by aberrations activating the cyclinD1/cyclin‐dependent kinase (CDK)4/6/CDK inhibitor 2a/retinoblastoma pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident preclinical efficacy, and development of acquired drug resistance. Emerging studies have explored therapeutic strategies to enhance the antitumor efficacy of CDK4/6 inhibitors by the combination with chemotherapy regimens, but their mechanism of action remains elusive. Approach and results Here, we report in vitro and in vivo synergy in BTC models, showing enhanced efficacy, reduced toxicity, and better survival with a combination comprising gemcitabine/cisplatin and CDK4/6 inhibitors. Furthermore, we demonstrated that abemaciclib monotherapy had only modest efficacy attributable to autophagy‐induced resistance. Notably, triplet therapy was able to potentiate efficacy through elimination of the autophagic flux. Correspondingly, abemaciclib potentiated ribonucleotide reductase catalytic subunit M1 reduction, resulting in sensitization to gemcitabine. Conclusions As such, these data provide robust preclinical mechanistic evidence of synergy between gemcitabine/cisplatin and CDK4/6 inhibitors and delineate a path forward for translation of these findings to preliminary clinical studies in advanced BTC patients.

Abstract Background:Biliary tract cancers (BTC) are rare, chemo resistant and are associated with a poor prognosis. Preclinical and early clinical work had demonstrated interesting anti-tumor activity from targeting fibroblast growth factor receptor (FGFR) pathway. We hypothesized that ponatinib, a multi-targeted tyrosine kinase inhibitor with activity against FGFR, would be active in BTC patients with FGFR alterations.Methods:This was a multi-center, single institution pilot study of ponatinib in patients with advanced, refractory BTC with FGFR alterations. The primary end point was overall response rate, with secondary points of overall survival (OS), progression-free survival (PFS) and Health Related Quality of Life (HRQoL) assessment. Results:Twelve patients were enrolled prior to early termination of the trial. Clinical benefit (defined as complete/partial response + stable disease) of 45.5% was observed. All observed toxicities were manageable and reversible. Toxicities were mild, with lymphopenia (75%), rash (63%) and fatigue (50%) being the most frequent. No significant detriment in global QoL was observed.Conclusions:Ponatinib as a single agent in FGFR altered BTC is tolerable with very modest clinical activity. This is the first report of prospective assessment of FGFR inhibition in BTC using ponatinib, and the first study to report its effect on HRQoL. Further development of ponatinib will involve correlative studies to better refine patient selection, focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy, and studies to better understand mechanisms of treatment resistance.

11026 Background: The Clinical and Translational Science Award (CTSA) Program currently supports more than 50 leading medical research institutions in the U.S. with the aims of training, promoting and developing future translational science researchers, with particular emphasis on advanced Clinical and Translational Research (CTR) education. No prior studies have evaluated career development in oncologists who have completed CTR training. The objective of this study is to examine the impact of advanced CTR training on career development, return-on-investment and research productivity in Oncology specialties. Methods: With IRB approval, we conducted a survey study of U.S.-based Hematology/Oncology (H/O), Radiation Oncology (RO), and Surgical Oncology (SO) members of the American Society of Clinical Oncology who completed CTR training. Data was anonymized and collected through Research Electronic Data Capture (REDCap). Outcomes were compared using Chi-square test for frequency data. Results: We received 225 survey responses (62.1% H/O, 23.3% RO, 13.2% SO, 1.4% others). About 28.4% (n = 64) of the respondents had a PhD or Master's degree in CTR (Group A) compared to 71.6% (n = 161) with graduate certificates or non-degree granting courses in CTR (Group B). Specialty ratio was equally distributed between both groups. Overall, 79.7% vs 57.5%; P < 0.001 of respondents worked in academia, of which 55.2% had tenure track positions. Over 49 different CTSA Programs throughout the U.S. were represented. In terms of impact with new research projects, the ability to secure funding and opportunities for multidisciplinary collaboration, satisfaction with CTR training was higher among Group A compared with Group B (P < 0.001; P < 0.01; P < 0.01 respectively). In terms of research output, higher satisfaction was seen in Group A (67.2% vs 47.4%; P < 0.01), however total publications per year were not statistically significant (P = 0.135). Usefulness of a CTR degree on career advancement, a difference of 50.0% vs 19.1%; P < 0.001 was noted. Similarly, usefulness regarding new job opportunities and return-on-investment also favored Group A (P < 0.001). Overall satisfaction with training was significantly higher in Group A (73.4% vs 48.7%; P = 0.004). Conclusions: This study is the first to report satisfaction ratings for CTR training among oncology specialties. Although no significant difference was observed in terms of publication output, those with higher levels of advanced degrees were more satisfied with their CTR training, and viewed it as more impactful to career advancement and research productivity. The evidence presented is useful for informing career development for oncology residents and fellows offered CTR degrees during their training.

e18518 Background: Initiatives enhancing equitable oncologic care are an increasingly emphasized priority. Our study aims to identify aspects of breast cancer (BC) care in which differences exist based on insurance coverage status. Methods: We performed a retrospective, case control study consisting of 39 Hispanic ethnicity uninsured patients (UP) with newly diagnosed BC at federally qualified health centers and 119 insured patients (IP) diagnosed at Mayo Clinic Arizona (MCA). Patients were matched 3:1 for age, stage, year of diagnosis, ER and HER2 status. Demographic information, clinical variables, and zip code level specific socioeconomic information were compared. Continuous variables were compared by Wilcoxon rank-sum test and categorical variables by chi-square test. All patients ultimately received their cancer treatment at MCA. Results: Similar treatment patterns with chemotherapy, surgery, and radiation treatment were observed between groups. Primary language was Spanish for 94% of UP and English for 97.5% of IP. The majority of UP were of Hispanic ethnicity (97.4%); IP were 83.2% non-Hispanic White, 9.2% Hispanic, 3.4% African American. Zip code level information reflected more unemployment with a median of 10.6% versus 6.9% p ˂ 0.001, percent of high school or lower (53.0 % v 23.2 %, p ˂ 0.001), and lower income for UP (33733.5 v 64728.0 p values ˂ 0.001). UP BMI was significantly higher (30.6 V 24.7, p=0.005), with presence of more co-morbidities; diabetes (28.2% v 5.0%, p ˂ 0.001), hypertension (35.9 % v 20.2%, p= 0.046), dyslipidemia (28.2% v 12.6%, p = 0.023), metabolic syndrome (p 23.7% v 8.5, p= 0.013), and tobacco use (17.9% v 2.5%, p ˂ 0.001). IP had higher alcohol use (52.9% v 5.3%, p ˂ 0.001). Genetics consultation was performed for 62.2% IP versus 35.9% UP (p=0.004), lower acceptance of oncology nutrition consultation for UP (29.4% vs 7.4%, p= 0.024) Median time from abnormal mammogram to biopsy (25.5 days vs. 14 days, p=0.056), and interval from diagnosis to treatment (62 days vs. 39 days) (p=0.001) were less favorable for UP compared to IP. Conclusions: In comparing the status of UP (primarily Hispanic, Spanish-speaking) and IP (primarily non-Hispanic White, English-speaking) with newly diagnosed BC we identified greater prevalence of co-morbidities and adverse social determinants of health in the former group. We identified access to genetic counseling services, access to oncology nutrition consultation, and timeliness of diagnostic biopsy and initiation of treatment as disparate features in the care pathway. These observations can allow development of tailored interventions to achieve greater equity in delivery of BC care.

4130 Background: Circulating cell-free tumor DNA (ctDNA) genomic profiling is an emerging tool for pancreatic cancer. The impact of detected genomic alterations in tumor response to systemic treatments and outcomes is under investigation. Methods: Patients with advanced pancreatic cancer and ctDNA collected at time of initial diagnosis were retrospectively evaluated. Results of ctDNA analysis were correlated with patients’ demographics, systemic treatment response, progression-free survival (PFS) and overall survival (OS). Results: A total of 104 patients were included in the analysis. The mean age was 70.5 years (SD: 8.3), 50% were male, 37% with locally advanced disease and 63% with metastatic disease. Somatic alterations were detected in 84.6 % of the patients, no genetic alterations were detected in 15.4%, and were associated more with locally advanced pancreatic cancer as opposed to metastatic, p = 0.025. 60.6 % of the cohort had ≥ 2 genomic alterations detected. 28% were treated with FOLFIRINOX and 63% with gemcitabine plus nab-paclitaxel as first-line systemic treatment. Patients with any detectable genomic alterations when compared to patients with no detectable variant had worse median PFS (6.2 versus 15.3 months, p = 0.005) and patients with ≥ 2 detectable genomic alterations had worse median PFS (5.6 versus 11.0 months, p < 0.001) and worse median OS (11.5 versus 24.2 months, p = 0.001). KRAS was detected in 62.5% of the patients and was associated with PD to systemic treatments (80.4% vs 19.6%, p = 0.006), worse median PFS (5.8 versus 13.0 months, p < 0.001) and worse median OS (11.5 versus 26.3 months, p = 0.002). TP53 was detected in 60% of patients and was associated with worse median PFS (5.9 versus 10.9 months, p = 0.02) and worse median OS (13.5 versus 24.2 months, p = 0.001). CCND2 was detected in 14% of the patients and was associated with worse median PFS (3.6 versus 8.2 months, p = 0.004). Conclusions: Our study showed that initial detection of ctDNA may identify different genomic alterations that help predict disease outcomes, confirmation of these findings in larger studies are warranted.