The European Guidelines on Diagnosis and Management of Neutropenia in Adults and Children: A Consensus Between the European Hematology Association and the EuNet-INNOCHRON COST Action.

Neutropenia, as an isolated blood cell deficiency, is a feature of a wide spectrum of acquired or congenital, benign or premalignant disorders with a predisposition to develop myelodysplastic neoplasms/acute myeloid leukemia that may arise at any age. In recent years, advances in diagnostic methodologies, particularly in the field of genomics, have revealed novel genes and mechanisms responsible for etiology and disease evolution and opened new perspectives for tailored treatment. Despite the research and diagnostic advances in the field, real world evidence, arising from international neutropenia patient registries and scientific networks, has shown that the diagnosis and management of neutropenic patients is mostly based on the physicians' experience and local practices.

Comparison of Gene Editing versus a Neutrophil Elastase Inhibitor as Potential Therapies for Neutropenia.

Heterozygous mutations in , the gene for neutrophil elastase, cause cyclic and congenital neutropenia through the programed cell death of neutrophil progenitors in the bone marrow. Granulocyte colony-stimulating factor is an effective therapy for these diseases, but alternative therapies are needed, especially for patients who do not respond well or are at high risk of developing myeloid malignancies. We developed an HL60 cell model for neutropenia and previously demonstrated that transient and regulated expression of mutant causes cell death by accelerated apoptosis.

Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%).

Mutant allele knockout with novel CRISPR nuclease promotes myelopoiesis in ELANE neutropenia.

Severe congenital neutropenia (SCN) is a life-threatening marrow failure disorder, usually caused by heterozygous mutations in . Potential genetic treatment strategies include biallelic knockout or gene correction via homology-directed repair (HDR). Such strategies, however, involve the potential loss of the essential function of the normal allele product or limited coverage of diverse monogenic mutations within the patient population, respectively.

A prospective study to evaluate febrile neutropenia incidence in patients receiving pegfilgrastim on-body injector vs other choices.

Purpose: We evaluated the incidence of febrile neutropenia (FN) and related clinical outcomes among patients treated with myelosuppressive chemotherapy for nonmyeloid malignancies who received pegfilgrastim on-body injector (OBI) or other options (Other) for FN prophylaxis.

Methods: In this prospective observational study, adult patients with breast, prostate, or lung cancer, or non-Hodgkin lymphoma at risk for FN were stratified into subgroups based on FN prophylaxis used in the first chemotherapy cycle: pegfilgrastim OBI vs Other (pegfilgrastim or biosimilar pegfilgrastim prefilled syringe, daily filgrastim, or no granulocyte colony-stimulating factor [G-CSF]) for up to 4 planned chemotherapy cycles.

Results: This US study enrolled 2575 eligible patients (OBI, 1624; Other, 951).

A prospective cohort study to evaluate the incidence of febrile neutropenia in patients receiving pegfilgrastim on-body injector versus other options for prophylaxis of febrile neutropenia: breast cancer subgroup analysis.

Background: Breast cancer chemotherapy often carries a high risk of febrile neutropenia (FN); guidelines recommend prophylaxis with granulocyte colony-stimulating factor (G-CSF), such as pegfilgrastim. Neulasta Onpro on-body injector (OBI) is a delivery device administering pegfilgrastim approximately 27 h after application.

Methods: This prospective study examined patients with breast cancer who received chemotherapy with a high risk of FN, receiving OBI ("OBI") or other options (other G-CSF or none; "other").

Use of prophylactic pegfilgrastim for chemotherapy-induced neutropenia in the US: A review of adherence to present guidelines for usage.

Evidence-based US guidelines provide recommendations for the use of granulocyte colony-stimulating factor (G-CSF) as supportive therapy in patients with cancer receiving chemotherapy. Pegfilgrastim is recommended for FN prophylaxis in patients with non-myeloid malignancies receiving a high-risk chemotherapy regimen, or an intermediate-risk regimen if one or more risk factors are present. The guidelines highlight the patient characteristics and chemotherapy regimens for solid tumors and hematologic malignancies that may influence a patient's overall risk of FN and may benefit from pegfilgrastim support.

Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.

To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53.

Neutropenia Is an Underrecognized Finding in Pediatric Primary Immunodeficiency Diseases: An Analysis of the United States Immunodeficiency Network Registry.

Background: The frequency of neutropenia in pediatric primary immunodeficiency disorders (PIDDs) is unknown and potentially underappreciated. Our study aimed to determine the overall frequency and severity of neutropenia in children diagnosed with a PIDD entered in the United States Immunodeficiency Network (USIDNET) patient registry.

Procedure: Neutropenia data and demographic/clinical information from 1145 patients younger than 21 years of age was obtained from the USIDNET registry.

A case of secondary acute myeloid leukemia on a background of glycogen storage disease with chronic neutropenia treated with granulocyte colony stimulating factor.

Congenital neutropenias due to mutations in ELANE, SBDS or HAX1 or in the setting of glycogen storage disease (GSD) which is caused by mutation, often require prolonged granulocyte colony stimulating factor (G-CSF) therapy to prevent recurrent infections and hospital admission. There has been emerging evidence that prolonged exposure to G-CSF in cases with congenital neutropenia other than GSD is associated with transformation to myelodysplastic syndrome/acute myeloid leukemia.

Registries for study of nonmalignant hematological diseases: the example of the Severe Chronic Neutropenia International Registry.

Purpose Of Review: Registries provide 'real world' perspectives on the natural history and outcomes for many clinical conditions. The purpose of this review is to identify registries for nonmalignant hematological disease and to describe the operation of a successful long-term registry for patients with severe chronic neutropenia.

Recent Findings: There was an upswing in registries about 20 years ago, based on optimism about their utility to improve patient care.

Family studies of warts, hypogammaglobulinemia, immunodeficiency, myelokathexis syndrome.

Purpose Of Review: WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency, myelokathexis, or WHIMs) is a very rare autosomal dominant immunodeficiency disorder attributable to mutations in CXCR4. We reviewed clinical manifestations in 24 patients in 9 families to expand understanding of this syndrome.

Recent Findings: Warts, cellulitis and respiratory infections are common in patients with WHIMs.

CRISPR/Cas9-mediated knockout enables neutrophilic maturation of primary hematopoietic stem and progenitor cells and induced pluripotent stem cells of severe congenital neutropenia patients.

A Autosomal-dominant mutations are the most common cause of severe congenital neutropenia. Although the majority of congenital neutropenia patients respond to daily granulocyte colony stimulating factor, approximately 15 % do not respond to this cytokine at doses up to 50 μg/kg/day and approximately 15 % of patients will develop myelodysplasia or acute myeloid leukemia. "Maturation arrest," the failure of the marrow myeloid progenitors to form mature neutrophils, is a consistent feature of associated congenital neutropenia.

Neutropenia in glycogen storage disease Ib: outcomes for patients treated with granulocyte colony-stimulating factor.

Purpose Of Review: Glycogen storage disease Ib (GSD Ib) is characterized by hepatomegaly, hypoglycemia, neutropenia, enterocolitis and recurrent bacterial infections. It is attributable to mutations in G6PT1, the gene for the glucose-6-phosphate transporter responsible for transport of glucose into the endoplasmic reticulum. Neutropenia in GSD Ib is now frequently treated with granulocyte colony-stimulating factor (G-CSF).

Neutropenia in Barth syndrome: characteristics, risks, and management.

Purpose Of Review: Barth syndrome (BTHS) is an X-linked disease characterized by defective remodeling of phospholipid side chains in mitochondrial membranes. Major features include neutropenia, dilated cardiomyopathy, motor delay and proximal myopathy, feeding problems, and constitutional growth delay. We conducted this review of neutropenia in BTHS to aid in the diagnosis of this disease, and to improve understanding of both the consequences of neutropenia and the benefits of treatment with granulocyte colony-stimulating factor (G-CSF).