Granulocyte transfusion therapy was an approach to bacterial and fungal infections related to severe neutropenia for more than 50 years; however, due to questionable results on the efficacy, adverse effects, and dosing of this treatment option, it began to fall out of favor, resulting in diminished use. Recently, though, the advent of granulocyte colony-stimulating factor (G-CSF) – and the possibility of greatly increasing the dose of granulocytes transfused by administering G-CSF to healthy donors – has renewed the interest in this therapeutic approach.
“Studies over the last 20 years have shown that three to four times as many granulocytes can be collected from donors stimulated with G-CSF and that the cells appear to function normally,” the authors of a recent Blood study, led by Thomas H. Price, MD, from the University of Washington in Seattle, wrote. “The evidence for clinical efficacy of high-dose granulocyte transfusion therapy has been elusive.”
Dr. Price and colleagues reported on the multicenter, randomized, controlled, phase III RING (Resolving Infection in Neutropenia with Granulocytes) trial, which assessed the efficacy of this therapy in patients with neutropenia (defined as absolute neutrophil count of <500/uL) and proven or probable infection.
Patients were recruited from 14 transfusion medicine/hemostasis clinical trials network and non-network sites. A total of 114 patients were randomized based on risk status and type of infection to receive one of the following treatment regimens:
- Standard antimicrobial therapy (controls; n=58)
- Standard antimicrobial therapy plus daily granulocyte transfusions from donor stimulated with 480 μg of G-CSF and 8 mg of dexamethasone taken orally (n=56)
For patients receiving G-CSF, 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 provided the patient received at least five granulocyte transfusions over at least a seven-day period
- Life-threatening toxicity
The study was terminated early, short of the desired enrollment, due to time limits on funding. Nine patients withdrew and another eight were not evaluable for the primary endpoint, leaving a total of 97 evaluable patients.
Transfused patients received a median of five transfusions, and the mean transfusion dose was 54.9×109 granulocytes.
The study’s primary endpoint was clinical success, defined as survival for 42 days after randomization and clinical response of infection at 42 days.
In the transfusion cohort, clinical success was 42 percent (20 out of 48 patients), compared to 43 percent in (21 out of 49 patients) in the control group (p>0.99). “Overall, granulocyte transfusion therapy had no effect on the primary outcome, whether analyzed by a modified intention-to-treat principle or per-protocol analysis,” Dr. Price and colleagues concluded. The success rates did not differ according to infection type, and survival through 90 days, a secondary endpoint, was also not affected by transfusion (p=0.35 for transfusion vs. control cohort).
Mild to moderate grade one to two transfusion-related adverse events were observed after one or more transfusions in 41 percent of patients, with reactions including fever, chills, and/or modest changes in blood pressure. More severe grade three to four reactions were observed after at least one transfusion in 20 percent of patients, with adverse events including hypoxia, tachycardia, hypotension, and allergic reaction.
In a post-hoc analysis designed to examine the safety and efficacy of a higher dose of granulocyte therapy among patients who received a higher average dose of granulocytes per transfusion (≥0.6×109 granulocytes/kg), Dr. Price and colleagues did find that the 29 patients receiving a higher dose of transfusion tended to have better outcomes than the 13 patients receiving a lower dose: Primary outcome success was 59 percent vs. 15 percent for high- and low-dose groups.
“The negative results [for the primary outcome] may reflect the true state of affairs, i.e., that granulocyte transfusions in this setting are not effective in clearing infection and prolonging survival,” the authors noted, but the results are limited in several ways – chiefly due to the low accrual rate.
Another limitation concerned the dose of granulocytes actually received by the subjects. The goal specified in the original protocol was a dose of at least 40×109 granulocytes per transfusion (0.6×109 granulocytes/kg). “Unfortunately, more than a quarter of the subjects received a mean dose less than this goal, often substantially less,” the authors noted.
“Because of limitations in this study, one cannot interpret these results as proof that granulocyte transfusions are ineffective,” they concluded. “Clinicians must base therapy decisions on these data and other existing evidence. If the decision is made to provide granulocyte transfusion therapy, it is important that clinicians determine that procedures at the collection facilities are adequate to ensure that high doses of granulocytes are actually delivered.”
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 September 2. [Epub ahead of print]