Prolonged Febrile Neutropenia Research Articles

Safety of empirical antibiotic therapy discontinuing for fever of unknown origin during high-risk neutropenia in children

ECIL-2021 recommends discontinuing empirical antibiotic therapy (EAT) in febrile-neutropenic children after 72h of treatment and at least 24-48h of apyrexia in the case of fever of unknown origin (FUO). These guidelines are rarely applied to high-risk children's neutropenia. We retrospectively included all consecutive FUO episodes occurring during profound neutropenia ≥10 days in children in our institution. We evaluated the safety of EAT discontinuation in patients for whom the ECIL guidelines were followed compared to those for whom they didn't. We used a combined criterion of mortality and intensive care unit admission at 30 days. We identified risk factors for recurrent fever after EAT discontinuation. Fifty-one FUO episodes occurred in 37 patients. EAT discontinuation followed ECIL guidelines in 19 (37%) episodes. No deaths and-or transfers in ICU occurred in the ECIL group. The duration of EAT was shorter by nine days in the group following ECIL guidelines (p<0.001). We observed 14 (27%) episodes of recurrent fever. Mucositis was significantly associated with recurrent fever (p<0.01). EAT discontinuation seems feasible and safe in FUO during prolonged febrile neutropenia in children. However, mucosal lesions should prompt thorough surveillance due to the risk of recurrent fever.

A comprehensive assessment of the prolonged febrile neutropenia evaluation in pediatric oncology patients.

Pediatric oncology patients with prolonged (≥96hours) febrile neutropenia (absolute neutrophil count<500/μL) often undergo an evaluation for invasive fungal disease (IFD) and other infections. Current literature suggests that beta-D-glucan (BDG), galactomannan, bronchoalveolar lavage (BAL), and computed tomography (CT) scans (sinus, chest, and abdomen/pelvis) may help determine a diagnosis in this population. In a retrospective cohort study of all cancer/stem cell transplant patients (diagnosed 2005-2019) from one pediatric hospital, all episodes with prolonged febrile neutropenia or IFD evaluations (defined as sending a fungal biomarker or performing a CT scan to assess for infection) were identified. In total, 503 episodes met inclusion criteria and 64% underwent IFD evaluations. In total, 36.4% of episodes documented an infection after initiation of prolonged febrile evaluation, most commonly Clostridioides difficile colitis (6.4%) followed by a true bacterial bloodstream infection (BSI) (5.2%), proven/probable IFD (4.8%), and positive respiratory pathogen panel (3.6%). There was no difference in sinus CTs showing sinusitis (74%vs 63%, p=0.46), whereas 32% of abdomen/pelvis CTs led to a non-IFD diagnosis, and 25% of chest CTs showed possible pneumonia. On chest CT, the positive predictive value (PPV) for IFD was 19% for nodules and 14% for tree and bud lesions. BDG had a PPV of 25% for IFD and GM 50%. BAL diagnosed IFD once and pneumocystis jirovecii pneumonia twice. Chest CTs and abdomen/pelvis CTs provide clinically relevant information during the prolonged febrile neutropenia evaluation, whereas BDG, galactomannan, BAL, and sinus CTs have less certain utility.

Empirical vs pre-emptive broad-spectrum antifungal therapy for acute myelogenous leukaemia in the era of antimould prophylaxis

This study compared clinical outcomes in patients with acute myelogenous leukaemia (AML) who developed prolonged (≥4 days) febrile neutropenia (FN) and received either empirical or pre-emptive antimould prophylaxis in order to evaluate the need for routine empirical antifungal therapy. This retrospective study reviewed adult patients (aged ≥18 years) with AML who developed prolonged FN and received antimould prophylaxis during induction or re-induction chemotherapy at a single centre between September 2016 and December 2020. Patients were categorized into pre-emptive or empirical groups based on whether or not there was clinical evidence of invasive fungal infection (IFI) at the start of antifungal treatment, respectively. Clinical outcomes were compared between the two groups after propensity score matching (PSM). In total, 229 chemotherapy episodes (36 and 193 in the empirical and pre-emptive groups, respectively) were analysed. In the pre-emptive group, broad-spectrum antifungal therapy was administered in 45 (23.3%) episodes. After 1:3 PSM, there were no significant differences between the empirical and pre-emptive groups in terms of the incidence of proven or probable IFI [0/36 (0%) vs 5/97 (5.2%); P=0.323], all-cause mortality [3/36 (8.3%) vs 4/97 (4.1%); P=0.388] and IFI-related mortality [0/36 (0.0%) vs 1/45 (2.2%); P=0.556]. The differences in clinical outcomes between empirical and pre-emptive antifungal therapy in patients with AML who received antimould prophylaxis were not significant. Therefore, broad-spectrum antifungal therapy in patients receiving antimould prophylaxis may be delayed until there is clear evidence of IFI.

First-in-human phase 1 clinical trial of anti-core 1 O-glycans targeting monoclonal antibody NEO-201 in treatment-refractory solid tumors

BackgroundNEO201 is a humanized IgG1 monoclonal antibody (mAb) generated against tumor-associated antigens from patients with colorectal cancer. NEO-201 binds to core 1 or extended core 1 O-glycans expressed by its target cells. Here, we present outcomes from a phase I trial of NEO-201 in patients with advanced solid tumors that have not responded to standard treatments.MethodsThis was a single site, open label 3 + 3 dose escalation clinical trial. NEO-201 was administered intravenously every two weeks in a 28-day cycle at dose level (DL) 1 (1 mg/kg), DL 1.5 (1.5 mg/kg) and DL 2 (2 mg/kg) until dose limiting toxicity (DLT), disease progression, or patient withdrawal. Disease evaluations were conducted after every 2 cycles. The primary objective was to assess the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of NEO-201. The secondary objective was to assess the antitumor activity by RECIST v1.1. The exploratory objectives assessed pharmacokinetics and the effect of NEO-201 administration on immunologic parameters and their impact on clinical response.ResultsSeventeen patients (11 colorectal, 4 pancreatic and 2 breast cancers) were enrolled; 2 patients withdrew after the first dose and were not evaluable for DLT. Twelve of the 15 patients evaluable for safety discontinued due to disease progression and 3 patients discontinued due to DLT (grade 4 febrile neutropenia [1 patient] and prolonged neutropenia [1 patient] at DL 2, and grade 3 prolonged (> 72 h) febrile neutropenia [1 patient] at DL 1.5). A total of 69 doses of NEO-201 were administered (range 1–15, median 4). Common (> 10%) grade 3/4 toxicities occurred as follows: neutropenia (26/69 doses, 17/17 patients), white blood cell decrease (16/69 doses, 12/17 patients), lymphocyte decrease (8/69 doses, 6/17 patients). Thirteen patients were evaluable for disease response; the best response was stable disease (SD) in 4 patients with colorectal cancer. Analysis of soluble factors in serum revealed that a high level of soluble MICA at baseline was correlated with a downregulation of NK cell activation markers and progressive disease. Unexpectedly, flow cytometry showed that NEO-201 also binds to circulating regulatory T cells and reduction of the quantities of these cells was observed especially in patients with SD.ConclusionsNEO-201 was safe and well tolerated at the MTD of 1.5 mg/kg, with neutropenia being the most common adverse event. Furthermore, a reduction in the percentage of regulatory T cells following NEO-201 treatment supports our ongoing phase II clinical trial evaluating the efficiency of the combination of NEO-201 with the immune checkpoint inhibitor pembrolizumab in adults with treatment-resistant solid tumors.Trial registrationNCT03476681. Registered 03/26/2018. Graphical

208. Clinical outcomes of empirical versus pre-emptive broad spectrum antifungal therapy in patients with acute myelogenous leukemia receiving antimold prophylaxis

Abstract Background Since antimold prophylaxis has been widely used in induction chemotherapy for acute myelogenous leukemia (AML), it should be re-evaluated whether broad spectrum antifungal therapy should be empirically used in prolonged febrile neutropenia. Therefore, we compared clinical outcomes of empirical versus pre-emptive antifungal therapy in patients with AML receiving antimold prophylaxis. Methods From September 2016 to December 2020, all adult AML patients (≥ 18 years) receiving antimold prophylaxis who had febrile neutropenia for ≥ 4 days during induction or re-induction chemotherapy at Seoul National University Hospital were retrospectively reviewed. They were classified into the empirical group (therapeutic broad spectrum antifungal agents had been used without evidence of invasive fungal infection [IFI]) or the pre-emptive group (antimold prophylaxis had been maintained until the emergence of IFI’s evidence). We compared clinical outcomes between the two groups after propensity score matching. Results A total of 229 chemotherapy episodes, 36 in the empirical group and 193 in the pre-emptive group, were analyzed. In the pre-emptive group, broad spectrum antifungal therapy was administered in 45 (23.3%) episodes. After 1:3 matching with age, gender, induction or re-induction chemotherapy, and worst qSOFA score at febrile neutropenia, incidence of proven or probable IFI (0/36 [0%] in the empirical group vs. 5/97 [5.2%] in the pre-emptive group, P=0.323) and all-cause mortality (3/36 [8.3%] in the empirical group vs. 4/97 [4.1%] in the pre-emptive group, P=0.388) were not different between the two groups. Conclusion Clinical outcomes of empirical versus pre-emptive broad spectrum antifungal therapy were comparable in patients with AML receiving antimold prophylaxis. Broad spectrum antifungal therapy could be delayed until the emergence of evidence of IFI, in the current era of antimold prophylaxis. Disclosures All Authors: No reported disclosures.

85. Plasma Cell Free Deoxyribonucleic Acid (cfDNA) Fungal Polymerase Chain Reaction (PCR): a Non-Invasive Diagnostic for Invasive Fungal Disease Evaluation in At-Risk Pediatric Oncology and Stem Cell Transplant Patients

Abstract Background Molecular diagnostics appear promising for early, non-invasive detection of invasive fungal disease (IFD) in immunocompromised patients. Our clinical lab developed and validated cell free DNA (cfDNA) fungal polymerase chain reaction (PCR) assays (Table 1), which have been in clinical use since November 2020 and were recently included in an institutional pediatric clinical care pathway for prolonged febrile neutropenia. We aimed to evaluate the performance of these plasma cfDNA fungal PCR assays in pediatric oncology and hematopoietic stem cell transplant (HSCT) patients with clinical concern for IFD. Methods We initiated an observational study of inpatient oncology and HSCT patients who had plasma mold panel (+/- Candida panel) cfDNA fungal PCR obtained as part of an IFD evaluation at our freestanding quaternary care children’s hospital. The primary outcome was IFD clinical diagnosis (proven, probable, possible, unlikely) as per EORTC/MSG† definitions within one month of the cfDNA fungal PCR, which was assigned independently by two physicians, with a third physician utilized in cases of discrepancy. Patient demographics, hospital course, imaging results, and clinical laboratory data were abstracted and maintained in an encrypted REDCap© database. Results In a preliminary analysis of October 2021-March 2022 data, there were 21 IFD evaluations for 18 patients (Table 2). Most oncology evaluations were for prolonged febrile neutropenia, while many HSCT were non-neutropenic, but on enhanced immunosuppression with new clinical concerns (e.g., respiratory symptoms, persistent fever). Plasma cfDNA detected a mold or yeast consistent with the clinical presentation in 100% of the five proven/probable cases (Figures 1 &amp; 2). All 14 possible IFD cases had a negative cfDNA fungal PCR. Proven cases are designated with blue icon, while the probable case is orange. All five cases were in oncology patients who did not have history of hematopoietic stem cell transplant. Cell free DNA (cfDNA) fungal polymerase chain reaction (PCR) results include the organism identified, followed by the cycle threshold (Ct) in parenthesis. Maximum Ct for the assay is 45. Abbreviations: AG: Aspergillus galactomannan index (Ref &amp;lt;0.5); ALL: acute lymphoblastic leukemia. BAL: bronchoalveolar lavage; 1,3-BDG: 1,3-beta-D-glucan (Ref &amp;lt;60 pg/ml); cfDNA: cell free deoxyribonucleic acid; CNS: central nervous system; EORTC/MSG: European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group &amp; the National Institute of Allergy &amp; Infectious Diseases Mycoses Study Group; L-AmB: liposomal amphotericin B; SARS-CoV-2: severe acute respiratory syndrome associated with coronavirus 2. Conclusion Upfront plasma cfDNA fungal PCR successfully detected a relevant mold or yeast with short turnaround time in 100% of cases that were later classified as proven/probable. This appears promising for early, noninvasive diagnosis that enables prompt optimization of antifungal and surgical management, particularly for mucormycosis cases. Additional data may permit consideration of Mucorales agents PCR as a new EORTC/MSG mycologic criteria. Disclosures Lauren E. Kushner, MD, Roman: Client of my husband's business..

Response to Hypomethylating Agents Plus Venetoclax in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome: Real World Data from a Developing Country

Background: Myelodysplastic syndrome (MDS) is a pre-malignant condition characterized by ineffective hematopoiesis, cytopenias and potential to transform into acute leukemia. Acute myeloid leukemia (AML) is a hematological malignancy deriving from myeloid progenitor cells. About one quarter of patients fail to respond to initial therapy (refractory AML). In addition, around 50% of initial responders relapse after a transient remission (relapsed AML). Commonly used salvage chemotherapy regimens include FLAG, FLAG-Ida, HIDAC and Hypomethylating agents (HMA) with or without Venetoclax. In patients who are ineligible for transplant or with poor functional status and in relapsed/refractory cases, treatment options are minimal. However recent data from Western countries has shown promising results with HMA plus Venetoclax in such patients. No such data is available from Pakistan. Objectives: To assess response of HMA plus Venetoclax in patients with AML and MDS treated at Armed Forces Bone Marrow Transplant Center, Rawalpindi, Pakistan. Methods: Study design: Single arm observational prospective study Research Setting: Armed Forces Bone Marrow Transplant Center, Rawalpindi, Pakistan. Study population: Cases included in study were patients of AML and MDS who received HMA plus Venetoclax. A total of 35 patients (25 AML, 10 MDS) were found eligible and included in the final analysis. The primary outcome measured was response to HMA plus Venetoclax. Results: Out of 25 AML patients 17 (68%) were male and 8 (32%) were female. Median age of patients was 44 (range 20-67). Six (24%) patients had AML MRC, 18 (72%) had AML NOS which included 2 (8%) AML-M0, 1 (4%) AML-M1, 9 (36%) AML-M2, 3 (12%) AML-M4 and 3 (12%) patients with AML-M5 while other 3 patients included 1 (4%) patient each of t-AML and AML transformed from Fanconi anemia and aplastic anemia. One (4%) AML-M2 patient had Monosomy 7 and 1 (4%) AML-M5 had trisomy 8. Three (12%), 16 (64%) and 6 (24%) patients were categorized into favorable, intermediate and high risk respectively. Nine (36%) had relapsed disease including 3 (12%) who had relapsed after allogenic HSCT, 8 (32%) had refractory disease while 7 (28%) were unfit for intensive chemotherapy due to advanced age or poor functional status. Median number of HMA+ Venetoclax cycles given were 3 (range 1-16). Overall response rate (ORR) was 44% (n=11), including 9 (36%) patients with CR and 1 (4%) with CRi. One (4%) patient had partial response (PR). Fourteen (56%) patients were non-responders. Of the 10 patients who responded, 6 (24%) achieved remission after 2 cycles while other 4 achieved remission, 1 (4%) patient each, after 1, 3, 5 and 6 cycles. Two (8%) patients underwent allogenic HSCT after achieving remission, including 1 (4%) who had relapsed after first HSCT and underwent second HSCT after achieving CR with HMA+Venetoclax. Out of 10 MDS patients 8 (80%) were male and 2 (20%) were female. Median age of patients was 51 (range 29-71). Two (25%) patients had MDS-MLD, 6 (60%) MDS-EB2 and 2 (20%) had fibrotic MDS. One (10%), 7 (70%) and 2 (20%) patients had intermediate, high and very high risk disease (as per R-IPSS score) respectively. One (10%) patient had relapsed after allogenic HSCT. Median no of cycles of HMA+Venetoclax given were 2 (range 1-6). Three (30%) patients achieved CR (after 2 cycles each), 2 (20%) had stable disease and 5 (50%) patients were non-responders. Two (20%) patients underwent allogenic HSCT after receiving HMA+Venetoclax (Table:1) Common side effects noted were prolonged cytopenias, febrile neutropenia and infections (cellulitis, perianal infections and fungal infections). No treatment related mortality was noted. Conclusion: HMA plus Venetoclax is effective treatment regimen in relapsed/ refractory AML and MDS, however our population shows inferior results as compared to Western population and further large randomized controlled trials are needed to validate this observation. Key Words: Relapsed AML, refractory AML, MDS, salvage chemotherapy, Hypomethylating agents, Venetoclax Research funding: None Word count: 691 Presentation type: Oral Category: Acute Leukemia/ Myelodysplastic syndrome Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

C-Reactive Protein Monitoring and Clinical Presentation of Fever as Predictive Factors of Prolonged Febrile Neutropenia and Blood Culture Positivity after Autologous Hematopoietic Stem Cell Transplantation-Single-Center Real-Life Experience.

Background: Febrile neutropenia (FN) is a medical emergency that requires urgent evaluation, timely administration of empiric broad-spectrum antibiotics and careful monitoring in order to optimize the patient’s outcome, especially in the setting of both allogeneic and autologous hematopoietic stem cell transplant (ASCT). Methods: In this real-life retrospective study, a total of 49 consecutive episodes of FN were evaluated in 40 adult patients affected by either multiple myeloma (thirty-eight) or lymphoma (eleven), following ASCT, with nine patients having fever in both of the tandem transplantations. Results: Febrile neutropenia occurred a median of 7 days from ASCT. Median duration of FN was 2 days, with 25% of population that had fever for at least four days. Ten patients had at least one fever spike superior to 39 °C, while the median number of daily fever spikes was two. Twenty patients had positive blood cultures with XDR germs, namely Pseudomonas aeruginosa and Klebsiella pneumoniae, present in seven cases. ROC analysis of peak C-reactive protein (CRP) values was conducted based on blood culture positivity and a value of 12 mg/dL resulted significant. Onset of prolonged fever with a duration greater than 3 days was associated with the presence of both a peak number of three or more daily fever spikes (p = 0.02) and a body temperature greater than 39 °C (p = 0.04) based on odds ratio (OR). Blood culture positivity and peak CRP values greater than 12 mg/dL were also associated with prolonged fever duration, p = 0.04, and p = 0.03, respectively. The probability of blood culture positivity was also greater in association with fever greater than 39 °C (p = 0.04). Furthermore, peak CRP values below the cut-off showed less probability of positive blood culture (p = 0.02). Conclusions: In our study, clinical characteristics of fever along with peak CRP levels were associated with a higher probability of both prolonged fever duration and positive blood culture, needing extended antibiotic therapy.

Venetoclax for Acute Myeloid Leukemia in Pediatric Patients: A Texas Medical Center Collaboration

Venetoclax for Acute Myeloid Leukemia in Pediatric Patients: A Texas Medical Center Collaboration

Newly Diagnosed Acute Lymphoblastic Leukemia in a Child with COVID-19 Complicated By MIS-C: A Case Report from Kuwait

Introduction:Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a major challenge worldwide. Data reporting manifestations of COVID-19 in pediatric cancer patients are limited. This report describes the presentation and initial management challenges of a newly diagnosed child with acute lymphoblastic leukemia (ALL) with positive (+) SARS-CoV-2 complicated by multisystem inflammatory syndrome in children (MIS-C).Case Description:A previously healthy 9-year-old female had (+)SARS-CoV-2 following a 4-day history of fatigability. This was followed by a day of severe gastroenteritis (GE) necessitating a visit to Jaber Al-Ahamed Hospital (JAH), the designated COVID-19 pandemic center. Examination revealed hypovolemic shock, hepatosplenomegaly (HSM) and cervical lymphadenopathy. Patient also had significant pancytopenia and high inflammatory markers (Table).Bone marrow aspiration (BMA) - done 7 days from diagnosis of SARS-CoV-2 - was consistent with B-ALL. Transfer to National Bank of Kuwait Children's Hospital (NBKCH) - the pediatric cancer center - was delayed for 11 days given her (+)SARS-CoV-2, but once tested negative, transfer was complete. Due to logistical issues, lumbar puncture and repeat BM were delayed. She then developed new fever, abdominal pain and vomiting. Her febrile neutropenia (FN) was managed according to local protocol including antifungal therapy for prolonged FN. Five days into her FN, she developed hematemesis and septic shock. In addition to pancytopenia, she also had disseminated intravascular coagulation with further raise in CRP (Table). She also had a new maculopapular rash (Image). Infectious work-up was negative except for (+)SARS-CoV-2 (after 10 days of negativity), fulfilling criteria of MIS-C. Patient was transferred back to JAH according to local pandemic protocol. Induction chemotherapy as perUK-MRC-ALL 2011 regimen Afor standard risk ALL - with modifications given her MIS-C - was started after 22 days (Figure). On day 5 of chemotherapy, patient was clinically stable with negative SARS-CoV-2, therefore transferred back to NBKCH for continuation of leukemia management.Discussion:Although children tend to have a milder course of COVID-19, this case described a fulminant presentation initially with GE, hypovolemic shock and complicated by MIS-C, lacking any respiratory symptoms throughout her course. Until more data reporting manifestations of SARS-CoV-2 in pediatric cancer patients are available, physicians should keep high index of suspicion for leukemia in presence of pancytopenia and HSM in spite of (+)SARS-CoV-2. Prompt diagnosis of ALL is fundamental to avoid delays in treatment and consequent effects on prognosis. Logistical issues such as lack of optimum COVID-19 isolation measures in our cancer center and paucity of blood products have led to delayed initiation of chemotherapy. These cancer-related challenges have been well described.Another interesting aspect of our case is the seroconversion to (+)SARS-CoV-2 after proved negativity. It is possible that protective antibodies were not well developed as she is immunocompromised, making such patients prone to recurrent SARS-CoV-2 infection. The re-emergence of SARS-CoV-2 has led to the diagnosis of MIS-C after fulfilling other criteria. This phenomenon of negative to (+)SARS-CoV-2 seroconversion has been reported in 20-40% of MIS-C cases.Increased risk of venous thromboembolism (VTE) is linked to the hyperinflammatory state of COVID-19. Chemotherapy is also identified as an independent risk factor for VTE in malignancy. To avoid the collateral effects of these factors, modifications of the planned chemotherapy were implemented in our case to minimize the VTE risk. The high steroid dose with chemotherapy was also planned as a treatment for MIS-C, which is consistent with different modalities of MIS-C treatment offered in literature.Conclusion:Children with B-ALL may suffer from fulminant clinical course when diagnosed with COVID-19 and could be prone to recurrent SARS-CoV-2 infection. Our experience highlights the importance of optimizing isolation measures and raising awareness for need of blood products to avoid treatment delay. Further research can aid in forming recommendations to prevent management pitfalls especially with the anticipation of a second wave of this pandemic.DisclosuresNo relevant conflicts of interest to declare.

The Trend of Changes in Paranasal CT Scan in Patients with Hematologic Malignancy Under Chemotherapy

ObjectivesThe aim of this study was to evaluate the clinical significance of early screening of computerized tomography scan of paranasal sinuses (PNS CT) in hematologic malignancies before chemotherapy and evaluation of changes after chemotherapy and during neutropenia.MethodsAll 40 new cases of hematologic malignancies with febrile neutropenia in a teaching referral hospital between 2018 and 2019 were enrolled in this study. All of these patients underwent paranasal sinus (PNS) CT scan before chemotherapy, along with other preliminary investigations. Symptoms and signs indicating the infectious process were meticulously followed and monitored before and during chemotherapy as well as the occurrence of febrile neutropenia. All patients were clinically and radiologically evaluated regarding the presumptive diagnosis of invasive fungal sinusitis during prolonged febrile neutropenia (more than 4 days). PNS CTs before and after chemotherapy of all patients were compared by two radiologists and were evaluated based on histopathologic findings of nasal and or paranasal biopsies.ResultsAround 50% of patients with PNS CT scan abnormality suspected inflammatory process including microbial and fungal sinusitis during prolonged febrile neutropenia (more than 4 days) were confirmed that have had similar involvement before starting chemotherapy and these abnormalities have been stable with no significant changes after chemotherapy. The histopathologic examination of sinuses also showed no evidence of invasive fungal infection by endoscopic biopsy. Therefore, the abnormal findings including mucosal thickening in PNS CT during prolonged febrile neutropenia were not consistent with the confirmed invasive fungal infection. The rate of mortality was 2.5% without association with invasive fungal sinusitis.ConclusionsA considerable number of patients with underlying hematologic malignancies have paranasal sinus involvement such as mucosal thickening that may be misdiagnosed as invasive fungal sinusitis during the hazardous phase of prolonging febrile neutropenia. Thus, performing PNS CT scan before initiation of chemotherapy even though in asymptomatic patients could be helpful to decrease the number of suspected and probable cases of fungal sinusitis based on abnormal findings in PNS CT scan followed by the number of cases undergoing sinus endoscopic surgery.

Cytomegalovirus viremia among pediatric oncology non-stem cell transplant patients with prolonged fever neutropenia

BackgroundCytomegalovirus (CMV) is a rare cause of prolonged febrile neutropenia (PFN) among pediatric oncology patients, especially in non-stem cell transplant setting (Non-SCTS). Infectious Diseases Society of America (IDSA) guidelines stated briefly that neutropenia is not considered as an indication of CMV re-activation, and thus preventive strategies are not needed; however, multiple studies pressed on the need to treat CMV viremia among patients with PFN even when there is no evidence of end-organ involvement. Therefore, this study aimed to prospectively investigate the significance of CMV as a cause of PFN among pediatric oncology patients in a Non-SCTS. Patients and methodsThis was a prospective cohort study that was done at Princess Norah Oncology Center, King Abdulaziz Medical City in Jeddah, Saudi Arabia. CMV viral load was monitored weekly once the subject was identified as a case of PFN until resolution. Subjects and treating physicians were blinded to CMV viral load results. ResultsThe data of 27 PFN episodes (48% males) were analyzed. The incidence of CMV viremia was reported as 29.6%. Both CMV positive and negative episodes of PFN had similar rate of spontaneous resolution (p=0.669), with overall mortality as 105 and 125 per 1000 PFN episodes, respectively. No subject received anti-CMV in the positive CMV group; however, one subject did in the negative group for reasons other than CMV infection. ConclusionThis study demonstrated that CMV was not a significant cause of PFN in Non-SCTS. CMV also had no significant role in terms of survival and severity of the PFN episode.

2187. Prediction of Patient Outcome During Febrile Neutropenia Despite Anti-infective Treatment Using Machine Learning Algorithms

BackgroundClinical management of prolonged febrile neutropenia despite broad-spectrum empirical antibacterial treatment is a clinical challenge, as standard empirical treatment has failed and a broad spectrum of differential diagnoses has to be considered. Growing prevalence of multi-resistant bacteria and fungi has made a balanced choice of effective anti-infective treatment more difficult. A reliable prediction of complications could indicate options for treatment optimization.MethodsWe implemented a supervised machine learning approach to predict death or admission to intensive care unit within 28 days in cancer patients with prolonged febrile neutropenia (neutrophils < 500/mm3 and body temperature ≥ 38°C longer than 3 days). We analyzed highly granular retrospective medical data of the Cologne Cohort of Neutropenic Patients (CoCoNut) between 2008 and 2014. Random forest and 10-fold cross-validation were used for classification. The neutropenic episodes from 2014 were used for evaluation of prediction.ResultsIn total, 927 episodes of prolonged febrile neutropenia (median age 52 years, interquartile range 42–62; 562/927 [61%] male; 390/927 [42%] acute myeloid leukemia; 297/927 [32%] lymphoma) with 211/927 (23%) adverse outcomes were processed. We computed 226 features including patient characteristics, medication, clinical signs, as well as laboratory results describing changes of state and interactions of medical parameters. Feature selection revealed 65 features with an area under the receiver operating characteristic curve (AUC) of 0.75. In the validation data set the optimized model had a sensitivity/specificity of 36% and 99% (AUC: 0.68; misclassification error: 0.12) and positive/negative predictive values of 89% and 88%, respectively. The most important features were albumin, age, and procalcitonin.ConclusionStructured granular medical data and machine learning approaches are an innovative tool that can be used in a retrospective setting for prediction of adverse outcomes in patients with prolonged febrile neutropenia. This study is the first important step toward clinical decision support based on predictive models in high-risk cancer patients.Disclosures All authors: No reported disclosures.

1740. Title: Outcomes of a Clinical Algorithm for the Early Diagnosis and Treatment of Invasive Fungal Sinusitis among Children with Hematologic Malignancy or Prior Hematopoietic Stem Cell Transplantation

BackgroundInvasive fungal sinusitis (IFS) is a cause of significant morbidity and mortality among children with hematologic malignancy and hematopoietic stem cell transplant (HSCT) recipients, with an estimated mortality of 18–80%. Since 2007, our center has employed a clinical algorithm for the early detection and treatment of IFS among children with prolonged febrile neutropenia.MethodsWe reviewed all EORTC defined cases of proven IFS among children with underlying hematologic malignancy or prior HSCT admitted to our institution between July 1, 2004 and December 31, 2018, and compared clinical characteristics and outcomes (including underlying malignancy, chemotherapy regimen at the time of viremia, absolute neutrophil count, absolute lymphocyte count, treatment regimens, and 6 month mortality) between the pre (July 1, 2004–December 31, 2006) and post-protocol (January 1, /2007–December 31, 2018) periods.ResultsWe identified 33 cases of proven IFS during the study period, with 6 in the pre-protocol and 27 in the post-protocol period. The most common underlying primary diagnosis was acute lymphoblastic leukemia (ALL) at > 50% with 8% of individuals with prior HSCT. Twenty-five cases (92%) during the protocol period were diagnosed via nasal endoscopy per protocol, with 17 (63%) reporting no clinical complaints of sinusitis. Median absolute neutrophil count (ANC) at the time of IFS diagnosis was 155/mm3 (IQR 0 – 375/ mm3; n = 12) with median duration of neutropenia 16.5 days (IQR 10.5–18.25, n = 12) at the time of diagnosis. Most individuals required one definitive debridement. Isolated fungal specimens included Bipolaris spp. (24%), Aspergillus spp. (20%), Curvularia spp. (20%), with Fusarium and Exserohilum spp. each at 12%, and Rhizopus spp. At least one patient had a co-infection with more than one fungal species. Pre-protocol cause-specific mortality at 6 months was 33.3% compared with 14.8% (P = 0.29) in the post- protocol period.ConclusionIFS is a cause of significant morbidity and mortality among children with hematologic malignancy or prior HSCT. An aggressive protocol with early nasal endoscopy and targeted debridement may help decrease morbidity and mortality associated with this entity. Additional well-designed studies are needed to assess the potential benefits of this approach in the diagnosis and management of IFS among high-risk children. Disclosures All authors: No reported disclosures.

Pneumocephalus as a complication of multidrug-resistant Klebsiella Pneumoniae bacteremia in patient with acute myeloid leukemia

Pneumocephalus indicates air in the cranial cavity and commonly results from craniofacial trauma and neurosurgical procedures. Infections can rarely cause pneumocephalus through formation of brain abscess, or as complication of chronic otitis media, or meningitis. Patients might present with headache, fever, change in mental status and diagnosis is confirmed by Brain CT scan. A 51 years old male diagnosed with acute myeloid leukemia (AML) and admitted for fourth cycle of consolidation chemotherapy. He developed prolonged febrile neutropenia and septic shock and multi-organ failure due to Klebsiella Pneumoniae MDR bacteremia. Patient had persistent bacteremia despite being on Meropenem, Colisten, Levofloxacin, Caspofungin, Tigecycline. Due to profound thrombocytopenia, he had severe pulmonary hemorrhage and bilateral diffuse subarachnoid hemorrhage. Repeated CT brain angiography later showed extensive pneumocephalus with finding suggestive of brain death. Ethical approval for case report obtained. Meningitis associated with pneumocephalus is rare and has been reported in gas-forming organisms such as E. coli, Klebsiella Pneumoniae, Bacteroides, mixed aerobic and anaerobic species and streptococcus infection. Treating the underlying meningitis might results in resolution of pneumocephalus, although fatal outcomes were reported. Pneumocephalus secondary to Klebsiella Pneumoniae meningitis is uncommon and one case reported successful treatment using meropenem and amikacin for MDR Klebsiella Pneumoniae meningitis associated with pneumocephalous resulting from chronic otitis media. Pneumocephalus associated with MDR K. pneumonia bacteremia is very rare and had high mortality rate especially in setting of febrile neutropenia with multi-organ failure. Intracerebral hemorrhage in setting of persistent bacteremia might increase the risk of pneumocephalus.

2050. Plasma Next-Generation Sequencing for Pathogen Detection in Pediatric Patients at Risk for Invasive Fungal Infection

BackgroundInvasive fungal infection (IFI) is a major cause of mortality and morbidity among immunocompromised patients. Microbiologic culture of biopsy samples remains the diagnostic gold standard. Noninvasive biomarker testing can provide clinically useful information, but does not give species-level identification. Next-generation sequencing (NGS) of cell-free plasma is a noninvasive approach for species-level identification of pathogens, and may guide specific treatment. We sought to describe the diagnostic utility of plasma NGS in high-risk immunocompromised pediatric patients, correlating results with standard microbiology studies.MethodsPlasma from at-risk immunocompromised patients with suspected IFI was tested using cell-free plasma NGS (Karius, Redwood City, CA). Human reads were removed, and remaining sequences aligned to a curated database including >1,000 pathogens. Organisms present above a predefined significance threshold were reported.ResultsForty evaluable patients were enrolled, the majority of whom had underlying oncologic diagnoses. Risk for IFI included prolonged febrile neutropenia (FN) in 22 patients, recrudescent FN in 7, concern for IFI on imaging in 8, and concern for IFI based solely on other clinical findings in 3. Six patients met established criteria for proven IFI, 1 for probable IFI, and 13 for possible IFI. NGS plasma testing identified a pathogen which was cultured from infected tissue or blood in 4 of 6 proven cases; one patient with localized cutaneous Rhizopus had negative NGS results. A patient with probable IFI (positive β-D-glucan) had P. jirovecii identified by NGS. Among 33 patients without proven or probable IFI, NGS testing identified a fungus in one (C. glabrata), no organism in 11, and potential alternative sources of fever in 16.ConclusionPlasma NGS testing can detect IFI from blood. The test identified fungi from proven IFI, and detected other pathogens in both probable and possible IFI cases. Many patients at risk received prolonged courses of antifungals despite negative testing, suggesting a possible future role for NGS testing in ruling out IFI. Future studies should more definitively evaluate the positive and negative predictive value for NGS testing in patients at risk of IFI.Disclosures R. Aquino, Karius, Inc.: Employee, Salary. D. Hollemon, Karius: Employee, Salary. D. Hong, Karius, Inc.: Employee, Salary.

Successful Treatment With Granulocyte Transfusion and Early Neutrophil Engraftment in Allogeneic Transplant Patients With Febrile Neutropenia: Does Granulocyte Transfusion Effect on Neutrophil Engraftment?

Background: Febrile neutropenia is very severe and urgent early complication after bone marrow transplantation before engraftment. Infection delays engraftments in these periods. Aim: In this study we evaluated the effect and outcome of granulocyte transfusion on febrile neutropenia and neutrophil engraftment in patients receiving allogeneic transplantation. The reasons for the use of the granulocyte transfusion were prolonged febrile neutropenia episode. Methods: Between 2015-2017, 16 patients receiving allogeneic bone marrow transplantation (BMT) were treated with granulocyte transfusion at the time of febrile neutropenia before engraftment. Sixteen patients (9 AML, and 7 ALL) underwent allogeneic transplantation. Nine of them transplanted from match sibling donors, 1 from unrelated donor, and 6 from mismatch family donor (haploidentic transplantation). They had febrile neutropenia after transplantation, before engraftment. They were given antimicrobial therapy. Granulocyte was collected from unrelated and same blood groups donors. We started granulocyte transfusion for 3-4 days. Results: Mean infused granulocyte counts were 3 × 1010 (1.2-4.8 × 1010)/d, and about 15%-20% of transfused granulocyte was monocyte. Before the granulocyte transfusion, on the 12th to 19th days of transplantation, their neutrophil counts were 0.02-0.09 × 103/dL. Twenty-four hours after granulocyte transfusion, mean neutrophil counts were 0.7 × 103/dL (0.4-1.2 × 103/dL). Neutrophil counts were 2.2 × 103/dL (1.7-2.6 × 103/dL) after 48 hour. After 72 hours, neutrophil counts were 3.2 × 103/dL (2.0- 4.6 × 103/dL). After 4th days of granulocyte transfusion, neutrophil counts were normal level (&gt;0.5 × 103/dL) in 12 patients, and less than normal level (&lt;0.5 × 103/dL) in 4 patients. Conclusion: Granulocyte transfusions during the febrile neutropenia, helped to better overcome febrile neutropenia periods in allogeneic transplant patients before engraftment. In addition, granulocytes transfusion also may help early neutrophil engraftments. The useful effect of granulocyte transfusion on neutrophil engraftment may be cause of cytokine (G-CSF) injection to donor before collection of granulocyte. Increased cytokine (G-CSF–GM-CSF–IL-3) level of transfused neutrophil and monocyte can also effect the neutrophil engraftment.

Acute bone marrow suppression and gastrointestinal toxicity following acute oral methotrexate overdose

Objective: Acute methotrexate overdose rarely causes systemic toxicity due to saturable absorption and rapid renal elimination. We present a case of methotrexate toxicity following acute overdose.Case Report: A 56-year-old female presented soon after an overdose of 1250 mg of methotrexate, zopiclone and tramadol. The methotrexate was initially under-reported (500 mg) and folinic acid was not provided. Despite normal renal function, the patient developed toxicity. She represented 5 days following the overdose with mucositis, bone marrow suppression and prolonged febrile neutropenia. Treatment included folinic acid, broad-spectrum antibiotics, filgrastim, red cell and platelet transfusion. Her bone marrow began to recover 12 days following the overdose. She was discharged home on Day 17.Discussion: Severe toxicity following an acute ingestion of a large amount of methotrexate is rarely reported. The development of toxicity was unexpected in this case given methotrexate’s pharmacokinetics and the patient’s normal renal function. The serum methotrexate concentrations were below the treatment threshold of the folinic acid rescue therapy nomogram suggesting that the nomogram should not be relied on in acute ingestions. Large acute oral methotrexate poisoning can result in systemic toxicity and folinic acid therapy should be provided in ingestions >1000 mg.

Cumulative D-Index Predicts the Duration of Febrile Neutropenia in AML Patients

Background: Prolongation of severe neutropenia is known to predict the onset of pneumonia and invasive fungal infection in patients undergoing chemotherapy. The D-index is a promising tool to assess the severity of neutropenia, and the utility of the D-index is being investigated in clinical research. However, there are a few reports regarding the association between the D-index and the onset of opportunistic infection. We undertook this study to examine whether the D-index is useful to predict the onset of various infections in febrile neutropenia (FN) patients.Methods: The D-index was originally developed by Portugal et al. It is calculated as the area between <500 cells/μL and over the neutrophil curve when grade 4 neutropenia is present. We retrospectively investigated the events of febrile neutropenia among patients with acute myeloid leukemia (AML) treated at our institute. We recruited consecutive patients, younger than 65 years of age, newly diagnosed between November 1998 and February 2015. We collected all FN events from a chart review and evaluated the association between FN degree and infectious events. Survey periods covered the start of the induction chemotherapy to the end of the last consolidation therapy. Patients with a poor performance status (≥3) were excluded. We also calculated the total cumulative D-index (cD-index) from the first chemotherapy to the onset of FN, and the total D-index from the first chemotherapy to the last chemotherapy, to evaluate additive effects of the neutropenia. We tentatively determined the possible infection sites of the patients at the onset of FN in each event to analyze the presumable focus of infection.Results: In total, 35 cases and 122 FN events were enrolled (18 females and 17 males). The median age was 51 years (range, 18-65 years). The demography of FAB classification was M0, n = 1; M1, n = 5; M2, n = 14; M4, n = 3; M5, n = 3; M6, n = 2; and secondary AML, n = 7. Induction therapy consisted of idarubicin and Ara-C, and consolidation therapy consisted of high-dose Ara-C or rotated anthracyclines and Ara-C. The chemotherapy regimen was applied according to the JALSG AML201 or AML97 protocols. The response rate to induction chemotherapy was 60.0% (21/35), and 97.1% (34/35) of patients were alive at the end of follow-up. Only one patient died during chemotherapy; the cause of death was bacteremia due to Stenotrophomonas maltophilia (UNP 24). The total D-index was associated to the onset of infection with or without an identification of documented pathogens. However, high-dose Ara-C regimen and total D-index statistically significantly contributed to the onset of infection according to multivariate analysis (P = 0.0009 and 0.0205, respectively). Furthermore, the cD-index was a statistically significant contributing factor to predict the duration of FN according to multivariate analysis (P = 0.0378). Subsequently, we performed subgroup analysis and defined a significantly prolonged FN duration in the patients with respiratory focus compared with other focus sites.Conclusion: The total D-index was associated to the onset of infection during FN. However, the total D-index is a retrospective assessment index, calculated after neutropenic recovery. Therefore, the total D-index cannot be applicable to the prediction of infection upon FN. Our study identified respiratory foci of infection upon FN in the patients with high cD-index (≥5000) is a risk marker for the prolongation of FN. Then, we speculate that a respiratory manifestation at the onset of FN after consolidation therapy indicates a need for more intensive antimicrobial therapy. DisclosuresNo relevant conflicts of interest to declare.

Is preemptive antifungal therapy a good alternative to empirical treatment in prolonged febrile neutropenia?

Patients with prolonged febrile neutropenia are at high risk of invasive fungal infection, so it has been standard practice to initiate empirical antifungal therapy in these cases. However, this strategy is associated with important toxicity, so diagnostic test-guided preemptive antifungal therapy has been proposed as an alternative. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified three systematic reviews including twelve studies overall. Four randomized controlled trials addressed the question of this article. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded it is not clear whether preemptive strategy affects mortality because the certainty of the evidence is very low, but it might slightly decrease the use of antifungal agents in patients with prolonged febrile neutropenia.