Evaluation of Neutrophil Elastase Inhibitors as Potential Therapies for Associated Neutropenia.

Neutrophil elastase () mutations are the most common cause of cyclic (CyN) and congenital neutropenia (SCN), two autosomal dominant disorders causing recurrent infections due to impaired neutrophil production. Granulocyte colony-stimulating factor (G-CSF) corrects neutropenia but has adverse effects, including bone pain and in some cases, an increased risk of myelodysplasia (MDS) and acute myeloid leukemia (AML). Hematopoietic stem cell transplantation is an alternative but is limited by its complications and donor availability.

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.

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).

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).

Cyclic thrombocytopenia with statistically significant neutrophil oscillations.

Cyclic thrombocytopenia is often misdiagnosed as immune thrombocytopenia due to similar clinical features, a fact of significance because cyclic thrombocytopenia generally responds poorly to treatments used successfully in immune thrombocytopenia. A precise diagnosis must establish the statistical significance of periodicity of the platelet counts using statistical methods (eg, Lomb-Scargle periodogram).

Analysis of Factors Associated With In-hospital Mortality in Lung Cancer Chemotherapy Patients With Neutropenia.

Lung cancer, compared with other solid tumors, is associated with high mortality rates from febrile neutropenia. The risk factors associated with in-hospital mortality were identified and compared for patients with lung cancer and patients with other solid tumors. Hospitalization data from the University Health Consortium database inclusive of 2004 to 2012 were analyzed.

Somatic mutations and clonal hematopoiesis in congenital neutropenia.

Severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome (SDS) are congenital neutropenia syndromes with a high rate of leukemic transformation. Hematopoietic stressors may contribute to leukemic transformation by increasing the mutation rate in hematopoietic stem/progenitor cells (HSPCs) and/or by promoting clonal hematopoiesis. We sequenced the exome of individual hematopoietic colonies derived from 13 patients with congenital neutropenia to measure total mutation burden and performed error-corrected sequencing on a panel of 46 genes on 80 patients with congenital neutropenia to assess for clonal hematopoiesis.

A systematic literature review of the efficacy, effectiveness, and safety of filgrastim.

Purpose: Filgrastim (NEUPOGEN) is the originator recombinant human granulocyte colony-stimulating factor widely used for preventing neutropenia-related infections and mobilizing hematopoietic stem cells. This report presents findings of a systematic literature review and meta-analysis of efficacy and safety of originator filgrastim to update previous reports.

Methods: A literature search of electronic databases, congress abstracts, and bibliographies of recent reviews was conducted to identify English-language reports of clinical trials and observational studies evaluating filgrastim in its US-approved indications up to February 2015.