A controlled trial of prophylactic granulocyte transfusions during induction chemotherapy for acute nonlymphoblastic leukemia. Prophylactic granulocyte transfusions: results of a randomized controlled trial in patients with acute myelogenous leukemia. A controlled trial of prophylactic granulocyte transfusions during initial induction chemotherapy for acute myelogenous leukemia. Prophylactic granulocyte transfusions during human bone marrow transplantation. Alloimmunization following prophylactic granulocyte transfusion. Therapeutic granulocyte transfusions for documented infections. A controlled trial in ninety-five infectious granulocytopenic episodes. Granulocyte-colony-stimulating factor-mobilized prophylactic granulocyte transfusions given after allogeneic peripheral blood progenitor cell transplantation result in a modest reduction of febrile days and intravenous antibiotic usage. Granulocyte transfusions for the prevention of infection in patients receiving bone-marrow transplants. Prophylactic human granulocyte colony-stimulating factor after induction therapy in pediatric acute myeloid leukemia.
Thirty-five noninfected patients undergoing induction chemotherapy for acute nonlymphoblastic leukemia (ANLL) were randomized to either receive (19 patients) or not receive (16 control patients) prophylactic granulocyte transfusions (PGT) when their granulocyte count fell below 0.5 X 10(9)/1. Both groups received identical anti-infectious and supportive care except for granulocyte transfusions. The authors found a nonstatistically significant decrease of the infection rate in the prophylactic group. However, the bacteriologically documented infections and septicemia incidence was significantly higher in the control than in the prophylactic group (P less than 0.05). In the control group they observed in 8 of 16 cases life-threatening infections in contrast with only 1 case in the prophylactic group (P less than 0.01). A significant reduction of deaths due to infectious causes in the prophylactic versus control group were also found (P less than 0.05). The authors did not find an increase of pneumonia or pulmonary infiltrates in the patients belonging to prophylactic in comparison to control group. A prospective randomized and controlled clinical trial of prophylactic granulocyte transfusions was conducted in an attempt to reduce the mortality from infection in newly diagnosed adults with acute myelogenous leukemia. Granulocytes were harvested from normal donors by cytapheresis, and transfused patients received a median of 1.45 x 10(10) granulocytes (range 0.28--3.45 x 10(10)) on alternate days during marrow aplasia caused by initial induction chemotherapy. Transfusion were started if the absolute peripheral granulocyte count was less than 500 microliters. Thirteen patients received from one to 12 granulocyte transfusions, and 11 control patients received no granulocytes. No significant advantage was demonstrated in the transfused patients compared with controls with regard to the following: 1) deaths due to infection, 2) reduction in the frequency of febrile episodes, 3) delay in the onset of fever, 4) reduction in the length of febrile episodes, or 5) reduction in the frequency of proven infection. To evaluate the role of prophylactic granulocyte transfusions during remission-induction chemotherapy for acute myelogenous leukemia (AML) we randomized 102 infected patients either to receive daily granulocyte transfusions when blood granulocytes fell below 0.5 x 10(9) per liter (54 patients) or not to receive them (48). Although the percentage of patients acquiring any infection was similar in the transfusion and control groups (46 and 42 per cent, respectively), granulocyte transfusions decreased the proportion of patients with bacterial septicemia (9 per cent of those with transfusions vs. 27 per cent of the controls; P = 0.01). Granulocyte transfusions did not reduce the incidence of other infections or improve bone-marrow recovery, remission rate and duration, or survival. Seventy-two per cent of the patients given transfusions had transfusion reactions. Pulmonary infiltrates were more common in the transfusion group than in the control group (57 per cent vs. 27 per cent; P = 0.002). Thirty-five per cent of the patients with pulmonary filtrates died, as compared with 5 per cent of those without filtrates. We conclude that prophylactic granulocyte transfusions should not be used during remission-induction chemotherapy in AML because the risks outweigh the benefits. Thirty-eight uninfected patients undergoing bone marrow transplantation were assigned at random to receive prophylactic granulocyte transfusions and oral nonabsorbable antibiotics (group 1) or oral nonabsorbable antibiotics alone (group 2) when their neutrophil count fell below 0.5 x 10(9)/liter. The two groups were comparable in terms of age, sex, underlying disease, immunosuppressive therapy and days of neutropenia. There were three cases of septicemia (all due to gram-positive organisms) in group 2 and none in group 1 (p = 0.23). There was no difference in the incidence of other documented infections, and survival between the two groups was comparable. Recipients of prophylactic granulocyte transfusions had a significantly higher incidence of cytomegalovirus (CMV) infections (13 of 18 versus six of 17, p = 0.043). These data suggest that prophylactic granulocyte transfusions may prevent septicemia, have no effect on other infections or survival in patients undergoing bone marrow transplantation, and are associated with a higher incidence of CMV infection. Oral nonabsorbable antibiotics alone are equally effective in preventing serious infections in bone marrow transplant recipients. Nineteen noninfected adults receiving initial induction chemotherapy for acute nonlymphocytic leukemia (ANLL) were randomized to receive either prophylactic granulocyte transfusion or platelet transfusion alone on an alternate-day schedule. An average of 11 granulocyte transfusions (range 3--19) were administered/patient with a mean dose of 11.5 X 10(9) granulocytes/transfusion. The groups were identical with respect to age, sex, number of days on study, granulocytopenic days, percent of days receiving systemic antibiotics, febrile days, complete remission rate, and incidence of minor infection. Significant transfusion reactions were much increased in the granulocyte transfusion group (7/10 versus 1/9 in controls) and were associated with the development of lymphocytotoxic antibodies (7/10 versus 4/9 controls), refractoriness to platelet transfusion, repeated fevers, and a pulmonary infiltrate in one patient. Alloimmunization to granulocytes occurred as early as the second week in some patients complicating platelet support during induction and maintenance. No severe infections occurred in the granulocyte transfusion group while three fungal infections occurred in the controls. The high rate of alloimmunization suggests that histocompatibility considerations indicate that prophylactic granulocyte transfusion should not be routine therapy and should be studied only in investigational settings. Patients with granulocytopenia (granulocyte count less than 0.5 x 10(9)/L) and a documented infection were randomized to receive or not to receive daily granulocyte transfusions in addition to antimicrobial therapy. Thirty-four of 47 control patients responded to therapy compared to 30 of 48 transfused patients (type 2 error, pneumonia, or a soft tissue infection, respective response rates for the control and transfused patients were 11 of 11 and 11 of 16 (Yates' corrected chi-squared test, p = 0.12). Response rates for patients with gram-negative septicemia were lower but were influenced by recovery of bone marrow function. Eleven of 12 control patients and seven of seven transfused patients with recovery of marrow function survived the gram-negative septicemia. In contrast, 12 of 24 control patients and 12 of 25 transfused patients survived gram-negative septicemia and persistent granulocytopenia (type 2 error p = 0.13). Two thirds of all fatal infections were associated with an underlying disease refractory to medical therapy. Therapeutic granulocyte transfusions had no substantial benefit over optimal antimicrobial therapy alone in managing infected patients with granulocytopenia. It was hypothesized that transfusion of two granulocyte-colony-stimulating factor (G-CSF)-mobilized prophylactic granulocyte components into allogeneic peripheral blood progenitor cell (PBPC) transplant patients during the regimen-related neutropenic interval would result in clinical benefit.
                HLA-matched sibling PBPC donors (n=151) were biologically randomized based on ABO mismatch to donate granulocyte components (Cohort G) or not donate granulocytes (control group, Cohort C). ABO-matched donors who did not meet other study-specific criteria were reassigned to Cohort C.
                Feasibility, defined as the proportion of ABO-matched donors who underwent granulocyte collections, was 42 percent (53 of 125). The percentage of patients who developed fever during the initial hospitalization was greater in Cohort C versus Cohort G (82.7% vs. 64.2%; p=0.03). In the interval from when granulocyte transfusions were initially given in Cohort G (Day +3 or Day +5) until neutrophil engraftment, the number of febrile days was less in Cohort G versus Cohort C (median, 0 vs. 1; Mann-Whitney p=0.003). The median number of days of intravenous antibiotics given during the initial hospitalization was less in Cohort G versus Cohort C (9 vs. 11; Mann-Whitney p=0.03), a difference accounted for in the interval from Day +3 or Day +5 to neutrophil recovery. There was no significant difference in length of the initial hospital stay, acute graft-versus-host disease rates, or 100-day survival between the two cohorts.
                This prospective study demonstrates a modest, but significant, benefit of G-CSF-mobilized HLA-matched prophylactic granulocyte transfusions in neutropenic allogeneic PBPC recipients. Prophylaxis by granulocyte transfusions against infection associated with granulocytopenia was studied in 69 patients receiving bone-marrow transplants for the therapy of hematologic neoplasia or aplastic anemia. Patients were randomized to receive or not to receive granulocyte transfusions when their circulating granulocyte levels fell to less than 200 per cubic millimeter during the period between transplantation and the development of graft function. During the first 21 posttransplant days, there were two local infections and no septicemias in 29 transfused patients. Seven local infections and 10 septicemias developed among the 40 controls. This protection was afforded by granulocytes collected by reversible leukoadhesion as well as by cells collected by continuous-flow centrifugation. Children with acute myelogenous leukemia (AML) have a high risk of infectious complications that might be reduced by prophylactic granulocyte colony-stimulating factor (G-CSF). However, G-CSF could induce AML blast proliferation. The prospective randomized trial AML-BFM 98 investigated the impact of G-CSF on hematopoetic recovery and infectious complications (primary endpoints) and on outcome (secondary endpoint) in children (aged 0-18 years) with de novo AML. Patients with more than 5% blasts in day-15 bone marrow or with FAB M3 were not included. Between 1998 and 2003, 161 children with AML were randomized to receive G-CSF after inductions 1 and 2, whereas 156 patients were assigned to the control group. Time of neutropenia after inductions 1 and 2 was significantly shorter in the G-CSF group (23 vs 18 days and 16 vs 11 days; P=.02 and=.001, respectively). G-CSF did not decrease the incidence of febrile neutropenia (72 and 36 patients vs 78 and 37 patients, respectively), microbiologically documented infections (27 and 25 patients vs 36 and 19 patients, respectively) and infection-associated mortality (5 vs 2 patients). Both groups had similar 5-year event-free survival (EFS; 59%+/-4% vs 58%+/-4%). Since G-CSF does not influence the risk of infectious complications or outcome in children undergoing therapy for AML, one cannot advocate the routine use of G-CSF in this patient group.
Implications for clinical practice: The controlled trials that have been identified raise the possibility that prophylactic granulocyte transfusions at a dose of at least 1 x 1010 may reduce the risk of mortality from infection. Overall mortality was not affected. However, the majority of studies were performed decades ago, and standards of supportive care have advanced considerably. These earlier trials were also based on transfusing lower yields of collected granulocytes than currently recommended. It is difficult to recommend prophylactic granulocyte transfusions outside the setting of ongoing controlled trials, given the resource and cost implications.
Implications for research: Larger trials are needed to establish the validity of the potential benefits raised by this review, in view of the methodological limitations, the small sample sizes and the heterogeneous definitions of infection that were encountered in the included studies.