Objectives

To compare the safety and effectiveness of granulocyte transfusions along with standard care versus standard care alone in improving survival rates in people with a bacterial or fungal infection during neutropenia.

Background

Thousands of people each year are hospitalized for neutropenia. Neutropenia commonly develops in people who have undergone chemotherapy or hematopoietic stem cell (HSC) transplantation. In neutropenia, the number of neutrophils, a type of granulocyte, is greatly reduced, weakening the body's immune system and increasing the risk of infection. Several older studies showed that the transfusion of donor granulocytes is effective in promoting the recovery of adequate numbers of granulocytes. However, since granulocyte transfusions can cause side effects, this therapy was rarely used. Interest in this therapy was renewed with the introduction of granulocyte colony-stimulating factor (G-CSF). Giving G-CSF to donors increases the number of granulocytes that can be collected. However, no clear answer on efficacy has yet resulted from the more recent clinic trials of high-dose granulocyte transfusion therapy. Therefore, this study was initiated to evaluate the safety and effectiveness of granulocyte transfusions in treating people with a bacterial or fungal infection during neutropenia.

Participants

Eligible patients were those of any age with neutropenia, defined as absolute neutrophil count (ANC) <500 cells per µL, due to aggressive chemotherapy, hematopoietic stem cell transplantation or underlying marrow disease (eg, aplastic anemia); and proven or presumed bacterial or fungal infection.

One hundred fourteen subjects were enrolled and randomized, 58 to the control arm and 56 to the granulocyte transfusion arm. Due to patient withdrawal or an inability to determine the success of the treatment regimen, only 97 subjects were evaluated for the primary outcome.

Design

TMH-RING was a randomized, open-label, phase 3 study. Subjects were randomized with equal allocation to receive either standard antimicrobial therapy or standard antimicrobial therapy plus daily granulocyte transfusions from normal donors stimulated with subcutaneous G-CSF (480 µg) and oral dexamethasone (8 mg). Subjects were stratified according to risk status (high risk = stem cell transplant or relapsed leukemia; low risk = other) and type of infection (invasive mold versus other).

Standard antimicrobial therapy was determined by the individual clinical sites, although recommended therapies for specific types of infections were provided in the protocol. For subjects in the transfusion arm, daily transfusions were continued for up to 42 days but were discontinued if one or more of the following occurred: neutrophil recovery, resolution or improvement of the underlying infection (at the discretion of the patient’s physician) provided the subject received at least 5 granulocyte transfusions over at least a 7-day period, or life-threatening toxicity.

Information was collected on all serious adverse events, unexpected adverse events at least possibly related to granulocyte transfusion, and a list of specific events that occurred during or within 6 hours following a granulocyte transfusion. Absolute neutrophil counts (ANCs) were obtained daily until engraftment, hospital discharge, or day 42, whichever came first, and then weekly after engraftment until discharge or day 42.

The primary end point was clinical success of the treatment regimen. To be considered a success, the subject had to meet 2 criteria: survival for 42 days after randomization and clinical response of the study-qualifying infection. Response for bloodstream infections was defined as a negative blood culture. For invasive bacterial or fungal infections, response was defined as resolution or improvement of clinical evidence of infection.

Conclusions

There were no significant differences between the granulocyte and control arms in survival or clinical response to infection in patients with neutropenia.

Price TH, Boeckh M, Harrison RW, et al. Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection. Blood. 2015;126(18):2153-2161. doi:10.1182/blood-2015-05-645986

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