A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia

Abstract

Patients with idiopathic, cyclic, and congenital neutropenia have recurrent severe bacterial infections. One hundred twenty-three patients with recurrent infections and severe chronic neutropenia (absolute neutrophil count < 0.5 x 10(9)/L) due to these diseases were enrolled in this multicenter phase III trial. They were randomized to either immediately beginning recombinant human granulocyte colony- stimulating factor (filgrastim) (3.45 to 11.50 micrograms/kg/d, subcutaneously) or entering a 4-month observation period followed by filgrastim administration. Blood neutrophil counts, bone marrow (BM) cell histology, and incidence and duration of infection-related events were monitored. Of the 123 patients enrolled, 120 received filgrastim. On therapy, 108 patients had a median absolute neutrophil count of = or = 1.5 x 10(9)/L. Examination of BM aspirates showed increased proportions of maturing neutrophils. Infection-related events were significantly decreased (P < .05) with approximately 50% reduction in the incidence and duration of infection-related events and almost 70% reduction in duration of antibiotic use. Asymptomatic splenic enlargement occurred frequently; adverse events frequently reported were bone pain, headache, and rash, which were generally mild and easily manageable. These data indicate that treatment of patients with severe chronic neutropenia with filgrastim results in a stimulation of BM production and maturation of neutrophils, an increase in circulating neutrophils, and a reduction in infection-related events.

Progenitor cell self‐renewal and cyclic neutropenia

“…The current model fits with observation that mutations in ELA2 have a local effect in cells where it is expressed (24). In particular, eqn (7) allows one to identify the compartment in which the coupling leads to undamped oscillations. Moreover, ELA2 is known to be expressed in cells at the myeloblast stage, which are the closest cells to CFU-GM in the haematopoietic cascade (8).…”

“…These will be present whenever the eigenvalues x 1,2 are purely imaginary. They can be readily computed as (5) with Ω j = 4ãλ j-1 -(μ j-1 -μ j + ã) 2 Whenever ã = μ j-1 + μ j , the real parts of the eigenvalues vanish, with Ω j reading (6) Hence, oscillations will persist without damping at a frequency given by (7) In other words, we have established a relationship between frequency of oscillations and compartment location. For convenience of the readers, a summary description of all parameters used in the model is provided in Table 1.…”

Granulocyte‐colony stimulating factor is neuroprotective in a model of Parkinson's disease

“…Nevertheless, a safety record for the chronic treatment of PD with G‐CSF, also with respective dose‐finding studies in humans, will have to be performed in phase IIa/b studies. Potential safety issues mostly relate to the known actions of G‐CSF in the hematopoietic system, however, safe applications of G‐CSF even over years have been reported (Dale et al . 1993; Bonilla et al .…”

Application of whole‐exome sequencing to unravel the molecular basis of undiagnosed syndromic congenital neutropenia with intellectual disability

“…Besides infectious complications, chronic neutropenia predisposes sufferers to leukemia and myelodysplastic syndromes [Boxer and Newburger, ]. Treatment is based on the prevention of recurrent infections, the use of hematopoietic growth factors (granulocyte‐colony‐stimulating factor, G‐CSF) and allogenic hematopoietic stem cell transplantation [Dale et al, ; Cottle et al, ; Ferry et al, ].…”