ALBERT

Description: Severe chronic neutropenia is a general term used to organize and study the inherited and acquired diseases causing blood neutrophils to be less than 0.5 × 109/L for months, years or a lifetime. The inherited or congenital disorders include severe congenital neutropenia (SCN) (the autosomal recessive form often called Kostmann syndrome), cyclic neutropenia, Shwachman-Diamond syndrome, Barth syndrome, myelokathexis or WHIM syndrome, and several other rare conditions. The genetic bases for many of these conditions are now known and the molecular, cellular and pathophysiological mechanisms are rapidly being discovered. The acquired disorders are less well characterized and include the immune, autoimmune and idiopathic neutropenias of childhood and adults. These disorders are often confused with the inherited disorders, particularly early in life. In 1994, the Severe Chronic Neutropenia International Registry (SCNIR) was established to study the causes, consequences, and treatment of severe chronic neutropenia with offices in Seattle WA, USA and Hannover, Germany. The total enrollment in the SCNIR-Seattle is currently 1100; 289 children (age less than 33 months at enrollment) and 811 patients (age greater than 33 months at enrollment). Of the 289 children, 119 were diagnosed with either idiopathic or autoimmune neutropenia. This analysis describes twenty children (8 male, 12 female, current age 3.6 to 16.6 years) with clinical diagnoses of idiopathic (11), autoimmune (5), cyclic (3), and congenital (1). These patients were enrolled in the SCNIR, followed with or without treatment of granulocyte colony stimulating factor (G-CSF), and spontaneously normalized their blood neutrophil counts. The median ANC for this population prior to G-CSF treatment was 0.263 × 109/L (range 0.061 to 0.926). All 20 patients had a pre G-CSF bone marrow examination read by a referring hematologist or pathologist and normal cytogenetics. In 15 patients there was normal maturation of the myeloid line. Five patients had “maturation arrest” at the myelocyte (1), metamyelocyte (1), or band (3) stage of neutrophil development. None were described as having early stage “maturation arrest” as is characteristically observed in SCN patients. Neutrophil recovery was defined by an increase in blood neutrophils to 2.0 × 109/L. Two patients had only mild symptoms and did not receive G-CSF before recovery occurred. The other 18 patients were treated with G-CSF, (median dose 1.375 mcg/kg/day, range 0.192 to 4.839 mcg/kg/day; duration median months 24.18, range 0.07 to 102.27 months). Before recovery, these 18 patients responded to G-CSF with an increase in the median ANC to 3.151 × 109/L, (range 0.120 to 14.553 × 109/L, all counts on G-CSF). All were reported to have diminution of recurrent fevers, mouth ulcers, and infections with G-CSF therapy. The daily dose during the first year of G-CSF treatment was positively correlated to the length of treatment: A low initial daily dose corresponded to less time to resolution (r=0.529; p=0.024). A similar relationship existed between a narrower dose range and the length of time a patient was neutropenic. Variability of dosing for this population ranged from 0.045 to 3.354 mcg/kg/day. Low variability between the highest and lowest doses was correlated to less time to resolution (r=0.66; p=0.0029). After recovery, the median ANC for 12 of the 18 patients was 3.337 × 109/L (range 2.181 to 9.282 × 109/L); the referring physicians reported normalization of blood cell counts in the other 6 cases, but did not submit documentation of these counts. No relapses and no evolution to myelodysplasia or leukemia (MDS/AML) have been reported with up to 8 years of follow-up for patients in this report. Similarly, the other 103 young children in the SCNIR with a diagnosis of idiopathic or autoimmune neutropenia have not transformed to MDS/AML. A retrospective review suggests that the patients in this report who were identified as having a diagnosis of cyclic or congenital neutropenia were probably misdiagnosed. These data confirm previous reports that spontaneous remissions may occur in children with idiopathic and autoimmune neutropenia. The data suggest that a normal marrow, normal cytogenetic analysis and response to a low dose of G-CSF are predictors of future recovery. In this patient group, treatment with G-CSF should be individualized and reserved for patients with a history of recurrent fevers and infections.