Differential Outcomes of Salvage with FLAG-IDA and Venetoclax-Based Regimens in Relapsed and Refractory Acute Myeloid Leukemia

Background: Sequencing and selection of salvage regimens for acute myeloid leukemia (AML) remains unclear. Venetoclax augmentation of a hypomethylating agent (HMA) backbone has joined the salvage armamentarium following impressive performance in the front-line setting. However, little is known about the outcomes with venetoclax in relapsed and refractory (R/R) AML. Survival and toxicity data remain scarce for venetoclax-based salvage, particularly when compared to intensive reinduction. This study characterizes outcomes between venetoclax-based salvage regimens and FLAG-IDA in the R/R setting. Patients & Methods: We retrospectively analyzed all patients with AML treated at Massey Cancer Center younger than 65 in the R/R setting with either FLAG-IDA (fludarabine, cytarabine, G-CSF, and idarubicin) or venetoclax in combination with decitabine, azacitidine, or low-dose cytarabine from June 2018 to December 2020. Baseline patient demographics and disease characteristics were obtained and recorded in RedCap. Statistical analyses using unpaired t-test with Welch's correction or the Mann-Whitney test, Fischer's exact test, and Kaplan-Meier survival analyses were computed and compared with log-rank tests using GraphPad Prism. The event for calculating the overall survival was the date of death with patients otherwise censored at the date of last contact. Results: Twenty-eight patients were identified meeting inclusion criteria: 19 underwent salvage with venetoclax-based regimens and 9 patients were treated with FLAG-IDA. Five patients (55.6%) in the FLAG-IDA cohort underwent salvage for refractory disease (primary induction failure), compared to only two (10.5%) in the venetoclax group, which was statistically significant (p = 0.019). The remaining patients in both cohorts were treated in the relapsed setting. There was no significant difference in sex (p = >0.999), ECOG performance status at diagnosis (p = 0.083), or Charlson Comorbidity Index (CCI) scores (p = 0.128). The median age of patients treated with FLAG-IDA was 39 (range: 24 - 62), the four most common molecular mutations in the FLAG-IDA cohort occurred at a frequency of 22.2% each: FLT3-ITD, NPM1, WT1, and biallelic CEBPA. Two patients (22.2%) had favorable cytogenetics at diagnosis, one (11.1%) had intermediate cytogenetics, five (55.6%) had adverse cytogenetics, and one was unknown. All were initially treated with a 7+3 backbone. The most common non-hematological toxicities were neutropenic fever (55.6%) and acute kidney injury (22.2%). Five (55.6%) achieved CR and one (11.1%) achieved CRi for an ORR of 66.7%. There were no deaths within 60 days of salvage. Five (55.6%) patients went on to receive allogeneic SCT. Median survival was not reached at a median follow-up of 430 days (14.1 months). In the venetoclax-based cohort of 19 patients, the median age was 58 (range: 23 - 65), At the time of initial diagnosis, the most common molecular aberrations were TP53 (26.3%), NPM1 (15.7%), followed by FLT3-TKD, RUNX1, and TET2 (10.5% each). Two (10.5%) patients had favorable cytogenetics at initial diagnosis, two (10.5%) had intermediate, 14 (73.7%) had adverse cytogenetics, and one patient had unknown cytogenetics. Seventeen (89.5%) patients were initially treated with 7+3, one (5.3%) was treated with azacitidine, and one (5.3%) was treated with CPX-351. The most common non-hematological toxicities were infection (42.1%), neutropenic fever (31.6%), and GI toxicity (15.8%). Two (10.5%) patients achieved CR and four (21.1%) achieved CRi for an ORR of 31.6%. There were 3 deaths in 30 days and 1 death within 60 days. Four (21.1%) went on to receive allogeneic SCT after venetoclax-based salvage. The median survival was 268 days (8.81 months) and was statistically significant from the FLAG-IDA cohort (p = 0.0029). Conclusion: Our results suggest the efficacy of FLAG-IDA compared to venetoclax-based regimens with respect to ORR, survival, toxicity, and progression to transplant in the R/R setting for presumable intensive induction candidates, as evidenced retrospectively by prior receipt of such regimens. These differences may be impacted by changes to disease biology between the relapsed and refractory settings and TP53 status. Larger prospective studies with separate analyses between the relapsed and refractory settings are needed to confirm these findings. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Clinical Outcomes of COVID-19 Infection Among Children with Cancer: A Single-Center Experience

Background Outcomes of COVID-19 infection among children with underlying malignancy remain unclear, with limited data available to date. Here we report clinical characteristics and outcomes following COVID-19 infection among children with underlying malignancy or a history of hematopoietic stem cell transplant (HSCT) during the first year of the global COVID-19 pandemic, in Dallas, TX. Methods: We retrospectively reviewed children with a history of malignancy or prior HSCT and positive SARS-CoV-2 polymerase chain reaction (PCR) result between March 1, 2020 - March 31, 2021. Demographic, clinical, and outcome data were reviewed, and analyzed according to underlying condition and disease severity. Results: Forty-six patients with underlying malignancy or HSCT met inclusion criteria. Median age was 9 years, with twenty (43%) female, and twenty-seven (59%) of Hispanic ethnicity. Underlying conditions included Acute Lymphoblastic Leukemia (67%), Acute Myelogenous Leukemia (9%), HSCT (11%), sarcoma (9%), solid tumors (9%), and Hodgkin's lymphoma (2%). Fifteen subjects (33%) were asymptomatic, with twenty-four children (52%) classified as having mild, five (11%) with severe, and two (4%) with critical COVID-19 disease. The most common symptoms at presentation were fever (46%), cough (39%), and gastroenteritis (19%). Thirty-four children (74%) were hospitalized, with seven (15%) requiring intensive care unit (ICU) care. 17% of patients were admitted for treatment of COVID-19 alone, with other indications including neutropenic fever, relapse, and chemotherapy. Six (13%) patients required non-invasive ventilation, and two patients (4%) required invasive mechanical ventilation. Median length of stay was 9 days (IQR 4.5-24.5), with median ICU stay of 3.5 days (IQR 2-26.7). Seven children (15%) received COVID-19 targeted therapy including steroids, remdesivir or convalescent plasma. Among severe and critically ill children, six (86%) had underlying hematologic malignancies (5 HR ALL, 1 AML), and two (28%) a prior history of HSCT. Two children (4%) died. Thirty-six patients (78%) achieved documented clearance of SARS-CoV-2 by PCR, at median of 43.5 days (IQR 28.7-65.2). Conclusion: Among children with underlying malignancy or a history of HSCT, COVID-19 results in a spectrum of illness ranging from asymptomatic disease to death. Rates of hospitalization are high compared to the general pediatric population, and illness may be complicated by additional factors including co-infection, neutropenic fever, relapse of malignancy and need for chemotherapy. Children with hematologic malignancy or a history of HSCT may be at increased risk for severe disease. Additional studies are urgently needed to elucidate risk factors for severe/critical COVID-19 disease among children with underlying malignancy. Disclosures No relevant conflicts of interest to declare.

Outcomes of Induction with Venetoclax in Combination with Decitabine, Azacitidine, or Low-Dose Cytarabine for Treatment of AML: A Real-World Retrospective Analysis

Background: The addition of venetoclax to a hypomethylating agent (HMA) backbone has been shown to augment responses when compared to HMA monotherapy or to low-dose cytarabine in the treatment of acute myeloid leukemia (AML). The aim of this retrospective analysis was to characterize venetoclax-based regimens in both the first-line and relapsed/refractory settings to determine efficacy and safety outcomes. Patients & Methods: We retrospectively analyzed 74 patients treated with venetoclax in combination with decitabine, azacitidine, or low-dose cytarabine treated from June 2018 to December 2020. This analysis included 41 patients in the upfront setting and 33 patients in the relapsed/refractory setting. Baseline patient demographics were obtained alongside ECOG performance status at diagnosis, cytogenetics and molecular profiling, dates and doses of induction, toxicity, responses, MRD analysis, and allogeneic hematopoietic stem cell transplant (HSCT) outcomes. The event for calculating the overall survival was the date of death and patients were otherwise censored at the date of last contact. Results: In the upfront setting of 41 patients, 25 (61%) were male and 16 (39%) were female, the median age was 72 (range: 37 - 85), the median ECOG score was 2 (range: 0 - 3), and the median Charlson Comorbidity Index (CCI) score was 6 (range: 3 - 12). There were four patients with favorable-risk cytogenetics (9.8%), six (14.6%) with intermediate cytogenetics, and 29 (70.7%) with adverse cytogenetics. Two (4.9%) patients had cytogenetics unknown at diagnosis. Eight (19.5%) had mutations in TP53. Thirty-three (80.5%) received venetoclax with 5-day decitabine, one (2.4%) with 10-day decitabine, six (14.6%) with azacitidine, and one (2.4%) with low-dose cytarabine. In the entire cohort, 37 (90.2%) experienced at least one grade 1 non-hematological toxicity during induction. Non-hematological adverse events were infection (58.5%), neutropenic fever (53.7%), and acute kidney injury (26.8%). Six (14.6%) patients had tumor lysis syndrome defined by Cairo-Bishop criteria and all six were spontaneous rather than therapy-induced. One (2.4%) died within 30 days of induction, nine (22.0%) died within 60 days, and 29 (70.7%) had no death during induction. Three (7.3%) achieved CR and 13 (31.7%) achieved CRi for an ORR of 39.0%. Two patients (4.9%) went on to receive HSCT. The median OS was 416 days (13.7 months) in the intermediate category and 281 days (9.2 months) in the adverse category. In the relapsed/refractory setting, 20 (60.6%) were male and 13 (39.4%) were female. The median age was 63 (range: 23 - 76), the median ECOG score was 1 (range: 0 - 4), and the median CCI score was 5 (range: 2 - 11). At the time of initial diagnosis, two patients (6.1%) had favorable cytogenetics, three (9.1%) had intermediate cytogenetics, 27 (81.8%) had adverse cytogenetics, and one had unknown cytogenetics. Seven (21.2%) patients had a TP53 mutation at initial diagnosis. Twenty-five (75.8%) received venetoclax with 5-day decitabine, 6 (18.2%) with azacitidine, one (3.0%) with low-dose cytarabine, and one with an unknown duration of decitabine. Common non-hematological toxicities included 13 (39.4%) with infection, 11 (33.3%) with neutropenic fever, and 3 (9.1%) with acute kidney injury. Five patients (15.2%) achieved CR and 5 (15.2%) achieved CRi for an ORR of 30.3%. Four (12.1%) died within 30 days, 3 (9.1%) within 60 days, and 25 (75.8%) with no death during induction. The median OS was 251 days (8.25 months). Conclusion: The combination of venetoclax with decitabine, azacitidine, or low-dose cytarabine demonstrates an ORR of 39.0% in the upfront setting and the OS was 13.7 months and 9.2 months in the intermediate and adverse categories, respectively. The relapsed/refractory setting featured a shorter OS at 8.25 months and an ORR of 30.3%, which does not appear to be substantially different from historical data with HMA monotherapy in relapsed disease (mOS = 6.7 months). These findings raise the question regarding the benefit of venetoclax in the relapsed setting for selected patients. Additionally, our findings augment the small sample of available data on the utility of HMA/venetoclax, particularly in the treatment of relapsed disease, with recent retrospective data showing a CR/CRi rate of 24% and a mOS of 6.1 months. Prospective trial designs are needed to confirm these findings. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Safety of Autologous Hematopoietic Stem Cell Transplantation in Patients over 75 Years Old. Single Center Experience Serving a Minority Population

Background: Autologous hematopoietic stem cell transplant (auto-HSCT) is a commonly used treatment for multiple myeloma (MM) and for relapsed/refractory non-Hodgkin lymphomas (NHL) for patients who are <65 years old. However, the majority of new diagnoses of MM and NHL are in patients >65 years old, and nearly half of those are in patients >75 years old. While some studies have evaluated the use of auto-HSCT in older patients 65-75 years of age, there are few studies evaluating the relative safety of this treatment in patients above the age of 75 years. Such patients and their providers require outcome data of auto-HSCT in the elderly in order to help guide informed decision-making. Methods: We conducted a retrospective cohort study comparing short-term outcomes for auto-HSCT in patients >75 years old and 55-65 years old for the diagnosis of MM or NHL, who were conditioned with either melphalan or BEAM (carmustine, etoposide, cytarabine, melphalan) respectively. To identify patients, we used an internal database of auto-HSCT performed between 2005 - 2021. The study group included patients >75 years old. The control group included patients 55-65 years old that were matched to the study group patients by sex and time of transplant. Medical records were reviewed to gather data on demographics, pre-transplant functional status, transplant indication and conditioning regimen, length of stay, admission mortality, 30-day rehospitalization rate, ICU admission, neutropenic fever and infectious workup results, and time to WBC and platelet engraftment. The primary outcomes of the study were admission mortality, length of stay, time to WBC and platelet engraftment incidence, incidence of neutropenic fever, positive blood culture, ICU admission, and 30-day rehospitalization rate. Averages were calculated using medians and IQR. Admission mortality was evaluated using log rank test. P values were calculated using Fisher's test for categorical data and Wilcoxon rank sum test for continuous data. Significance was denoted by α =0.05. Results: We identified 43 patients aged >75 years old who underwent autologous stem cell transplant for multiple myeloma or lymphoma with melphalan or BEAM conditioning at Montefiore Medical Center between 2005-2021. Patient characteristics (Table 1) The earliest transplant in out cohort was in 12/2005 and the latest was in 3/2021. The median time between transplants of patients in the study and cohort groups was 14 [7.5, 24] days. 24 (55.8%) patients were female. The median age in the study group was 77.1 [76.2, 77.9] years old and 61.9 [57.4, 63.0] years old in the control group. Both groups predominantly included patients from minority populations: 55.8 and 46.5% were Spanish/Hispanic/Latino and 25.6% and 14.0% were African American, in study and control groups respectively. Multiple myeloma was the most common indication for auto-HSCT. Primary outcomes (Table 2) Admission mortality did not differ significantly between the groups, with only one death in the control group (p = 0.083). The length of stay was comparable at 18 [17, 22] days and 19 [16, 20] days (p = 0.2) for study and control groups, respectively. Time to WBC engraftment in the study group was 12 [11, 12] days and 11 [11, 12] days in the control group (p = 0.032). Time to platelet engraftment in the study group was 14 [12, 15] days and 12 [11, 14] days in the control group (p = 0.014). Although both time to WBC and platelet engraftment was significantly longer in the study group, the clinical significance of this finding is questionable, especially as it did not seem to prolong length of stay. There was no significant difference between incidence of neutropenic fever, or between incidence of positive blood cultures in patients with neutropenic fever. There was a non-statistically significant increase in the rate of ICU admissions in the study group vs control group 4/43 and 0/43 respectively (p=0.12). 30-day rehospitalization rate was comparable between the two groups. Conclusion: We did not find a statistically significant increase in morbidity or mortality for patients 75-80 years of age undergoing auto-HSCT compared with patients 55-65 years old. To our knowledge this is the largest cohort to date demonstrating the safety of auto-HSCT in this elderly population. Figure 1 Figure 1. Disclosures Gritsman: iOnctura: Research Funding. Shastri: Onclive: Honoraria; GLC: Consultancy; Kymera Therapeutics: Research Funding; Guidepoint: Consultancy. Verma: Medpacto: Research Funding; Curis: Research Funding; Eli Lilly: Research Funding; Stelexis: Consultancy, Current equity holder in publicly-traded company; Novartis: Consultancy; Acceleron: Consultancy; Celgene: Consultancy; Stelexis: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company; Incyte: Research Funding; GSK: Research Funding; BMS: Research Funding.

Time Spent at Home Among Older Adults with AML Treated with Hypomethylating Agents and Venetoclax

Introduction The prognosis for older adults with acute myeloid leukemia (AML) is poor. Of approximately 12,000 adults age ≥ 60 diagnosed with AML in the U.S. annually, less than 40% survive 1 year from diagnosis. Prior research has shown that adults with AML feel time at home is a critical consideration in treatment selection. However, to date, no study has adequately described the amount of time older adults can expect to spend at home following initiation of AML therapy. In this study, we aimed to (1) quantify this time and (2) assess the impact of venetoclax (VEN) combination therapy on time at home for older adults with AML. Methods We queried records from University of North Carolina Health to identify individuals age ≥ 60 newly diagnosed with AML from 2015 to 2020. First-line AML therapy was identified, and those receiving azacitidine (AZA) and/or VEN were included. Dates of diagnosis, first remission, death, last follow up, and all oncology clinic / emergency department (ED) / inpatient encounters were captured. Patients with incomplete records were excluded. The primary outcome was proportion of days at home (PDH). PDH was calculated for each patient by subtracting the number of care days (days hospitalized or seen in an ED / oncology clinic / infusion center) from the total days of follow up, divided by total days of follow up. Overall survival (OS) was calculated via the Kaplan-Meier method. Covariates including demographics and disease risk (per European Leukemia Net 2017) were captured. PDH was evaluated via summary statistics for the full cohort and stratified by each categorical variable, both for the full follow up period and on a month-by-month basis among survivors. Associations between PDH and covariates were further assessed via linear regression with adjustment for length of follow up, with significance assessed via Wald Chi-square test. Results From 2015-2020, 137 older adults receiving first-line AZA and/or VEN were identified. 24 were excluded due to incomplete records. Among the remaining 113, mean age was 76 (range 60-99), 80.4% were white, and 43.4% were female. Most received AZA+VEN (51.3%) followed by AZA monotherapy (39.0%) and other VEN-containing combinations (9.7%). The majority had adverse-risk AML (61.3%). Baseline covariates including age and ELN risk were similar across therapy groups. Over the full follow up period, mean PDH was 0.58 (95% confidence interval 0.54-0.63) with a median of 0.63. PDH was similar among those with adverse-risk (mean 0.55, CI 0.49-0.61) and intermediate-risk AML (0.64, CI 0.56-0.72). PDH did not differ among therapy groups: AZA+VEN (0.60, CI 0.54-0.66), AZA alone (0.57, CI 0.49-0.66), and other VEN-containing regimens (0.54, CI 0.40-0.69). When adjusted for length of follow up, no covariate had a significant association with PDH (all p > 0.05). When evaluated month-by-month, the proportion of days at home rose over time among survivors. For example, of patients who survived the full month, mean PDH was 0.51 (CI 0.47-54, n = 105) in month 1 following diagnosis and 0.77 (CI 0.72-0.82, n = 57) in month 6. Figure 1 summarizes person-days at home or engaged in care for 12 months following diagnosis (including contributions from those who did not survive the full month). 34.5% of patients achieved composite complete remission, with higher rates among those receiving AZA+VEN (51.7%) than AZA alone (13.6%) (OR 6.8, p = 0.0002). Median OS was 0.64 years (CI 0.32 - 0.91) and was similar across therapy groups. Conclusion Burden of care for older adults with AML treated with first-line AZA or VEN is high. These individuals spend nearly half (cohort mean 42%) of days following diagnosis engaged in oncology care. In randomized studies, the addition of VEN to AZA improves OS and increases remission rates though results in higher rates of neutropenic fever. Although this study may be underpowered to detect small differences, the superior remission rates with AZA+VEN did not translate to more days at home, perhaps due to increased admissions for neutropenic fever and office/infusion visits. Given the importance of time at home to older adults with AML identified in prior research, these data provide new information to support shared decision making regarding treatment options. Future prospective trials should evaluate burden of care, including time at home, as an endpoint. While awaiting these data, larger analyses of the impact of treatment regimen on burden of care would be useful. Figure 1 Figure 1. Disclosures Bryant: Carevive: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Servier Pharmaceuticals: Honoraria, Speakers Bureau. Coombs: Alexion Pharmaceuticals: Research Funding; Machaon Diagnostics: Research Funding. Foster: Macrogenics: Research Funding; Rafael Pharmaceuticals: Research Funding; Macrogenics: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Bellicum Pharmaceuticals: Research Funding.

Outcomes of High-Intensity Versus Low-Intensity Induction in Elderly Patients with AML: A Retrospective Analysis of Real-World Outcomes

Background: The optimal induction strategy for patients with acute myeloid leukemia (AML) older than 65 years remains unknown. The use of lower intensity therapies in this population has become routine. The inclusion of venetoclax to intensify a hypomethylating agent backbone has efficacy outcomes approaching those of anthracycline-based inductions in elderly adults. This retrospective analysis sought to compare venetoclax-based induction combinations to anthracycline-based regimens. Patients & Methods: We retrospectively analyzed all patients with AML older than 65 treated with 7+3 or liposomal daunorubicin and cytarabine (CPX-351) versus venetoclax with either decitabine or azacitidine from June 2018 to December 2020 at our institution. Patients were included in the analysis only if ECOG performance status prior to induction supported intensive induction (≤2). Baseline patient demographics, cytogenetic risk, molecular profiling (through next-generation sequencing), toxicity, responses, and MRD analysis were obtained. Kaplan-Meier curves were constructed using censoring at date of last contact for those that did not have a death event in the specified time period. Results: The intensive cohort included 28 patients, 15 (53.6%) males and 13 (46.4%) females. The median age at diagnosis was 69 (range: 65 - 76), the median ECOG score was 1, and the median CCI score was 6. The anthracycline in the 7+3 cohort was daunorubicin in 15 patients (53.6%) and idarubicin in 1 (3.6%) patient. This cohort also included 12 (42.9%) patients treated with CPX-351. Two (7.1%) patients had favorable cytogenetics, 6 (21.4%) had intermediate cytogenetics, and 20 (71.4%) had adverse cytogenetics. The most common non-hematological toxicities that Grade 1 or higher were neutropenic fever (85.7%), infection (71.4%), GI/hepatobiliary (42.9%), cardiovascular (35.7%), and acute kidney injury (32.1%). One (3.8%) of the 26 evaluable patients died within 30 days and one (3.8%) died within 60 days. Fourteen patients (50.0%) achieved CR and 3 (10.7%) achieved CRi for an ORR of 60.7%. Six of the 17 patients with CR or CRi were analyzed for MRD and two (33.3%) were MRD-negative. Six (21.4%) received an allogenic stem cell transplant (SCT). The median OS in the intensive cohort was not reached at a median follow-up of 711 days (23.4 months). The lower intensity cohort totaled 28 patients, 18 (64.3%) males and 10 (35.7%) females. The median age at diagnosis was 75 (range: 65 - 85), median ECOG score was 1, and the median CCI score was 6. There were no differences in ECOG score (p = 0.930), CCI (p = 0.195), or cytogenetic risk (p = 0.924) between the two groups. Venetoclax was given in combination with 5-day decitabine (78.6%) or azacitidine (21.4%). Of the 28 patients with evaluable cytogenetics, 2 (7.1%) were favorable, 5 (17.9%) were intermediate, and 19 (67.9%) were adverse. The most common non-hematological toxicities were infection (57.1%), neutropenic fever (50.0%), GI/hepatobiliary (28.5%), cardiovascular (25.0%), and acute kidney injury (21.4%). Of the 28 evaluable patients, one (3.6%) died within 30 days and 7 (25.0%) died within 60 days, though not statistically significant compared to the intensive group (p = 0.103). Two (7.1%) achieved CR and 12 (39.3%) achieved CRi for an ORR of 46.4%. Two of the 13 patients were evaluated for MRD and none were MRD-negative after induction. Two (7.1%) patients received allogeneic SCT. The median OS in the venetoclax cohort was 354 days (11.6 months), though no statistically significant difference was detected when compared to the intensive cohort (p = 0.0735). However, when the two cohorts were selected for adverse cytogenetic risk and compared, the median OS was not reached in the intensive group at a median follow-up of 636 days but was 91 days in the venetoclax group (p = 0.025). Conclusion: Elderly patients had superior responses and survival to intensive induction when compared to venetoclax-based strategies when analyzed with respect to cytogenetic risk. Additionally, though the rates of toxicities were higher in the intensive cohort, the mortality during induction appeared to be lower, but did not reach statistical significance. Our work indicates that careful selection of intensive induction candidates is warranted, as those who can tolerate intensive regimens may be undertreated by selecting a less-intensive therapeutic strategy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Circulating Metabolomics Suggest Neutropenic Fever As a Metabolic Derangement Related to Intestinal Tissue Damage and Gut Dysbiosis

Introduction: Despite antibiotic prophylaxis, most patients with acute myeloid leukemia (AML) develop neutropenic fever (NF) during intensive chemotherapy, suggesting a non-infectious etiology in many cases. In addition, escalated antibiotics used to treat NF increase the risk of Clostridioides difficile infection, promote pathogen colonization, prolong hospitalization, and increase healthcare costs. More effective prevention of NF, preferably using non-antibiotic approaches, is needed. We hypothesized that a longitudinal analysis of the circulating metabolome may reveal novel aspects of NF pathogenesis and identify potential targets for new preventative interventions. Methods: We analyzed 128 longitudinal serum samples from 17 intensively treated adult patients with AML between hospital admission and day 28 of chemotherapy. Samples were collected between 6-8 AM every Mon and Thu. Samples were subjected to ultrahigh performance liquid chromatography-tandem mass spectrometry. Results: All patients developed NF. A total of 1,031 metabolites were identified. Principal components analysis of the circulating metabolome could not resolve individual patients (Fig. 1a). In contrast, pre- vs. post-NF samples were partially clustered (Fig. 1b), suggesting a metabolomic shift associated with NF. After correcting for false discovery, 26 and 27 metabolites were higher in pre- and post-NF samples, respectively (q<0.05, |log fold-change| >1; Fig. 1c). The most significant metabolite that was different between post- and pre-NF samples was citrulline, with a mean concentration ratio of 0.65 between the two groups (q<10-5, Fig. 1c). Citrulline is a known biomarker for total enterocyte mass and its lower levels in post-NF samples indicate intestinal tissue damage as a potential etiology for NF. Another notable metabolite was 3-indoxyl sulfate (3-IS), a tryptophan metabolite and biomarker of gut microbiota diversity and clostridia abundance. 3-IS levels also decreased in post-NF (post vs. pre ratio: 0.45, q=0.02; Fig. 1c), suggesting a protective role for commensal microbiota against NF. Indoles act via the aryl hydrocarbon receptor to repair the intestinal epithelial barrier. Sparse partial least squares discriminant analysis (sPLS-DA) further improved group separation (Fig. 1d). Significantly altered metabolites in the first analysis along with the top 50 metabolites in sPLS-DA were fed into a random forest which generated the final list of 47 metabolites with largest contributions to group separation, including 3-IS and several citrulline metabolites (top 10 metabolites in Table 1). The most frequent metabolites on this list were those in amino acid (n = 17) and lipid (n = 14, including a secondary bile acid) pathways. Conclusions: This first-time analysis of the circulating metabolome in AML patients with NF suggests NF as a metabolic derangement rather than an infectious event in many patients. Augmenting the intestinal epithelium and maintaining a commensal clostridia-rich gut microbiome may help prevent NF. In addition, our list of altered metabolites introduces an unexplored niche for the development of novel, non-antibiotic-based approaches to prevent NF. Figure 1 Figure 1. Disclosures Holtan: Incyte: Consultancy, Research Funding; Generon: Consultancy. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding.

In Patients with Acute Myeloid Leukemia, Hidac Administered on Days 1, 2 and 3 of Consolidation Course Is As Efficacious As Hidac Given on Days 1, 3 and 5, but Is Better Tolerated

Introduction: High-dose Ara-C (HiDAC) is a post-remission consolidation protocol commonly used in patients with acute myeloid leukemia (AML). The optimal regimen of HiDAC administration is not fully established. Recent studies suggest that a short and condensed schedule of HiDAC consolidation therapy given on days 1, 2 and 3 (HiDAC123) may be superior to the traditional days 1, 3 and 5 regimen (HiDAC135). The current retrospective study compared the impact of these two therapeutic approaches on the outcomes of AML patients treated at the Rambam Leukemia Unit. Methods: This retrospective cohort analysis included patients diagnosed with AML between the years 2015-2020 who were candidates for aggressive chemotherapy. Fifty-seven patients received a total of 76 courses of HiDAC135 mainly between 2015 and 2017, while 77 other patients received a total of 135 courses of HiDAC123 mainly between 2017 and 2020. The HiDAC dose in the two groups was 3 g/m 2 for patients aged less than 55 years, and 1.5 g/m 2 for patients aged 55-65 years. Patient demographics, the ELN leukemia risk category and NPM1 status were compared. The analysis also included data on complications per course of HiDAC therapy, need for hospitalization, the number of days of hospitalization if needed, the occurrence of neutropenic fever per course, the need for blood products (packed red blood cells and platelets), neurotoxicity and death within the 28 days of the course. Results: The HiDAC123 and HiDAC135 groups were comparable in terms of the ELN risk category and NPM1 status. The groups significantly differed in age (median of 49.8 years and 55.9 years, respectively; p=0.01), which was most likely to be related to the use of venetoclax and azacitidine during the period when HiDAC123 was prescribed. Similar percentage of patients achieved complete remission (CR) after induction chemotherapy (93.5% and 94.7%, in the HiDAC123 and HiDAC135 groups, respectively). There were no differences in the overall survival (OS) and event-free survival (EFS) between the two groups (Figure 1). Significantly more patients in the HiDAC135 group were hospitalized for more than 4 days compared with the HiDAC123 group (51.3% vs 31.9%; p=0.008) and significantly more patients in the HiDAC135 group needed more than 2 units of packed red blood cells than in the HiDAC123 group (38.2% vs 21.5%, p=0.011). There was no difference in the percentage of patients in need of platelet transfusion. Likewise, there was no difference between the two groups in either the number of hospitalizations post-HiDAC therapy, the occurrence of neutropenic fever events or the incidence of death within the first 28 days after the HiDAC therapy. Conclusions: The present analysis demonstrates that HiDAC123 is as safe and efficacious as HiDAC135 in terms of OS and EFS and is associated with shorter hospitalization and lower requirement for blood products. These results show that HiDAC123 could be the regimen of choice as consolidation therapy in AML patients. Figure 1 Figure 1. Disclosures Zuckerman: Orgenesis Inc.: Honoraria; BioSight Ltd: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Cellect Biotechnology: Honoraria. Ofran: Pfizer: Consultancy; AbbVie: Consultancy; Medison Israel: Consultancy; Astellas: Consultancy; Janssen: Consultancy.

Rates of Neutropenic Fever in Patients with Hematologic Malignant Diseases with Central Venous Access

Background: Patients who are diagnosed with hematologic malignant diseases (HMD) almost invariably receive placement of central venous catheters (CVCs), whether temporary or permanent. These catheters are used for administration of various chemotherapies, antibiotics and even nutrition. Although the patients with HMD are immunocompromised, prophylactic use of antibiotics among these patients, especially related to CVC placement, remains controversial. This retrospective analysis evaluates the rates of development of neutropenic fever in patients with HMD with CVCs receiving prophylactic antibiotics. Methods: Data were collected retrospectively in a cohort of 268 patients with HMD who received treatment at our academic institution between 2002 to 2019. Demographic and other related data was abstracted and descriptive analysis was performed using Epi-Info - 7 software. Results: Of the 268 patients with HMD, 175 patients (65.3%) received prophylactic antibiotics and among these patients, 180 (67.2%) had a permanent CVC and 109 (40.7%) had a temporary CVC. Comparatively, 93 patients (34.7%) did not receive prophylactic antibiotics and among these individuals, 64 (68.8%) had a permanent CVC and 34 (36.6%) had a temporary CVC. In patients with a permanent central line, 84.3% of patients receiving prophylactic antibiotics developed neutropenic fever while 85% of those who did not receive prophylactic antibiotic also developed neutropenic fever. Among the individuals with a temporary CVC, 79.7% of patients receiving prophylactic antibiotics developed neutropenic fever and 65.4% of patients who were not receiving prophylactic antibiotics also developed neutropenic fever. None of the differences were statistically significant (p=0.8990 and p=0.1547 respectively). Conclusion: In this cohort of HMD patients, the rate of neutropenic fever development in patients with central venous access receiving prophylactic antibiotic was not significantly different compared to the rate of neutropenic fever development in patients with central venous access who did not receive any prophylactic antibiotic. This data suggests that there does not appear to be a significant clinical utility for prophylactic antibiotics in the prevention of neutropenic fever in patients with HMD who have central venous catheters in place. Further studies analyzing the impact of prophylactic antibiotics on true infections as an etiology for neutropenic fevers in patients with HMD and central venous catheters is warranted. Disclosures No relevant conflicts of interest to declare.