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• W2063077818 abstract "In spite of modern antimicrobials and supportive therapy, the problem of infection in the setting of aggressive chemotherapy and hematopoietic peripheral blood progenitor cell (PBPC) transplantation has not gone away, and therapy-related neutropenia remains the major risk factor for the development of bacterial or fungal infection.1, 2 The spectrum of these infections has shifted in the past 20 years with fungal infections, particularly invasive molds such as Aspergillus, Fusarium, and Zygomyces emerging as the principal infectious cause of mortality and morbidity.3-8 The incidence of invasive Aspergillus infection in patients undergoing allogeneic bone marrow transplantation (BMT) is approximately 15 percent, with mortality rates of 30 to 80 percent.3, 5Fusarium infection in these patients is fatal in 70 percent of cases.7 When these infections occur during periods of neutropenia, it seems obvious that the transfusion of normally functioning neutrophils should help, and initially there was great enthusiasm for this approach. A series of controlled clinical trials in the 1970s and 1980s produced mixed results,9 but on aggregate, these studies indicated a survival advantage for transfused patients. Nevertheless, granulocyte transfusion therapy all but disappeared from clinical use from about 1985 to 1995. This change in practice occurred for several reasons. Improvement in antibiotic and general supportive care rendered refractory bacterial infection a less common clinical problem. Reports also surfaced of adverse effects of granulocyte transfusion, particularly adverse pulmonary reactions. Finally, and probably most important, the clinical results in most patients were, at best, marginal, an effect most likely attributable to two causes. First, the dose of neutrophils supplied to patients with the best standard collection techniques (20 × 109-30 × 109) was probably inadequate. The second problem was that neutrophils rapidly undergo apoptosis after collection, a phenomenon that may be responsible for both the failure of the transfused cells to circulate and the short shelf life of these components. The evidence for the importance of granulocyte dose comes from several sources. First, in the early uncontrolled trials of granulocyte transfusion therapy, where large doses of cells could be obtained from donors with chronic myelocytic leukemia, clinical responses appeared to be dose-related. Morse and coworkers10 observed that the increase in the patient's neutrophil count was directly related to the cell dose and was detectable only with doses exceeding 1010 per m2. The clinical response, as defined by defervescence, was also proportional to the dose, the fraction of patients responding ranging from 30 to 100 percent with mean doses of 2.6 × 1010 and 15.6 × 1010 per m2, respectively. Lowenthal and colleagues11 reported that patients with clinical responses received, on average, four times as many cells as patients without responses. Second, retrospective analysis of the controlled trials of therapeutic granulocyte transfusion therapy suggested that higher doses of cells were provided in those studies that showed efficacy.9, 12 Third, the experience with the provision of granulocytes to neonates, in whom the dose per body weight is much higher, suggested that efficacy was related to dose.13-15 Finally, studies in animals indicated the importance of dose. Appelbaum and associates16 examined the clinical effect of granulocyte support in dogs with Pseudomonas sepsis and showed that dogs receiving 108 cells per kg did not survive the infection, whereas 100 percent (five of five) survived when they were given 2 × 108 cells per kg. Epstein and Chow17 provided granulocytes to dogs with Candida albicans meningitis and showed a direct relationship between the dose of cells administered, the blood granulocyte increments, and the number of granulocytes migrating to the cerebrospinal fluid. The notion that the doses provided clinically were inadequate was also consistent with what is known about normal granulocytopoiesis. Neutrophil production in an average-sized normal adult is approximately 60 × 109 cells per day.18 The normal marrow is probably capable of increasing production severalfold in the presence of severe infection. Thus, the daily number of neutrophils routinely provided to patients undergoing neutrophil transfusion therapy (20 × 109-30 × 109) was likely only about 1/10th of the need. The dose of granulocytes obtained by leukapheresis depends on the volume of blood processed, the efficiency of the collection procedure, and the donor's neutrophil count. There is a limit to the improvement in yield that can be accomplished by altering the first two of these variables. Most facilities process 7 to 10 L of blood during a collection; to increase this amount significantly will not easily be tolerated by many volunteer donors. Collection efficiency is already in the 40 to 50 percent range, so yields can no more than double with maximal theoretic improvement. One can effect large changes in the donor's blood neutrophil count, however, and with the availability of recombinant granulocyte–colony-stimulating factor (G-CSF), the possibility of greatly increasing the number of granulocytes for transfusion raised the hope that the efficacy of granulocyte transfusion therapy could be improved.2, 19 The use of G-CSF to stimulate normal granulocyte donors has been reported by numerous investigators.20-27 The dose of G-CSF in these studies ranged from 5 to 10 µg per kg, resulting in the collection of a mean of 40 × 109 to 60 × 109 granulocytes. Substantially higher mean granulocyte yields (80 × 109) were achieved by administering both G-CSF and dexamethasone (8 mg) to normal subjects.26, 27 Optimal yields were obtained if leukapheresis was begun approximately 12 hours after stimulation.28 In contrast to the situation in traditional granulocyte transfusion therapy, the postinfusion neutrophil increments seen in patients receiving cells from G-CSF-stimulated donors are quite large. Hester and associates22 reported a mean posttransfusion neutrophil increment of 0.6 × 103 per µL after infusion of 40 × 109 granulocytes, and the value remained higher than the baseline value for 24 hours. In the study of Adkins and colleagues,24 patients received a mean granulocyte dose of 51 × 109 and exhibited a mean posttransfusion neutrophil increment of 1 × 103 per µL, a value that was maintained for 1 to 1.5 days. With even higher cell doses (mean, 82 × 109), as reported by Price and coworkers,27 posttransfusion neutrophil increments were 2.6 × 103 per µL, with a mean next morning count of 2.6 × 103 per µL. It thus appears that donors stimulated with G-CSF and corticosteroids are able to provide enough granulocytes to sustain a normal or near-normal blood neutrophil count in the most severely neutropenic patients. Granulocytes collected after G-CSF–corticosteroid stimulation have been shown to function normally by both in vitro and in vivo measurements. Bactericidal and chemotactic activity is normal, and there appears to be increased fungicidal function. Several studies have shown that these granulocytes are also capable of migrating to extravascular sites in vivo. Dale and associates29 demonstrated that neutrophils collected from G-CSF-stimulated normal donors were able to accumulate in skin chambers. Adkins and colleagues30 reported that indium-111-labeled granulocytes obtained from G-CSF-stimulated donors localized to areas of infection in neutropenic recipients. Price and colleagues27 measured buccal neutrophil accumulation in neutropenic granulocyte recipients and demonstrated the ability of the transfused cells to migrate to the extravascular compartment. Thus it has been known for 5 to 10 years that large numbers of granulocytes can be collected after stimulation with G-CSF (with or without corticosteroids), that these cells circulate in recipients and result in substantial increases in the patient's neutrophil count, and that the cells appear to function normally. Yet the proof that this high-dose therapy is clinically useful has been elusive. The evidence to date is largely limited to that derived from case reports31-34 and from uncontrolled series. Hester and associates22 transfused 15 patients with fungal infection and reported that 60 percent responded. Results were more discouraging in the study of Grigg and associates,23 in which 3 of 3 patients with bacterial infection survived, but 5 of 5 with fungal infection died. Kerr and coworkers35 prophylactically transfused G-CSF–dexamethasone–stimulated granulocytes in 9 allogeneic PBPC transplant patients considered to be at high risk for the development of invasive fungal infection. Six of the patients had previous invasive Aspergillus infection, and 2 had prolonged neutropenia. Results were compared to that of 18 untransfused patients. Patients receiving prophylactic granulocytes were significantly less likely to develop fever (25% vs. 100%), and the mean number of days with fever was less (2.5 vs. 7.1). In a prospective uncontrolled study, Lee and coworkers36 treated 32 patients with neutropenia-related infection with a mean of 3.8 G-CSF-stimulated granulocyte transfusions. Clinical responses were reported in 80, 67, and 50 percent of fungal, gram-negative bacterial, and gram-positive bacterial infections, respectively. The fate of infused Tc99m-labeled granulocytes was measured in 2 responders and 2 nonresponders; the cells localized to the area of infection in both responders but failed to so localize in the nonresponders, suggesting that efficacy depended on the cells’ ability to migrate to the site of infection. Peters and associates37 administered granulocyte transfusions to 30 children with documented infection. Fifty-eight percent of the granulocyte concentrates were from G-CSF-stimulated donors. Because the patients were children, the mean dose of granulocytes per kilogram was relatively high. In this uncontrolled series, recovery from bacterial and fungal infection was 82 and 54 percent, respectively. Rutella and colleagues38 treated 20 patients with a variety of bacterial and fungal infections with G-CSF-stimulated granulocytes. Overall 50 percent of patients responded, response rates being equivalent for those with bacterial or fungal infection. No patient with a localized invasive fungal infection responded, however. Price and associates27 treated 19 BMT recipients; infection resolved in 8 of 11 patients with invasive bacterial infections or candidemia, but none of the 8 patients with invasive mold infection survived 30 days to document clearance of infection. More recently, Nichols and coworkers39 reported on a Phase II multicenter feasibility trial in which 39 patients with neutropenia and documented infection were treated with daily granulocytes transfusions from G-CSF-stimulated donors.39 A microbial response was observed in 38, 60, and 40 percent of patients with invasive mold infection, tissue bacterial infection, and bacteremia-fungemia, respectively. In the current issue of this journal, Oza and colleagues40 examine the effect of prophylactic granulocyte transfusions in 151 patients undergoing hematopoietic PBPC transplantation. The patients’ HLA-matched PBPC donors served as the granulocyte donors, the study being controlled in the sense that patients were enrolled in the treatment arm if these donors were suitable as granulocyte donors. Two granulocyte transfusions were given within the week after transplantation. The clinical effects were modest, but there was a significant decrease in the fraction of patients experiencing fever (64% vs. 82%), the median number of febrile days, the number of days on intravenous antibiotics (9 vs. 11), and the percentage of patients with bacteremia (13 vs. 30). There was no difference in hospital length of stay or in 100-day survival. In a retrospective case-controlled study, Hubel and associates41 examined the effect of G-CSF-stimulated granulocyte transfusion therapy on the course of infection and on overall survival in 74 patients undergoing BMT. These results were compared to a matched cohort of 74 patients who received antimicrobial therapy alone. The fraction of patients with progressive infection was actually greater in the transfused group (57% vs. 39%), although the difference was not significant for patients with fungal infection. No differences were seen in the overall survival rate. These negative results must be interpreted with caution. This study was not a prospective randomized study, the “controls” were partly historical, and the patients selected to receive granulocyte transfusions were likely to have had more severe illness. Regardless, these data do not provide clear evidence that granulocyte transfusions are clinically effective. In another case-controlled study, Safdar and coworkers42 analyzed 491 patients with candidemia. Twenty-nine of these patients received granulocyte transfusions; 429 did not. Short-term survival was comparable (48% in the transfused group, 45% in the control group) in spite of the fact that risk factors for higher mortality (e.g., longer duration of neutropenia, higher incidence of breakthrough invasive fungal infection) were more common in the patients receiving granulocytes. The authors interpreted these findings to be supportive of the notion that the transfusions were effective. Of note, many of these trials were conducted before the availability of antifungal agents that are more effective and less toxic than conventional amphotericin B, including the third-generation triazole voriconazole. It is possible that the administration of more effective therapy would allow the incremental benefit of granulocyte therapy to be more clearly demonstrated, but this hypothesis remains to be proven. The bottom line is that it is not clear whether even these large doses of granulocytes are useful in clearing infections or prolonging survival in neutropenic immunocompromised patients. Most studies to date have been limited to small numbers of patients. Some suggest efficacy; others do not. Because there are adverse effects associated with both the collection and the transfusion of granulocytes, the situation is currently one of clinical equipoise. One cannot say with confidence whether there are benefits to this rather expensive therapy and, if there are, whether they outweigh the risks. Such uncertainty is the ideal setting for a randomized controlled efficacy trial. The recently established NHLBI Transfusion Medicine/Hemostasis Clinical Trials Network provides a unique opportunity to answer this question. A Phase III randomized controlled clinical trial of high-dose granulocyte transfusion therapy has been proposed and is now working its way through the approval and implementation process. As currently configured, patients eligible for entry will be those made neutropenic (ANC < 500/µL) by either chemotherapy or hematopoietic PBPC transplantation conditioning regimens. They must have a proven or probable bacterial or fungal infection as specifically defined in the protocol. Patients will be randomized to receive either standard antimicrobial therapy or standard antimicrobial therapy plus daily G-CSF–dexamethasone-stimulated granulocyte transfusions. Granulocyte transfusion therapy will continue until recovery from neutropenia, resolution and/or improvement of the infection, or unacceptable toxicity. The primary endpoint will be survival to 42 days and a microbial response at 42 days. That is, a positive outcome requires that there be an improvement in the infection at 42 days and that the patient survive. Survival will be easy to determine. Whether or not a microbial response has occurred will be determined by a blinded adjudication panel. Secondary endpoints will include the adequacy of the transfusion support, safety of G-CSF administration to donors, adverse effects in patients, development of alloimmunization, the relationship between the granulocyte increments and the primary outcome and alloimmunization, the effect of transfusion on the clearance of fungal antigenemia, and mortality at 3 months. To detect a clinically meaningful effect of the granulocytes, more than 200 patients will be required. These kinds of numbers can only be achieved with a multicenter trial. Fifteen to 20 clinical sites are expected to participate, and the study will probably take 3 or 4 years to complete. The transfusion medicine community has waited more than 10 years to find out whether optimized granulocyte transfusion therapy works or not. Now is the time to find out." @default.
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• W2063077818 title "Granulocyte transfusion therapy: it's time for an answer" @default.
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