scholarly journals Application of Spectral Density/Periodogram Analysis to Serial Neutrophil Counts to Diagnose Cyclic Neutropenia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4608-4608
Author(s):  
Nicholas J. Dobbins ◽  
Audrey Anna Bolyard ◽  
Robert T. Chang ◽  
Julian Self ◽  
Gabriel Provencher Langlois ◽  
...  
Keyword(s):  
At Risk ◽  
Statistical Analysis ◽  
Clinical Diagnosis ◽  
Count Data ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Simple Method ◽  
Cyclic Neutropenia ◽  
Serial Blood ◽  
Periodogram Analysis

Abstract Background: Cyclic neutropenia is characterized by oscillatory fluctuations in blood neutrophil counts, usually with nadirs <0.2 x 109/L at approximately 3 week intervals. Visual inspection of graphs of serial counts is usually the basis for diagnosis. Detection of mutations in ELANE is helpful but not diagnostic because of the overlap of the specific mutation patterns with those associated with severe congenital neutropenia. Making the correct diagnosis of cyclic neutropenia is important because these patients are not thought to be at risk of developing myelodysplasia or acute myeloid leukemia (MDS/AML). In contrast, patients with severe congenital neutropenia, whose counts are usually lower, are at risk of developing MDS/AML. Methods: We have implemented a website application for easy and direct data entry of serial blood counts to detect statistically significant periodicities using the Lomb periodogram. Physicians, nurses, other healthcare providers or patients can directly enter the blood count data for analysis on a website to allow immediate visualization of the serial counts and calculation of the probability of statistically significant cycling and the period, i.e., length of the cycle. Results: We have analyzed the counts from 42 patients (21 ELANE positive, 8 ELANE negative, 13 ELANE unknown) enrolled in the Severe Chronic Neutropenia International Registry with a clinical diagnosis of cyclic neutropenia to determine the accuracy of clinical diagnoses based on this form of statistical analysis. Our preliminary results showed that it is easy to learn how to use this program. We estimate that at least 20 counts obtained at 2-3 day intervals for 6 weeks are the minimum needed to detect cyclic neutropenia on a statistically sound basis, while 20-40 counts obtained at 2-3 day intervals over an 8-10 week period was more likely to yield statistical and clinical certainty about the diagnosis. The figure below shows readouts for the periodogram analysis for one patient. It shows the influence of 17 counts versus 31 counts for a patient with the clinical diagnosis of cyclic neutropenia and a mutation in ELANE. The confidence intervals (95%) and (99%) are exceeded for the series of 31 counts but not for the shorter series. The peak, approximate cycle length is 22 days for this series of counts. As of yet, we do not have the sufficient daily count data to determine if more frequent testing (e.g. daily testing) is better than testing every 2-3 days. We are currently testing the patterns of neutrophil fluctuations in patients on G-CSF to see if cyclic neutropenia can be diagnosed in patients that are on (or during) treatment. We have learned that many patients with the clinical diagnosis of CyN do not have sufficient serial blood cell count data to confirm this diagnosis on a statistical basis. Conclusion: We have developed a simple method for making periodogram analysis much more widely available to clinicians and patients on a world-wide basis. Statistical analysis of carefully collected serial data will help to secure the diagnosis of cyclic neutropenia and provide patients with important prognostic information. Figure 1. Figure 1. Disclosures Dale: Amgen: Consultancy, Honoraria, Research Funding.

Cyclic Neutropenia Is Not Associated with Transformation to MDS and AML.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3306-3306
Author(s):  
David C. Dale ◽  
Audrey Anna Bolyard ◽  
Peter E. Newburger ◽  
Mary Ann Bonilla ◽  
George Kannourakis ◽  
...  
Keyword(s):  
Severe Disease ◽  
Clinical Information ◽  
Clinical History ◽  
Careful Analysis ◽  
Severe Neutropenia ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Cyclic Neutropenia ◽  
Serial Blood ◽  
Complete Blood Counts

Abstract Cyclic neutropenia is a rare hematological disorder characterized by recurrent severe neutropenia, mouth ulcers, fever and infections beginning soon after birth. The diagnosis depends primarily on observing regular periods of severe neutropenia (neutrophils <500/μL, usually <200/μL) lasting for 2–4 days at approximately 21-day intervals, documented by serial blood counts (a minimum of 2–3 complete blood counts per week for at least six weeks). Severe congenital neutropenia is a similar, but usually more severe disease. Mutations of the ELA2 gene are regarded as the cause of most cases of both cyclic neutropenia and severe congenital neutropenia. However, only patients with severe congenital neutropenia, not cyclic neutropenia, are thought to be at risk of evolution to MDS/AML. Since its founding in 1994, the Severe Chronic Neutropenia International Registry (SCNIR) has utilized data from previous studies and enrolled patients with cyclic neutropenia based on the clinical information from their treating physicians. We reviewed 190 cases of cyclic neutropenia (including 30 families) enrolled for 0.5 to 19.9 years, (median 11 years) with a total of 2,035 patient years of observation. 173 of 190 patients were treated with G-CSF (median dose 2.82 mcg/kg/day). We identified three patients who were reported to have developed MDS/AML. Further analysis by three experts from the SCNIR revealed that all three patients lacked sufficient serial blood count data to show well-defined neutrophil cycles prior to G-CSF. Two of the three patients lacked a clinical history of mouth ulcers and fevers consistent with the diagnosis, and the bone marrow evaluation was not consistent with cyclic neutropenia in all three cases. One of two patients tested did not have an ELA2 mutation. Thus, using standard criteria for the diagnosis of cyclic neutropenia, none of the three patients fully satisfied the criteria for this diagnosis. In addition, previous family studies, reviews of the published literature, and personal experience of the authors have revealed only one case of leukemia. This case of CML emerged in a 35 year-old patient, who was never treated with G-CSF, 31 years after the diagnosis of cyclic neutropenia. Based upon the review of these cases, we believe it is extremely important to make the diagnosis of cyclic neutropenia by careful analysis of serial blood counts. When the diagnosis is made confidently, it is also important to assure patients that with or without G-CSF treatment, the possibility of evolution to leukemia is unlikely.

A New Insight of Effect of Ampicillin-Gentamicin Through Chlorinative Stress Mechanism in Saliva of Newborn at Risk of Sepsis

2017 ◽  
Vol 8 (02) ◽  
Author(s):  
Ari Yunanto ◽  
Pudji Andayani ◽  
Astarini Hidayah ◽  
Devi A. Kusumawardani ◽  
Iskandar Thalib ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
At Risk ◽  
Statistical Analysis ◽  
General Hospital ◽  
Clinical Diagnosis ◽  
Advanced Oxidation Protein Products ◽  
Gentamicin Treatment ◽  
Before And After ◽  
Objective Indicators ◽  
Stress Parameters

Clinical diagnosis of sepsis in neonate is difficult, because many signs of sepsis are nonspecific. There are several salivary biomarkers of stress as objective indicators of stress reactions.This study was designed to investigate the effect of ampicillin-gentamicin treatment to chlorinative stress parameters insaliva of newborn at risk of sepsis. Four chlorinative stress parameters were used, hydrogen peroxide (H2O2) levels, myeloperoxidase (MPO) activity, advanced oxidation protein products (AOPPs) levels, and chlorinative index (CI). This study was performed in May until September 2016. Saliva samples were taken from 26 newborns at risk of sepsis treated in Ulin General Hospital, Banjarmasin, South Kalimantan, Indonesia. All newborns were given ampicillin-gentamicin three until ten days. The H2O2 levels, MPO activity, AOPPs levels, and CI were measured from the saliva taken from both pre and post treatment. Statistical analysis of the parameters were obtained from before and after the ampicillin-gentamicin treatment, using Mann-Whitney test. The used ofampicillin-gentamicin for treatment of newborns at risk of sepsis showed significant decrease in the H2O2 levels, MPO acitivity, AOPPs levels, and significant increases in the CI. From this results, it can be concluded that Ampicillin-gentamicin could reduce the chlorinative stress in newborn at risk of sepsis

Defective Expression of LEF-1 Transcription Factor mRNA and - Protein in Patients with Severe Congenital Neutropenia (Kostmann’S Syndrome).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 782-782
Author(s):  
Julia Skokowa ◽  
Gunnar Cario ◽  
Zheng Wang ◽  
Cornelia Zeidler ◽  
Martin Stanulla ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mrna Expression ◽  
Progenitor Cells ◽  
Healthy Controls ◽  
Severe Congenital Neutropenia ◽  
Healthy Individuals ◽  
Congenital Neutropenia ◽  
Cyclic Neutropenia ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

Abstract Severe congenital neutropenia (SCN) is characterized by “maturation arrest” of myeloid progenitor cells at the promyelocytic/myelocytic stage with the absence or only few mature neutrophils in the bone marrow and peripheral blood. Significant progress in the treatment of SCN patients has been achieved in the last 15 years by administration of granulocyte colony-stimulating factor (G-CSF), which significantly increases the number of neutrophils leading to an improvement of the quality of life. To date, the pathophysiology and underlying genetic defect in patients with congenital neutropenia is still under investigation. Wnt signalling pathway orchestrates a number of cellular programs such as proliferation, differentiation and cell fate determination in many tissues. In the present study we investigated the mRNA and protein expression patterns of Wnt signalling peptides, such as the High Mobility Group (HMG) box containing transcription factors such as lymphoid enhancer factor-1 (LEF-1) and T cell factors (TCFs), as well as β-catenin in CD33+ bone marrow myeloid progenitor cells from SCN patients (n = 6) in comparison to those of patients with cyclic neutropenia (n = 4) and G-CSF-treated healthy controls (n = 3). All SCN and cyclic neutropenia patients are under G-CSF therapy. mRNA expression of genes of interest was measured by quantitative real-time PCR. Protein expression was assessed by immunofluorescence staining, visualized and recorded by confocal microscopy. We found that CD33+ cells from patients with SCN exhibited 20 times lower or even absent expression of LEF-1 mRNA and protein, as compared to healthy G-CSF treated controls (mRNA expression ratio: SCN patients 0.83 ± 0.38 AU vs. healthy controls: 15.1 ± 0.4 AU; p < 0.0001). Intriguingly, LEF-1 mRNA expression levels on CD33+ cells from cyclic neutropenia patients were comparable to those of healthy controls. Immunostaining with anti-LEF-1 polyclonal antibody (kindly provided by Dr. R. Grosschedl) and confocal microscopy analysis revealed that LEF-1 protein was detectable at the expected level in CD33+ cells from healthy G-CSF treated controls. In patients with cyclic neutropenia LEF-1 protein expression in myeloid progenitor cells was comparable to healthy individuals. In contrast, in CD33+ cells from patients with SCN, LEF-1 protein was not detectable. mRNA expression of other TCFs: TCF-1, TCF-3, TCF-4 in SCN was not significantly different from healthy individuals. However, the expression level of LEF-1 binding partner in the Wnt pathway, β-catenin, was increased in SCN patients (SCN patients: 224.7 ± 42.4 AU vs. healthy controls: 107.2 ± 7.3 AU, p = 0.052). The defect in LEF-1 expression in SCN patients was further substantiated by the fact that mRNA expression of LEF-1 target genes such as c-myc, cyclin D1, survivin and neutrophil elastase were also significantly downregulated. In conclusion, our results suggest that defective LEF-1 expression might have an impact on the pathogenesis of SCN. In addition, it may help to distinguish SCN from cyclic neutropenia patients.

Incidence of SCN-Assoicated Gene Mutations in Severe Congenital Neutropenia Patients in North America

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3553-3553
Author(s):  
Jun Xia ◽  
Audrey Anna Bolyard ◽  
Elin Rodger ◽  
Steven Stein ◽  
Andrew AG Aprikyan ◽  
...  
Keyword(s):  
North America ◽  
North American ◽  
Barth Syndrome ◽  
North American Population ◽  
Compound Heterozygous ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Cyclic Neutropenia ◽  
The North ◽  
Two Samples

Abstract Severe congenital neutropenia is a genetically heterogeneous syndrome associated with mutations in several different genes including ELA2, HAX1, GFI1, WAS, and CSF3R. The goal of this study was to define the mutation frequency of these genes in the North American SCN patient population. We also sequenced SBDS, since mutations of SBDS have been associated with congenital and acquired neutropenia. A total of 159 patients were identified in the North American Severe Chronic Neutropenia International Registry (SCNIR) for whom informed consent and genomic DNA samples adequate for sequencing were available. To accommodate our semi-automated high-throughput sequencing pipeline, 94 samples were chosen for sequencing. Since ELA2 sequencing had already been performed in most cases, preference was given to those samples without known ELA2 mutation. Among the samples, 73 were from patients with SCN, 4 with cyclic neutropenia, 10 with idiopathic neutropenia, 2 with Shwachman-Diamond Syndrome (SDS), and 3 with Barth syndrome. Two samples were excluded because of poor sequence quality. Singleton cases with validated mutations of GFI1 (N382S) and WAS (L270P) were observed. The N382S GFI1 mutation was associated with striking monocytosis. A novel nonsense mutation of GFI1 (R412X) was detected in one additional case. As expected, compound heterozygous mutations of SBDS were present in the two cases of SDS. In addition, heterozygous mutations of SBDS (84Cfs3X and Q94X) were observed in two cases of SCN. Typical truncation mutations of CSF3R were detected in 4 cases, all developing MDS or AML. Surprisingly, no mutations of HAX1 were detected. Considering only patients with a diagnosis of SCN who were from North America (125 of the total 159 cases), the incidence of ELA2 mutations was 68%. Eleven novel ELA2 mutations were identified. In 28.8% of cases, no mutation of any gene were detected. Based on these data, we recommend that ELA2 genotyping be performed in all patients with suspected SCN. In the North American population mutations in HAX1, GFI1, SBDS, and WAS are rare and routine genotyping is not indicated. Finally, the data suggest that there are yet undiscovered genetic causes of SCN.

High Insta High Instability Of The CSF3R Gene In Severe Congenital Neutropenia Patients As Judged By Multiple CSF3R Mutations In The Majority Of Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2264-2264
Author(s):  
Maksim Klimiankou ◽  
Murat Uenalan ◽  
Siarhei Kandabarau ◽  
Lutz Wiehlmann ◽  
Anna-Lena Hagemann ◽  
...  
Keyword(s):  
Deep Sequencing ◽  
Conflicts Of Interest ◽  
Cell Clone ◽  
Stop Codon ◽  
Severe Congenital Neutropenia ◽  
Sequencing Data ◽  
Congenital Neutropenia ◽  
Cyclic Neutropenia ◽  
Extracellular Region ◽  
Inherited Mutations

Abstract It has been reported by us and others that approx. 30 % of all patients with congenital neutropenia (CN) acquire CSF3R mutations in their life time. More than 80 % of the CN patients who develop myeloid leukemia (CN/AML) harbour CSF3R mutations. This suggests that they are the first hit in leukemogenesis. However, detecting sequence changes e.g. by Sanger sequencing reveals only mutations presented in more than 20 % of the cells due to its technical detection limit. Therefore, we asked whether there is a systematic underestimation of cell clones harbouring CSF3R mutations, which might have been traditionally overlooked. We applied the deep-sequencing technology (SOLID 5500xl) to identify CSF3R mutations in myeloid cells from 158 patients with different types of neutropenia (86 severe congenital neutropenia (CN) patients with known inherited mutations (ELANE, HAX1, G6PC3), 21 cyclic neutropenia (CyN) patients, 28 patients with severe chronic neutropenia with so far unknown inherited mutations, 11 patients with SBDS-associated neutropenia) as well as a group of 12 healthy individuals. All neutropenia patients were treated with G-CSF and notably 21 CN patients developed leukemia or MDS. Deep sequencing data were processed according to our custom NGS pipeline (annotation of sequences and prediction of damaging effects on the coding sequence by Polyphen2, removal of known dbSNP variants, and accepting significant Phred-scores at the variant calling stage). Overall the read numbers ranged between 18 and 128069 (median 716), while only variants with at least two percent of the reads were accepted for further consideration (the statistically significant limit is between one and two percent of all reads). All together, we detected 92 CSF3R mutations in 42 CN patients leading to 49 distinct amino acid exchanges (38 missense and 11 stop-codon mutations). The frequency of the mutant alleles ranged from 2 to 96 %. In contrast, in CyN only five out of 21 patients harbour CSF3R mutations; interestingly, two of them in isoform IV of CSF3R (p.P752T). Most notably, whereas 18 patients displayed only one CSF3R mutation, 24 individuals had more than one CSF3R mutation (2-10 mutations, in total 74 mutations). During follow up of some patients, we could demonstrate that the number of mutations increased over time. The majority of mutations were located in the cytoplasmatic region (aa 651-831) of CSF3R, while 15 patients presented mutations within the extracellular region of CSF3R. Intriguingly, in 16 patients we detected 23 non-sense mutations, where 20 of these are stop-codon mutations affecting glutamine (Q) 768, 770, 776, and 781. This suggests that this part of CSF3R is highly instable. In two patients who did not respond to Filgrastim treatment, we detected a stop codon at aa 546 and 547, respectively, affecting the Fibronectin type-III like part of the CSF3R. Twelve patients who developed leukemia (CN/AML) had more than one CSF3R mutations (two to ten) , whereas eight with CN/AML harbored only one mutation. None of the healthy controls, only three neutropenia patients with unknown inheritance, and only one SBDS patient revealed mutations in CSF3R. Taken together, this data suggests that CSF3R is highly prone to genetic instability in severe congenital neutropenia, because more than one mutation in half of the patients was observed and various CSF3R mutations during the course of life accumulated. Once a cell clone harboring CSF3R mutation obtains a second hit (e.g. RUNX1 mutation), they are prone to undergo leukemic transformation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Contributions to Neutropenia from PFAAP5 (N4BP2L2), a Novel Protein Mediating Transcriptional Repressor Cooperation between Gfi1 and Neutrophil Elastase

2009 ◽  
Vol 29 (16) ◽  
pp. 4394-4405 ◽  
Author(s):  
Stephen J. Salipante ◽  
Meghan E. B. Rojas ◽  
Brice Korkmaz ◽  
Zhijun Duan ◽  
Jeremy Wechsler ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Target Genes ◽  
Transcriptional Repressor ◽  
Theoretical Models ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Cyclic Neutropenia ◽  
Reporter Assays ◽  
Neutrophil Differentiation ◽  
Novel Protein

ABSTRACT “Neutropenia” refers to deficient numbers of neutrophils, the most abundant type of white blood cell. Two main forms of inherited neutropenia are cyclic neutropenia, in which neutrophil counts oscillate with a 21-day frequency, and severe congenital neutropenia, in which static neutropenia may evolve at times into leukemia. Mutations of ELA2, encoding the protease neutrophil elastase, can cause both disorders. Among other genes, severe congenital neutropenia can also result from mutations affecting the transcriptional repressor Gfi1, one of whose genetic targets is ELA2, suggesting that the two act through similar mechanisms. In order to identify components of a common pathway regulating neutrophil production, we conducted yeast two-hybrid screens with Gfi1 and neutrophil elastase and detected a novel protein, PFAAP5 (also known as N4BP2L2), interacting with both. Expression of PFAAP5 allows neutrophil elastase to potentiate the repression of Gfi1 target genes, as determined by reporter assays, RNA interference, chromatin immunoprecipitation, and impairment of neutrophil differentiation in HSCs with PFAAP5 depletion, thus delineating a mechanism through which neutrophil elastase could regulate its own synthesis. Our findings are consistent with theoretical models of cyclic neutropenia proposing that its periodicity can be explained through disturbance of a feedback circuit in which mature neutrophils inhibit cell proliferation, thereby homeostatically regulating progenitor populations.

A Novel Homozygous Mutation in G6PC3 Presenting as Cyclic Neutropenia and Severe Congenital Neutropenia in the Same Family

2013 ◽  
Vol 33 (8) ◽  
pp. 1403-1406 ◽  
Author(s):  
Abdullah A. Alangari ◽  
Abdulrahman Alsultan ◽  
Mohamed Elfaki Osman ◽  
Shamsa Anazi ◽  
Fowzan S. Alkuraya
Keyword(s):  
Homozygous Mutation ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Cyclic Neutropenia

Mice expressing a neutrophil elastase mutation derived from patients with severe congenital neutropenia have normal granulopoiesis

Blood ◽  
2002 ◽  
Vol 100 (9) ◽  
pp. 3221-3228 ◽  
Author(s):  
David S. Grenda ◽  
Sonja E. Johnson ◽  
Jill R. Mayer ◽  
Morgan L. McLemore ◽  
Kathleen F. Benson ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Blood Analysis ◽  
Severe Congenital Neutropenia ◽  
Normal Numbers ◽  
Granulocytic Differentiation ◽  
Congenital Neutropenia ◽  
Gene Encoding ◽  
Cyclic Neutropenia ◽  
Related Disorder ◽  
Increased Risk

Abstract Severe congenital neutropenia (SCN) is a syndrome characterized by an isolated block in granulocytic differentiation and an increased risk of developing acute myeloid leukemia (AML). Recent studies have demonstrated that the majority of patients with SCN and cyclic neutropenia, a related disorder characterized by periodic oscillations in the number of circulating neutrophils, have heterozygous germline mutations in the ELA2 gene encoding neutrophil elastase (NE). To test the hypothesis that these mutations are causative for SCN, we generated transgenic mice carrying a targeted mutation of theirEla2 gene (“V72M”) reproducing a mutation found in 2 unrelated patients with SCN, one of whom developed AML. Expression of mutant NE mRNA and enzymatically active protein was confirmed. Mice heterozygous and homozygous for the V72M allele have normal numbers of circulating neutrophils, and no accumulation of myeloid precursors in the bone marrow was observed. Serial blood analysis found no evidence of cycling in any of the major hematopoietic lineages. Rates of apoptosis following cytokine deprivation were similar in wild-type and mutant neutrophils, as were the frequency and cytokine responsiveness of myeloid progenitors. The stress granulopoiesis response, as measured by neutrophil recovery after cyclophosphamide-induced myelosuppression, was normal. To define the leukemogenic potential of V72M NE, a tumor watch was established. To date, no cases of leukemia have been detected. Collectively, these data suggest that expression of V72M NE is not sufficient to induce an SCN phenotype or leukemia in mice.

scholarly journals Myelodysplasia, Leukemia, Lymphoid Malignancies, and Other Cancers in Patients with Severe Chronic Neutropenia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 16-16
Author(s):  
David C Dale ◽  
Audrey Anna Bolyard ◽  
Blanche P. Alter ◽  
Mary Ann Bonilla ◽  
James Connelly ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Clinical Diagnosis ◽  
Lymphoproliferative Disorder ◽  
Hematological Malignancies ◽  
Severe Neutropenia ◽  
Autoimmune Neutropenia ◽  
Congenital Neutropenia ◽  
Cyclic Neutropenia ◽  
Favorable Prognosis ◽  
Chronic Neutropenia

Abstract Background: Since 1994 the Severe Chronic Neutropenia International Registry (SCNIR) has enrolled children and adults with > 3 absolute neutrophil counts (ANCs) < 0.5 x 109/L during a 3 month period to understand the pathobiology, natural history and treatment responses for severe chronic neutropenia. We have previously reported on the frequency and risk of myelodysplasia (MDS) and acute myeloid leukemia (AML) in patients with congenital neutropenia. For this report we reviewed patterns of hematological complications and malignancies occurring in all patients enrolled through the North American office of the SCNIR. Methods: Enrollment required informed consent, and patients and their physicians provided demographic, clinical and laboratory data including bone marrow results. Genetic testing was not required. Patients were followed with annual reports on blood counts, infections, malignancies and hospitalizations. Results: From 1994 to 2018 the Seattle SCNIR office has enrolled 1672 patients in the following categories: congenital 637 (38%), cyclic 259 (15%), and idiopathic / autoimmune 776 (47%), and many have been followed now for more than 15 years. There are approximately 17,577 person years of the observational data in this Registry. The congenital category now includes patients with mutations in ELANE, SBDS, TAZ, COH1, CXCR4, SLC37A4, G6PC3, WAS, CSF3R, SRP54, GFI1, VPS45, JAGN1, HAX1 and also patients with severe neutropenia from an early date in childhood without a genetic diagnosis. Cyclic neutropenia patients have demonstrated oscillations in ANC. The idiopathic and autoimmune category includes children and adults including some with large granular lymphocytes (LGL) syndrome without recognized features of a lymphoproliferative disorder. Most patients in all categories have been treated with granulocyte colony-stimulating factor (G-CSF). Findings: MDS or AML has occurred in 70 of the 1672 patients; 99% have clinical diagnosis of a hereditary type of neutropenia: severe congenital neutropenia (55), glycogen storage disease 1b (3), congenital immunodeficiency (2), Shwachman-Diamond syndrome (SDS) (5), WHIM syndrome (1),Wiskott-Aldrich syndrome (2), cyclic neutropenia (1) and idiopathic neutropenia (1). The median age at diagnosis of AML/MDS was 15.3 years (mean 18.3, +/- 1.79 SEM [range 0.40 - 70.6]); 69 of 70 were treated with G-CSF, median dose = 7.1 mcg/kg/day (mean 7.3, +/- 1.3 SEM )(range 0.18 - 100). One Shwachman-Diamond patient never received G-CSF. Outcomes for AML/MDS patients receiving chemotherapy with HSCT before 2000 were poor with 3/17 (18%) survivors. Since 2000 there were 35/53 (66%) survivors. Five patients developed myelofibrosis (4 congenital and 1 idiopathic). Two of the congenital patients later developed AML (1 living after treatment with a HSCT, 1 deceased). The clinical diagnosis of cyclic neutropenia has a favorable prognosis with G-CSF treatment, with only one probable case in 3,833 person years of clinical observation. 1 Twelve patients developed T-cell lymphoproliferative disorder (1 autoimmune neutropenia, 3 congenital neutropenia, 8 idiopathic neutropenia (4 with LGL features)). Five of these patients are living, all in the idiopathic group, 3 of 5 living patients have features of the LGL syndrome. Ten patients have reported other hematological malignancies; CML in a congenital patient after treatment with HSCT (living), CLL in a cyclic patient (living), CMML in an idiopathic patient after treatment with a HSCT (deceased). Six of the 10 patients have developed lymphoma; cyclic neutropenia (1), idiopathic/autoimmune neutropenia (5). Only one SDS patient has developed aplastic anemia. Other cancers/non-hematological malignancies have occured mostly in older patients: breast cancer (15) colon cancer (6), dermatological malignancies (13), hepatoma (1), lung cancer (1), prostate cancer (1), thyroid cancer (1). Conclusions: The hematological consequences of severe chronic neutropenia depend on the underlying etiology. MDS and AML occur largely in patients with the congenital or hereditary neutropenias. The diagnosis of cyclic neutropenia and chronic idiopathic / autoimmune neutropenia portends a favorable prognosis, based on a total of 10482 person years of observation. Marrow failure and aplastic anemia are not expected consequences of severe chronic neutropenia. Disclosures Dale: Athelas, Inc.: Equity Ownership; Amgen: Consultancy, Research Funding; Sanofi-Aventi: Consultancy, Honoraria; Cellerant: Other: Scientific Advisory Board; Hospira: Consultancy; Prolong: Consultancy; Beheringer-Ingelheim: Consultancy; Coherus: Consultancy. Newburger:X4 Pharmaceutics: Consultancy, Honoraria; TransCytos LLC: Consultancy; Janssen Research & Development, LLC: Consultancy, Honoraria.

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