Granulocyte Transfusions at Appropriate Doses Improve Survival in Hematological Patients with Febrile Neutropenia

Introduction. The granulocyte  transfusions (GTXs) are used to booster antimicrobial drugs in severely neutropenic hematological patients. However, the optimal GTX dose and the actual efficacy of this practice are debated.  

Methods. We retrospectively evaluated the infection-attributable mortality (IAM, i.e. the mortality at 30 days after the last GTX) in 84 consecutive patients with hematological malignancies receiving GTXs (January 2009- December 2014). The indications for GTXs were i) presence of absolute neutrophil count (ANC) <0.5 x 10^9/l ii) fever with evidence of bacterial or fungal infections or symptoms of infections and iii) unresponsiveness to appropriate antimicrobial therapies for at least 48 hours.

Results. Among 84 patients, 101 infectious episodes requiring GTXs were recorded (422 transfusions in total). Patients characteristics are summarized in Table I. Bacterial infections were documented in 94 episodes (Klebsiella pneumonia in 35 cases, Escherichia coli in 16 and Pseudomonas aeruginosa in 13), invasive fungal infections (IFI) in 34 cases (including 18 pulmonary aspergillosis and 14 candidemia); 8 cases were considered as FUO. The infection was mono-microbial in 60 cases and poly-microbial in 33. Sepsis occurred in 67 cases. The overall IAM was 26.7 % (27 deaths among 101 infective episodes). At univariate analysis we failed to detect  statistical association between IAM and several evaluated variables, either patient-related (age, sex, diagnosis, status of disease, allo-HSCT, aplasia duration) or infection-related (bacterial infection or IFI, sepsis, XDR, G-SCF concurrent administration) or GTX-related (number of GTXs received, PMN /Kg/course, PMN/Kg/day of neutropenia). However, when we grouped patients according to the value of the median dose of PMN per transfusion, we found that patients receiving 1.5 - 3 x 10^8/kg (GTXs A) had a lower IAM than patients receiving less than 1.5 (GTXs B) or more than 3 x 10^8 /kg (GTXs C) (15,7%, 35,3% and 44,4%, for GTXs A, B and C, respectively, p=0,014 at chi-square test). The dose's cut off were derived from the Guide to the preparation, Use and Quality assurance of Blood Components of the European Committee on Blood Transfusion (16th Edition). If the analysis was carried out by pooling together GTXs B and C, the association between PMN dose and IAM was even more pronounced (p value =0.006 at Fisher test for GTXs A versus  GTXs B+C). At Kaplan-Meier analysis, the median survival was 59 days for GTXs A-patients and 30 days for GTXs B+C-patients (p =0,010). When patients with bacterial of fungal infections were separately evaluated, the effect of PMN dose on IAM was confirmed  in bacterial (n=54, p=0,008) but not in fungal (n=23, p=0,588) infections. We then introduced the PMN dose (GTXs A or GTXs B+C) in a Cox proportional-hazards regression model together with variables with p<0.1 at univariate analysis (sepsis) or other clinically relevant factors (Allo-HSCT, age over 60 years, disease status categorized as  onset/ remission  or  relapse/resistance ). The PMN dose  was the unique variable significantly associated with IAM (HR=3,0; 1,1-8,0 95% CI, p=0,020).    

Conclusions. These findings suggest that appropriate GTX doses can improve the post-infection survival of severely neutropenic hematological patients. Transfusion-related immunomodulation, leukostasis or transfusion-associated GVHD may underlie the detrimental effect of high PMN doses  and  deserve to be better explored.

Table 1. Clinical characteristics of 84 patients treated with GTXs. A total of 101 courses were recorded.

Characteristics
Age (years, median value range)	46 (20-74)
Male/Female	54/30
Underlying disease (n, %) Acute myeloid leukemia Lymphoma Acute lymphoblastic leukemia Myelodysplastic syndrome Multiple myeloma Chronic lymphocytic leukemia	63 (75%) 12 (14%) 5 (6%) 2 (3%) 1 (1%) 1 (1%)
Disease status at PMN transfusion (n, %) Onset Relapse/resistance Complete remission	49 (48,5%) 41 (40.5%) 11 (10.8%)
Duration of neutropenia (days, median value, range)	18 (3-79)
Site of infection (n, %) Sepsis Lung Bowel Others Multiples (≥3 involved sites)	67 (66.3%) 22 (21.9%) 4 (3.9%) 8 (7.9%) 4 (4%)
Allo-HSCT Yes No	21(20.7) 80(79.2)
Transfusions per course (median value, range)	4 (1-14)
PMN x 108/kg/course  (median value, range)	8.78 (0.53-53.23)
PMN x 108/kg/transfusion  (median value, range)	2.11 (0.46-7.34)