The RING study: A Randomized Controlled Trial of GCSF-stimulated Granulocytes in Granulocytopenic Patients

Abstract

Bacterial and fungal infections continue to be a major clinical problem in patients with prolonged severe neutropenia due to hematopoietic stem cell transplantation or aggressive chemotherapy. Although early controlled trials suggested that granulocyte transfusions were modestly effective in this setting, the doses of granulocytes provided in these studies were considered to be inadequate. Renewed interest in this therapy came with the possibility of greatly increasing the dose transfused by administering granulocyte colony-stimulating factor (G-CSF) ± dexamethasone to normal granulocyte donors. Subsequent studies showed that three to four times as many granulocytes could be collected from such donors, that these cells circulated in neutropenic recipients, and that the cells appeared to function normally both in vitro and in vivo. The evidence for clinical efficacy of this high-dose therapy has been inconclusive. The RING study is a recently completed randomized controlled study examining the efficacy of high-dose granulocyte transfusion therapy, carried out as part of the NHLBI Transfusion Medicine/Hemostasis Clinical Trials Network. Fourteen clinical sites participated. Subjects eligible for the study were those with neutropenia (ANC<500) and proven/probable/presumed bacterial or fungal infection. Subjects were randomized to receive either: 1) standard antimicrobial therapy; or 2) standard antimicrobial therapy plus daily granulocyte transfusions from normal donors stimulated with G-CSF (450µg) and dexamethasone (8mg). The primary endpoint was a composite one: survival plus a microbial response, both evaluated 42 days after randomization. Microbial response was determined by a blinded adjudication panel. Desired sample size was 236 subjects, designed to have 80% power to detect a 20% difference in success rates between the treatment and control groups. One hundred and fourteen subjects were enrolled. Subjects in both arms were well matched in terms of demographics, underlying disease, types and sites of infection, and severity of illness. Of the 56 subjects randomized to the granulocyte arm, 51 received at least one transfusion. Among these 51 subjects, the median number of transfusions was five (quartiles 3 and 9) given over a median of six days (quartiles 4 and 11). The median number of granulocytes administered per transfusion was 54.9x109 (quartiles 26.1x109, 72.5x109). Among subjects with sufficient data to determine the primary outcome, success rates were 42% (20/48) and 43% (21/49) for the granulocyte and control groups, respectively (p> 0.99) on Intention to Treat analysis, and 49% (17/35) and 41% (16/39), respectively, for subjects who adhered to their assigned treatments (Per Protocol analysis; p=0.64). Overall, patient infections were 36% invasive fungal, 27% invasive bacterial, 11% fungemia, and 26% bacteremia. Differences in primary endpoint success rates for granulocyte and control arms were not statistically significantly different for any infection type whether analyzed by Intention to Treat or Per Protocol. Because of the low accrual, the power of this study to detect a 20% difference in the overall success rates was reduced to approximately 40%; it is thus possible that a true effect was missed, particularly if the effect is limited to certain subject subsets. Disclosures Off Label Use: In the study being discussed, G-CSF is administered to normal blood donors. This is an off-label use of G-CSF. .