Infections In Neutropenic Patients Research Articles

GRAIN Study - Granulocytes Against Infections - Use of granulocyte transfusion in haematopoietic stem cell transplant

Granulocyte transfusions (GTx) combat infections in neutropenic patients. However, immune-mediated off-target effects in transplant settings are unknown. Between January 2020 and December 2021, all transplants that used GTx during the peri-transplant period were analysed. Engraftment, infections, and days to clearance were retrieved from clinical records. Overall survival is compared with the mean total PMN count and the different products. Pooled buffy coat was used in 110 patients (98 %), of which 38 (34 %) additionally received an apheresed product. The median days of GTx was 4. The median bags pooled to prepare a single buffy coat product was 4. The mean total PMN count was 0.98 × 1010/ L granulocytes per pooled buffy coat and 1.93 × 1010/L granulocytes per apheresis product. A higher PMN count (>1 × 1010/L) was achieved in 48 % with pooled buffy coat versus 85 % with apheresis. Respiratory worsening occurred in 39 % receiving GTx. All patients who received granulocytes had engrafted with a median time of 14 days for neutrophil and 20 days for platelet engraftment. Blood cultures cleared in 81 %, whereas only 28 % cleared other cultures. Fungal pneumonia cleared in 25 %, and invasive fungal sinusitis or otitis cleared in 50 %. Overall survival was 47 %, non-significantly higher (57 % vs 39 %, P = 0.1) with a higher PMN dose. The pooled buffy coat is an affordable alternative to apheresis for an effective PMN dose. Ease of availability and low cost of pooled buffy coat, with comparable overall survival points toward a safe and efficacious product, in the peri-transplant period.

Optimized high-dose granulocyte transfusions for the treatment of infections in neutropenic patients: A single-center retrospective analysis.

Granulocyte transfusions for patients with prolonged neutropenia and severe infections has been a controversial practice. Previous studies suggest a benefit of high-dose granulocyte transfusions (≥0.6 × 109/kg), although, until recently, the consistent production of high-dose units has been challenging. Here, we present our experience and results utilizing high-dose granulocyte transfusions at a large, tertiary academic medical center for the treatment of infections in adult, neutropenic patients. A retrospective chart review (2018-2021) was conducted for all patients who received high-dose granulocyte transfusions from donors stimulated with granulocyte colony-stimulating factor (G-CSF) and dexamethasone. Gathered parameters included patient demographics, clinical history, infection status, dose, clinical outcomes, pre- and post-absolute neutrophil count (ANC), and transfusion times including time between granulocyte collection, administration, and posttransfusion ANC count. Gathered parameters were summarized using descriptive statistics, outcomes were assessed utilizing Kaplan-Meier curves/log-rank/regression testing. Totally 28 adult, neutropenic patients refractory to antimicrobial agents and/or G-CSF received a total of 173 granulocyte concentrates. Median ANC increased from 0.7 × 109/L pre-transfusion to 1.6 × 109/L posttransfusion. The mean granulocyte yield was 77.4 × 109 resulting in an average dose per kilogram of 0.90 × 109 ± 0.30 × 109 granulocytes. Composite day 42 survival and microbial response was 42.9% (n = 12/28) without significant adverse reactions. Here, we demonstrate the successful and safe implementation of high-dose granulocyte transfusions for neutropenic patients. Given the rapid and consistent production, distribution, and improved granulocyte quality, further investigations to determine the clinical efficacy of G-CSF primed granulocyte transfusions is now possible.

The prevalence of neutropenia and association with infections in patients with systemic lupus erythematosus: a Swedish single-center study conducted over 14 years

Hematologic abnormalities are common manifestations of SLE, although neutropenia is observed less frequently and is not included in the classification criteria. Nonetheless, neutropenia is a risk factor for infections, especially those caused by bacteria or fungi. We aimed to evaluate the impact of neutropenia in SLE through a systematic investigation of all infections in a large cohort of well-characterized patients, focusing on neutropenia, lymphopenia, and hypocomplementemia. Longitudinal clinical and laboratory parameters obtained at visits to the Rheumatology Unit, Linköping University Hospital, and linked data on all forms of healthcare utilization for all the subjects included in our regional SLE register during 2008–2022 were assessed. Data regarding confirmed infections were retrieved from the medical records. Overall, 333 patients were included and monitored during 3,088 visits to a rheumatologist during the study period. In total, 918 infections were identified, and 94 occasions of neutropenia (ANC < 1.5 × 109/L) were detected in 40 subjects (12%). Thirty neutropenic episodes in 15 patients occurred in association with infections, of which 13 (43%) required in-hospital care, 4 (13%) needed intensive care, and 1 (3%) resulted in death. Bayesian analysis showed that patients with ≥ 1 occasion of neutropenia were more likely to experience one or more infections (OR = 2.05; probability of association [POA] = 96%). Both invasiveness (OR = 7.08; POA = 98%) and severity (OR = 2.85; POA = 96%) of the infections were significantly associated with the present neutropenia. Infections are common among Swedish SLE patients, 12% of whom show neutropenia over time. Importantly, neutropenia is linked to both the invasiveness and severity of infections. Awareness of the risks of severe infections in neutropenic patients is crucial to tailor therapies to prevent severe illness and death.

Levofloxacin prophylaxis for pediatric leukemia patients: monitoring of outcomes for sustained benefit and consequences.

Levofloxacin prophylaxis reduces bloodstream infections in neutropenic patients with acute myeloid leukemia or relapsed acute lymphoblastic leukemia. A retrospective, longitudinal cohort study compares incidence of bacteremia, multidrug-resistant organisms (MDRO), and Clostridioides difficile (CDI) between time periods of levofloxacin prophylaxis implementation. Benefits were sustained without increasing MDRO or CDI.

The Use of Low-Dose Chest Computed Tomography for the Diagnosis and Monitoring of Pulmonary Infections in Patients with Hematologic Malignancies.

The study aimed to assess the image quality and diagnostic performance of low-dose Chest Computed Tomography (LDCCT) in detecting pulmonary infections in patients with hematologic malignancies. A total of 164 neutropenic patients underwent 256 consecutive CT examinations, comparing 149 LDCCT and 107 Standard-Dose Chest CT (SDCCT) between May 2015 and June 2019. LDCCT demonstrated a 47% reduction in radiation dose while maintaining acceptable image noise and quality compared to SDCCT. However, LDCCT exhibited lower sensitivity in detecting consolidation (27.5%) and ground glass opacity (64.4%) compared to SDCCT (45.8% and 82.2%, respectively) with all the respective p-values from unadjusted and adjusted for sex, age, and BMI analyses being lower than 0.006 and the corresponding Odds Ratios of detection ranging from 0.30 to 0.34. Similar trends were observed for nodules ≥3 mm and ground glass halo in nodules but were not affected by sex, age and BMI. No significant differences were found for cavitation in nodules, diffuse interlobular septal thickening, pleural effusion, pericardial effusion, and lymphadenopathy. In conclusion, LDCCT achieved substantial dose reduction with satisfactory image quality but showed limitations in detecting specific radiologic findings associated with pulmonary infections in neutropenic patients compared to SDCCT.

Molecular diagnosis, phylogenetic analysis, and antifungal susceptibility profiles of Candida species isolated from neutropenic oncological patients

BackgroundNeutropenia is the most important cause of life-threatening invasive fungal infections (IFIs). Here, we studied the frequency and antifungal susceptibility profiles of Candida species that colonized or caused infections among neutropenic patients with solid or hematological malignancies.MethodsA total of 362 clinical samples were collected from 138 patients. After initial isolation using a mix of mycological methods, isolates were screened using chromogenic culture media. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied for molecular identification. Positive or suspected cases were confirmed using the reference method of sequencing. Antifungal susceptibility testing for voriconazole and caspofungin was carried out using the microbroth dilution method. An in-silico assay was applied for phylogenetic analysis.ResultsThirty-four Candida strains were isolated. C. albicans (47.06%) and C. glabrata (29.41%) were the most frequent strains. Antifungal treatment reduced the chance of Candida colonization by almost 76% in neutropenic patients (OR: 1.759; 95% CI: 1.349 to 2.390; p value: 0.000). An unusual and non-resistant strain, C. lambica, was reported from the bloodstream of a 56-year-old man with hematologic malignancy (HM). Eight isolates were non-susceptible, and one isolate was resistant to voriconazole. Also, four isolates were non-susceptible to caspofungin.ConclusionWe can conclude that there is a cause-and-effect relationship between neutropenia, HM background, and Candida species separated from neutropenic patients, which can lead to possible infections. Further and repetitive studies are recommended using different molecular methods for better prediction and management of fungal infections in neutropenic patients.

Fluoroquinolone prophylaxis in patients with neutropenia at high risk of serious infections: Exploring pros and cons.

The use of fluoroquinolones to prevent infections in neutropenic patients with cancer or undergoing hematopoietic stem cell transplantation (HSCT) is a controversial issue, with international guidelines providing conflicting recommendations. Although potential benefits are clear, concerns revolve around efficacy, potential harms, and antimicrobial resistance (AMR) implications. Fluoroquinolone prophylaxis reduces neutropenic fever (NF) bloodstream infections and other serious bacterial infections, based on evidence from systematic reviews, randomized controlled trials, and observational studies in adults and children. Fluoroquinolone prophylaxis may also reduce infection-related morbidity and healthcare costs; however, evidence is conflicting. Adverse effects of fluoroquinolones are well recognized in the general population; however, studies in the cancer cohort where it is used for a defined period of neutropenia have not reflected this. The largest concern for routine use of fluoroquinolone prophylaxis remains AMR, as many, but not all, observational studies have found that fluoroquinolone prophylaxis might increase the risk of AMR, and some studies have suggested negative impacts on patient outcomes as a result. The debate surrounding fluoroquinolone prophylaxis calls for individualized risk assessment based on patient characteristics and local AMR patterns, and prophylaxis should be restricted to patients at the highest risk of serious infection during the highest risk periods to ensure that the risk-benefit analysis is in favor of individual and community benefit. More research is needed to address important unanswered questions about fluoroquinolone prophylaxis in neutropenic patients with cancer or receiving HSCT.

Fusariosis in patients with hematological malignancies: Two case reports

Immunosuppressed patients with hematological malignancies are at risk for invasive fungal infections (IFI), including infections with Fusarium species (spp.), which are increasingly reported. Particularly at risk are patients with acute myeloid leukemia (AML) treated with high-dose cytarabine as remission-induction therapy. Whether cytarabine increases the risk of IFI in comparison to other chemotherapy remains not fully determined. Additionally, no clear correlation between the in vitro established minimal inhibitory concentrations (MICs) of antifungal agents and clinical outcome has been established for fusariosis. To increase awareness and knowledge of invasive fusariosis, we report two cases of Fusarium spp. infections in neutropenic patients following treatment with cytarabine for AML. Despite high MICs for azoles both patients were treated with an azole in combination with liposomal amphotericin B. The combination therapy was successful in one patient, however the other patient did not survive the disseminated Fusarium infection.

Characteristics, Outcomes, and Clinical Indicators of Bloodstream Infections in Neutropenic Patients with Hematological Malignancies: A 7-Year Retrospective Study.

The aim of this study was to investigate the current epidemiology, its changes during the study years, and inflammatory biomarkers of bacterial bloodstream infections (BSIs) in neutropenic patients with hematological malignancies. We assessed mortality risk factors and multidrug-resistant (MDR) gram-negative BSI predictors. We conducted a retrospective study from January 2015 to December 2021, which included adult neutropenic oncohematological patients with confirmed BSIs. We used univariable and multivariable analyses to analyze the risk factors. Each index's reliability for bacterial BSI diagnosis was assessed using the receiver-operating characteristic curve and area under the curve. A total of 514 isolates were obtained from the 452 patients. The average mortality was 17.71%. Gram-negative organisms were the predominant causes of BSI. Escherichia coli was the most common microorganism (49.90%). The overall variation trend of the isolation rate of MDR and carbapenem-resistant gram-negative bacteria increased. Multivariate analysis indicated that: 1) neutropenia that lasted for more than 7 days, patients ≥ 60 years of age, septic shock, hospitalization for >20 days, BSI with a carbapenem-resistant strain, and treatment with linezolid or vancomycin in infections lasting less than 30 days were independent mortality risk factors; 2) severe neutropenia exceeding 7 days, unreasonable empirical therapy, and receipt of aminoglycosides or 3rd or 4th generation cephalosporins in infections lasting less than 30 days were independent risk factors of MDR gram-negative bacteria. Procalcitonin, absolute neutrophil count, and white blood cell indicate higher diagnostic accuracy for BSIs. Moreover, bacteria time to detection was better at differentiating Gram-negative and Gram-positive bacterial infections. We analyzed the risk factors for BSI neutropenic patients with hematological malignancies, the distribution of bacteria, antibiotic resistance, and the changes in clinical parameters. This single-center retrospective study may provide clinicians with novel insights into the diagnosis and treatment of BSI to improve future clinical outcomes.

The evaluation of presepsin level and bacterial infection in neutropenic patients

Aim: Neutropenia is a life-threatening condition that is seen as a complication of chemotherapy, especially in cancer patients, if the patient is infected. Early treatment of the infection has aimportant effect on mortality. Our aim in this study is to investigate the usability of presepsin in terms of diagnosis of bacterial infection in patients who are neutropenic after chemotherapy. Methods: In this study, presepsin, erythrocyte sedimentation rate (ESR), CRP (C-reactive protein), and procalcitonin were measured in 25 neutropenic patients, and a comparison was made between those who were culture positive and negative, those who had a fever and those who did not. In addition, presepsin and CRP values were compared with the control group of 22 people. Results: Presepsin, CRP, ESR and procalcitonin were significantly higher in those who did not reproduce in each culture (p&lt;0.001, p=0.003, p=0.026, p&lt;0.01, respectively) compared to those who did not have a fever (p&lt;0.001, p&lt;0.001, p &lt; 0.001, p=0.019, respectively). Conclusion: Presepsin has the potential to be used in the early evaluation of bacterial infection in neutropenic patients. However, more work should be done on this issue.

Leuconostoc lactis Bacteremia and Neutropenic Fever

Abstract The epidemiology of bacteremic infections in neutropenic patients has shifted from a previous majority involving gram-positive cocci to an increasing preponderance of gram-negative Enterobacteriaceae species and Pseudomonas aeruginosa. Recommended empiric antimicrobial treatment regimens include an antipseudomonal β-lactam or carbapenem agent while considering risk factors for the possibility of extended-spectrum β-lactamase– or carbapenemase-producing organisms. The addition of vancomycin is generally reserved for the chance of gram-positive cocci infection, principally in patients with central intravascular catheters or soft tissue infections. Persistent or breakthrough bacteremia despite receiving this glycopeptide drug should prompt the clinician to contemplate not only the possibility of vancomycin-resistant enterococci, but also other organisms that possess intrinsic resistance vancomycin, including Leuconostoc species.

EPIDEMIOLOGY, PREDISPOSING FACTORS AND OUTCOME OF STAPHYLOCOCCUS AUREUS BACTEREMIA IN NEUTROPENIC PATIENTS

Staphylococcus aureus is a common cause of bloodstream infection in neutropenic patients. We analyzed trends in incidence, epidemiology, predisposing factors and outcome of S. aureus bacteremia (SAB) in febrile neutropenic patients. We reviewed a database of febrile neutropenia at a single institution in Brazil in a 30-year period (January 1991 to December 2020). We divided in 3 periods: 1991-1994 (period 1), 2001-2010 (period 2) and 2011-2020 (period 3), and looked at incidence rates, risk factors and mortality. Risk factors and prognostic factors were evaluated by univariate (Fisher or Chi-square for categorical variables and Wilcoxon test for continuous variables) and multivariate (logistic regression) analysis. We diagnosed 62 (3%) episodes of SAB in 2,243 episodes of febrile neutropenia, 23 (38%) of which were caused by methicillin-resistant S. aureus (MRSA). The incidence of SAB per 1,000 days of neutropenia was 1.57, 2.53 and 1.50 in periods 1, 2 and 3, respectively (p > 0.05), and of MRSA was 0.49, 0.84 and 1.07, respectively (p > 0.05). Most infections (70%) were diagnosed in the first day of fever and the clinical presentation were skin infection (19%), catheter-related infection (14%) and pneumonia (3%). Complications like endocarditis or osteomyelitis were not observed. The only factor associated with S. aureus bacteremia by multivariate analysis was cellulitis at site of catheter exit site or tunnel on day 1 of fever (odds ratio [OR] 4.34, 95% confidence interval [CI] 2.05 – 9.16), whereas quinolone prophylaxis was protective (OR 0.37, 95% CI 0.18 - 0.74). The crude mortality of SAB was 30.6%, compared 13.8% in patients without this infection (p < 0.001). However, early mortality (within 3 days of start of empiric antibiotic therapy) was not significantly different (4.8% vs. 1.9%, p = 0.08). The mortality with MRSA was higher than with methicillin-susceptible S. aureus (47.8% vs. 13.9%, p < 0.001), but no difference was found regarding early mortality (5.0 vs 1.7%, p = 0.27). Among various predictors of death during febrile neutropenia MRSA bacteremia (but not methicillin-sensitive) was associated with an increased risk of death by multivariate analysis. The median time from febrile neutropenia to death in MRSA episodes was 19 days. The incidence of SAB over the period remained stable. Complication of SAB were not common. Although the crude mortality was higher with SAB (including MRSA), it was not associated with early deaths, thus not demanding anti-staphylococcal coverage in the first day of febrile neutropenia. MRSA bacteremia was associated with increased risk of death, with most deaths occurring after 2 weeks of febrile neutropenia.

Risk stratification by 30-day prognostic factors of clinical outcomes after granulocyte transfusion in acute myeloid leukemia: A single-center retrospective study.

BackgroundGranulocyte transfusions (GTs) have been used to treat infections in neutropenic patients undergoing chemotherapy or hematopoietic stem cell transplantation. However, there is persistent controversy regarding their outcomes. We aimed to analyze accumulated clinical and laboratory data from patients with acute myeloid leukemia (AML) who underwent GT at our institution in the last 10 years to determine optimal parameters to estimate the GT effect. We hypothesized that patients grouped according to prognostic factors would have inconsistent clinical outcomes.Materials and methodsIn this single-center retrospective study, we collected medical records of 219 GT-treated patients diagnosed with AML from 2009 to 2019. Prognostic factors, including clinical and laboratory parameters, were assessed. Serial measurements of laboratory parameters before and after GT were collected, and the area under the curve of the white blood cells (AUC-WBC) was calculated using the trapezoidal method. A prognostic scoring system using 8 factors from multivariate analysis was analyzed. The primary outcome was survival at 30 days (D30) after GT initiation.ResultsThe 8 factors for the prognosis scoring system included secondary AML, mean AUC-WBC, prothrombin time, and levels of blood urea nitrogen (BUN), bilirubin, alanine aminotransferase (ALT), phosphorus, and lactate dehydrogenase (LDH). Patients were grouped into 4 risk groups (low, medium, high, and very high), and the D30 survival rates for each group were as follows: 87.6% (99/113), 55.9% (33/59), 21.1% (4/19), and 0% (0/19), respectively. Hematopoiesis, liver, and renal function affected the outcome. FLT3 mutation acted as a favorable factor for D30 survival.ConclusionsGT response in patients with AML seemed to be reflected by 8 score markers, and GT was significantly effective in the low-risk group. We suggest that it is important to evaluate the risk assessment of patients before GT to achieve better outcomes.

Commentary on White blood cell transfusions for control of infections in neutropenic patients by Vallejos C. (Transfusion 1975; 15(1):28-33).

Commentary on White blood cell transfusions for control of infections in neutropenic patients by Vallejos C. (Transfusion 1975; 15(1):28-33).

Toll-like Receptor 4, Osteoblasts and Leukemogenesis; the Lesson from Acute Myeloid Leukemia.

Toll-like receptor 4 (TLR4) is a pattern-recognizing receptor that can bind exogenous and endogenous ligands. It is expressed by acute myeloid leukemia (AML) cells, several bone marrow stromal cells, and nonleukemic cells involved in inflammation. TLR4 can bind a wide range of endogenous ligands that are present in the bone marrow microenvironment. Furthermore, the TLR4-expressing nonleukemic bone marrow cells include various mesenchymal cells, endothelial cells, differentiated myeloid cells, and inflammatory/immunocompetent cells. Osteoblasts are important stem cell supporting cells localized to the stem cell niches, and they support the proliferation and survival of primary AML cells. These supporting effects are mediated by the bidirectional crosstalk between AML cells and supportive osteoblasts through the local cytokine network. Finally, TLR4 is also important for the defense against complicating infections in neutropenic patients, and it seems to be involved in the regulation of inflammatory and immunological reactions in patients treated with allogeneic stem cell transplantation. Thus, TLR4 has direct effects on primary AML cells, and it has indirect effects on the leukemic cells through modulation of their supporting neighboring bone marrow stromal cells (i.e., modulation of stem cell niches, regulation of angiogenesis). Furthermore, in allotransplant recipients TLR4 can modulate inflammatory and potentially antileukemic immune reactivity. The use of TLR4 targeting as an antileukemic treatment will therefore depend both on the biology of the AML cells, the biological context of the AML cells, aging effects reflected both in the AML and the stromal cells and the additional antileukemic treatment combined with HSP90 inhibition.

Editorial introductions.

Editorial introductions.

Development of an efficient gene-targeting system for elucidating infection mechanisms of the fungal pathogen Trichosporon asahii

Trichosporon asahii is a pathogenic fungus that causes severe, deep-seated fungal infections in neutropenic patients. Elucidating the infection mechanisms of T. asahii based on genetic studies requires a specific gene-targeting system. Here, we established an efficient gene-targeting system in a highly pathogenic T. asahii strain identified using the silkworm infection model. By comparing the pathogenicity of T. asahii clinical isolates in a silkworm infection model, T. asahii MPU129 was identified as a highly pathogenic strain. Using an Agrobacterium tumefaciens-mediated gene transfer system, we obtained a T. asahii MPU129 mutant lacking the ku70 gene, which encodes the Ku70 protein involved in the non-homologous end-joining repair of DNA double-strand breaks. The ku70 gene-deficient mutant showed higher gene-targeting efficiency than the wild-type strain for constructing a mutant lacking the cnb1 gene, which encodes the beta-subunit of calcineurin. The cnb1 gene-deficient mutant showed reduced pathogenicity against silkworms compared with the parental strain. These results suggest that an efficient gene-targeting system in a highly pathogenic T. asahii strain is a useful tool for elucidating the molecular mechanisms of T. asahii infection.

Lack of Certain Level of Myelosuppression during Induction Phase Is Associated with Poor Prognosis in Children and Adolescent with B-Cell Precursor Acute Lymphoblastic Leukemia

Background: Risk stratification and subsequent optimization of therapy for acute lymphoblastic leukemia (ALL) is indispensable. Early response to induction therapy has been known as an important prognostic factor; however, impact of myelosuppression during induction phase on prognosis has not been assessed. D-index that reflects both intensity and duration of neutropenia was originally developed to estimate risk of invasive fungal infection in neutropenic patients under chemotherapy. Primary aim of this study was to assess the association between D-index during induction phase and prognosis of children and adolescents with B-cell precursor (BCP) ALL.Methods: Sixty-nine children or adolescents diagnosed with BCP-ALL treated at our hospital were consecutively enrolled from April 2007 to March 2017. Their median age was 5 years (range, 1-23). Children less than 1 year of age were excluded from this study since they were treated with an infant ALL protocol. We performed multivariate analysis to estimate the effect of D-index and other known factors including age, white blood cell (WBC) count at onset, and early response to prednisolone (the number of day 8 peripheral blasts) on poor prognosis. The D-index was calculated based on a graph that plotted the absolute neutrophil counts over the course of the episode of neutropenia. The D-index was defined as the difference between the observed area under the curve, which was calculated by the trapezoidal method, and the expected neutrophil area (500/mm3 × days with neutropenia) if the patient did not develop neutropenia (Figure). Survival distribution was assessed using the Kaplan-Meier method, and differences were compared using the log-rank test. Multivariate analyses were performed to investigate whether D-index might serve as a prognostic factor, using Cox proportional hazards regression analysis or Fine-Gray proportional hazards regression analysis. The duration of event-free survival (EFS) was defined as the time from the initiation of therapy to either treatment failure (relapse, death, or diagnosis of secondary cancer) or to the last day when the patient was confirmed to be in remission.Results: D-index during induction phase ranged from 0 to 20,095 with a median of 7,985. The overall survival (OS) for patients with D-index greater than or equal to 3,000 (n=62) was 96.4+/-2.5% at 4 years, whereas that for patients with low D-index less than 3,000 (n=7) was 0% (P <0.001). The EFS for patients with D-index greater than or equal to 3,000 was 88.1+/-4.7% at 4 years, whereas that for patients with low D-index less than 3,000 was 0% (P=0.002). As a result of multivariate analysis, poor OS was associated with low D-index (<3,000) during induction phase (hazard ratio [HR], 24.34; 95% confidence interval [CI], 3.317-178.6; P=0.002). Likewise, poor EFS was associated with low D-index (<3,000) during induction phase (HR, 10.42; 95% CI, 1.655-65.57; P=0.013). Treatment-related mortality (TRM) was not associated with low D-index (<3,000) during induction phases, however cumulative incidence of relapse was associated with low D-index (<3,000) during induction phase (HR, 6.832; 95% CI, 1.640-76.09; P=0.012) as well as age at onset greater than or equal to 10 years of age (HR, 4.960; 95% CI, 1.188-34.25; P=0.014).Conclusion: The results of our study highlight the importance of a novel risk factor for poor prognosis in children and adolescents with BCP-ALL, not previously considered-low D-index during induction phase. Poor OS and EFS in patients with low D-index might be associated with increased risk for relapse. Lack of a certain level of myelosuppression may correlate with insufficient therapeutic effect. Further research involving a larger multicenter cohort is needed to confirm and explain this finding. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Dose adjustment of venetoclax when co-administered with posaconazole: clinical drug-drug interaction predictions using a PBPK approach.

Venetoclax, a targeted anticancer agent approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, is a substrate of cytochrome P450 (CYP) 3A enzyme (CYP3A4). Posaconazole, commonly used to prevent invasive fungal infections in neutropenic patients with hematological malignancies, potently inhibits CYP3A4. The purpose of this evaluation was to predict venetoclax exposures following co-administration of posaconazole at doses not previously studied clinically. Two physiologically based pharmacokinetic (PBPK) models were developed for posaconazole based on published parameters, one for an oral suspension and another for delayed released tablets. Parameter optimization, guided by sensitivity analyses, was conducted such that the models could replicate clinical exposures of posaconazole and drug-drug interactions with sensitive CYP3A substrates including venetoclax. The clinically verified posaconazole PBPK models were then utilized to predict DDI with a previously published venetoclax PBPK model at clinically relevant dosing scenarios. The posaconazole PBPK models predicted posaconazole exposure and DDI related fold changes with acceptable prediction errors for both posaconazole formulations. The model predicted exposures of venetoclax, when co-administered with a 300mg QD dose of delayed release tablets of posaconazole, were in concordance with observed data. Increasing the posaconazole dose to 500mg QD increased venetoclax exposures by about 12% relative to 300mg QD, which were still within the venetoclax safe exposure range. The posaconazole PBPK models were developed and clinically verified. Predictions using the robust PBPK model confirmed the venetoclax label recommendation of 70mg in the presence of posaconazole at doses up to 500mg QD.

1364. Effect of Cefepime Prophylaxis on Bacterial Bloodstream Infections in Neutropenic Patients with Acute Myelogenous Leukemia

BackgroundBacteremia is a major cause of morbidity and mortality among children with acute myelogenous leukemia (AML) and chemotherapy-induced neutropenia. Data evaluating the utility of bacterial prophylaxis in this pediatric population are limited. In April 2014, Children’s Health (CH) implemented the use of cefepime bacterial prophylaxis for AML patients undergoing induction and intensification chemotherapy. The objective of this study was to evaluate the impact of this practice on the frequency of documented bacterial bloodstream infections (BSIs).MethodsThis was an observational, retrospective cohort study of patients < 21 years of age with AML admitted at CH from January 2010 through December 2018. The primary outcome was frequency of documented BSIs before (PRE; Jan 2010 to Mar 2014) and after (POST; Apr 2014 to Dec 2018) implementation of routine bacterial prophylaxis. Secondary outcomes included differences in total antibiotic days per neutropenia days and the occurrence of neutropenia-associated C. difficile infection between groups.ResultsOf 90 patients with AML who met the cohort inclusion criteria, 38 and 52 were treated during the PRE and POST prophylaxis periods, respectively. The incidence rate of documented BSIs per 1000 neutropenia days decreased from 15.5 to 2.8 after the implementation of routine cefepime prophylaxis (incidence rate ratio 0.18, Poisson regression 95% CI 0.09 to 0.33, P< 0.001). Patients were more likely to have febrile neutropenia in the PRE group (OR 11.9, 95% CI 6.6 to 20.8). The POST group had more antibiotic days per total neutropenia days (0.76 PRE vs 0.97 POST, P< 0.0001), but the frequency of first-episode C. difficile infection was not significantly different between groups (OR 0.36, 95% CI 0.1 to 1.4).ConclusionUniversal cefepime prophylaxis for children with AML and chemotherapy-induced neutropenia was associated with a significant reduction in the incidence of febrile neutropenia and neutropenia-associated BSIs without increasing the incidence of C. difficile infection.Disclosures All Authors: No reported disclosures