Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection

Abstract

High-dose granulocyte transfusion therapy has been available for 20 years, yet its clinical efficacy has never been conclusively demonstrated. We report here the results of RING (Resolving Infection in Neutropenia with Granulocytes), a multicenter randomized controlled trial designed to address this question. Eligible subjects were those with neutropenia (absolute neutrophil count <500/μL) and proven/probable/presumed infection. Subjects were randomized to receive either (1) standard antimicrobial therapy or (2) standard antimicrobial therapy plus daily granulocyte transfusions from donors stimulated with granulocyte colony-stimulating factor (G-CSF) and dexamethasone. The primary end point was a composite of survival plus microbial response, at 42 days after randomization. Microbial response was determined by a blinded adjudication panel. Fifty-six subjects were randomized to the granulocyte arm and 58 to the control arm. Transfused subjects received a median of 5 transfusions. Mean transfusion dose was 54.9 × 10(9) granulocytes. Overall success rates were 42% and 43% for the granulocyte and control groups, respectively (P > .99), and 49% and 41%, respectively, for subjects who received their assigned treatments (P = .64). Success rates for granulocyte and control arms did not differ within any infection type. In a post hoc analysis, subjects who received an average dose per transfusion of ≥0.6 × 10(9) granulocytes per kilogram tended to have better outcomes than those receiving a lower dose. In conclusion, there was no overall effect of granulocyte transfusion on the primary outcome, but because enrollment was half that planned, power to detect a true beneficial effect was low. RING was registered at www.clinicaltrials.gov as #NCT00627393.

Figure 1

Flow diagram of the study. A total of 114 patients were randomized, 56 to the granulocytes group and 58 to the control group. Nine subjects withdrew from the study, and an additional 14 subjects withdrew from treatment.

Figure 2

Distribution of the average number of granulocytes per transfusion per kilogram (×10⁹). Forty-nine subjects received at least 1 G-CSF–stimulated granulocyte transfusion with sufficient information to calculate dose.

Figure 3

Scatterplot of posttransfusion ANC increments (×10⁹/L) and granulocyte dose per kilogram (×10⁹). The 209 of the 316 G-CSF–stimulated granulocyte transfusions (66%) that had sufficient dose information and ANC values recorded within proper timeframes were included.

Figure 4

Forest plots. (A) Forest plot of primary outcome success stratified by infection. The percentage of subjects considered a success and the total number of subjects within each infection subgroup for both MITT and PP analyses are provided. Log₁₀ ORs comparing success in the granulocyte arm to the control arm are displayed on the right; values >0 favor the granulocyte arm. (B) Forest plot of day 42 survival status stratified by infection. The percentage of subjects deceased at day 42 and the total number of subjects within each infection subgroup for both MITT and PP analyses are provided. Log₁₀ ORs comparing day 42 death status in the granulocyte arm to the control arm are displayed on the right; values >0 indicate a higher rate of death at day 42 in the granulocyte arm.

Figure 5

Survival to 90 days by treatment arm. Analyzed using Kaplan-Meier methodology. Three subjects were censored prior to day 90 due to missing information.

Figure 6

Survival to 42 days by dose group. Analyzed using Kaplan-Meier methodology. Two subjects were censored prior to day 42 due to missing information.