Introduction: severe chronic neutropenia.

THIS ISSUEOF Seminars in Hematology presents a series of articles on the mechanisms, diagnosis, and treatment of severe chronic neutropenia (SCN). SCN is an inclusive term, coined in the 1980s, for hematological diseases that cause blood neutrophil counts to be less than 0.5 10/L for months or years. Like severe chronic anemia, SCN is not a disease, but a cluster of conditions having common clinical manifestations. SCN patients are predisposed to recurrent bacterial infections because the mobilization of neutrophils to sites of acute inflammation are blunted due to reduced neutrophil production and a reduced neutrophil supply. The focus is on diseases that primarily cause neutropenia, without deficiencies of other cells. Included are discussions of severe congenital neutropenia, cyclic neutropenia, Shwachman-Diamond syndrome, glycogen storage disease, the neutropenias associated with inherited immunodeficiency syndromes, autoimmune neutropenia, idiopathic neutropenia, and the neutropenia associated autoimmune diseases. Not included are several important and common causes for acute and transient neutropenia, such as infections, hematological malignancies, and drugs. Aplastic anemia and myelodysplasia are also important causes for neutropenia, not covered in this issue. Before the discovery and development of the hematopoietic growth factors, particularly granulocyte colony-stimulating factor (G-CSF), there was no predictably effective therapy for SCN. Beginning in the late 1980s, a series of clinical trials clearly established that congenital, cyclic, and idiopathic neutropenia can be very effectively treated with G-CSF, administered daily or every other day. For patients with SCN, the hematological effectiveness and improvement in the quality of life with this treatment was truly remarkable. Patients who were previously often ill with fevers and infections, and unable to attend school or work, became able to live essentially normal lives with long-term G-CSF therapy. For the families of these patients, the shift from being a constant caregiver to having normal parental and sibling relationships was truly remarkable. As detailed in several articles in this issue of Seminars, most patients with SCN treated with G-CSF achieve and sustain hematological and clinical responses as long as therapy is continued. The Severe Chronic Neutropenia International Registry (the Registry) was organized to evaluate the long-term safety of G-CSF treatment and to foster research on the causes and consequences of the diseases causing SCN, following approval of marketing of G-CSF for treatment of SCN by the Food and Drug Administration in the United States, and the cooperative authorities for approval of new drugs in Europe. The Registry now enrolls more than 1,000 patients. Through the Registry, we have learned that most patients respond to G-CSF treatment and no other therapy appears to be as effective as G-CSF. We have also learned that patients with congenital neutropenia and the Shwachman-Diamond syndrome are at risk to evolve to develop acute myelogenous leukemia; understanding themechanisms for leukemogenesis in these disorders has become a major focus of