Course Of Neutropenia Research Articles

Outcome of neutropenic enteropathy during induction phase of treatment of childhood acute lymphoblastic leukemia

BackgroundNeutropenic enteropathy is one of the important causes of death during intensive phase of chemotherapy in children with acute lymphoblastic leukemia (ALL). It follows a prolonged course of neutropenia and carries a mortality rate up to 30%. The study aimed to find out the outcomes of typhlitis during induction phase of treatment of childhood ALL. Material and methodsThis prospective case control study was conducted in the Department of Pediatric Hematology and Oncology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh from November 2018 to January 2021. Children (<19 years) with ALL who developed neutropenic enteropathy during induction phase of chemotherapy without any comorbid condition were included in this study. The clinico-radiological diagnosis of neutropenic enteropathy was based on a standard diagnostic criteria. Complete blood count, serum electrolytes, albumin, blood culture, stool culture, abdominal X-ray and ultrasonogram were performed in all the cases. ResultsThirty-six patients developed neutropenic enteropathy. 8 (22.2%) died. Thrombocytopenia (p = 0.001), hypoalbuminemia (Odd ratio 21.0, p < 0.001), positive blood culture (Odds ratio 6.11, p = 0.026). ConclusionThis study found a mortality rate of 22.2% amongst the pediatric patients with ALL who developed neutropenic enteropathy during induction chemotherapy. Thrombocytopenia, hypoalbuminemia, and a positive blood culture predicted mortality.

Prospective analysis of febrile neutropenia patients with bacteraemia: the results of an international ID–IRI study

Bacteraemia during the course of neutropenia is often fatal. We aimed to identify factors predicting mortality to have an insight into better clinical management. The study has a prospective, observational design using pooled data from febrile neutropenia patients with bacteraemia in 41 centres in 16 countries. Polymicrobial bacteraemias were excluded. It was performed through the Infectious Diseases-International Research Initiative platform between 17 March 2021 and June 2021. Univariate analysis followed by a multivariate binary logistic regression model was used to determine independent predictors of 30-d in-hospital mortality (sensitivity, 81.2%; specificity, 65%). A total of 431 patients were enrolled, and 85 (19.7%) died. Haematological malignancies were detected in 361 (83.7%) patients. Escherichia coli (n=117, 27.1%), Klebsiellae (n=95, 22% %), Pseudomonadaceae (n=63, 14.6%), Coagulase-negative Staphylococci (n=57, 13.2%), Staphylococcus aureus (n=30, 7%), and Enterococci (n=21, 4.9%) were the common pathogens. Meropenem and piperacillin-tazobactam susceptibility, among the isolated pathogens, were only 66.1% and 53.6%, respectively. Pulse rate (odds ratio [OR], 1.018; 95% confidence interval [CI], 1.002-1.034), quick SOFA score (OR, 2.857; 95% CI, 2.120-3.851), inappropriate antimicrobial treatment (OR, 1.774; 95% CI, 1.011-3.851), Gram-negative bacteraemia (OR, 2.894; 95% CI, 1.437-5.825), bacteraemia of non-urinary origin (OR, 11.262; 95% CI, 1.368-92.720), and advancing age (OR, 1.017; 95% CI, 1.001-1.034) were independent predictors of mortality. Bacteraemia in our neutropenic patient population had distinctive characteristics. The severity of infection and the way to control it with appropriate antimicrobials, and local epidemiological data, came forward. Local antibiotic susceptibility profiles should be integrated into therapeutic recommendations, and infection control and prevention measures should be prioritised in this era of rapidly increasing antibiotic resistance.

Abstract P4-01-31: High Incidence of Palbociclib Related Neutropenia in Asian Patients Associated with Genetic Polymorphisms

Abstract CDK4/6 inhibitors (CDK4/6i) is well established as the current standard of care for hormone positive (HR(+)) metastatic breast cancer (mBC), in combination with endocrine therapy. CDK4/6i extend a chemotherapy-free, progression free survival (PFS) that preserves quality of life in patients. The most common side effect of CDK4/6i is myelosuppression, with neutropenia the most prevalent adverse effect, especially for palbociclib and ribociclib. In PALOMA-2 and MONALEESA-2, where neutropenia was prevalent (any grade neutropenia 79.5%, grade 3/4 neutropenia 66.5% in PALOMA-2, and any grade neutropenia: 74.3%, grade 3/4 55.3% in MONALEESA-2), although febrile neutropenia seldom occurred (1.8%). Several studies have proposed different genetic factors predisposing to CDK4/6 inhibitor induced neutropenia, including Duffy antigen polymorphisms, ABCB1 and ERCC1 polymorphisms (ABCB1_rs1128503, ABCB1_rs1045642, ERCC1_rs11615, ERCC1_rs3212986), CDK6 polymorphisms, and others. Subgroup studies from the PALOMA trials have suggested that Asian patients receiving palbociclib have higher rates of neutropenia, although the exact explanation is unknown. We conducted a retrospective analysis of 102 Taiwanese patients who received palbociclib for HR(+) mBC at the Taipei Veterans General Hospital for the clinical features, incidence and time course of neutropenia were analyzed. Significant neutropenia incidence was observed (&amp;gt; 95% of all grade neutropenia, 74.5% grade 3/4 neutropenia). In addition, in our clinical cohort, one of the patients was a long term peritoneal dialysis patient newly diagnosed of HR(+) mBC and started on Palbociclib, initially 125mg, later decreased dosage to 100mg after neutropenia occurrence. By Liquid chromatography–mass spectrometry (LC–MS), we quantified the levels of palbociclib in her serum and peritoneal fluid at various time points, while on different dosage use. To our knowledge, this is the first pharmacokinetics analysis on a peritoneal dialysis patient receiving CDK4/6i. To investigate a possible genetic association for the high prevalence of neutropenia, we queried the Taiwan biobank, a nationwide biospecimen repository with 129,586 healthy individual genome wide DNA sequencing data deposited. We investigated the prevalence of the 4 SNPs previously reported to be related to neutropenia in the PALOMA studies. By comparing the Taiwan biobank data to SNP databases from different ethnicities, we observed interesting findings on ethnicity differences of SNP distribution and higher prevalence of neutropenia SNPs. Collectively, in this study we report real world data, biobank genome wide analysis, and a novel report of pharmacokinetic study in a peritoneal dialysis patient, providing novel insights into the real world use of palbociclib and CDKi. Table 1. Median TTF of each subsequent therapy after PAL+ET Characteristics of the clinical cohort treated with palbociclib at TVGH Citation Format: Kuan-Jung Huang, Ting-Hao Kuo, Ta-Chung Chao, Chun-Yu Liu, Yi-Fang Tsai, Chi-Cheng Huang, Ling-Ming Tseng, Cheng-Chih Richard Hsu, Jiun-I Lai. High Incidence of Palbociclib Related Neutropenia in Asian Patients Associated with Genetic Polymorphisms [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-31.

Вроджені нейтропенії в дітей: короткий і довгий шлях до діагнозу

The diagnosis of neutropenia is based, first of all, on the results of the assessment of the absolute number of neutrophils in the complete blood count and the clinical picture. Genetic confirmation of the diagnosis of congenital neutropenia can be long and not always successful. The purpose of work - to analyze the clinical course and laboratory features of congenital neutropenia in children on bases of two clinical cases in order to pay the doctors’ attention to the diagnosis of these diseases. We present clinical cases that confirm the variability of clinical and laboratory manifestations and the severity of the course of neutropenia. In the first case, congenital neutropenia was manifested by profound clinical signs with cyclicity, was accompanied by fever, aphthous stomatitis, and gingivitis. The absolute neutrophil count was consistent with severe neutropenia, but it took several years for genetic confirmation of the diagnosis. The second case of cytopenia, including neutropenia in a boy, was found in twins by chance, as the children had no clinical manifestations associated with neutropenia. Despite the obviousness of neutropenia in the general blood test with or without clinical manifestations, the path to a complete diagnosis is not always simple. Cytopenia in children, including neutropenia, requires a multidisciplinary approach to diagnosis, excluding both the causes of secondary neutropenia, hematological pathology, and immune disorders, primarily the phagocytic defects. Genetic testing can help verify an accurate diagnosis in patients with inborn errors of immunity, however, the genetic variants of a large number of congenital neutropenias remain unknown. Isolated neutropenia in children, as well as in combination with other cytopenias, require careful monitoring and the selection of optimal management tactics, as they can have serious complications. Following of patients will make it possible to expand knowledge about the disease course, the dynamics of symptoms, the occurrence of complications in order to prevent them. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of all participating institutions. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Сучасні підходи до лікування вроджених нейтропеній

Neutropenia is common in the practice of both primary care physicians and physicians of sub-speciality. Congenital neutropenia are rare diseases; they can be both isolated independent diseases and accompany a number of other inborn errors of immunity. The clinical course of neutropenia can range from asymptomatic in patients with mild neutropenia to life-threatening infections in cases of severe neutropenia. Treatment of congenital neutropenia remains discutable to this day. The most common and accessible method of treatment of severe congenital neutropenia is granulocyte colony-stimulating factor, although it does not cure the disease and does not prevent the development of malignant transformation. On the other hand, the use of granulocyte colony-stimulating factor in the correct doses can improve the clinical course of the disease, the quality of life of patients, avoid severe septic complications. Hematopoietic stem cell transplant is an effective treatment for severe congenital neutropenia that does not respond to granulocyte colony-stimulating factor therapy. Modern methods of genetic therapy open new perspectives in the treatment of patients with severe congenital neutropenia. No conflict of interests was declared by the author. Key words: congenital neutropenia, treatment, Granulocyte colony-stimulating factor (G-CSF).

Neutropenia Following Intravenous Immunoglobulin Therapy in Adult Patients with Immune Thrombocytopenic Purpura

BackgroundImmune thrombocytopenic purpura (ITP) is an autoimmune disease in which anti-platelet antibodies accelerate the destruction of platelets. Traditional therapies such as steroid therapy, intravenous immunoglobulin (IVIG) therapy, and splenectomy generally reduce the peripheral destruction of platelets. However, they may cause significant side effects. In particular, it has been recently reported that neutropenia sometimes develops in children as an adverse effect after IVIG administration. On the other hand, there is no previous report on neutropenia developing as a complication of IVIG therapy in adult patients with ITP. The aim of this study was to further investigate the incidence and course of neutropenia following IVIG therapy in adults with ITP.MethodsWe performed a retrospective chart review of 88 ITP patients who had received IVIG to manage severe thrombocytopenia between January 2006 and March 2016 at Pusan National University Hospital in Korea. Inclusion criteria were the following: age ≥ 18 years, ITP diagnosis according to the American Society of Hematology guidelines (platelet count of less than 100 × 109/L in the absence of other causes or disorders that may be associated with thrombocytopenia). Exclusion criteria included other diseases known to be associated with ITP, such as human immunodeficiency virus or hepatitis C virus infection, lympho-proliferative disorders, thyroid or liver disease, and definite systemic lupus erythematosus. Patients included in this study had a complete and differential blood count performed before and after the IVIG treatment. Patients were treated according to a standard protocol, consisting of IVIG administration (1 g/kg per day for two days).ResultsThe baseline characteristics of patients are shown in Table 1. Among 88 patients, 24 (27.3%) were male, and 64 (72.7%) were female. The median ages were 45 years in the group that developed neutropenia and 41 years in the group that did not develop neutropenia. The groups were comparable in age, sex distribution, initial white blood cell (WBC) count, and absolute neutrophil count (ANC). Neutropenia developed in 43 patients (48.9%) after IVIG treatment. In patients with a decrease in WBC count and ANC compared to baseline, median WBC count decreased from 6,280/μL to 4,530/μL after IVIG therapy, and median ANC decreased from 3,840/μL to 2,840/μL after IVIG therapy. Only two patients in this study developed a post-treatment ANC of less than 1,000/μL, and only one patient developed neutropenic fever, which subsided soon without any treatment. The neutropenia induced by IVIG had resolved spontaneously after several days, and the mean recovery time was 8.72 days after the completion of the IVIG treatment (Table 1, Figure 1 and 2). Including the present case, we identified previous reports of neutropenia developing as a complication of IVIG therapy in the English literature (Table 2). The majority of reports of neutropenia following IVIG therapy are pediatric patients with ITP. There were two reports on the incidence of neutropenia induced IVIG in adults except for pediatric patients with ITP. Matsuda M et al. reported neutropenia induced by high-dose IVIG in adult patients with neuro-immunologic disorders. And Lemos S et al. reported acute neutropenia in patients with primary antibody-deficiencies, after receiving IVIG. However, as mentioned earlier, there has been no reports of neutropenia following IVIG therapy in adult patients with ITP. Therefore, this study is the first report of neutropenia after IVIG therapy in adult patients with ITP. Although further studies are required in order to clarify the precise mechanism of neutropenia following IVIG treatment, this would be the important report of neutropenia following IVIG therapy in adult patients with ITP.ConclusionsThe results of this study suggest that IVIG may cause neutropenia commonly in adults with ITP, and it seems to be transient and self-limited. This study is meaningful as the first report that not only pediatric ITP patients may develop neutropenia post IVIG administration, but also adult patients suffering ITP. Therefore, an awareness of this common association of neutropenia following IVIG treatment in adult patients with ITP is likely to aid physicians in caring for these patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pro-inflammatory cytokine ratios determine the clinical course of febrile neutropenia in children receiving chemotherapy

BackgroundFebrile neutropenia is a common and serious complication during treatment of childhood cancer. Empirical broad-spectrum antibiotics are usually administered until neutrophil cell count recovery. It was the aim of this study to investigate cytokine profiles as potential biomarkers using in-vitro sepsis models to differentiate between distinct clinical courses of febrile neutropenia (FN).MethodsWe conducted an observational study in FN episodes of pediatric oncology patients. Courses of neutropenia were defined as severe in case of proven blood stream infection or clinical evidence of complicated infection. We collected blood samples at various time points from the onset of FN and stimulated ex vivo with lipopolysaccharide (LPS) and Staphylococcus epidermidis (SE) for 24 h. Twenty-seven cytokine levels were measured in the whole blood culture supernatants by a multiplex immunoassay system.ResultsForty-seven FN episodes from 33 children were investigated. IL-8, IL-1β, and MCP-1 expression increased significantly over time. IL-8, MIP-1α, MIP-1β, MCP-1, and TNF-α showed significantly lower concentration in patients with a clinically severe course of the FN.ConclusionsDistinct patterns of cytokine profiles seem to be able to determine infectious FN and to predict the severity of its clinical course. If these data can be verified in a multi-centre setting, this may finally lead to an individualized treatment strategy facilitating antibiotic stewardship in these patients.

Incidence and time course of neutropenia in patients treated with rituximab‐based therapy for non‐malignant immune‐mediated hematologic diseases

Incidence and time course of neutropenia in patients treated with rituximab‐based therapy for non‐malignant immune‐mediated hematologic diseases

Incidence and Time Course of Neutropenia in Patients Treated with Rituximab-Based Therapy for Non-Malignant Immune-Mediated Hematologic Diseases

Background : Rituximab (RTX) is approved for various malignant hematologic and rheumatologic disorders. A noteworthy side effect, late-onset neutropenia, has been reported in patients (pts) treated for hematologic malignancies, often in combination therapies of RTX and chemotherapy with an incidence of 3% to 27%. Conversely, the lack of prospective data and the off-label use of RTX in non-malignant immune-mediated hematologic diseases (NMIHD) limits the availability of evidence on the rate, severity and time course of neutropenia on this patient population, particularly in RTX monotherapy. The present study was performed to determine the frequency, severity, and time course of development and resolution of neutropenia in NMIHD pts treated with RTX, with the goal of providing evidence for clinicians on the safety and potential implications of RTX use in this patient population. Methods : We retrospectively analyzed patients diagnosed with autoimmune hemolytic anemia (AIHA), acquired coagulation factor deficiency (ACFD), thrombotic thrombocytopenic purpura (TTP), immune thrombocytopenic purpura (ITP), and antiphospholipid syndrome (APS) between January 2013 and October 2017. Patients with a minimum of 1 laboratory visit every 8 weeks with 1-year of follow-up were included. Date of initial and last RTX infusion, RTX dosing and number of doses, and pre-treatment absolute neutrophil count (ANC) were obtained. ANCs were reviewed from first RTX infusion to at least 12 months from last infusion. For those pts who developed neutropenia, ANC nadir and date when ANC was 1 to 1.5 (mild), 0.5 to &amp;lt;1 (moderate), and &amp;lt;0.5 ˣ 103 cells/µL (severe neutropenia) was recorded. The time to recovery from neutropenia was determined from the time of first neutropenia occurrence to an ANC&amp;gt;1.5. Episodes of febrile neutropenia (FN), hospitalization, infection, and use of granulocyte-colony stimulating factor (GCSF) were also obtained. Kaplan-Meier estimators, and Log-rank Tests were applied to compare between groups. Results : 197 patients (ITP=94, TTP=34, AIHA=34, ACFD=22, APS=13) treated with RTX monotherapy (73%), or in combination with other immunosuppressant were included. Clinical features, treatment characteristics and outcomes are summarized in the table. The median age at diagnosis was 51 years (58% female) with a median ANC prior to RTX initiation of 5.6 ˣ 103 cells/µL. Most pts received RTX at 375 mg/m2 in 4 doses (83%). The 1-year estimated probability of developing neutropenia (ANC&amp;lt;1.5) was 18% (Figure 1). Of those who developed neutropenia, the median ANC nadir and time to neutropenia from initial RTX infusion was 1.2 ˣ 103 cells/µL and 4.4 months, respectively. Development of neutropenia was not statistically different by gender, age, hematologic disease type, or RTX dosing. However, RTX given for ≥ 4 doses (p=0.04), or in combination with other immunosuppressant different than steroids (p&amp;lt;0.01) were significantly associated. Severe neutropenia was frequent in pts receiving RTX in combination with other immunosuppressant (36% versus 2%) with longer time to recovery from first neutropenia occurrence to an ANC&amp;gt;1.5 (2.5 versus 1.1 months) (Figure 2) compared to pts receiving RTX alone or with steroids. No episodes of FN were reported, 3 pts were hospitalized for neutropenia workup, and 2 pts had documented infections (pneumonia and cellulitis) with uncomplicated clinical course. One pt, treated with 6-mercaptopurine, received GCSF. Conclusions : To the best of our knowledge, this is the first study reporting on the incidence, degree and time-course of development of neutropenia in patients treated with RTX for different NMIHD. Our analysis demonstrates an 18% rate of neutropenia at 1 year, mostly mild neutropenia. Conversely, RTX in combination with other immunosuppressant, as opposed to RTX alone or with steroids, represented a significant risk factor for the development of neutropenia, especially severe neutropenia with longer time to ANC recovery. The rate of hospitalizations, infections and the use of GCSF was low, even in severe neutropenia cases. In conclusion, development of neutropenia in pts treated with RTX for NMIHD is an expected but relatively benign side effect. Neutropenia is more frequent if RTX is given with other immunosuppressant other than steroids, and when the number of doses of RTX given are higher. Disclosures No relevant conflicts of interest to declare.

102 Patients with Primary Autoimmune Neutropenia : An Analysis of the European Severe Chronic Neutropenia International Registry (SCNIR)

Background: Primary Autoimmune Neutropenia (AIN) is the most frequent type of neutropenia in children with a prevalence of 1/100,000 between infancy and 10 years of age. Primary AIN is caused by anti-neutrophil antibodies binding to neutrophil-specific antigens, resulting in a decrease of circulating neutrophils in the blood, but normal numbers of mature neutrophils in the bone marrow. Typically, primary AIN is present from infancy on until spontaneous remission in early childhood, when anti-neutrophil antibodies disappear. Patients with primary AIN show severe to moderate neutropenia but only rarely suffer from serious infections. Patients remain in the registry for follow up after normalization of blood counts to evaluate late secondary events. Aims: Here we describe the cohort of AIN pts with positive anti-neutrophil antibody testing documented by the European Branch of the SCNIR. We analyzed the course of neutropenia, the frequency of G-CSF treatment for AIN, the incidence of severe bacterial infections and administration of AB prophylaxis. Methods: We identified 102 primary AIN patients within the neutropenia cohort documented by the European Branch of the SCNIR since 1994. We classified primary AIN by positive anti-neutrophil antibody testing (95 pts) or severe neutropenia in peripheral blood with normal bone marrow morphology in patients with age under 5 years (7 pts). Results: Primary AIN has been identified in 102 (61 female; 41 male) pts. The median age of the cohort is 5.18 years (range 1.37-22.71 years), with 630.28 pt years under observation. Median age at diagnosis was 12.07 months (range 0.9-70 months). All pts are currently alive, 40 patients already resolved from primary AIN at a median age of 3.02 years (range 0.83-9.08 years). Median follow-up time after neutropenia had resolved was 2.25 years (range 0-9.27 years). Sixteen of 102 pts (15.7%) received intermittent G-CSF treatment with a median dose of 4.5 µg/kg/day compared to 4.77 µg/kg/day for the congenital neutropenia cohort of the SCNIR Europe. Analysis of infections (tab.1) showed less minor and severe infections comparing to congenital neutropenia (CN) pts. Life-threatening infections like liver abscesses were not seen in primary AIN patients but in 1.8% of CN pts. Twelve AIN pts (11.7%) have received antibiotic prophylaxis for prevention of infection, 6 pts intermittent and 6 pts continuously. However, antibiotic prophylaxis was usually stopped before termination of AIN. Due to the milder course of infections most AIN pts were able to go to Kindergarten and to live a normal life. In 3 pts additional auto-immune related diseases were identified (autoimmune thrombocytopenia, allergic colitis and Kawasaki syndrome) during AIN. Sixteen of 102 AIN patients received genetic analysis, with no mutation being detected. In addition to the 102 AIN pts we identified another 31 CN pts who have initially been classified as AIN due to positive anti-neutrophil antibodies, but who were later genetically confirmed as CN (15 ELANE+, 8 HAX1+, 2 SBDS+, 2 CXCR4+, 2 CSF3R+, 1 G6PC3+). This proportion of pts showed more and more severe infections compared to primary AIN. Genetic testing has been performed in these pts due to ongoing infections and prolonged neutropenia until school age. Conclusions: Pts suffering from primary AIN present with severe to moderate neutropenia. A minority of pts might require G-CSF treatment on demand/interventionally due to antibiotic resistant infections, but long-term G-CSF treatment is regularly not indicated. Primary AIN is a self-limiting condition and in most pts neutropenia resolves until early childhood. Accumulation of secondary diagnoses like autoimmune related diseases, though postulated, has not been confirmed for AIN pts by our data. In AIN pts with severe infections, or prolonged neutropenia CN should be ruled out by genetic analysis and/or bone marrow morphology. Registries are needed to document long-term data on primary AIN pts to analyse potential additional features of primary AIN, possibly other accompanying autoimmune diseases. Disclosures No relevant conflicts of interest to declare.

Early versus late onset bloodstream infection during neutropenia after high-dose chemotherapy for hematologic malignancy.

The length of neutropenia has a significant impact on the incidence of bloodstream infection (BSI) in cancer patients, but limited information is available about the pathogen distribution in late BSI. Between 2002 and 2014, BSI episodes in patients with neutropenia receiving chemotherapy for hematologic malignancies were prospectively identified by multicenter, active surveillance in Germany, Switzerland and Austria. The incidence of first BSI episodes, their microbiology and time to BSI onset during the first episode of neutropenia of 15,988 patients are described. The incidence rate of BSI episodes was 14.7, 8.7, and 4.7 per 1000 patient-days in the first, second, and third week of neutropenia, respectively. BSI developed after a median of 5 days of neutropenia (interquartile range [IQR] 3-10days). The medium duration of neutropenia to BSI onset was 4 days in Escherichiacoli (IQR 3-7days), Klebsiella spp. (2-8days), and Staphylococcus aureus (3-6days). In contrast, BSI due to Enterococcus faecium occurred after a median of 9 days (IQR 6-14days; p < 0.001 vs. other BSI). Late onset of BSI (occurring after the first week of neutropenia) was also observed for Stenotrophomonas maltophilia (12days, IQR 7-17days; p < 0.001), and non-albicans Candida spp. (13days, IQR 8-19days; p < 0.001). Over the course of neutropenia, the proportion of difficult to treat pathogens such as E. faecium, S. maltophilia, and Candida spp. increased. Among other factors, prior duration of neutropenia may help to guide empiric antimicrobial treatment in febrile neutropenia.

PF353 PATIENTS WITH SEVERE CHRONIC NEUTROPENIA SUBTYPES TREATED WITH BIOSIMILAR FILGRASTIM: A STUDY BY THE EUROPEAN BRANCH OF THE SEVERE CHRONIC NEUTROPENIA INTERNATIONAL REGISTRY

Background:Severe chronic neutropenia (SCN) is a group of very rare blood disorders, characterised by low levels of neutrophils (&lt;500/μl) lasting for extended periods of time, while other blood‐cell counts remain close to or within normal range. Since the introduction of granulocyte colony‐stimulating factor (G‐CSF) therapy in 1987, the prognosis and quality of life of patients with congenital neutropenia has vastly improved. The Severe Chronic Neutropenia International Registry (SCNIR), established in 1994, has gathered data on over 2,000 patients with SCN worldwide in order to monitor the clinical course, treatment and disease outcomes of patients with these rare diseases.Aims:This report by the European Branch of the SCNIR aims to compare results of patients with SCN treated with G‐CSF products (reference filgrastim, pegfilgrastim, lenograstim) with those who received Sandoz biosimilar filgrastim (Zarzio® or Filgrastim Hexal®) from July 2011 to March 2018.Methods:Since 1994, the European Branch of the SCNIR has been establishing a network including 26 European countries, Israel, Russia and Turkey. Clinical data on the course of neutropenia is collected after written informed consent by the patient or their legally authorised representative; all consent forms have been standardised and accepted by all local ethics committees.Results:Between 2011 and 2018, 789 patients were enrolled in the European registry, 578 (73.3%) of which had received G‐CSF. Of all G‐CSF treated patients (median age stable at approximately 14 years), the most common neutropenia diagnosis was congenital (n = 377), then cyclic (n = 88), idiopathic (n = 62), autoimmune (n = 30) and other (n = 21). Median G‐CSF dose was 3.01 μg/kg/day.Twenty‐one patients (median age 14.5 years; range 0.7–48.2 years) had received Sandoz biosimilar filgrastim (Zarzio®, n = 15; Filgrastim Hexal®, n = 6). Of the 21 patients, 16 had changed medication from other G‐CSF products. The most common diagnosis of neutropenia among these patients was congenital (n = 12) followed by cyclic (n = 6), idiopathic, autoimmune and other (n = 1 each). Median treatment duration was 1.5 (range, 0.1–4.4) years and median dose was 2.27 (range, 0.25–40) μg/kg/day. Absolute neutrophil counts (ANCs) during treatment indicated that all patients responded well to Sandoz biosimilar filgrastim. ANCs remained stable in the 16 patients who changed medication.Of the 578 patients who received G‐CSF, 50 have developed leukaemia secondary to SCN. Only one of these patients received Sandoz biosimilar filgrastim (Filgrastim Hexal® from March 2009 to November 2011); this patient suffered from congenital neutropenia and underwent successful stem cell transplant. So far, there have been no reports of osteoporosis, severe splenomegaly, splenic rupture, severe side effects or immunogenicity in any patient that received Sandoz biosimilar filgrastim.Summary/Conclusion:Efforts to register all patients with SCN within the co‐operating countries are ongoing, with the aim of estimating the incidence and prevalence of these rare disorders and the incidence of severe secondary events like leukaemia. G‐CSF remains the treatment of choice for patients with congenital neutropenia to maintain their ANC above 1,000/μL, which is required for the prevention of severe infections. With Sandoz biosimilar filgrastim, no new safety signals were observed and only one patient has developed leukaemia secondary to SCN during the observation period. In general, secondary leukaemia in congenital neutropenia patients is related to the underlying genetic disorder.

Outcomes Associated with Antimicrobial Use during High Dose Cytarabine Consolidation in Acute Myeloid Leukemia

Introduction: Patients with acute myeloid leukemia (AML) undergoing consolidation chemotherapy with high dose cytarabine (HiDAC) are often placed on prophylactic antimicrobials. This practice is largely based on the defined benefit of antimicrobial prophylaxis for AML patients during induction chemotherapy. Recent concerns regarding antimicrobial prophylaxis include increased risk of Clostridium difficile colitis, antimicrobial toxicities, and the potential for fostering multidrug-resistant pathogens. These emerging concerns coupled with the relatively shorter duration of neutropenia for AML patients with consolidative chemotherapy raised the question of whether antimicrobial prophylaxis in this setting is necessary. Therefore we examined the role of antimicrobial prophylaxis in HiDAC consolidation within our institution.Methods: This retrospective review included all adult patients who received HiDAC consolidation chemotherapy between January 2007 and March 2018. HiDAC was defined as a dose of 1g/m2 or greater. In patients receiving more than one cycle of HiDAC, data from each cycle was included. Patients prescribed antibiotics, antiviral medications, or antifungal medications at the time of discharge following HiDAC were considered to have received prophylactic antimicrobials. Several baseline patient characteristics were documented including age, sex, Charlson Comorbidity Index, and ECOG PS. The primary endpoint was incidence of febrile neutropenia (FN), while secondary endpoints consisted of hospitalizations for any cause as well as incidence of bacteremia, invasive fungal infection, Clostridium difficile colitis, and death from infection. Patients admitted within one month following HiDAC consolidation were considered to have been hospitalized following therapy. Data was then analyzed based on whether or not patients received antibiotic and antimicrobial prophylaxis. Patients less than 60 and 60 years of age an older where also analyzed separately regarding the use of prophylactic antibiotics to determine if older patients benefited from antibiotic prophylaxis.Results: One hundred twenty patients met inclusion criteria, and data from two hundred thirty-three cycles of HiDAC was analyzed. No significant demographic differences were detected amongst patients who did and did not receive antimicrobial prophylaxis (Table 1). There was no difference in incidence of FN or the number of hospitalizations for each cycle of HiDAC consolidation amongst the prophylaxis and no prophylaxis cohorts. The only statistically significant difference between groups was that in cycle 2 the mean length of hospital stay following HiDAC consolidation was less (p=0.02) in patients prescribed prophylactic antimicrobials. The rates of bacteremia and Clostridium difficile colitis were also similar across both groups in all three cycles of HiDAC consolidation (Table 1). In the setting of HiDAC consolidation, only one patient was found to have an invasive fungal infection and zero patients died as a result of infection. When only antibiotic prophylaxis was analyzed there was likewise no difference in the rates of FN across all 3 cycles of HiDAC nor was there a difference in incidence of FN for patients < 60 and patients ≥ 60 (Figure 1). Furthermore, there was no difference in demographics or other outcomes amongst the antibiotic prophylaxis and no prophylaxis cohorts (data not shown).Discussion: Neither antibiotic nor antimicrobial prophylaxis during consolidation chemotherapy with HiDAC reduced the incidence of FN or frequency of hospitalizations. Additionally, there was no difference in the rates of bacteremia, Clostridium difficile colitis, or invasive fungal infections between the two groups. Importantly, no patients in either cohort died from infectious complications following HiDAC consolidation. In patients with acute myeloid leukemia undergoing HiDAC consolidation, the role of prophylactic antimicrobials remains unclear. Prophylactic antimicrobials may not be necessary for all patients consolidated with HiDAC due to a potentially shorter course of neutropenia when compared to patients with AML undergoing induction chemotherapy, especially amongst younger AML patients. The use of antimicrobial prophylaxis should take into context patient and institutional factors. [Display omitted] DisclosuresReagan:Pfizer: Research Funding; Takeda Oncology: Research Funding; Alexion: Honoraria.

Clinical Course of Neutropenia in Previously Healthy Children

Clinical Course of Neutropenia in Previously Healthy Children

Neutrophil Dynamics in Peritoneal Carcinomatosis Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Oxaliplatin

Peritoneal carcinomatosis is an abdominal metastatic manifestation of a life-threatening tumour progression requiring standard palliative surgery and/or chemotherapy treatment. The aim of this study was to characterize the immediate neutrophilia response induced by cytoreductive surgery (CRS) and the myelosuppression effect of hyperthermic intraperitoneal oxaliplatin (HIO) in peritoneal carcinomatosis patients. Absolute neutrophil counts (ANCs) from 45 patients treated with CRS and HIO diluted in isotonic 4 % icodextrin (cohort A), 21 patients undergoing CRS followed by HIO diluted in isotonic 5 % dextrose (cohort B) and 18 patients treated with CRS without HIO (cohort C) were used to estimate the system-related parameters [baseline ANC (Circ₀), mean transit time (MTT) and feedback on proliferation (γ)] and drug-specific (α) parameters of a modified Friberg's model that accounts for the surgical stress-induced neutrophilia. The plasma oxaliplatin concentrations, C(p), were assumed to reduce the proliferation rate of the progenitor cells according to the function α × C(p). Model evaluation and simulations were undertaken to evaluate the effect of the dose, treatment duration and carrier solution on the incidence of severe neutropenia. The typical values [between-subject variability, expressed in coefficient of variation values (%)] of the Circ₀, MTT, γ and α were estimated to be 3.58 × 10⁹ cells/L (41.2 %), 144 h (70.9 %), 0.155 and 0.066 L/mg (134.9 %), respectively. Surgical stress induced a maximal 3.37-fold increase in the proliferation rate that was attenuated with a half-life of 10 days, and a maximal 68 % reduction in the MTT that was attenuated with a half-life of 28 days. Age, body surface area, sex, total proteins and carrier solution did not impact the model parameters. The model evaluation evidenced an accurate prediction of the incidence of neutropenia grade ≥2 and/or ≥3. Simulations indicated that (i) the neutropenia was reversible and short-lasting; and (ii) the HIO dose and treatment duration were the main determinants of the severity and duration of neutropenia. The time course of neutropenia was well characterized by the model that was developed, which simultaneously accounts for the acute-immediate neutrophilia response induced by CRS and the HIO myelosuppressive effect produced in the bone marrow. This model suggests that higher doses than those evaluated to date could be used in peritoneal carcinomatosis patients without substantially increasing the risk of severe neutropenia.

Population Pharmacokinetic–Pharmacodynamic Analysis of Neutropenia in Cancer Patients Receiving PM00104 (Zalypsis®)

PM00104 (Zalypsis(®)) is a novel marine-derived compound that has shown antineoplastic activity against a number of human tumour cell lines. Myelosuppression was found to be a PM00104 dose-limiting toxicity during phase I studies. The objective of this study was to characterize the time course of neutropenia after intravenous PM00104 administration in cancer patients. Absolute neutrophil counts (ANCs) and pharmacokinetic data from 144 patients receiving PM00104 doses ranging from 0.053 to 5mg/m(2) were used to estimate the system-related (baseline ANC [Circ(0)], mean transit time [MTT], feedback on proliferation [γ] and maturation [δ]) and drug-specific (first-order elimination rate constant from effect compartment [k(e0)] [α and β]) parameters of a modified Friberg's model. The concentrations in the effect compartment (C(e)) were assumed to reduce the proliferation rate of the progenitor cells according to the function [Formula: see text] Model evaluation and simulations were undertaken to evaluate the effect of dose intensity, dose density and the intravenous infusion duration on severe neutropenia incidence. The typical values (between-subject variability [%]) of the Circ(0), MTT, γ, δ, k(e0), α and β were estimated to be 5.66×10(9) cells/L (13%), 149h (29%), 0.136, 0.191, 0.00639h(-1) (32%), 0.332 L/µg (24%) and 1.47, respectively. Age, bodyweight, sex, serum albumin, total protein, liver metastases, number of previous chemotherapy lines and performance status were not associated with model parameters. The model evaluation evidenced an accurate prediction of the neutropenia grade 3 and/or 4 incidence. Simulations indicated that PM00104 dose and dosing interval, but not infusion duration, were the main determinants of the neutropenia severity and duration. The time course of neutropenia following PM00104 was well characterized by the model developed. The model-predicted time course of the ANCs and its variability confirmed that neutropenia is reversible, of short duration and non-cumulative.

Characterization of Neutropenic Pediatric Patients sent to a referral centre

Aim: Neutropenia is a relatively common cause of patient referral to the Immunology and Pediatric Rheumatology Department of the National Children’s Hospital. The present study characterizes the cases of neutropenia referred to this department between November 1988 and June 2008.Methods: Eighty four patients between 0 and 12 years of age, were referred from November 6th, 1988 and June 1st, 2008. We performed a comprehensive descriptive analysis of the characteristics exhibited by these patients in terms of clinical course, pattern of infection, most common causative germs, complications and treatment applied. Results: Neutropenia resolved spontaneously in 52.2% of the patients, and they were classified as transient neutropenia, 21.7% of the cases developed cyclic neutropenia, 13% of were categorized as benign chronic neutropenia, 7.2% developed severe chronic symptomatic neutropenia, 2.9% had neutropenia associated with type 1B glycogenosis and 2.9% of the cases were not classifiable in any of the proposed categories. More than 50% of the cases were associated with an abnormal pattern of infection in terms of frequency, severity, multiplicity of systems involved, or the presence of opportunistic microorganisms. The upper respiratory tract was the most commonly affected system with infection. Prophylactic antibiotics were used in 39.1% of the cases and granulocyte colony stimulating factor was required in 11.6% at some stage of the course. The most frequently involved pathogens in infection were Pseudomonas aeruginosa, Staphylococcus sp and E. coli. Conclusion: The vast majority of neutropenic patients had a benign clinical course. The same germs described in other series, caused infections in our patients. The absolute neutrophil count at diagnosis has no effect on the incidence of recurrent infection, but the type or clinical course of neutropenia does.

Pharmacokinetic and Pharmacodynamic Analysis of Hyperthermic Intraperitoneal Oxaliplatin-Induced Neutropenia in Subjects with Peritoneal Carcinomatosis

The objective of this study was to characterize the pharmacokinetics and the time course of the neutropenia-induced by hyperthermic intraperitoneal oxaliplatin (HIO) after cytoreductive surgery in cancer patients with peritoneal carcinomatosis. Data from 30 patients who received 360 mg/m(2) of HIO following cytoreductive surgery were used for pharmacokinetic-pharmacodynamic (PK/PD) analysis. The oxaliplatin plasma concentrations were characterized by an open two-compartment pharmacokinetic model after first-order absorption from peritoneum to plasma. An oxaliplatin-sensitive progenitor cell compartment was used to describe the absolute neutrophil counts in blood. The reduction of the proliferation rate of the progenitor cells was modeled by a linear function of the oxaliplatin plasma concentrations. The typical values of oxaliplatin absorption and terminal half-lives were estimated to be 2.2 and 40 h, with moderate interindividual variability. Oxaliplatin reduced the proliferation rate of the progenitor cells by 18.2% per mg/L. No patient's covariates were related to oxaliplatin PK/PD parameters. Bootstrap and visual predictive check evidenced the model was deemed appropriate to describe oxaliplatin pharmacokinetics and the incidence and severity of neutropenia. A peritoneum oxaliplatin exposure of 65 and 120 mg·L/h was associated with a 20% and 33% incidence of neutropenia grade 4. The time course of neutropenia following HIO administration was well described by the semiphysiological PK/PD model. The maximum tolerated peritoneum oxaliplatin exposure is 120 mg L/h and higher exposures should be avoided in future studies. We suggest the prophylactic use of granulocyte colony stimulating factor for patients treated with HIO exposure higher than 65 mg L/h.

Semi-Mechanistic Model for Neutropenia after High Dose of Chemotherapy in Breast Cancer Patients

To describe the absolute neutrophil counts (ANC) profile in breast cancer patients receiving high-dose of chemotherapy and peripheral blood stem-cells (PBSC) transplantation. Data from 41 subjects receiving cyclophosphamide, thiotepa and carboplatin were used to develop the ANC model consisting of a drug-sensitive progenitor cell compartment, linked to the peripheral blood compartment, through three transition compartments. PBSC were incorporated into the first transit compartment following a zero-order process, k(in), and the rebound effect was explained by a feedback mechanism. A 'kinetics of drug action' model was used to quantify the HDC effect on the progenitor cells according to a linear function, with a slope (alpha). The typical of the ANC at baseline (Circ(0)), mean transit time (MTT), feedback parameter (gamma), k(in) and alpha were estimated to be 5,610 x 10(6)/L, 3.25 days, 0.145, 0.954 cell/kg/day and 2.50 h/U, respectively. rHuG-CSF shortens the MTT by 92% and increases the mitotic activity by 120%. Bootstrap analysis, visual predictive check and numerical predictive checks evidenced accurate prediction of the ANC nadir, time to ANC nadir and time to grade 4 neutropenia recovery. The time course of neutropenia following high-dose of chemotherapy and PBSC transplantation was accurately predicted. Higher amount of CD34+ cells in the PBSC transplantation and earlier administration rHuG-CSF were associated with faster haematological recovery.

A Case of Neonatal Neutropenia Due to Anti-Fc Gamma Receptor IIIb Isoantibodies Treated with Recombinant Human Granulocyte Colony Stimulating Factor

Alloimmunization to granulocyte-specific antigens can occur during pregnancy. Maternal antibodies of IgG class can cross the placenta to result in alloimmune neonatal neutropenia. Antibodies to human neutrophil antigens anti-HNA-1a, HNA-1b, and HNA-2a have been most commonly reported to cause alloimmune neonatal neutropenia. Isoantibodies to Fc gamma RIIIb (CD16) if mother is a HNA-null phenotype are rarely involved in neonatal neutropenia. We report on a case of severe neutropenia (440 neutrophils/μL) due to anti-Fc gamma RIIIb (CD16) isoimmunization. On day 14 severe omphalitis developed, which was treated for 7 days by an antibiotic (ceftriaxone in a dose of 80 mg/kg/d) according to umbilical swab finding. Omphalitis persisted for 10 days in spite of antibiotic therapy and only resolved upon the introduction of rhG-CSF therapy. Therapy with rh-GCSF proved efficient and led to neutrophil count increase to 1970/μL and cure of omphalitis. However, therapeutic effect on granulocyte count was of transient nature, as granulocyte count fell to 760 n/μL on day 4 of therapy discontinuation. Neutropenia persisted for 2 months. The newborn was discharged from the hospital on day 26 with normal clinical status with clinical and laboratory control examinations at 2-week intervals. No additional infections were observed during the course of neutropenia.