Children
Infections in neutropenic patients are associated with a severe prognosis, despite treatment with broad-spectrum antibiotics. In children with malignancy and septic shock, mortality can be greater than 40 % [
35] or even higher, up to 85 %, in specific patient subpopulations, such as bone marrow transplant recipients with invasive aspergillosis [
8]. Use of G-CSF and recent improvements in apheresis techniques allow the collection of large quantities of granulocytes, which result in increases in granulocyte counts in the transfusion recipients, particularly in children [
36]. The main criteria for the clinical use of GTX in children have included the presence of severe neutropenia with absolute neutrophil counts <0.5 × 10
9/L [
37‐
41], 0.2 × 10
9/L [
42] or 0.1 × 10
9/L [
43], associated with documented severe infection, not responsive to broad-spectrum antibiotics and/or antifungal treatments. Published and ongoing clinical trials in children are summarized in Table
2.
Table 2
Clinical trials in children
27 | Prospective, phase II | Severe neutropenia and infections | Donor mobilization: 7.5 μg/kg G-CSF; resolution of infection in 92.6 % of patients; 81.5 % OS on day +30; early administration after a median infection period of 6 days | |
49 | Prospective | Neutropenia and invasive bacterial or fungal infection | Donor mobilization with 5 μg/kg G-CSF + 50 mg PDN. Mixed cohort, including 10 adults; 72 % OS on day +28 and 52 % OS on day +100 | |
13 | Prospective phase I/II | Neutropenia and severe infection | Donor mobilization with 5–10 μg/kg G-CSF; Collection through the bag method. 69 % OS on day +30 | |
3 | Prospective | CGD and invasive aspergillosis | Donor’s mobilization with 450 μg G-CSF + 8 mg DXM; one patient died for ARDS, one was lost at follow-up and died 1 year after discharge, one is alive | |
35 | Retrospective | Febrile neutropenia or defective granulocyte function | Donor mobilization with 480 μg G-CSF + 8 mg DXM; OS 77.1 and 65.7 %, respectively, on day +30 and +60; 82.4 % infection-related OS | |
32 | Retrospective | Sepsis and neutropenia | Donor mobilization with single-dose lenograstim + DXM 8 mg; 59 % OS (8/32 pts died for the underlying infection and 8/32 pts for non-infectious causes) | |
16 | Retrospective | Severe neutropenia and documented bacterial and/or fungal infections in HSCT recipients | Donor mobilization with 8 mg DXM after 2007; unstimulated donors before 2007; 50 % OS on day +30 | |
10 | Retrospective | High risk febrile neutropenia with/without microbiologically documented severe infection | Donor mobilization with 5 μg/kg G-CSF + 8 mg DXM; Clinical response rate 62.9 %, 40 % infection-related mortality, 40 OS % | |
13 | Retrospective | Febrile neutropenia | Resolution of the documented infection in 9/12 (75 %) pts; good early survival (12/14 courses of GTX, 86 %); poor long-term survival (5/13 pts, 39 %) | |
13 | Retrospective | Severe infections and neutropenia | Donor mobilization with G-CSF 300 μg from day -3; complete or partial recovery in 6 and 3 of the 15 courses of GTX (40 and 20 % respectively) | |
13 | Retrospective | Granulocyte dysfunction or severe neutropenia and acute life-threatening infections | Donor mobilization with 600 μg G-CSF + 8 mg DXM; complete or partial clinical response in 12/13 pts (92 %); 15 % infection-related mortality and 42 % OS | |
3 | Retrospective | Secondary prophylaxis of invasive fungal infections during neutropenic episodes | Donor mobilization with G-CSF; concomitant combination antifungal therapy; no infection-related mortality | |
3 | Prospective | Prophylaxis in HSC recipients with chronic infections | Donor mobilization with 480 μg G-CSF + 7.5 mg DXM; after transplant, no flares of the infections (active S. aureus liver abscesses, chronic pulmonary aspergillosis, soft tissue mucormycosis) | |
20 | Prospective | Proven fungal or bacterial infection, unresponsive to anti-microbial therapy (n = 16). Poor control of fungal infection prior to allogeneic HSCT (n = 4) | In the curative group, infection was controlled in 11 out of 16 children. All patients treated pre-emptively survived the HSCT procedure | |
10 | Prospective | CGD with severe infections | Resolution of infection in 9 out of 10 patients, despite the fact that 8 patients were alloimmunized and had poor recovery of transfused granulocytes | |
To date, there have been no randomized controlled GTX trials in children, and most available data are derived from observational studies [
44]. Sachs et al. assessed the feasibility, safety and efficacy of early-onset G-CSF-mobilized GTX in an open, single-center, and prospective phase II clinical trial in immune-compromised children with neutropenia and severe infections, who failed to respond to broad-spectrum antibiotics [
41]. The study utilized granulocytes collected from community donors and which were crossmatch compatible with the recipients’ serum. Twenty-seven children at high risk of infection-related mortality were treated between 2000 and 2004. Some patients also received either G-CSF or GM-CSF. GTXs were well tolerated, without any pulmonary transfusion reactions due to alloimmunization. Twenty-five of 27 patients cleared their initial infection. All six patients with invasive aspergillosis showed clinical and radiological improvement [
41]. A noteworthy finding in this study was the remarkable response rate, probably due to the early initiation of GTX, i.e., after a median infection period of 6 days (range 3–18 days), compared with 8 days (range 1–28 days) [
45], 12 days (range 2–36 days) [
46], and 12 days (range 5–28 days) in other studies [
43].
A retrospective analysis including 13 children with neutropenia and proven or suspected infection also supports the efficacy of granulocyte transfusions. Although short-term survival was promising, eight of the 13 patients ultimately died of their infection [
47]. In another study of 35 children with high-risk febrile neutropenia or with granulocyte function defects, GTX were given for 3 consecutive days. The mean granulocyte content per concentrate was 27.4 × 10
9. Infection-related survival and overall survival rates were 82 and 77 %, respectively, at day 30 [
40]. Another retrospective study in children with febrile neutropenia or defective granulocyte function [
40], who were given GTX for 3 consecutive days, showed overall survival rates of 77 and 63 %, respectively, at day +30 and +90 after GTX.
A 59 % overall survival rate was obtained in a cohort of 32 children, with particularly favorable results in bacterial infections (8/11 patients with documented bacterial infection survived) and fungal infection (4/6 patients with documented fungal invasive infection survived) [
39]. In another case series, 13 children with sepsis who received 14 courses of GTX were reported to have a good short-term survival (12/14 courses, 86 %), whereas long-term outcome remained dismal (5/13 patients, 39 %) [
47].
Seidel et al. [
42] showed that neither body weight nor granulocyte dose impacted on infection outcome and survival in pediatric patients. Nonetheless, this study suggested that a tight schedule with daily transfusions of at least 1.4 × 10
8 granulocytes/kg likely contributed better clinical outcomes. This minimum recommended dose was derived from a Cochrane meta-analysis [
48]. They also reported the effect of daily GTX over at least 5 days containing a minimum of 3 × 10
8/kg neutrophils per concentrate was able to generate a stable ANC increment, to shorten the duration of neutropenia, and to support the control of infections in neutropenic patients with high-risk infections.
Granulocyte transfusion therapy has been used in three patients with chronic granulomatous disease (CGD) and disseminated invasive aspergillosis. Healthy donors were mobilized with 450 µg G-CSF and dexamethasone approximately 12 h before collection. Patients received between 0.4 and 3.0 × 10
9/kg granulocytes. Two out of three patients survived the infectious episode [
49].
Some studies also suggest a role for granulocyte transfusions in preventing infections or progression of infections in children who are expected to experience prolonged neutropenia after HSCT or chemotherapy [
39,
50]. Granulocyte transfusions from family volunteers were used prior to allogeneic HSCT in three children with poorly controlled bacterial or fungal infections. No transfusion-related reactions and no flares of the infection were observed. All HSCT procedures were successful [
50].
Concern for potentially serious pulmonary complications is one of the major limiting factors for the routine use of GTX. Some studies of GTX recipients have documented acute pulmonary transfusion reactions with shortness of breath, dyspnea, hypoxemia, and lung edema [
38,
43,
45,
51]. In a Cochrane meta-analysis (see also below), adverse events occurred in 15 % of the transfusions that had been collected by apheresis, but no reactions occurred in pre-medicated patients receiving granulocytes collected by apheresis. [
48]. Moreover, the procedure of HLA-matching of the granulocyte donor and GTX recipient in a tight schedule of therapeutic GTX, as in Seidel’s prospective study [
42], might carry the disadvantage of delayed treatment or lower granulocyte dosage.
Although randomized controlled trials are not available in children yet, the current evidence supports the early use of GTX, especially for patients with bacterial infections. However, patients should be closely monitored for adverse pulmonary transfusion reactions.
Adults
Published and ongoing clinical trials in adults are summarized in Table
3. A meta-analysis published in 1997 reviewed eight randomized controlled trials conducted between 1970 and 1995 and were designed to assess the efficacy of prophylactic granulocyte transfusions [
5]. The results suggested that daily prophylactic transfusions of compatible granulocytes could reduce the risk of bacterial or fungal infection, death or death from infection in patients with severe neutropenia. The study found that both granulocyte dose and granulocyte compatibility were determinants of the efficacy of granulocyte transfusions.
Table 3
Clinical trials in adults
22 | Retrospective | Grade IV febrile neutropenia | G-CSF only for neutrophil mobilization; when >1010 PMNs were infused, clinical benefit compared with historical controls | |
11 | Case series | Invasive Fusarium infection | Ninety-one percent response rate | |
74 | Retrospective | Treatment of infections | In 34 patients (46 %), GTXs were discontinued due to clinical response and neutrophil count recovery | |
56 | Retrospective | Severe infection in SAA | GTX + G-CSF; Survival at 30, 90 and 180 days was 89, 70 and 66 %, respectively. Survival rate correlated with hematopoietic recovery | |
24 | Retrospective | Invasive opportunistic infections | GTX + IFN-γ1b + G-CSF or GM-CSF. 60 % ORR 4 weeks after treatment | |
25 | Prospective | Progressive uncontrolled infections | Donors given G-CSF and dexamethasone, either alone or in combination. Favorable responses in 40 % of patients (especially in those with fungal or Gram-negative infections). One death from severe pulmonary reaction | |
20 | Pilot | Neutropenia refractory to G-CSF | Favorable response in 8 out of 15 assessable patients (53 %) | |
19 | Phase I/II | Infections after HSCT | GTXs from community donors (94 %). G-CSF + dexamethasone. Resolution of infection in 8/19 patients (42 %). Overall, four of the 19 patients were alive on day 30 after HSCT. None of the patients with invasive aspergillosis (n = 5) cleared the infection | |
30 | Retrospective | Neutropenia and severe infections | G-CSF + dexamethasone. In 11 patients, resolution of infection could be related to granulocyte transfusions. Three of these patients became long-term survivors | |
52 | Prospective | Control or prevention of severe infections | Control of infections was achieved in 82 % of life-threatening episodes. No reactivation of infections occurred under prophylactic granulocyte transfusions | |
100 | Randomized (GRANITE study) | Febrile neutropenia | Ongoing national, multi-center trial; Patients aged 1–75 years (www. drks.de/DRKS00000218); Date of first enrollment: October 2014; Arm 1 (intervention-group): transfusion of standardized leukapheresis products of granulocytes on every other day + standard therapy; arm 2 (control group): standard-therapy without granulocyte transfusions | NA |
30 | Prospective (GIN1 study) | Febrile neutropenia | Granulocytes derived from whole blood; risk of adverse events comparable to other granulocyte components; recovery of neutrophils and survival in all patients except for two adult patients who died | |
114 | Randomized (RING study) | Febrile neutropenia | Composite endpoint was survival + microbial response 42 days after randomization; 42 and 43 % success rates for the granulocyte and control groups, respectively | |
A community blood bank GTX program was developed at the Fred Hutchinson Cancer Research Center. Donors received G-CSF and dexamethasone. This program treated 19 patients with documented fungal or antibiotic resistant bacterial infections who were either waiting for or recently given HSCT [
52]. Adverse reactions occurred in 7 % of the transfusion episodes, with no clear relationship with the presence or development of leukocyte antibodies. Overall, infection resolved in 8 patients. However, none of the 5 patients with aspergillosis cleared their infection.
In another study G-CSF-mobilized GTX collected from related donors were administered to 15 neutropenic patients with hematologic malignancies and fungal infections [
53]. Eleven patients had favorable responses and eight of them remained free of infection 3 weeks after therapy.
In a similar study, thirty patients with hematological malignancies received granulocyte transfusions for neutropenia and severe infections during a 12-year period [
54]. The donors were given G-CSF and intravenous dexamethasone. A median of 3 transfusions was administered to the patients. For 11 patients (37 %), defervescence and resolution of signs of infection could be attributed to granulocyte transfusions. Mortality at 30 and 180 days after granulocyte transfusions was 40 and 72 %, respectively. No infection-related mortality was reported in patients who responded clinically to the granulocyte transfusions.
A prospective, non-randomized study evaluated the efficacy of granulocyte transfusions for controlling and preventing recurrence of severe infections in patients with hematological malignancies [
55]. Fifty-two patients were enrolled between 1997 and 2003, with a total of 67 infectious episodes. The underlying infections were predominantly of fungal origin. In the interventional group, a favorable response was documented in 82 % of the infectious episodes, especially in patients with bacterial infections. In the prophylactic group, no single reactivation of a previous infection occurred. Survival at day 100 after granulocyte transfusions was 64 and 65 % in the interventional and prophylactic group, respectively. With a median follow-up of 3.5 years, 42/52 patients had died, mostly due to the underlying progressive disease.
The RING study is a recently completed randomized controlled study carried out by the NHLBI Transfusion Medicine/Hemostasis Clinical Trials Network which evaluated the efficacy of high-dose granulocyte transfusion therapy [
56]. The desired sample size was 236 subjects, in order to have 80 % power to detect a 20 % difference in success rates between the treatment and control groups. Fourteen clinical sites participated and 114 subjects were enrolled. Patients were neutropenic and had a proven/probable/presumed bacterial or fungal infection. Subjects were randomly assigned to receive standard antimicrobial therapy with or without GTX collected from normal donors stimulated with G-CSF and dexamethasone. The median number of granulocytes administered per transfusion was 54.9 × 10
9. The composite primary endpoint was survival plus a microbial response evaluated 42 days after randomization. The median number of transfusions in subjects randomized to the GTX arm was five. Success rates were 42 % (20/48) and 43 % (21/49) for the granulocyte and control groups, respectively, on intention-to-treat analysis, and 49 % (17/35) and 41 % (16/39), respectively, on per-protocol analysis. Because of low accrual, the power of this study to detect a 20 % difference in the overall success rates was reduced to approximately 40 %. Thus, it cannot be ruled out that a true effect was missed, particularly if the effect is limited to specific patient subsets [
56].
A retrospective analysis of 74 patients with refractory hematological malignancies, receiving granulocyte transfusions, showed that patients with documented severe infections might have better survival rates compared with those who do not have severe infection [
12]. Patients who died by 12 weeks after granulocyte transfusion initiation were more likely to have leukemia and not to have had recovery of neutrophil counts. Furthermore, the use of G-CSF and IFN-γ as adjuvant therapy were more common in patients who survived the infectious episode. This observation may suggest that the benefits of granulocyte transfusions are greater in the presence of documented severe bacterial or fungal infection. Importantly, these survival benefits were only observed when GTX were administered prior to disease progression and multisystem failure, requiring the use of mechanical ventilation in critical care units.
A recent single-center case series of 11 patients with invasive
Fusarium infections who were treated with GTX showed a 91 % response rate [
57]. Three patients who failed to achieve hematopoietic recovery did not survive, implying that GTX may improve response rates by bridging periods of neutropenia or bone marrow suppression.
Granulocyte transfusions have been combined with G-CSF administration in 56 patients with severe aplastic anemia and severe infections [
58]. The median number of granulocyte components transfused was 18; survival at 30, 90 and 180 days were 89, 70 and 66 %, respectively. Among the 31 patients with invasive fungal infections, survival at 30 days, 90 days and 180 days was 87, 58 and 52 %, respectively. Among the 25 patients with refractory severe bacterial infections, survival at 30, 90 and 180 days were 92, 84 and 84 %, respectively. Importantly, survival rate was correlated with hematopoietic recovery. This study suggests that granulocyte transfusions combined with G-CSF could be an adjunctive therapy for treating severe infections in patients with severe aplastic anemia.
It has been shown that accumulation of the transfused granulocytes at sites of infection can help predict the clinical response. In four patients given
99mTc-HMPAO- labeled granulocytes, planar imaging at 1 h (early) and 4 h (delayed) after granulocyte infusion allowed the identification of responders and non-responders based on granulocyte uptake, as assessed by the lesion-to-normal lung ratio. By contrast, granulocyte scintiscans of two patients who were non-responders did not show any granulocyte uptake into the infiltrative lung lesions [
59].
The clinical results of the transfusion of granulocytes collected from community donors vs. family donors may be similar [
60]. The use of granulocytes collected from community donors bears the advantage of requiring less time to begin the GTX course. In addition, higher increments of the absolute neutrophil count were recorded in patients receiving GTX from G-CSF and dexamethasone-stimulated community donors, compared with patients receiving GTX from G-CSF-stimulated family donors. Overall, 57 and 56 % of patients receiving granulocytes collected from unrelated community and related donors, respectively, had a progressive or fatal course of infection.
Collectively, the available evidence points to the efficacy of GTX as an adjunct treatment modality for severely neutropenic patients who are likely to experience hematopoietic recovery.