Days Of Neutropenia Research Articles

A practical approach to febrile cancer patients: Diagnostic stewardship in Oncology units

Introduction Cancer and cytotoxic chemotherapy used for its treatment predispose to severe and often fatal infections. Prompt diagnosis and timely antibiotic therapy are crucial, with delays in therapy initiation having high mortality. Complete blood count (CBC) is an inexpensive, standardized, and preliminary investigation for the management and follow-up of cancer patients with diagnostic and prognostic value. Method We studied the types of infections associated with various cancers treated with chemotherapy, their etiologies and susceptibility patterns, and the hematological profile of these patients as predictors of infection. Results A total of 21 patients (12 solid and 9 hematological malignancies) presented with 31 febrile episodes. White Blood cell count (2079 cells/cu. mm), percentage of neutrophils (52.9%), absolute neutrophil (137.5 cells/cu. mm), and platelet count (1,77,507 cells/cu. mm) were significantly lower in the 11 patients with febrile neutropenia. The absolute lymphocyte count (412.7 cells/cu. mm) was reduced with a strikingly low Neutrophil-to-lymphocyte ratio (NLR) (6.07) in patients with neutropenia. Laboratory and radiological evidence were present in 14/15 episodes of hematological malignancies (p-0.218) whereas unexplained clinical sepsis was common in solid malignancies (p-0.0202). The majority of documented infections were bacterial, caused by gram-negative bacilli, often showing multi-drug resistance. Infectious etiologies were identified in 71.4% of the patients with febrile neutropenia for >5days. Bacterial infections developed within 2 days of neutropenia, whereas viral and fungal infections manifested in prolonged neutropenia. Multi-site infections and higher mortality rates were observed in patients with febrile neutropenia. (p<0.04) Conclusion Febrile neutropenia is a common complication among patients receiving chemotherapy for cancer, with an increased risk of morbidity and mortality. Early, rapid, and accurate diagnosis is key to prompt intervention. Hematological parameters such as Total Leukocyte count, platelet count, NLR, and Platelet-to-lymphocyte ratio are promising biomarkers in conjunction with morphological changes in neutrophils, thus proving that CBC and peripheral smears are simple, easily available, cost-effective, and highly dependable screening tools, especially in resource-poor settings.

A practical approach to febrile cancer patients: Diagnostic stewardship in Oncology units

Introduction Cancer and cytotoxic chemotherapy used for its treatment predispose to severe and often fatal infections. Prompt diagnosis and timely antibiotic therapy are crucial, with delays in therapy initiation having high mortality. Complete blood count (CBC) is an inexpensive, standardized, and preliminary investigation for the management and follow-up of cancer patients with diagnostic and prognostic value. Method We studied the types of infections associated with various cancers treated with chemotherapy, their etiologies and susceptibility patterns, and the hematological profile of these patients as predictors of infection. Results A total of 21 patients (12 solid and 9 hematological malignancies) presented with 31 febrile episodes. White Blood cell count (2079 cells/cu. mm), percentage of neutrophils (52.9%), absolute neutrophil (137.5 cells/cu. mm), and platelet count (1,77,507 cells/cu. mm) were significantly lower in the 11 patients with febrile neutropenia. The absolute lymphocyte count (412.7 cells/cu. mm) was reduced with a strikingly low Neutrophil-to-lymphocyte ratio (NLR) (6.07) in patients with neutropenia. Laboratory and radiological evidence were present in 14/15 episodes of hematological malignancies (p-0.218) whereas unexplained clinical sepsis was common in solid malignancies (p-0.0202). The majority of documented infections were bacterial, caused by gram-negative bacilli, often showing multi-drug resistance. Infectious etiologies were identified in 71.4% of the patients with febrile neutropenia for >5days. Bacterial infections developed within 2 days of neutropenia, whereas viral and fungal infections manifested in prolonged neutropenia. Multi-site infections and higher mortality rates were observed in patients with febrile neutropenia. (p<0.04) Conclusion Febrile neutropenia is a common complication among patients receiving chemotherapy for cancer, with an increased risk of morbidity and mortality. Early, rapid, and accurate diagnosis is key to prompt intervention. Hematological parameters such as Total Leukocyte count, platelet count, NLR, and Platelet-to-lymphocyte ratio are promising biomarkers in conjunction with morphological changes in neutrophils, thus proving that CBC and peripheral smears are simple, easily available, cost-effective, and highly dependable screening tools, especially in resource-poor settings.

Epidemiological changes of invasive fungal disease in children with cancer: Prospective study of the National Child Program of Antineoplastic Drugs network, Chile.

Invasive fungal diseases (IFD) are high morbidity and mortality infections in children with cancer suffering episodes of high-risk febrile neutropenia (HRFN). IFD epidemiology has changed in the last two decades, with an increasing incidence in recent years due to the growing number of immunocompromised children at risk for IFD. The aim of this study was to evaluate the incidence of IFD in children with cancer in the period 2016-2020 compared to 2004-2006 in six hospitals in Chile. Prospective, multicentre study, carried out between 2016 and 2020 in six hospitals in Chile. The defined cohort corresponds to a dynamic group of HRFN episodes in patients <18 years old with cancer, who at the fourth day of evolution still presented fever and neutropenia (persistent HRFN). Each episode was followed until resolution of FN. The incidence of IFD was calculated between 2016 and 2020 and compared with data obtained in the period 2004-2006. The incidence rate was estimated. A total of 777 episodes of HRFN were analysed; 257 (33.1%) were considered as persistent-HRFN occurring in 174 patients. The median age was 7 years (IQR: 3-12 years) and 52.3% (N = 91) were male. Fifty-three episodes of IFD were detected: 21 proven, 14 probable and 18 possible. Possible IFD were excluded, leaving 239 episodes of persistent-HRFN with an IFD incidence of 14.6% (95% CI 10.5-19.9) and an incidence rate of 13.6 IFD cases per 1000 days of neutropenia (95% CI 9.5-20.0). Compared to 2004-2006 cohort (incidence: 8.5% (95% CI 5.2-13.5)), a significant increase in incidence of 6.1% (95% CI 0.2-12.1, p = .047) was detected in cohorts between 2016 and 2020. We observed a significant increase in IFD in 2016-2020, compared to 2004-2006 period.

Early Antibiotic Deescalation and Discontinuation in Patients with Febrile Neutropenia after Cellular Therapy: A Single-Center Prospective Unblinded Randomized Trial

The optimal duration of empiric antimicrobial therapy of febrile neutropenia in patients after cellular therapy is unclear. Early deescalation has been suggested by some authorities; however, data are lacking for cellular therapy recipients. We performed a randomized controlled study of cellular therapy recipients with febrile neutropenia to evaluate the safety and noninferiority of an early deescalation and discontinuation antibiotic strategy (EDD arm) versus standard broad-spectrum antibiotic treatment until recovery of neutropenia (standard duration arm). The primary outcome was the fraction of antibiotic-free neutropenia days. We randomized 110 patients to the standard duration arm (n=51) or EDD arm (n=59). The fraction of antibiotic-free neutropenia days was higher in the EDD arm compared to the standard duration arm (median, .8 [interquartile range (IQR), .62 to .86] versus .51 [IQR, .17 to .86]; P=.016). This was true for the per-protocol, allogeneic hematopoietic cell transplantation (HCT), autologous HCT, and anti-CD19 chimeric antigen receptor T cell therapy subgroups. Treatment success rate, subsequent fever, death within 30 days, and other common cellular therapy-related toxicities were all similar between the 2 study arms. An EDD antibiotic strategy in patients after cellular therapy was safe and associated with a substantial reduction in broad-spectrum antibiotic utilization without compromising cellular therapy outcomes.

High Molecular Response Rate and Overall Survival with FLT3 Inhibitors As MRD-Guided Salvage Treatment for Molecular Failure in AML

BackgroundFLT3 inhibitors (FLT3i) represent an important new salvage option in patients with relapsed FLT3 mutated AML but response rates are low and survival outcomes remain poor. Many patients with FLT3 AML have co-occurring mutations suitable for sequential molecular monitoring by RT-qPCR, which can be used to identify impending haematological relapse (Heuser, Blood 2021; Ommen, Blood 2010). However, treatment strategies for molecular relapse are not well defined and many patients receive multi-agent chemotherapy or proceed directly to allogeneic stem cell transplant (allo-SCT) despite evidence of poor outcomes (Hourigan, JCO 2019; Dillon, Blood 2020). We aimed to describe response rates and outcomes in patients treated with FLT3 inhibitors for molecular persistence, progression or relapse (collectively 'molecular failure'). Methods In the UK, molecular monitoring for AML is largely centralised, and intervention with FLT3i monotherapy at the time of molecular failure is suggested for patients who had a FLT3 mutation at diagnosis. Consecutive patients undergoing FLT3i salvage were retrospectively identified from 27 participating hospitals. Patients met ELN criteria for molecular failure: persistence >2% after chemotherapy, relapse after previously negative results or progression of ≥1 log10 from low-level positivity. Response was assessed by sequential MRD measurement and was censored at the time of allo-SCT, donor lymphocyte infusion (DLI) or subsequent chemotherapy. Molecular response (MR) was defined as a ≥1 log10 reduction from the pre-treatment result. CRMRD-, overall (OS) and event-free survival (EFS) were defined as per ELN. Molecular event-free survival (mEFS) included molecular progression or relapse, haematological relapse or death. Stored pre and post-treatment samples were retrospectively analysed using a sensitive NGS-based FLT3-MRD assay (Blatte, Leukemia 2019). Results Forty eight patients were identified, aged 5 to 76 years. Thirty-nine (81%) had NPM1 mutations, 4 NUP98::NSD1 fusion, 3 DEK::NUP214, and 1 each CBFB::MYH11 and RUNX1::RUNX1T1. At diagnosis, 44 (92%) had a FLT3-ITD, 6 FLT3-TKD and 2 had both. Molecular failure occurred at a median of 9.6 months (range 0.9 - 31) from AML diagnosis and comprised molecular persistence in 6 (12%), molecular progression in 19 (40%) and molecular relapse in 23 (48%). Patients had received a median of 1 prior line of therapy (range 1-3), which included a FLT3i in 25 (52%) and allo-SCT in 13 (27%). Thirty-two (67%) patients were treated with gilteritinib while 8 (17%) received quizartinib and 8 (17%) sorafenib. Data on treatment toxicity in the first 4 cycles was available for 21 patients. The median number of days of neutropenia and thrombocytopenia and median number of transfusions per cycle was 0. Only 6 of the 21 patients required hospitalisation at any time in the first 4 cycles. Response was assessable in 47 patients, with 30 (64%) achieving MR of whom 19 (40%) had CRMRD-. Six patients (13%) had stable disease and 11 (23%) progressed, including 5 with haematological relapse. Patients treated for molecular relapse had the highest rate of CRMRD- at 55%. CRMRD- was lower in patients with prior FLT3i but the rate of MR was similar, apart from patients currently receiving FLT3i at the time of molecular failure of whom 6 of 13 (46%) had progressive disease. Patients with prior allo-SCT had a high response rate, with 92% achieving MR. Stored pre-treatment samples were available for FLT3 NGS-MRD analysis in 24 patients, with an ITD detected in 20 at a median VAF of 0.04%. The response rate in these patients was 70%. Twenty-four patients received allo-SCT after FLT3i salvage, 18 without requiring additional therapy prior to transplant. Seven patients received DLI. Responses deepened after allo-SCT or DLI, with 77% achieving CRMRD-. At 24 months, OS was 80% (95% confidence interval [CI] 67-96), EFS was 73% (95%CI 59-90) and mEFS was 53% (95%CI 39-72). Late relapses after stopping therapy were noted in 4 patients. Conclusions In contrast with FLT3i monotherapy at the time of frank relapse, treatment at molecular failure is associated with low toxicity, high rates of molecular response and encouraging overall survival, with many patients able to be bridged to allo-SCT or DLI. These results suggest that in patients with an appropriate marker, sequential molecular MRD monitoring should be utilised and the results used to guide pre-emptive therapy Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Granulocyte Transfusion in Haematology Patients with Febrile Neutropenia - a Single Centre Retrospective Cross Sectional Study

BACKGROUND: Febrile neutropenia (FN) and subsequent infection related mortality and morbidity remains a challenge during treatment of haematological malignancies and Hematopoietic Stem Cell Transplantation (HSCT). Opportunistic fungal infections and multi drug resistant(MDR) bacterial infections remain important causes of morbidity and mortality in neutropenic individuals. Historically from 1960 onwards granulocyte collection and transfusions for neutropenic patients have been used to treat febrile neutropenia. Previous studies to assess the role of granulocyte transfusion(GT) as bridging therapy before neutrophil engraftment have been inconclusive . Most of these studies had an absolute neutrophil coun(ANC)<0.5 X 10^9/l as inclusion criteria. Our hypothesis was that the benefit of GT may be in the subset of patients with ANC < 0.2 X 10^9/l. The objective was to analyse the outcomes of two retrospective cohorts, one with and another without GT . METHODS: Electronic medical records of patients more than 18 years of age and undergone Induction therapy for AML and Allogenic HSCT at the institution between 2015 to 2022 were screened. Patients who developed FN with ANC < 0.2 x 10^9/l were included and those with higher ANCs at the time of GT were excluded .Patients with age less than 18 years ,those with other haemato-oncologic malignancies and patients who underwent AML induction with regimen other than 7 days of cytarabine + 3 days of daunorubicin (7+3)were excluded. Apheresed GT was available during 2020-2022 period and was used as per treating physician's discretion. Those who developed FN but having lung infection were also excluded . Patients who met the same inclusion and exclusion criteria who developed FN but did not receive GT (2015-2019 period ) were analysed as control group. Granulocytes were collected after administration of 450mcg of Granulocyte Colony Stmulating Factor (GCSF) and oral Dexamethasone 8mg 12 hours prior to collection to ABO group matched donors. Apheresis was done using Spectra Optia Apheresis System. GT was continued till infection was controlled and there were robust signs of bone marrow recovery. Forty two day survival, total duration of neutropenia and hospital stay between the two groups were compared. Data was entered in Microsoft excel version 2019 and analysed using SPSS version 21. Data were compared between two cohorts using Chi-square test and t-test for equality of means. RESULTS:The demographic details of the the two cohorts is given in Table 1.Among 33 patients who received GT, 1 patient expired (3%). There were 5 patient deaths in the control cohort (n=37, 13.5%). Even though 10.5 % difference in the 42 day survival between the control and the study cohorts was noted, Chi-square analysis did not show a statistically significant difference (p =0.118). Mean duration of hospital stay for the study cohort was 34.30 days (±7.239) as compared to 30.62 days (± 5.663) for the control cohort (p = 0.020). Mean days of neutropenia for study cohort was 14.03 days (± 6.252) and 12.38 days (±4.152) for the control cohort (p=0.193).There were no grade III/IV adverse events attributable to the GT documented in the medical records of the subjects in the study cohort. CONCLUSIONS: Although patient deaths were lower in the study cohort (with a 10% difference from the control cohort), it did not achieve statistical significance. This might have been due to the limited number of patients in both the cohorts.The study is also limited by the retrospective design.Since the study cohort and the control cohort received treatment in two different time periods, there could have been a difference in the supportive care . Inspite of all these limitations our findings may point towards the need for conducting a prospective Randomised controlled trial in patients with very severe neutropenia (ANC<0.2x 10^9/L) and other potential risk factors for MDR infections. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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.

Comparative study on the effects of filgrastim and pegfilgrastim in the treatment of fever and neutropenia in patients with leukemia in the west of Iran

Background: The current research seeks to present a comparative study of the effect of filgrastim and pegfilgrastim in the treatment of fever and neutropenia in leukemia patients.&#x0D; Materials and Methods: The present study is a blind randomized clinical trial. The study population is comprised of 120 children with acute lymphoblastic leukemia (ALL) who were admitted to the hospital due to mild febrile neutropenia during 2019. Included patients were divided into two groups. Filgrastim (10 micrograms/ kilogram, daily subcutaneously) and pegfilgrastim (100 micrograms per kilogram of a subcutaneous dose) were used for groups, respectively. Fever monitored every 6 hours, and neutrophil count was performed every 48 hours. The questionnaire designed in the study included age, type of drug side effects, number of days of neutropenia, and fever cessation time. Then, the data were analyzed by SPSS software.&#x0D; Result: Leukemic children with fever and neutropenia (N=120) were included in the study, which was 59 (49.1%) male and 61 (50.9%) female by the mean age of 79±44 months. The mean days of neutropenia correction in the filgrastim and pegfilgrastim groups were 5 and 4 days, respectively, which was not significantly different (p =0.08). There was no correlation between patients’ complications and types of treatments (p&gt;0.05). Muscular pain was the most common complication observed among 4 cases and 1 case following filgrastim and pegfilgrastim administration, respectively. Furthermore, hyperleukocytosis following pegfilgrastim consumption was observed in two cases.&#x0D; Conclusion: There was no significant correlation between the duration until the cessation of fever and the number of neutropenia days in the two groups receiving pegfilgrastim and filgrastim. Therefore, the fever and neutropenia improve with pegfilgrastim earlier than filgrastim; besides, fewer injections, patient comfort, and less musculoskeletal pain can be observed.

Antibiotic Stewardship in Patients after Cellular Therapy with Febrile Neutropenia- a Single Center Prospective Unblinded Randomized Trial

Background: Neutropenic fever is a life-threatening condition which is common in patients undergoing allogeneic/autologous hematopoietic cell transplantation (HCT) or chimeric antigen receptor - T cell (CAR-T) therapy. Empirical treatment includes monotherapy with a beta-lactam containing anti-pseudomonal activity. Nevertheless, stewardship of antibiotic in this vulnerable population is controversial.Methods: This was a single center, prospective, unblinded randomized study, of patients after HCT or CAR-T therapy that were enrolled between January 2020 and March 2021. Allocation was concealed in sequentially numbered sealed opaque envelopes. All patients signed informed consent and the study was approved by the Tel Aviv Medical Center Institutional Review Board. Patients were randomly assigned to receive either standard empiric antibiotic ( piperacillin/tazobactam or ceftazidime) that was continued until recovery of counts (control group), or standard empiric antibiotic that was discontinued after 48-72 hours providing there was no evidence of clinical or microbiology documented infection (intervention group). Rapid identification of bloodstream infections was performed with BioFire filmarray multiplex PCR assay (bioMerieux), and results were used to adjust antibiotic treatment early. The primary outcome was the percentage of days without empiric antibiotic (antibiotic-free-neutropenia days). Secondary outcome included successful response to treatment, defined as the combination of- continuation of clinical improvement on day 5 after initiation of antibiotic, no reoccurrence of bacetermia/fever/clinical infection signs on day 5, and no need for additional therapy on day 4-5 after starting antibiotic. Breakthrough fever, death within 30 days of episode onset, duration of hospitalization, duration of neutropenia, graft vs. host disease (GVHD) and characteristics of cytokine release syndrome (CRS) were also evaluated, as appropriate.Results: 110 patients were randomized to standard therapy (control group, n=51) and antibiotic stewardship strategy (intervention group, n=59), Figure 1. The patients' baseline characteristics were well-balanced between the 2 groups, Table 1. Febrile neutropenia occurred in 91 of the patients, and these patients were eligible for the per-protocol analysis. In the intention-to-treat population, the fraction of antibiotic-free neutropenia days was significantly higher for patients allocated to the stewardship arm, compared to those allocated to the standard arm (median [IQR], 0.8 [0.62-0.86] versus 0.51 [0.17-0.86], respectively, p=.0016). This was also true for the subgroups of patients treated per-protocol (median [IQR], 0.75 [0.61-0.83] versus 0.42 [0.12-0.72], respectively, p<.001) and in the subgroups of patients after allogeneic HCT, autologous HCT and CAR-T therapy (0.75 [0.57-0.86] vs. 0.5 [0.40-0.51], p=.0046; 0.66 [0.62-0.83] vs. 0.59 [0.19-0.81], p=.077; and 0.7 [0.45-0.82] vs 0.06 [0-0.28], p=.025, respectively), Figure 2. There was no difference in the success rate between the 2 groups (84.7% vs. 78%, P =0.45). Thirty-day death rate was similarly low in both groups. Other outcome are depicted in Table 2. Linear regression was used to assess the interaction of patient and treatment variables with the fraction of antibiotic-free days. Assignment to the stewardship arm was significantly associated with a higher fraction of antibiotic-free days (p=.003), whereas CART treatment was associated with a lower fraction of antibiotic-free days (p=.004).Conclusions: This is the first randomized study showing in a homogenous population of patients after cellular therapy, the safety of antibiotic stewardship. Optimization of antibiotic schedule is a widely available and cost-effective strategy to improve treatment outcomes in patients with high risk febrile neutropenia after cellular therapy. [Display omitted] DisclosuresRam: Gilead: Honoraria; Novartis: Honoraria. Avivi: Kite, a Gilead Company: Speakers Bureau; Novartis: Speakers Bureau.

Invasive Fungal Disease in Patients with Newly Diagnosed Acute Myeloid Leukemia.

This single-center retrospective study of invasive fungal disease (IFD) enrolled 251 adult patients undergoing induction chemotherapy for newly diagnosed acute myeloid leukemia (AML) from 2014–2019. Patients had primary AML (n = 148, 59%); antecedent myelodysplastic syndrome (n = 76, 30%), or secondary AML (n = 27, 11%). Seventy-five patients (30%) received an allogeneic hematopoietic cell transplant within the first year after induction chemotherapy. Proven/probable IFD occurred in 17 patients (7%). Twelve of the 17 (71%) were mold infections, including aspergillosis (n = 6), fusariosis (n = 3), and mucomycosis (n = 3). Eight breakthrough IFD (B-IFD), seven of which were due to molds, occurred in patients taking antifungal prophylaxis. Patients with proven/probable IFD had a significantly greater number of cumulative neutropenic days than those without an IFD, HR = 1.038 (95% CI 1.018–1.059), p = 0.0001. By cause-specific proportional hazards regression, the risk for IFD increased by 3.8% for each day of neutropenia per 100 days of follow up. Relapsed/refractory AML significantly increased the risk for IFD, HR = 7.562 (2.585–22.123), p = 0.0002, and Kaplan-Meier analysis showed significantly higher mortality at 1 year in patients who developed a proven/probable IFD, p = 0.02. IFD remains an important problem among patients with AML despite the use of antifungal prophylaxis, and development of IFD is associated with increased mortality in these patients.

Association between the dietary regimen and infection-related complications in neutropenic high-risk patients with cancer

BackgroundMany haematology/oncology departments still provide a germ-free diet for neutropenic patients (neutropenic diet, ND) to minimise pathogen exposure, even though evidence on benefits is missing. We analysed the effects of a standard diet (SD) in neutropenic high-risk patients with cancer while focussing on infection-related outcomes. Patients and methodsBased on the Cologne Cohort of Neutropenic Patients, we conducted a propensity score–matched case-control study in haematological/oncological patients with a period of neutropenia longer than five days treated at our department between January 2004 and December 2012 (implementation of SD in January 2008). We assessed the association between an SD and selected infection-related end-points in an adjusted multivariable regression model and time-to-event analysis. ResultsIn total, 2086 neutropenic episodes (1043 per diet group) were included into analysis. The median days of neutropenia were 9 (interquartile range 7–16). The adjusted multivariable model revealed no association between the SD and severity and persistence of fever, death within 28 days, antibiotic treatment and weight loss >3 kg and a non-significant adjusted association between SD and duration of antibiotic treatment and blood stream infections. There was a significant association between SD and incidence of diarrhoea (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.45–0.68; P < 0.001), nausea (OR, 0.53; 95% CI, 0.43–0.66; P < 0.001) and weight loss >1 kg (OR, 0.93; 95% CI, 0.89–0.98; P = 0.002) with fewer events in SD than in the ND group. The hazard ratios of SD for the analysed end-points were non-significant. ConclusionIn our study, the implementation of an SD for high-risk neutropenic patients with cancer was safe regarding infection-related end-points.

Pediatric Invasive Fungal Risk Score in Cancer and Hematopoietic Stem Cell Transplantation Patients With Febrile Neutropenia.

Invasive fungal diseases (IFDs) are opportunistic infections that result in significant morbidity and mortality in pediatric oncology patients. Predictive risk tools for IFD in pediatric cancer are not available. We conducted a 7-year retrospective study of pediatric oncology patients with a diagnosis of febrile neutropenia at UCM Comer Children's Hospitals. Fourteen clinical, laboratory, and treatment-related risk factors for IFD were analyzed. Stepwise variable selection for multiple logistic regression was used to develop a risk prediction model for IFD. Two comparative analyses have been conducted: (i) all suspected IFD cases and (ii) all proven and probable IFD cases. A total of 667 febrile neutropenia episodes were identified in 265 patients. IFD was diagnosed in 62 episodes: 13 proven, 27 probable, and 22 possible. In the final multiple logistic regression models, 5 variables were independently significant for both analyses: fever days, neutropenia days, hypotension, and absolute lymphocyte count <250 at the time of diagnosis. The odds ratio and a relative weight for each factor were then calculated and summed to calculate a predictive score. A risk score of ≤4 and ≤5 (10/11 maximum) for each model signifies low risk, respectively (<1.2% incidence). Model discrimination was evaluated by the area under the receiver operator characteristics curve with an area under the curve of 0.95/0.94 for each model. Our prediction IFD risk models perform well, are easy-to-use, and are based on readily available clinical data. Profound lymphopenia absolute lymphocyte count <250 mm3 could serve as a new important prognostic marker for the development of IFD in pediatric cancer and hematopoietic stem cell transplant patients.

Outpatient supportive care for pediatric acute myeloid leukemia: a single institution’s experience

Infections are responsible for most treatment-related morbidity and mortality in pediatric acute myeloid leukemia (AML). Children’s Oncology Group (COG) recommends hospitalization following chemotherapy until early absolute neutrophil count (ANC) recovery. No standard guidelines exist for antibiotic prophylaxis and discharge practices vary. Our objective was to report our institution’s experience with outpatient supportive care management following early discharge. A retrospective chart review of pediatric AML patients treated at our institution from 2010 to 2019 was conducted. Data was collected on length of hospitalization, antibiotics administered, infections, and neutropenia duration. Seventeen patients underwent 60 chemotherapy cycles. All were discharged after completion of chemotherapy if clinically stable. Patients were re-admitted for fever and discharged on empiric antibiotics if afebrile with negative cultures. Prophylactic antibiotics were administered in 55 cycles. There were 12 infections in 11 patients and no deaths due to infection. Patients remained outpatient for a mean of 15.8 neutropenia days per cycle. Outpatient supportive care for children with AML may be feasible and safe. Further studies are needed to establish outpatient supportive care guidelines.

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

1158. D-index as a Novel Index to Predict Invasive Fungal Disease in High-Risk Neutropenic Pediatric Cancer Patients and Hematopoietic Stem Cell Transplantation

BackgroundProlonged and profound neutropenia are risk factors for invasive fungal disease (IFD) during febrile neutropenia (FN) episodes. The D-index combines both depth and duration of neutropenia in a single assessment and has been proposed as a useful tool to exclude or predict IFD in high-risk adult patients. We assessed the D-index as a predictor of IFD in pediatric cancer patients.MethodsWe conducted a retrospective study of pediatric oncology patients with FN at UCM Comer Children’s Hospitals. IFD was stratified as possible, probable, and proven according EORTC/MSG criteria. Patients considered high risk of IFD were receiving intensive chemotherapy with expected prolonged neutropenia >7 days, including, but not limited to, AML, high-risk acute ALL, and hematopoietic stem cell transplantation (HSCT). The D1-index was equal to 2t1 + 3t2, where t1, and t2 are the number of days from the first day of neutropenia < 500mm3 and < 100/ mm3 respectively, until the development of IFD. The D2-index approximates the area over the neutrophil curve during neutropenia. A cumulative D-index (c-D-index) was also calculated using the first day of neutropenia until the date of the first clinical manifestation of IFD. We compared duration of neutropenia vs D-index vs c-D-index as a predictor of IFD using receiver operating characteristic curve (ROC)/AUC analysis.Figure 1 Figure 2 ResultsWe identified 455 FN episodes in 203 high-risk patients. 53/455 (11.6%) had IFD, 12 (2.6%) proven, 23 (5%) probable, and 18 (4%) possible. The median of D1, D2 indexes and c-D-index were significantly higher in patients developing IFD (38, 5225, 7352) compared to the non-IFD group (26, 3857, 5169) (P=.001, P=.001, and P=.01) respectively. The ROC curve of D-index and c-D-index (figure 1,2,3) showed better performance (AUC of 0.85,0.89, 0.81) respectively compared to the duration of neutropenia alone. The ROC was highest when D-index was combined with prolonged fever >5 days (AUC 0.94)Figure 3 Figure 4 ConclusionThe D-index may be a useful tool to stratify high-risk pediatric patients according to risk of IFD. The c-D-index, particularly, may be a useful tool to guide for empiric antifungal therapy and diagnostic testing. Prospective multi-center studies using these tools are required to refine the clinical approach to IFD.Disclosures All Authors: No reported disclosures

The Utility of Granulocyte Colony Stimulating Factor in Patients Receiving Chimeric Antigen Receptor T-Cell Therapy with Axicabtagene Ciloleucel

Background: Infection during the period of neutropenia following chemotherapy represents a major cause of morbidity and mortality in patients with malignancy.(Freifeld, et al, 2011, Baden LR, et al, 2012) Several guidelines recommend granulocyte colony stimulating factor (GCSF) to reduce the duration and severity of chemotherapy-induced neutropenia and abate infection risk.(Lyman, et al 2018, Aapro, et al, 2011, Smith, et al, 2015). Optimal GCSF administration following chimeric antigen receptor (CAR) T-cell therapy remains undefined and requires characterization. Methods: The Mayo Institutional Review Board approved this retrospective, single-center study. Electronic medical records for patients prescribed axicabtagene ciloleucel were reviewed until disease relapse, death, or a maximum of 60 days after infusion. Baseline characteristics and laboratory values were abstracted prior to lymphodepleting chemotherapy. GCSF support was originally prescribed when the absolute neutrophil count (ANC) declined below 500 cells/mm3 and discontinued when the ANC exceeded 1000 cells/mm3 (neutropenia) for 2 consecutive days. A practice change was made where GCSF was recommended only in those with febrile neutropenia and an increased concern for infection. The primary endpoint was the difference in the total days of neutropenia for patients receiving and not receiving GCSF. Secondary outcomes compared total days of severe neutropenia, number of neutropenia episodes, infection rates by GCSF use, and outcomes by protocol change. Neutropenia and severe neutropenia were defined as an ANC below 500 cells/mm3 and 100 cells/mm3, respectively. Updated data with more patients will be presented at the conference. Results: The 60 included patients had a median age of 59 (IQR: 44, 63) years, 38 (63%) were male and 53 (88%) were Caucasian. Significantly fewer patients were prescribed GCSF according to infection-related concerns compared to ANC-based indication, 18% vs. 94%, p&amp;lt;0.001. Because only 3 subjects received GCSF based on infection-related concerns, results based on GCSF use versus no use is shown here. GCSF was prescribed to 35 (58%) patients for a median of 8 (IQR: 6, 12) doses with a median cumulative dosage of 3840 mcg (IQR 2100-5400) and median time to first dose of 3 days (IQR: 1, 4) post CAR T-cell infusion. Table 1 displays additional baseline characteristics and laboratory parameters according to GCSF support utilization. GCSF prescribed: Table 2 displays outcomes by GCSF use. Total days of neutropenia were similar between groups (13 vs. 16, p=0.52) with a trend towards significantly fewer days of severe neutropenia when prescribed GCSF (6 vs. 9, p=0.129). Patients prescribed GCSF were more likely to experience multiple episodes of neutropenia (83% vs. 43% p=0.002) with a significantly greater median number of episodes (3 vs. 1, p=0.002) when compared to those not prescribed GCSF. GCSF use significantly decreased the median days of the first neutropenia episode (6 vs. 12, p=0.001). There was a trend for decreased median days of severe neutropenia in the first episode with GCSF (5.0 vs. 8.0, p=0.236). Figure 1 displays a trend towards a lower overall risk of infection (HR 0.55, 95%CI: 0.16-1.87, p=0.34) and lower risk of bacterial infection (HR: 0.49, 95% CI: 0.18-1.31, p=0.15); however, these were not statistically significant. Conclusion: Patients prescribed GCSF according to ANC-based indication were significantly more likely to experience multiple neutropenia episodes; however, duration of first neutropenic episode and days of severe neutropenia during the first neutropenic episode were significantly reduced. Interestingly, the total days of neutropenia and severe neutropenia were similar between groups. It is possible that using the parameter of ANC more than 1000 cells/mm3 for 2 consecutive days is not the optimal criteria for stopping GCSF. Risk of overall and bacterial infection was lower with ANC-based initiation of GCSF, although non-significant likely due to small sample size. The potential benefit for using CSF and the optimal timing after CAR T-cell infusion requires further, rigorous, prospective investigation. Disclosures Ansell: ADC Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; AI Therapeutics: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding. Bennani:Purdue Pharma: Other: Advisory Board; Kite/Gilead: Research Funding; Affimed: Research Funding; Verastem: Other: Advisory Board. Lin:Kite, a Gilead Company: Consultancy, Research Funding; Vineti: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gamida Cells: Consultancy; Takeda: Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding.

Breakthrough Invasive Fungal Infections (bIFI) Are Uncommon in Patients with Newly Diagnosed Acute Leukemia Receiving Primary Antifungal Prophylaxis

Introduction: Mold-active primary antifungal prophylaxis (PAP) is widely recommended in neutropenic patients (pts) with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) who undergo remission-induction chemotherapy (RIC). Posaconazole (PCZ) prophylaxis resulted in fewer invasive fungal infections (IFIs) when compared to fluconazole and was associated with a survival advantage in this population (Cornely et al, 2007). Similarly, pts with acute lymphoblastic leukemia (ALL) undergoing RIC are also at risk of IFI due to prolonged neutropenia. Although PCZ is the preferred agent for PAP, the incorporation of targeted agents into acute leukemia therapy calls for more individualized choices in PAP. Other mold-active agents including voriconazole (VCZ) and isavuconazole (ISA) or the echinocandins are alternatives which may be preferred in individual settings due to variations in toxicity, patient co-morbidities, drug interactions, and cost. Little contemporary data exists to compare the incidence of breakthrough IFI (bIFIs) in pts with AML or ALL receiving PCZ, VCZ, or ISA as prophylaxis during RIC. Methods: We reviewed the medical records of all consecutive pts with newly diagnosed AML/MDS or ALL treated at our institution from 3/2016-7/2019. Included pts received high-intensity chemotherapy, or a lower-intensity venetoclax (VEN)-containing regimen, for RIC. Therapy with high-dose (&amp;gt; 1g/m2/day) cytarabine (HiDAC), continuous cytarabine plus an anthracycline (3+7), or HyperCVAD was considered high-intensity therapy. Patients receiving PCZ, VCZ, or ISA for &amp;gt; 5 days beginning during induction therapy were included. Baseline evidence of prior mold infection and treatment with a concomitant echinocandin were not allowed. Echinocandin use preceding mold-active PAP was allowed, however prior use of an amphotericin B product was not. bIFI were defined according to ECMM criteria (Cornely et al, 2019). Results: We identified 232 pts with AML/MDS (n=186), ALL (n=43), and biphenotypic leukemia (n=3). Among the AML/MDS pts, 31% (n=57) received a lower-intensity VEN-containing regimen, while 69% (n=129) received a high-intensity regimen with or without VEN. Nearly all pts with ALL and biphenotypic leukemia received high-intensity RIC with HyperCVAD or a HiDAC containing regimen. Of the 232 pts, PCZ (n=111), VCZ (n=84), or ISA (n=37) were used as PAP, respectively (Table 1). Most pts (n=157; 68%) received an echinocandin for a median of 6 days (range, 0-38), prior to transitioning to a mold-active triazole. Ten (4.3%) pts had a bIFI (6 proven, 1 probable, 3 possible) during induction therapy while receiving PAP (Table 2) including 9 (4.8%) pts with AML/MDS and 1 (2.3%) patient with ALL. An equal number of pts with bIFI were receiving lower-intensity, VEN-based therapy, or high-intensity therapy. Among the 84 pts receiving VCZ, 4 (4.8%) had a bIFI (4 proven); 3 pts (2.7%) receiving PCZ had a bIFI (2 proven, 1 possible); 3 pts (8.1%) receiving ISA had a bIFI (1 probable, 2 possible). C. glabrata (n=3), and C. krusei, Cryptococcus spp. and Fusarium spp. (one each) accounted for the 6 proven bIFIs. One patient had both C. glabrata and C. krusei fungemia. The probable bIFI was pneumonia with a positive Aspergillus GM from BAL. The 3 possible bIFI were pneumonia (n=2) and sinusitis (n=1). Eight pts (80%) were neutropenic (ANC &amp;lt; 500 cells/mm3) for &amp;gt;14 days at the time of bIFI, 1 pt was neutropenic for &amp;gt;7 days, and 1 pt had ANC &amp;gt; 500 cells/mm3. Seven pts with bIFI received a prior echinocandin for a median of 3 days (range, 0-15) prior to initiation of triazole PAP. Seven pts were neutropenic for &amp;lt; 7 days (n=2), 7-14 days (n=3), or &amp;gt; 14 days (n=2) at the time of azole initiation. bIFI occurred after a median of 20 days (range, 5-72) of azole PAP and a median of 24 days (range, 12-71) from the initiation of RIC. One patient with bIFI deceased within 42 days of starting RIC and did not achieve a response after RIC (bIFI-related mortality: 0.44%). Conclusion: The incidence (&amp;lt;5%) and mortality (&amp;lt; 0.5%) due to bIFI in a contemporary cohort of pts with newly diagnosed acute leukemia receiving PAP is low. bIFI occurred late in induction therapy and most often in pts with &amp;gt; 14 days of neutropenia. Prophylaxis with VCZ, PCZ, or ISA, with or without a prior echinocandin, appear to be comparable options for PAP in pts with newly diagnosed AML or ALL undergoing RIC. Disclosures Bose: CTI BioPharma: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Promedior, Inc.: Research Funding; Pfizer, Inc.: Research Funding; NS Pharma: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding. Kontoyiannis:Gilead Sciences: Honoraria; United Medical: Honoraria; Astellas Pharma: Consultancy; Cidara Therapeutics: Consultancy; Amplyx Pharmaceuticals: Consultancy; Mayne Pharma: Consultancy; Pharma Pharmaceutical Industries: Consultancy; Merck &amp; Co.: Consultancy, Honoraria. OffLabel Disclosure: Voriconazole and isavuconazole are approved for the treatment of invasive fungal infections rather than the prevention, as discussed in this abstract.

Impact of neutropenia evaluated in terms of the D-index on invasive fungal disease while on empiric or preemptive antifungal treatment strategy in the early phase after allogeneic hematopoietic stem cell transplantation.

We retrospectively evaluated the association between the D-index, which reflects both the depth and duration of neutropenia, and proven/probable invasive fungal disease (IFD) early after allogeneic hematopoietic stem cell transplantation (HSCT) at our center (n=394). The D-index was defined as the area over the neutrophil curve during neutropenia. The cumulative D-index from the start of neutropenia until the development of infection (c-D-index) was also evaluated as a real-time assessment of neutropenia. There were 19 cases of early proven/probable IFD before and within 1week after engraftment. Fifteen cases (78.9%) were seen as breakthrough infection while on empiric (n=7), preemptive (n=4) or prophylactic (n=4) antifungal administration with mold-active agents. The c-D-index and lower performance status were identified as independent significant predictive factors for IFD. A receiver operating characteristic (ROC) curve analysis showed that the D-index and c-D-index were more accurate than the simple duration of neutropenia and as accurate as the duration of profound neutropenia for predicting IFD. The sensitivity, specificity, and positive and negative predictive values of the c-D-index using an appropriate cutoff (CO) value (10644) determined by ROC curve analysis were 73.1%, 63.2%, 9.1%, and 97.9%, respectively. The advantage of the c-D-index to cumulative days of neutropenia in terms of positive and negative predictive values seemed to be small. The appropriate CO value for the c-D-index for predicting IFD was as high as 10644 in allogeneic HSCT with a more frequent use of empiric antifungal therapy. The c-D-index is useful for assessing the risk of breakthrough IFD.

Incidence of mucositis in patients undergoing autologous hematopoietic stem cell transplantation at a single center

Goal: The aim of this study was to describe the incidence of oral mucositis (OM) in patients undergoing autologous hematopoietic stem cell transplantation (auto-HSCT), relating it to the main clinical factors. Methodology: Descriptive analysis based on a randomized clinical study was conducted with patients undergoing HSCT at the University Hospital of Federal University of Juiz de Fora between January 2018 and June 2019. The World Health Organi­zation oral toxicity scale was used to assess the degree of oral mucositis and adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) 4.0 version. Results: Thirty-eight patients were evaluated. The incidence of OM and severe oral mucositis (SOM) was 57.9% and 21.0%, respectively. The mean duration of OM was 7.2 ± 2.6 days and the lomustine, etoposide, cytarabine and cyclophosphamide protocol (LEAC) pre­sented the longest mean time 8.1 ± 3.1 days (p-value 0.02). The number of viable CD34+ cells and the onset day of neutropenia were predictors of SOM. Conclusion: The incidence of OM in patients undergoing HSCT was lower than reported in the literature, being more severe in patients who received less CD34+ cells and in patients with early onset of neutropenia.

Cardiac safe hematopoietic stem cell transplantation for systemic sclerosis with poor cardiac function: a pilot safety study that decreases neutropenic interval to 5 days.

We compared three fludarabine-based regimens for systemic sclerosis patients with a high-risk cardiac phenotype that according to EBMT criteria would be a contraindication for a high-dose cyclophosphamide (200 mg/kg) transplant regimen. All three regimens included fludarabine, ATG, and cyclophosphamide (60 mg/kg), while two regimens also included rituximab with or without IVIG. Treatment related mortality (TRM) was 2.4%. The mean number of days of neutropenia (ANC < 500) was 5.2, the mean number of platelet and red blood cell transfusions was 0.3 and 1.85, respectively. Skin score, forced vital capacity (FVC), and total lung capacity (TLC) improved with all three regimens. For patients whose regimen did not include rituximab versus those that included rituximab, 1-year overall relapse rate was higher 36% (5/14) versus 3.6% (1 of 28) (p = 0.01), secondary autoimmune diseases were higher 21% (3/14) versus 0% (0/28) (p = 0.03), and upper respiratory tract infections were higher 28% (4/14) versus 3.6% (1/28) (p = 0.04). In this safety study, a fludarabine-based regimen was relatively safe with a TRM of 2.4% and a neutropenic interval of only 5.2 days in systemic sclerosis patients with a high-risk cardiac phenotype. The addition of rituximab decreased 1-year relapse rate, risk of late secondary autoimmune diseases, and upper-respiratory tract infections.