Search

Introduction Studies suggest that patients with cancer are more likely to experience severe outcomes from COVID-19. Therefore, cancer centers have undertaken efforts to care for patients with cancer in COVID-free units. Nevertheless, the frequency and relevance of nosocomial transmission of COVID-19 in patients with cancer remain unknown. The goal of this study was to determine the incidence and impact of hospital-acquired COVID-19 in this population and identify predictive factors for COVID-19 severity in patients with cancer. Methods Patients with cancer and a laboratory-confirmed diagnosis of COVID-19 were prospectively identified using provincial registries and hospital databases between March 3rd and May 23rd, 2020 in the provinces of Quebec and British Columbia in Canada. Patient’s baseline characteristics including age, sex, comorbidities, cancer type, and type of anti-cancer treatment were collected. The exposure of interest was incidence of hospital-acquired infection defined by diagnosis of SARS-CoV-2 ≥ 5 days after hospital admission for COVID-unrelated cause. Co-primary outcomes were death or composite outcomes of severe illness from COVID-19 such as hospitalization, supplemental oxygen, intensive-care unit (ICU) admission and/or mechanical ventilation. Results A total of 252 patients (N=249 adult, and N=3 pediatric) with COVID-19 and cancer were identified, and the majority were residents of Quebec (N=233). One-hundred-and-six patients (42.1%) received active anti-cancer treatment in the last 3 months prior to COVID-19 diagnosis. During a median follow-up of 25 days, 33 (13.1%) required admission to the ICU, and 71 (28.2%) died. Forty-seven (19.1%) had a diagnosis of hospital-acquired COVID-19. Median overall survival was shorter in those with hospital-acquired infection, compared to a contemporary community-acquired population (27 days vs unreached, HR 2.3, 95% CI 1.2-4.4, p=0.0006). Multivariate analysis demonstrated that hospital-acquired COVID-19, age, ECOG status, and advanced stage of cancer were independently associated with death. Interpretation Our study demonstrates a high rate of nosocomial transmission of COVID-19, associated with increased mortality in both univariate and multivariate analysis in the cancer population, reinforcing the importance of treating patients with cancer in COVID-free units. We also validated that age and advanced cancer were negative predictive factors for COVID-19 severity in patients with cancer., Highlights • We found a high rate of nosocomial transmission of COVID-19 in patients with cancer. • Nosocomial COVID-19 increased mortality compared to community-acquired infection. • Nosocomial COVID-19, age, ECOG, and stage were independently associated with death. • COVID-free units and infection control procedures are required to protect patients.

The myeloid nuclear differentiation antigen (MNDA) is a stress-induced protein that promotes degradation of the anti-apoptotic factor MCL-1 and apoptosis in myeloid cells. MNDA is also expressed in normal lymphoid cells and in B-cell clones isolated from individuals with chronic lymphocytic leukemia (CLL), a disease characterized by abnormal apoptosis control. We found that MNDA expression levels inversely correlate with the amount of the anti-apoptotic proteins MCL-1 and BCL-2 in human CLL samples. We report that in response to chemotherapeutic agents that induce genotoxic stress, MNDA exits its typical nucleolar localization and accumulates in the nucleoplasm of CLL and lymphoid cells. Then, MNDA binds chromatin at Mcl1 and Bcl2 genes and affects the transcriptional competence of RNA polymerase II. Our data also reveal that MNDA specifically associates with Mcl1 and Bcl2 (pre-) mRNAs and favors their rapid turnover as a prompt response to genotoxic stress. We propose that this rapid dynamic tuning of RNA levels, which leads to the destabilization of Mcl1 and Bcl2 transcripts, represents a post-transcriptional mechanism of apoptosis control in CLL cells. These results provide an explanation of previous clinical data and corroborate the finding that higher MNDA expression levels in CLL are associated with a better clinical course.

e15589 Background: Worldwide treatment for 1st line (1LTx) mCRC included doublet or triple chemotherapy with or without bTAs. In Quebec, the anti-EGFR therapy (panitumumab or cetuximab) was only recently approved in this setting for patients RAS WT, Bevacizumab (B) not eligible. In this study we evaluated the rational and outcomes using bTAs. Methods: Retrospective study assessing mCRC pts treated with or without bTAs at any time throughout the course of therapy at the Jewish General Hospital between 2010-2018. Pts were divided in 3 groups according to their 1LTx for analysis: Chemotherapy alone (1LChA), Chemotherapy plus B (1LChB), and anti-EGFR with or without chemotherapy (1LaEGFR). The primary objective was to assess the rational of bTAs prescription based in 1LTx selection. Secondary objectives included safety, PFS and OS. Results: Among a total of 463 pts with mCRC; 196 pts (42.3%) received 1LChA, 246 pts (53.2%) 1LChB, and 21 pts (4.5%) 1LaEGFR respectively. 1LChA group, 51% omitted bTAs for physician-patient preferences, 96 pts (49%) had contraindications for B, and 79 pts (40.3%) were potentially candidates for aEGFR, but did not receive it. 152/196 (77.5%) pts continued to 2LTx and 34.8% received bTAs. As for the 3LTx, 78/196 (40%) received a treatment, 48.7% received bTAs. The most common grade 3-4 adverse events (AEs) were hypertension and bowel perforation in B, gastrointestinal (GI) symptoms and skin reaction (SR) in aEGFR. 1LChB group, 31 pts (12.6%) presented AEs related to B. 191/246 pts (77.6%) continued to 2LTx with 48 pts (25%) receiving ChB despite progression in 1LTx on this bTA and 19 pts (10%) receiving aEGFR. The most common AEs reported in 2LTx were GI symptoms and neuropathy. In 3LTx, 54/91pts (59.3%) received aEGFR therapy and 8 pts (14.8%) had SR AEs. 46 pts (18.6%) continued to 4LTx, 13/46 pts (28.2%) received aEGFR. 1LaEGFR group, the most common AEs were SR and GI symptoms. 11/21 pts (52.3%) continued to 2LTx; 5 pts (45.4%) switching bTA class and receiving ChB. 81% pts started treatment between 2017-2018 and had at least two contraindication criteria for. The median PFS for the 1LChA and 1LChB groups were 10 and 11.5 months, respectively, and were not statistically significant (p=0.22). The OS with 1LChA and 1LChB was 33.26 vs. 27.80 months (p=0.27). The PFS and OS between 1LChA and 1LaEGFR were 10 vs 11 months (p= 0.27) and 33.26 vs. 35.07 months (p=0.13). Conclusions: The outcome and tolerability of bTAs in mCRC appear similar in our institution and randomised trials. We were not able to detect any significant difference among the three groups of comparison. The 1LaEGFR available data in this subset of patients are limited. Our data highlights the importance of optimal therapeutic sequencing to prolong OS. Dedicated studies are needed in order to determine the best bTAs therapeutic strategy in mCRC.

Background: Studies suggest that patients with cancer are more likely to experience severe outcomes from COVID-19. Therefore, cancer centers have undertaken efforts to care for patients with cancer in COVID-free zones. Nevertheless, nosocomial transmission of COVID-19 in patients with cancer likely occurs, but the frequency and relevance of these events remain unknown. The goal of this study was to determine the incidence and impact of hospital-acquired COVID-19 in this population and identify prognostic factors for COVID-19 severity in patients with cancer. Methods: Patients with cancer and a laboratory-confirmed or presumed diagnosis of COVID-19 were prospectively identified using provincial registries and hospital databases between March 3rd and May 23rd, 2020, in the provinces of Quebec and British Columbia. Patients’ baseline characteristics including age, sex, comorbidities, cancer type, and type of anticancer treatment were collected. The primary outcome was incidence of hospital-acquired infection defined by diagnosis of SARS-CoV-2 5 days after hospital admission for COVID-unrelated cause. Co-primary outcomes were death or composite outcomes of severe illness from COVID-19 such as hospitalization, supplemental oxygen, intensive-care unit (ICU) admission, and/or mechanical ventilation. Results: A total of 253 patients (N=250 adult and N=3 pediatric) with COVID-19 and cancer were identified, and the majority were residents of Quebec (N=236). Ninety patients (35.6%) received active anticancer treatment in the last 3 months prior to COVID-19 diagnosis. During a median follow-up of 23 days, 209 (82.6%) required hospitalization, 38 (15%) required admission to ICU, and 71 (28%) died. Forty-seven (19%) had a diagnosis of hospital-acquired COVID-19. Median overall survival was shorter in those with hospital-acquired infection, compared to a contemporary community-acquired population (27 days vs. 71 days, HR 2.2, 95% CI 1.2-4.0, p=0.002). Multivariate analysis demonstrated that hospital-acquired COVID-19, age, ECOG status, and advanced stage of cancer were independently associated with death. Conclusion: Our study demonstrates a high rate of nosocomial transmission of COVID-19, associated with increased mortality in both univariate and multivariate analysis in the cancer population, reinforcing the importance of treating patients with cancer in COVID-free zones. We also validated that age, poor ECOG, and advanced cancer were negative prognostic factors for COVID-19 in patients with cancer. Citation Format: Arielle Elkrief, Antoine Desilets, Neha Papneja, Lena Cvetkovic, Catherine Groleau, Yahia Abdelali Lakehal, Layla Shbat, Corentin Richard, Julie Malo, Wiam Belkaid, Erin Cook, Stephane Doucet, Thai Hoa Tran, Patrice Savard, Kevin Jao, Nathalie Daaboul, Eric Bhang, Jonathan Loree, Wilson Miller, Donald Vinh, Nathaniel Bouganim, Gerald Batist, Caroline Letendre, Bertrand Routy. High mortality among hospital-acquired COVID-19 infection in patients with cancer: An observational cohort study from Quebec and British Columbia [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S12-01.

IKAROS is a critical regulator of hematopoietic cell fate and its dynamic expression pattern is required for proper hematopoiesis. In collaboration with the Nucleosome Remodeling and Deacetylase (NuRD) complex, it promotes gene repression and activation. It remains to be clarified how IKAROS can support transcription activation while being associated with the HDAC-containing complex NuRD. IKAROS also binds to the Positive-Transcription Elongation Factor b (P-TEFb) at gene promoters. Here, we demonstrate that NuRD and P-TEFb are assembled in a complex that can be recruited to specific genes by IKAROS. The expression level of IKAROS influences the recruitment of the NuRD-P-TEFb complex to gene regulatory regions and facilitates transcription elongation by transferring the Protein Phosphatase 1α (PP1α), an IKAROS-binding protein and P-TEFb activator, to CDK9. We show that an IKAROS mutant that is unable to bind PP1α cannot sustain gene expression and impedes normal differentiation of IkNULL hematopoietic progenitors. Finally, the knock-down of the NuRD subunit Mi2 reveals that the occupancy of the NuRD complex at transcribed regions of genes favors the relief of POL II promoter-proximal pausing and thereby, promotes transcription elongation., Author Summary Perturbation of the expression level of IKAROS, a transcription factor critical during hematopoiesis, is associated with malignant transformation in mice and humans. The importance of IKAROS expression levels for the control of target-gene regulation was addressed in hematopoietic progenitor cells. The collaboration between IKAROS and the Nucleosome Remodeling and Deacetylase (NuRD) complex can promote gene activation or repression. IKAROS can also interact with the Positive-Transcription Elongation Factor b (P-TEFb) and the Protein Phosphatase 1 (PP1), an important P-TEFb regulator. Immunoaffinity purification of IKAROS interacting proteins and Fast Protein Liquid Chromatography analysis revealed a dynamic interaction between IKAROS, PP1 and the newly defined NuRD-P-TEFb complex. This complex can be targeted to specific genes in cells expressing high levels of IKAROS to promote productive transcription elongation. Based on our results we suggest that, in addition to P-TEFb, the NuRD complex and PP1 are required to facilitate transcription elongation of IKAROS-target genes and normal differentiation of hematopoietic progenitor cells.