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ii. Granulocyte Transfusion

A. Granulocyte transfusions in neutropaenic children: a systematic review of the literature. van de Wetering MD, Weggelaar N, Offringa M, Caron HN, Kuijpers TW. Eur J Cancer. 2007;43:2082-2092.

Granulocyte transfusions (GTX) have been used for decades in pediatric neutropenic patients, but uncertainty remains regarding their effectiveness.

Two meta-analyses were performed in the nineties retrieving studies on GTX published between 1970 and 1994. Both studies concluded that GTX were effective for treatment of severe infection if there was a low survival rate of the controls (<40%), if an adequate number of granulocytes was transfused (>10 X 10⁹), and if compatibility of granulocytes was assessed prior to transfusion. However, all the GTX studies performed previously differ in many aspects: the variety of patients included, indications for use, supportive care measures, granulocyte collection procedures and transfusion methods. This makes it very difficult to interpret the data.

Also, two Cochrane reviews have been published. In one review, 4 RCTs were analyzed including 44 neonates. The results showed no evidence for use of GTX in septic neonates but all studies transfused a relatively low dose with a mean of 0.3-1.0 x 10⁹/kg. The other study included 8 RCTs; 4 trials included children but the pediatric data were not presented separately. In this review, all but the neonatal RCTs were considered with a total of 310 patient episodes. The relative risk (RR) for mortality extracted from 6 studies was 0.64, but if only studies were included which administered granulocyte counts >10 X 10⁹, mortality was significantly reduced (RR= 0.37).

The authors of this report reviewed all the pediatric data available on GTX, to gain a insight in to the indications for use, favorable effects and side effects in patients and donors. A comprehensive search was done in MEDLINE, EMBASE, LILACS and CENTRAL (1966 until 2006). All studies including children (1-18 years) who received GTX were included.

A total of 66 observational studies were reviewed, seven using prophylactic and 59 therapeutic GTX. Of the therapeutic studies 55 reported a proven sepsis caused by gram-negative bacteria (34%) or fungal disease (48%) as the indication for GTX. Concerning effectiveness 70% survival was reported, but no controlled studies were identified. Side effects were mentioned in 27 studies including mild respiratory symptoms, allergic reactions and infection related complications (CMV). Side effects in the donor were mainly flu-like illness.

In summary, the authors reviewed 30 years of experience on the use of GTX in children and found no randomized evidence showing a positive benefit-risk ratio. They further state that observational evidence alerts us to the potential harms or benefits of a treatment. Given the results of this review, there remains doubt on the efficacy of the use of GTX in reducing mortality without increasing morbidity in pediatric neutropenic patients.

B. Granulocyte transfusion therapy: it's time for an answer. Price TH. Transfusion. 2006;46:1-5.

In this editorial the author points out that there initially there was great enthusiasm for granulocyte transfusions for patients who had extended periods off neutropenia. A series of controlled clinical trials in the 1970s and 1980s produced mixed results and granulocyte transfusion therapy all but disappeared from clinical use from about 1985 to 1995.

Evidence for the importance of granulocyte dose came from several sources. In early uncontrolled trials of granulocyte therapy where large doses of cells could be obtained from donors with chronic myelogenous leukemia, clinical responses appeared to be dose-related. Also, more recent work demonstrated 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 was also proportional to the dose.

It has been know 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 author reviews several modern studies of granulocyte transfusion therapy and summarizes by stating that the bottom line is that it is not clear whether even large doses of granulocytes are useful in clearing infections or prolonging survival in neutropenic immunocompromized patients. Some suggest efficacy; others do not. One cannot say with confidence whether there are benefits to this rather expensive therapy and, if there are, whether they outweigh the risks. A Phase III randomized controlled clinical trial has been proposed within the NHLBI Transfusion Medicine/Hemostasis Clinical Trials Network and is now working its way through the approval and implementation process. To detect a clinically meaningful effect of the granulocytes, more than 200 patients will be required. It is expected that the study will 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.

C. 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. Oza A, Hallemeier C, Goodnough L, Khoury H, Shenoy S, Devine S, Augustin K, Vij R, Trinkaus K, Dipersio JF, Adkins D. Transfusion. 2006;46:14-23.

The authors 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.

The authors concluded that this prospective study demonstrates a modest, but significant, benefit of G-CSF-mobilized HLA-matched prophylactic granulocyte transfusions in neutropenic allogeneic PBPC recipients.

D. Granulocyte transfusions in the G-CSF era. Where do we stand? Robinson SP, Marks DI. Bone Marrow Transplant. 2004;34:839-46.

The efficacy of granulocyte transfusions in either prevention or treatment of neutropenic sepsis has been a controversial issue, with inconclusive results from controlled studies. Using steroid mobilized granulocytes, 1 to 3 x 10¹⁰ granulocytes could be obtained from donors. As a consequence of G-CSF mobilization of granulocytes and continuous flow leukopheresis, the mean harvest of neutrophils is reliably in excess of 4 x 10¹⁰. Repeated daily or alternate day administration of G-CSF enables the harvesting of similar yields over a 14 day period from the same donor. Infusion of G-CSF stimulated granulocytes results in measurable increases in the recipients' neutrophil count and may reduce the duration and severity of neutropenia.

Several studies suggest that granulocyte transfusions may be helpful in treating established sepsis in neutropenic patients. However, most of these reports are single center phase I/II studies involving small numbers of patients and no control group. In one controlled study there was a non-significant trend to a worse outcome in recipients of granulocyte transfusions. In a subgroup analysis, the outcome for patients with bacterial sepsis was significantly worse for recipients of granulocyte transfusions. However, for all patients the overall survival and event-free survival at 6 months from the onset of infection was no different between recipients of granulocyte transfusions and controls. It is therefore currently unclear as to whether the provision of daily G-CSF primed granulocytes transfusion for patients with established neutropenic sepsis has any significant clinical impact.

Several groups have reported the use of prophylactic granulocyte transfusions administered every 2-4 days employing friends and relatives of the recipient as donors. The number of days of neutropenia may thereby be reduced compared to historical controls, and there is also some evidence of a reduction in the number of days of fever, maximum CRP levels and antibiotic usage. However, such studies involve small numbers of patients and/or are reported only in abstract form. At the authors' institution, prophylactic granulocyte transfusions have now been employed in 22 patients with a previous history of fungal infection ("two proven, four probable and 16 possible") who underwent allogeneic stem cell transplantation. Three patients experienced transient progressive radiological abnormalities suggestive of invasive fungal infection, although this subsequently improved in all three patients. There was no other evidence of progressive fungal infection. Although these results suggest that prophylactic granulocyte transfusions may be effective in limiting the period of neutropenia, it must be emphasized, however, that the published results to date represent preliminary findings and the efficacy of prophylactic granulocyte transfusion requires further study in large well-controlled trials.

E. The role of granulocyte transfusions in neutropenic patients. Bishton M, Chopra R. Br J Haematol. 2004;127:501-8.

The authors review the early clinical studies using granulocytes collected with glucocorticoid stimulation and conclude that there was no conclusive trend to the efficacy of granulocyte transfusions. Therefore, granulocyte transfusion became a seldom-used technique in the 1980s and early 1990s.

The availability of hematopoetic growth factors, particularly granulocyte colony-stimulating factor (G-CSF) raised the possibility of harvesting larger cell doses, and renewed interest in the procedure. Optimal yields appear to be obtained by administering G-CSF with 8-12 mg of dexamethasone or 60 mg of prednisolone approximately 12 hours prior to collection. The range of average cell yields is 50-70 x 10⁹ neutrophils, which enables the restoration of normal neutrophil levels. Granulocytes should be transfused daily and at least a 4 day treatment is recommended with continuation after this time based upon clinical judgment and patient response. Products to be used in severely immunosuppressed patients should be irradiated to prevent transfusion-associated GVHD.

The authors suggest that reasonable indications include (1) a resistant severe clinical infection in a neutropenic patient that has shown no response to aggressive antibiotic treatment with no recovery in neutrophil count expected for more than 7 days, and (2) severe infections, e.g., systemic fungal infections/necrotizing fasciitis or severe neutropenic typhlitis progressing on appropriate anti-fungal or grand spectrum antibiotics, in neutropenic patients, and no recovery in neutrophil count expected for more than l7 days.

The authors review published data and indicate that newer studies have shown preliminary evidence that suggest G-CSF-stimulated granulocytes may be a safe therapeutic measure with beneficial effects in neutropenic patients with serious infections. The literature however is confined to small, uncontrolled series and case reports; there are no well-designed trials with clinically relevant endpoints. The recommendation of the Infectious Diseases Society of America is that the routine use of granulocyte transfusion cannot be recommended.

Data published in abstract form alone suggest that prophylactic granulocyte infusions post-allogeneic BMT may reduce antibiotic utilization, febrile days and may improve survival. However, larger randomized studies are required to fully evaluate the use of prophylactic G-CSF-mobilized donor granulocytes.

F. The use of stimulated granulocyte transfusions to prevent recurrence of past severe infections after allogeneic stem cell transplantation. Kerr JP, Liakopolou E, Brown J, Cornish JM, Fleming D, Massey E, Oakhill A, Pamphilon DH, Robinson SP, Totem A, Valencia AM, Marks DI. Br J Haematol. 2003;123:114-8.

The authors describe nine patients with either previous invasive aspergillosis (IA) or considered to be at high risk of developing IA who underwent allogeneic hematopoietic cell transplantation, and who received prophylactic granulocyte transfusions. Eighteen contemporaneous controls matched for conditioning regimen were identified. Conditioning protocols were uniform in patients with particular diseases and of certain ages and, as a result, these factors were also controlled. Anti-bacterial theapy was uniform in the two groups, but antifungal prophylaxis differed.

The study group, when compared with the control group, had a significant reduction in the incidence and duration of fevers (P < 0.05) and maximum C-reactive protein (P < 0.05). There were significantly fewer days of neutropenia (P < 0.05). There was also radiological improvement of pulmonary infiltrates in four out of seven assessable patients; there were no proven fungal infections in the control group. No serious toxicity was encountered in donors or recipients. On the basis of this small study, the authors concluded that prophylactic granulocyte donations can be given safely, and that they significantly reduce the number of days of neutropenia. Further studies are warranted to determine whether granulocyte donations can prevent the recurrence of IA in patients at risk of fungal infection.

G. International forum: granulocyte transfusions. Engelfriet CP, Reesink HW, Klein HG, Murphy MF, Pamphilon D, Devereux S, Hocker P, Adkins D, Boyce N, Tobin S, Grigg A, Strauss RG, Liles WC, Price TH, Dale DC, Norol F. Vox Sang. 2000;79:59-66.

In this international forum, numerous investigators from Europe, the United States and Australia answer a series of 9 questions such as "What do you consider indications for granulocyte transfusions?" and "What has been the benefit of granulocyte transfusions for the patients?"

The opinions of the experts regarding effectiveness varied and few data were provided. Experiences are described as "anecdotal" or with the statement that definitive data are not available to judge the efficacy and potential toxicity of modern granulocyte concentrates. Nevertheless, some opinions were, "clear clinical benefits were regularly observed in children, for whom larger doses are easier to provide", "the impression is that transfusions are of benefit to the majority of patients", "patients responded well, with either a decrease in temperature or clearing of local infections when myelopoiesis also recovered during the course of treatment", "we have found clinical benefits in the majority of patients with progressive fungal sepsis when transfusions are used therapeutically for fungal infection" and "when used prophyloactically, granulocyte infusion has controlled localized fungal infections in those undergoing stem cell transplantation."

H. G-CSF-mobilised granulocyte transfusion to an ALL patient complicated by cytomegalovirus transmission. Meyer-Koenig U, Hufert FT, Duffner U, Neumann-Haefelin D, Henschen M. Bone Marrow Transplant. 2004;34:1095-6.

The authors describe a 15-year-old seronegative girl who received an allogeneic BMT from her CMV-seronegative sister. She developed life-threatening infections posttransplant and therefore received three granulocyte transfusions within 1 week. The granulocytes were obtained after G-CSF mobilization from a CMV seropositive donor. Primary CMV infection, attributed to these transfusions, ensued and subsequently led to the patient's death.

The authors comment that donors of granulocytes are usually sought among highly motivated family members or friends with an identical blood group. It might therefore be difficult to recruit a CMV-seronegative donor, as was true in this instance. The authors cite a reference indicating that prophylactic granulocyte transfusions from CMV seropositive donors had little effect on the incidence of CMV viremia in CMV seronegative recipients, but that this case does not confirm these results. They emphasize the importance of highly sensitive CMV serology of donor and recipient and frequent monitoring of high-risk patients. If CMV incompatibility cannot be avoided, they encourage antiviral prophylaxis with foscarnet for aplastic patients.

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