Long‐term safety of treatment with recombinant human granulocyte colony‐stimulating factor (r‐metHuG‐CSF) in patients with severe congenital neutropenias

Abstract

Congenital neutropenias include a heterogenous group of diseases characterized by a decrease in circulating neutrophils. In phase I/II/III studies in patients with severe congenital and cyclic neutropenia, treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) resulted in a rise in the absolute neutrophil counts (ANC) and a reduction in infections. We report the effects of long-term safety of subcutaneous r-metHuG-CSF administration in 54 patients (congenital n = 44. cyclic n = 10) treated for 4-6 years. A sustained ANC response was seen in 40/44 severe congenital neutropenia patients and 10/10 cyclic neutropenia patients. Two patients required an increase of > 25% in dose to maintain a clinical response; one patient became refractory to therapy. A significant decrease in the incidence of severe infections and the need for intravenous antibiotics was noted. Significant adverse events noted which may or may not be related to therapy included: osteopenia (n = 15), splenomegaly (n = 12), hypersplenism (n = 1), vasculitis (n = 2), glomerulonephritis (n = 1), BM fibrosis (n = 2), MDS/leukaemia (n = 3), and transient inverted chromosome 5q with excess blasts (n = 1). R-metHuG-CSF has been well tolerated in the majority of patients and resulted in a long-term improvement in their clinical status.

Effect of Recombinant Granulocyte Colony-Stimulating Factor on Blood Neutrophil Concentrations among Patients with “Idiopathic Neonatal Neutropenia”: A Randomized, Placebo-controlled Trial

“…7 Indeed, children who have any of the varieties of severe chronic neutropenia, such as Kostmann syndrome, [8][9][10] cyclic neutropenia, 8,11 Barth syndrome, 12 or Schwachman Diamond syndrome 13 are likely to have repeated bacterial infections. Patients with profound but relatively transient neutropenia, such as following chemotherapy, can also have problems with bacterial infections during the neutropenic period.…”

Osteoporosis in severe congenital neutropenia: Inherent to the disease or a sequela of G-CSF treatment?

“…Osteoporosis within the context of SCN and G-CSF treatment was first described by Zeidler et al [2], who reported radiologic signs of osteoporosis for 12/32 (38%) patients; in six of these patients, osteoporosis had been found prior to G-CSF therapy, based on plain radiographs. In a report by Bonilla et al [3], these results have been extended by enrolling additional patients from two other centers, theraby documenting 15/54 (28%) patients with osteoporosis, again six of these prior to G-CSF therdpy. Not a single case of osteoporosis was reported by Dale et al [4], however, in their phase I11 study of G-CSF treatment in 123 patients with SCN.…”

Assignment of the gene locus for severe congenital neutropenia to chromosome 1q22 in the original Kostmann family from Northern Sweden

“…of infections dramatically [1][2][3][4]. Autosomal recessive SCN was first described in a large consanguineous kindred from Northern Sweden in 1956 [5].…”