Abstract: Objective: The use of serum ammonia as a novel marker for sepsis compared to lactic acid levels in intensive care unit (ICU) patients. Design and Interventions: Single arm, prospective clinical trial to collect arterial blood samples from patients with sepsis. Serial ammonia and lactic acid levels were sent every six hours for a total of three days. Measurements and results: Compare mean levels of ammonia and lactic acid in terms of diagnosing sepsis and patient outcome, including length of stay and mortality. A total of 30 patients were enrolled in the pilot study. On admission, mean ammonia level was 35.7 μmol/L and lactic acid was 3.06 mmole/L. Ammonia levels checked at the end of day 2 (ammonia 2-4) and the beginning of day 3 (ammonia 3-1) were higher in patients who had a microbial culture-proven sepsis (p-values 0.029 and 0.002, respectively) compared to those without culture-positive sepsis. Ammonia levels did predict a longer hospital stay; ammonia level of more than 40 μmol/L had a mean hospital stay of 17.6 days vs. patients with normal levels who had a mean hospital stay of 9.62 days (p-value 0.0082). Conclusion: Elevated ammonia level can be a novel biomarker for sepsis, comparable to conventional markers. Ammonia levels have a prognostic utility as elevated levels were associated with longer hospital stay.

Abstract: Gilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3‐mutation ( FLT3 mut+ ). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3 mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CR i  + CR with incomplete platelet recovery [CRp]) was 48.7% ( n  = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen‐activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value 〈 .01.

Abstract: Background: Liposomal daunorubicin/cytarabine (CPX-351) and hypomethylating agent+venetoclax (HMA+V) have shown survival advantage as frontline therapies for older and biologically adverse AML. Although HMA+V is approved for chemotherapy ineligible pts, there is increased use of the combination in older fit pts. with biologically adverse AML. However, clinical outcomes between the two treatments have not been compared and will have a major clinical impact. Our aim was to compare CPX-351 vs HMA+V as upfront treatment for newly diagnosed AML using a multi-center retrospective study. Methods: This is a multicenter retrospective study drawing from 4 large U.S. academic medical centers (Weill Cornell, Northwestern, Moffitt, Memorial Sloan Kettering). Eligibility included pts who received either CPX-351 or HMA+V as frontline therapy for AML. Response was determined using ELN 2017 guidelines. To evaluate the association between treatment type and categorical factors of interest, and the primary outcome variable of treatment response, the chi-square test or Fisher's exact test was used. For the outcome variable of bone marrow response status, multivariable logistic regression analysis was performed. For the relapse free survival (RFS) and overall survival (OS) outcomes, Kaplan-Meier survival analysis was performed, and the log-rank test was employed to compare between categories of treatment-type and prognostic factors of interest. Multivariable cox proportional hazards regression analysis was performed to assess the independent effect of treatment and demographic/prognostic factors of interest on outcomes of RFS/OS. Results: Our study included 211 CPX-351 and 226 HMA+V treated pts. 11 pts were excluded due to missing age or ELN risk. Pt. characteristics and univariate analyses are summarized in Table 1 and 2. Overall CR+CRi rates, median RFS and OS for CPX-351 vs. HMA+V were 57.8% vs. 56.6%, 32.5 vs. 14.1 months (p=0.11) and 17.3 vs. 11.1 months (p=0.007). In multivariable analysis, after adjusting for age, ELN risk, prior myeloid malignancy, and prior HMA therapy, there was no difference between CPX-351 vs. HMA+V in CR+CRi (HR 1.32, p=0.23, 95% CI 0.8-2.1) and RFS (HR 0.92, p=0.75, CI 0.59-1.46). There was a significant difference favoring CPX-351 for OS (HR 0.74, p=0.04, CI 0.55-0.99). When analyses were restricted to pts aged 60-75 years (n= 152 CPX-351, n= 100 HMA+V), rates of CR+CRi were 59.2% vs. 54.0% (p=0.41), and median RFS and OS for CPX-351 vs. HMA+V treated pts was 32.5 vs. 13.3 months (p= 0.80) and OS 17.1 vs. 10.3 months (p=0.12). Multivariable analysis after adjusting for above variables showed no difference in CR+CRi, RFS and OS between CPX-351 vs. HMA+V (CR+CRi: HR 1.28, p=0.55, 95% CI 0.77-2.27, RFS: HR 0.70, p=0.17, CI 0.42-1.17 and OS: HR 0.80, p=0.20, CI 0.57-1.12). Multivariable subgroup analyses demonstrated significant advantage favoring CPX-351 for RFS in TP53 mutated pts (HR 0.37, 95% C.I. 0.14-0.96, p=0.04). Subgroup analyses for OS are summarized in Figure 2. Among patients where minimal residual disease (MRD) data was available (n=93 CPX-351, n=133 HMA+V), MRD negativity by flow was 34.4% (n=32) and 39.1%(n=52) for CPX-351 and HMA+V pts, respectively (p=0.47). Among pts aged 60-75 years, 47.7% and 19% of patients underwent HSCT in CPX-351 and HMA+V groups (p & lt;0.001). Because HSCT was a significant predictor for RFS and OS (p & lt;0.001), we conducted multivariable analysis in pts aged 60-75 years who did not receive a transplant and found no difference in OS (HR 0.99, p=0.96, 95% CI 0.68-1.43). There was no difference in RFS and OS post-transplant between CPX-351 and HMA+V groups (OS: 64 vs NA months, p=0.69). RFS could not be inferred statistically due to small number of patients transplanted in the HMA+V group. Our study will be further expanded to include additional centers and comorbidity analyses. Conclusion: Our analysis demonstrated significant difference in OS favoring CPX-351 in the overall cohort and in several clinical subgroups, while no difference in CR+CRi and RFS was seen. The survival advantage in the CPX-351 group may be due to higher HSCT rates in CPX-351 treated pts. Among pts that did not proceed to HSCT, there was no difference in CR+CRi, RFS and OS between the treatment groups. We suspect that greater HSCT rates in the CPX-351 cohort were due to fewer comorbidities among CPX-351-treated pts or other biases, and comorbidity analyses are pending and will be reported. Figure 1 Figure 1. Disclosures Ritchie: Bristol Myers Squibb: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; NS Pharma: Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; Protaganist: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Speakers Bureau; ARIAD Pharmaceuticals: Ended employment in the past 24 months, Speakers Bureau; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Celgene/BMS: Consultancy, Other: travel support, Speakers Bureau. Lee: Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Goldberg: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog: Research Funding; Aprea: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; DAVA Oncology: Honoraria; Celularity: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dinner: Pfizer: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria. Sweet: AROG: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Roboz: Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Glaxo SmithKline: Consultancy; Jazz: Consultancy; Astex: Consultancy; Blueprint Medicines: Consultancy; Mesoblast: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; Jasper Therapeutics: Consultancy; Roche/Genentech: Consultancy; Helsinn: Consultancy; Amgen: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Agios: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Janssen: Research Funding. Desai: Agios: Consultancy; Kura Oncology: Consultancy; Takeda: Consultancy; Astex: Research Funding; Bristol Myers Squibb: Consultancy; Janssen R & D: Research Funding.

Abstract: Background Myeloid sarcoma (MS) is the rare extramedullary proliferation of myeloid blasts that disrupts the normal architecture of various tissues in patients with Acute myeloid leukemia (AML). MS can present concurrently with untreated AML or present as relapsed AML. Based on our clinical observations and emerging immune checkpoint inhibitor (ICI) studies in AML (Davids et al NEJM 2016), MS appears to behave differently based on transplant status and tends to have better ICI sensitivity. One of the prominent mechanisms of relapse post-transplant is immune escape via the loss of leukemia recognition by the graft. This is mediated by down regulation of HLA expression. We hypothesize that the immune signatures in the bone marrow (BM) microenvironment are distinct from those from the local MS microenvironment. Thus, we aimed to comprehensively explore the MS microenvironment at single-cell level, providing clues for more effective therapies including ICI, and insights into the molecular pathogenesis, clinicopathological features and outcomes of MS. Methods This is an investigator-initiated study where we collected paired fresh MS tissues and BM samples from patients with MS as well as retrospective collection of paired MS and BM samples that are already sectioned and paraffin-embedded. Eligible patients were consentable adults & gt; 18 years old and have MS lesions whether at diagnosis or at relapse of their AML disease. We excluded patients who have multiple malignancies or patients who are unable to provide samples. Accepted samples are 10-millimeter tissue or 1 million cells per milliliter. The fresh samples were cryopreserved and used for single cell RNA sequencing and ex vivo immune cellular assays. The sectioned tissues were used for multiplex immunohistochemical staining (mIHC) that tested a panel of 6 antibodies (CD3, CD68, CD4, CD33, PDL-1 and HLA-DR). We sought to further perform spatial transcriptome analysis (Visium) that complements mIHC for in-depth characterization of the MS microenvironment and immunopathogenesis. The clinical and genomic annotations for these samples were abstracted from the patients' charts. We have utilized Next generation sequencing (NGS) panels that interrogated 24- 180 oncogenes, including FLT3, IDH, CALR, NPM1, KRAS, NRAS, and TP53. Survival estimates using K-M curves and multivariate analysis were performed via SPSS. Results Our study recruited 30 patients so far. Mean age at diagnosis was (57.6 ± 14 years); 63.3% of the patients were males (n=19) and 80% of the patients were Caucasian (n=24). In our cohort, 46.6% of the patient had MS diagnosed as the cause of relapse after stem cell transplant (n=14) while the rest had MS at the initial diagnosis of AML. The most common cytogenetic abnormality in our cohort was complex karyotype in 30% of the patients. Molecular landscape of MS at diagnosis and relapse was done in 90% of the patients and shown in figure 1A,B. MS conferred a poor prognosis if diagnosed on initial presentation vs a new presentation at relapse post stem cell transplant with a median OS (4 months vs 25 months p 0.003) (HR 3.9 - 95% CI 1.4-11.1) figure 2. Interestingly, we have noticed that patients who received Venetolcax based therapies have poor prognosis compared to other therapies (IDH/FLT3 inhibitors, conventional chemotherapies, or ICI); median OS (9.3 months vs 24 months p 0.02) (HR 3.9 - 95% CI 1.2-12.6) figure 3. In a prelim analysis using validated mIHC, we have observed abundant HLA-DR expression in both blast cells and nonmalignant stromal cells of the MS microenvironment (n=4) figure-4. By contrast, PD-L1 was expressed mainly on a number of stromal cells rather than blast cells in the MS microenvironment. Further special localization analysis of tumor immune infiltrates (TILs) is being conducted to disclose clinical outcomes and biological significance of PD-L1, HLA-DR and TILs in MS. Spital transcriptomics are in process and will be presented. Conclusion MS diagnosed concurrently with untreated AML appears to confer a poor prognosis and behave differently than MS diagnosed as relapse post-transplant. MS appears to be resistant to Venetoclax based therapies and patients tends to do worse on this therapy. In contrast to BM microenvironment, blast cells within MS appears to have abundant expression of HLA-DR in both neoplastic tumor cells and nonmalignant stromal cells promoting immune recognition which might explain their sensitivities to ICI. Figure 1 Figure 1. Disclosures Abaza: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dinner: Pfizer: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria. Altman: Glycomimetics: Other: data monitoring committee; ALX Oncology Inc.: Research Funding; Loxo: Research Funding; ImmunoGen: Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding; Aprea: Research Funding; Astellas: Honoraria, Research Funding; Aptos: Research Funding; Boehringer Ingelheim: Research Funding; Celgene: Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Fujifilm: Research Funding; Biosight: Membership on an entity's Board of Directors or advisory committees, Other: reimbursement for travel, Research Funding; Kura Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kartos Therapeutics: Research Funding.