How are granulocytes for transfusion best used? The past, the present and the future.

Granulocyte transfusions continue to be used in clinical practice, predominantly for treatment of refractory infection in the setting of severe neutropenia. There is biological plausibility for effectiveness in these patients with deficiencies of neutrophils, either as a consequence of disease or treatment. However, there is a chequered history of conducting and completing interventional trials to define optimal use, and many uncertainties remain regarding schedule and dose. Practice and clinical studies are severely limited by the short shelf life and viability of current products, which often restricts the timely access to granulocyte transfusions. In the future, methods are needed to optimise donor-derived granulocyte products. Options include use of manufactured neutrophils, expanded and engineered from stem cells. Further possibilities include manipulation of neutrophils to enhance their function and/or longevity. Granulocyte transfusions contain a heterogeneous mix of cells, and there is additional interest in how these transfusions may have immunomodulatory effects, including for potential uses as adjuncts for anti-cancer effects.

Survival among children and adults treated with granulocyte transfusions: Twenty years' experience at a Brazilian blood center.

BACKGROUND: It remains controversial whether granulocyte transfusions as a supportive treatment improve survival in patients with febrile neutropenia or granulocyte dysfunctions. We describe survival rates subsequent to granulocyte transfusions in pediatric and adults patients treated at a major blood center in Brazil. MATERIAL AND METHODS: We retrospectively reviewed the clinical charts of pediatric and adult patients treated with granulocyte transfusions at our institution from January 2000 to October 2019. We assessed demographic characteristics, clinical features, indications for transfusion, units transfused, dose of granulocytes administered and survival rates 30 and 100 days after the initial transfusion. RESULTS: We identified 64 pediatric and 67 adult patients treated with 262 granulocyte transfusions. An optimal dose (> 0.6 × 109 granulocytes per kilogram per transfused unit) was available for transfusion in 80.4 % of pediatric patients but in only 19.6 % of adults (p = 0.017). Thirty days after their first granulocyte transfusion, 38 (59.4 %) pediatric and 61 (91 %) adult patients had died. Patients receiving the optimal dose of granulocytes had better survival outcomes, but even among this sub-group, adults were more likely to die than were children either at 30 days (OR = 8.67, 95 %CI 2.69-34.9) or 100 days (OR = 6.27, 95 %CI 1.86-25.9) after their initial granulocyte transfusion. CONCLUSION: Survival rates following granulocyte transfusion varied by the dose transfused and were higher in children than in adults.

Successful neutrophil engraftment supported by granulocyte transfusion in adult allogeneic transplant patients with peri-transplant active infection.

Active infection at the time of allogeneic hematopoietic stem cell transplantation (HSCT) is a risk for non-relapse mortality (NRM) after HSCT. Granulocyte transfusion (GTX) has been used to prevent or treat life-threatening infections in patients with severe neutropenia. However, data are limited on the clinical benefits of GTX during HSCT. We retrospectively analyzed the transplant outcomes of HSCT patients who had undergone GTX between 2012 and 2020. Altogether, 20 patients with documented infection had received 55 GTXs during HSCT. No adverse events were observed during the GTX infusion. The average number of granulocytes was 0.40 (range, 0.10-1.59) × 109/kg. The median neutrophil increment one day after GTX was 515 (range, -6 to 6630)/µl, which was significantly correlated with the infused granulocyte dose (p = 0.0007). A total of 17 of 20 patients achieved neutrophil engraftment. The number of infused granulocytes tended to higher in clinical responders (p = 0.12), and patients receiving ≥ 0.5 × 109/kg showed trend toward to better transplant outcomes (GTX-high vs. GTX-low, 1-year OS; 33% vs. 11%, p = 0.19. 1-year NRM; 44% vs.77%, p = 0.11). The type of red blood sedimenting agents was significantly correlated with the amounts of granulocyte collection. In conclusion, GTX, especially with a high amount of containing granulocytes, could be a safe bridging therapy for neutrophil engraftment after HSCT in patients with active infection.

Current state of nonengrafting donor leukocyte infusion (focus on microtransplantation for acute myeloid leukemia).

PURPOSE OF REVIEW: Microtransplantation (or micro-stem cell transplantation, MST) is one permutation of alloreactive immunotherapy increasingly studied in clinical trials. It is most commonly applied to patients with myeloid malignancies who are not suitable candidates for allogeneic hematopoietic cell transplantation. This review highlights the past 2 years of work on stem/progenitor cell products in the field of nonengrafting donor leukocyte infusion (NE-DLI), with a focus on applications of MST in acute myeloid leukemia (AML). RECENT FINDINGS: Assessing the utility of MST is hampered by lack of randomized controlled trials and by variability in donor selection algorithms, treatment timing, and unknown factors. The inherent complexity of the bidirectional alloreactive reactions, implicating many cell types, makes it challenging to move beyond correlative, population-level biology toward mechanistic explanations for MST's actions in any given patient-donor pair. Yet there are indicators that by stimulating a recipient-vs.-tumor effect, MST might substantially improve complete remission rates in AML and that it might find a role in postremission therapy. SUMMARY: The mechanistic underpinnings of MST are gradually being disentangled and its clinical development remains in early stages.

Granulocyte transfusions in the management of invasive fungal infections.

Granulocyte transfusions have a long history of being used in patients with neutropenia or neutrophil dysfunction to prevent and treat invasive fungal infections. However, there are limited and conflicting data concerning its clinical effectiveness, considerable variations in current granulocyte transfusion practices, and uncertainties about its benefit as an adjunct to modern antifungal therapy. In this review, we provide an overview on granulocyte transfusions and summarize the evidence on their role in the prevention and treatment of invasive fungal infections.

Granulocyte transfusions: A concise review for practitioners.

Granulocyte transfusions (GTXs) have been used to treat and prevent infections in neutropenic patients for more than 40 years, despite persistent controversy regarding their efficacy. This narrative review attempts to complement recent systematic reviews by the Cochrane Collaboration and provide both historical context and critical assessment of the most significant clinical studies published over the years. The data suggest that properly collected and promptly infused granulocytes are active against infections, both bacterial and fungal. The most important question that remains unanswered is in which patients the administration of granulocytes will be beneficial. The preponderance of evidence suggests that granulocyte transfusions may be efficacious in few select cases as a temporizing measure to control an infection that is expected (or proven) to be refractory to optimal antimicrobial treatment, and that could otherwise be controlled by marrow recovery, which is expected to happen. In this regard, they are best considered a "bridge" that grants enough time for the recipient to develop their own response to the infection. The challenges to use GTXs successfully are both clinical, in terms of timely identifying the patients who may benefit, and logistical, in terms of optimal selection of donors and collection technique.

Leukocyte and plasma activation profiles in chronically transfused patients with a history of allergic reactions.

BACKGROUND: Allergic transfusion reactions are drawbacks to the benefits of transfusion. Classically, allergic transfusion reactions depend on histamine release from mast cells or basophils, but other leukocyte subsets may also be important. Thus, we propose to better define the exact leukocyte subsets involved in allergic transfusion reactions. STUDY DESIGN AND METHODS: The overall objective of the current study was to compare the activation of specific peripheral blood leukocyte subsets (monocytes, neutrophils, eosinophils, and basophils) in a cohort of 13 patients who received chronic transfusions and had a history of allergic transfusion reactions compared with a control group of patients who received chronic transfusions and had no history of allergic transfusion reactions. Leukocyte subsets were analyzed by flow cytometry at baseline and after red blood cell transfusion, and cytokine levels in platelet-free plasma collected at the same time points were measured by Luminex assay. RESULTS: Flow cytometry and cytokine profiles before and after transfusion did not differ significantly between patients who did and did not have a history of allergic transfusion reactions (p > 0.05). However, post-transfusion samples from both groups showed a decrease in CD63 expression in basophils, monocytes, and eosinophils and a decrease in CD45 expression in all leukocyte subsets compared with pretransfusion samples. Interleukin 10 levels increased after transfusion in the group with a history of allergic transfusion reactions (p = 0.0469), and RANTES (regulated upon activation, normal T-cell expressed and secreted) was significantly decreased post-transfusion in all patients (p = 0.0122). CONCLUSION: None of the leukocyte subsets from patients who had a history of allergic transfusion reactions significantly increased in activation either before or after transfusion. All leukocyte subsets from patients who did and did not have a history of allergic transfusion reactions decreased in their activation profile upon transfusion challenge.

Update on granulocyte transfusions: accumulation of promising data, but still lack of decisive evidence.

PURPOSE OF REVIEW: Inconsistent results regarding the clinical efficacy of granulocyte transfusions for the treatment or prophylaxis of life-threatening infections in neutropenic patients have been attributed to insufficient number of transfused neutrophils. Since the introduction of granulocyte colony-stimulating factor (G-CSF) to the granulocyte mobilization regimen in the 1990s, the number of transfused cells significantly increased, which directly translated to a significant increase in absolute neutrophil counts in the transfused patients. RECENT FINDINGS: For therapeutic granulocyte transfusions, neither of the two randomized controlled studies in the G-CSF era could demonstrate a clear clinical benefit. However, a number of small studies or case series have suggested its clinical efficacy, including one that demonstrated the clinical response against drug-resistant invasive fusariosis. For prophylactic granulocyte transfusions, there have been scarce reports in the G-CSF era. A pulmonary reaction is the most significant adverse event after granulocyte transfusions, although its reported frequency varies among studies. SUMMARY: Despite the expectation that the increased number of transfused neutrophils enables the clear demonstration of the clinical benefit, the role of therapeutic granulocyte transfusions remains controversial. Future directions may include: identifying the patient population who would benefit most from granulocyte transfusions; minimizing the risk of adverse events by identifying the risk factors and the prevention methods; and finding a way to prove the clinical benefit of granulocyte transfusions in therapeutic and prophylactic settings.

Hydroxyethyl starch and granulocyte transfusions: considerations of utility and toxicity profile for patients and donors.

Hydroxyethyl starch (hetastarch) is a synthetic glucose compound with extensive clinical use as a volume expander. Because of its red blood cell-sedimenting properties, hetastarch plays a major role in preparation of granulocyte products. Recent concerns have been raised about the use of hetastarch in critically ill patients for the development of renal injury and other severe adverse events. In contrast, granulocyte donors receive much less of this compound during collection procedures, and over many years, minimal toxicity has been documented in these individuals. Furthermore, granulocyte products contain very little hetastarch, and ill effects on renal function have not been associated with their administration. This review assesses available information about the toxicity profile of hetastarch in critically ill patients requiring a volume expander as well as granulocyte donors and recipients. Because of the lack of toxicity in these latter two groups, hetastarch should be available for preparation of granulocyte products and their administration.

Granulocyte transfusions for preventing infections in people with neutropenia or neutrophil dysfunction.

BACKGROUND: Despite modern antimicrobials and supportive therapy, bacterial and fungal infections are still major complications in people with prolonged disease-related or therapy-related neutropenia. Since the late 1990s there has been increasing demand for donated granulocyte transfusions to treat or prevent severe infections in people who lack their own functional granulocytes. This is an update of a Cochrane review first published in 2009. OBJECTIVES: To determine the effectiveness and safety of prophylactic granulocyte transfusions compared with a control population not receiving this intervention for preventing all-cause mortality, mortality due to infection, and evidence of infection due to infection or due to any other cause in people with neutropenia or disorders of neutrophil function. SEARCH METHODS: We searched for randomised controlled trials (RCTs) and quasi-RCTs in the Cochrane Central Register of Controlled Trials (Cochrane Library 2015, Issue 3), MEDLINE (from 1946), EMBASE (from 1974), CINAHL (from 1937), theTransfusion Evidence Library (from 1980) and ongoing trial databases to April 20 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing people receiving granulocyte transfusions to prevent the development of infection with a control group receiving no granulocyte transfusions. Neonates are the subject of another Cochrane review and were excluded from this review. There was no restriction by outcomes examined, but this review focuses on mortality, mortality due to infection and adverse events. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: Twelve trials met the inclusion criteria. One trial is still ongoing, leaving a total of 11 trials eligible involving 653 participants. These trials were conducted between 1978 and 2006 and enrolled participants from fairly comparable patient populations. None of the studies included people with neutrophil dysfunction. Ten studies included only adults, and two studies included children and adults. Ten of these studies contained separate data for each arm and were able to be critically appraised. One study re-randomised people and therefore quantitative analysis was unable to be performed.Overall, the quality of the evidence was very low to low across different outcomes according to GRADE methodology. This was due to many of the studies being at high risk of bias, and many of the outcome estimates being imprecise.All-cause mortality was reported for nine studies (609 participants). There was no difference in all-cause mortality over 30 days between people receiving prophylactic granulocyte transfusions and those that did not (seven studies; 437 participants; RR 0.92, 95% CI 0.63 to 1.36, very low-quality evidence).Mortality due to infection was reported for seven studies (398 participants). There was no difference in mortality due to infection over 30 days between people receiving prophylactic granulocyte transfusions and those that did not (six studies; 286 participants; RR 0.69, 95% CI 0.33 to 1.44, very low-quality evidence).The number of people with localised or systemic bacterial or fungal infections was reported for nine studies (609 participants). There were differences between the granulocyte dose subgroups (test for subgroup differences P = 0.01). There was no difference in the number of people with infections over 30 days between people receiving prophylactic granulocyte transfusions and those that did not in the low-dose granulocyte group (< 1.0 x 10(10) granulocytes per day) (four studies, 204 participants; RR 0.84, 95% CI 0.58 to 1.20; very low-quality evidence). There was a decreased number of people with infections over 30 days in the people receiving prophylactic granulocyte transfusions in the intermediate-dose granulocyte group (1.0 x 10(10) to 4.0 x 10(10) granulocytes per day) (4 studies; 293 participants; RR 0.40, 95% CI 0.26 to 0.63, low-quality evidence).There was a decreased number of participants with bacteraemia and fungaemia in the participants receiving prophylactic granulocyte transfusions (nine studies; 609 participants; RR 0.45, 95% CI 0.30 to 0.65, low-quality evidence).There was no difference in the number of participants with localised bacterial or fungal infection in the participants receiving prophylactic granulocyte transfusions (six studies; 296 participants; RR 0.75, 95% CI 0.50 to 1.14; very low-quality evidence).Serious adverse events were only reported for participants receiving granulocyte transfusions and donors of granulocyte transfusions. AUTHORS' CONCLUSIONS: In people who are neutropenic due to myelosuppressive chemotherapy or a haematopoietic stem cell transplant, there is low-grade evidence that prophylactic granulocyte transfusions decrease the risk of bacteraemia or fungaemia. There is low-grade evidence that the effect of prophylactic granulocyte transfusions may be dose-dependent, a dose of at least 10 x 10(10) per day being more effective at decreasing the risk of infection. There is insufficient evidence to determine any difference in mortality rates due to infection, all-cause mortality, or serious adverse events.

Highly efficient prion transmission by blood transfusion.

It is now clearly established that the transfusion of blood from variant CJD (v-CJD) infected individuals can transmit the disease. Since the number of asymptomatic infected donors remains unresolved, inter-individual v-CJD transmission through blood and blood derived products is a major public health concern. Current risk assessments for transmission of v-CJD by blood and blood derived products by transfusion rely on infectious titers measured in rodent models of Transmissible Spongiform Encephalopathies (TSE) using intra-cerebral (IC) inoculation of blood components. To address the biological relevance of this approach, we compared the efficiency of TSE transmission by blood and blood components when administrated either through transfusion in sheep or by intra-cerebral inoculation (IC) in transgenic mice (tg338) over-expressing ovine PrP. Transfusion of 200 µL of blood from asymptomatic infected donor sheep transmitted prion disease with 100% efficiency thereby displaying greater virulence than the transfusion of 200 mL of normal blood spiked with brain homogenate material containing 10³ID50 as measured by intracerebral inoculation of tg338 mice (ID50 IC in tg338). This was consistent with a whole blood titer greater than 10³·6ID50 IC in tg338 per mL. However, when the same blood samples were assayed by IC inoculation into tg338 the infectious titers were less than 32 ID per mL. Whereas the transfusion of crude plasma to sheep transmitted the disease with limited efficacy, White Blood Cells (WBC) displayed a similar ability to whole blood to infect recipients. Strikingly, fixation of WBC with paraformaldehyde did not affect the infectivity titer as measured in tg338 but dramatically impaired disease transmission by transfusion in sheep. These results demonstrate that TSE transmission by blood transfusion can be highly efficient and that this efficiency is more dependent on the viability of transfused cells than the level of infectivity measured by IC inoculation.

Numerous granulocyte transfusions to a patient with severe aplastic anemia without severe complication.

One of the most important morbidity causes of aplastic anemia is invasive fungal infections. It could not be possible to take control of infection without neutrophils despite the recent developments in the antifungals. In this presented case, a patient with severe aplastic anemia, granulocyte transfusion were administered as 46 times because of the presence of widely invasive aspergillosis and resistance. Only fever reaction was observed as a complication of transfusion amongst the other complications such as acute lung damage, alloimmunisation, and graft-versus-host disease. Granulosit transfusions should not be avoided in patients who had an indication for.

The granulocytes in neutropenia 1 (GIN 1) study: a safety study of granulocytes collected from whole blood and stored in additive solution and plasma.

OBJECTIVE/AIM: To evaluate the safety of transfusing pooled, whole blood-derived granulocytes in additive solution and plasma (GASP) in 30 recipients. BACKGROUND: Demand for granulocytes in England has increased five-fold. With the advantages of reduced red cell, plasma and overall volume, GASP maintains function in vitro. METHODS AND MATERIALS: Observations were recorded prior to and post transfusion. Increments were recorded at 1 h and the following morning. Leucocyte antibody screening was undertaken prior to and at 1-6 months following transfusion. RESULTS: Thirty patients aged between 8 months and 68 years received 221 GASP in 148 transfusion episodes. GASP contained an average of 1.0 × 10(10) granulocytes in 207 mL. Adults usually received two packs and children 10-20 mL kg(-1). Children and adults received a median [interquartile range (IQR)] dose of 12.5 (9.1-25.3) and 19.7 (12.0-25.8) × 10(9) granulocytes per transfusion, respectively. There was one episode of transfusion-associated circulatory overload (TACO) in a patient with chronic cardiac failure following 600 mL of unpooled granulocytes, other fluids and one GASP. New leucocyte alloimmunisation occurred in 3/30 recipients 10%. No other significant reactions were reported. Median peripheral blood neutrophil increments at 1 h post transfusion were 0.06 (IQR, 0.01-0.17) in children and (0.03) (IQR, 0-0.16) in adults. CONCLUSION: GASP has a similar safety profile to other sources of granulocytes for patients with refractory infection or in need of secondary prophylactic transfusion. Further studies are required to clarify the role of GASP in the treatment of neutropenic patients.

Granulocyte transfusions.

Neutrophils play an essential role in the defense of the body against bacterial and fungal infections. Disorders of their number or function significantly increase the risk of life-threatening infection. In spite of the development of growth factors, new broad spectrum antibiotics and antifungal drugs against nearly all known pathogens, severe neutropenia associated with bacterial or invasive fungal infections remains a major cause of morbidity and mortality in patients undergoing aggressive cancer chemotherapy or hematopoietic stem cell transplantation. Lately, an interest about granulocyte transfusions was renewed, what is a logical approach in the management of patients with prolonged 'reversible' severe neutropenia and severe infection, which is not controlled with appropriate antimicrobial and supportive treatment, including recombinant hematopoietic growth factors. It was a consequence of advances in the field of apheresis science, use of sedimenting agents and especially advances in mobilization of granulocytes to the peripheral blood. It became now possible to collect large numbers of neutrophils. Therefore, the clinical use of granulocyte transfusions, as a potential life saving treatment option in patients with severe neutropenia and uncontrolled infection in spite of appropriate antimicrobial therapy should be considered, with regard to possible benefits and risks (Ref. 74).

Therapeutic granulocyte transfusions for the treatment of febrile neutropenia in patients with hematologic diseases: a 10-year experience at a single institute.

BACKGROUND AIMS: This single-center 10-year retrospective study assessed clinical efficacies and adverse events and determined prognostic factors in patients with hematologic disease and febrile neutropenia treated with granulocyte transfusions (GT) from unrelated healthy donors stimulated with recombinant human granulocyte-colony-stimulating factor (rhG-CSF) and dexamethasone. METHODS: Between September 1999 and June 2009, 1027 therapeutic GT were performed for the treatment of 170 episodes of febrile neutropenia in 157 patients. Efficacy analysis included 979 GT for 138 episodes in 128 patients who received at least three GT per episode. Adverse event analysis included all patients who received at least one GT. RESULTS: The median granulocyte dose was 0.96 × 10(9)/kg/transfusion (range 0.47-1.80 × 10(9)/kg/transfusion). Infection was controlled in 73 episodes (52.9%). The 28-day infection-related survival rate was 64.7 ± 4.1%. The dose of granulocytes transfused did not correlate with clinical outcome. Multivariate analysis revealed that septic shock and pneumonia/multiple primary infection sites were related to infection control failure. Furthermore, refractory underlying disease and septic shock were associated with shorter infection-related survival. Massive hemoptysis (3.5%) and respiratory failure (5.9%) occurred in a few patients. Prior pneumonic infiltration, azotemia and a larger volume of daily GT were associated with serious respiratory complications. CONCLUSIONS: GT therapy is a viable adjunctive treatment option for febrile neutropenia as a bridge to autologous hematopoietic recovery in patients with hematologic disease with tolerable toxicity. GT therapy requires close monitoring in patients with prior pneumonic infiltration and azotemia. It is recommended that transfusion with higher volumes is avoided.

Polycythemia in an infant secondary to granulocyte transfusions.

Granulocyte transfusions may be useful for neutropenic pediatric patients with refractory bacterial or fungal infections. Many potential adverse sequelae associated with granulocyte transfusions are well recognized, including febrile reactions, fluid overload, alloimmunization, and lung injury. Other potential adverse sequelae, however, are less well known. This case report describes an infant with familial hemophagocytic lymphohistiocytosis who developed polycythemia (hemoglobin 10-17.6 g/dl) following four daily transfusions of 20 ml/kg of apheresis collected, steroid stimulated donor granulocytes. Expanded knowledge of potential risks of transfused granulocytes will allow for rapid recognition of transfusion-related complications, should they occur.

Effects of allogeneic leukocytes in blood transfusions during cardiac surgery on inflammatory mediators and postoperative complications.

OBJECTIVE: To investigate whether the higher prevalence of postoperative complications in cardiac surgery after transfusion of leukocyte-containing red blood cells can be related to inflammatory mediators. DESIGN: Analysis of inflammatory markers interleukin-6, interleukin-10, interleukin-12, and procalcitonin in patients participating in a randomized trial comparing leukocyte-depleted with leukocyte-containing, buffy-coat-depleted red blood cells. SETTING: Two university-affiliated hospitals in the Netherlands. SUBJECTS: A total of 346 patients undergoing cardiac valve surgery with a complete series of pre- and postoperative blood samples. MEASUREMENTS AND MAIN RESULTS: There were no differences in the cytokines and procalcitonin concentrations between both study arms when the patients arrived in the intensive care unit. In subgroups, patients who received zero to three red blood cell transfusions showed similar cytokine concentrations in both study arms, whereas patients with > or = 4 red blood cell transfusions had significantly higher interleukin-6 concentrations in the leukocyte-containing, buffy-coat-depleted red blood cell group. Patients who developed postoperative infections and multiple organ dysfunction syndrome showed, respectively, increased concentrations of interleukin-6 and interleukin-12 in the leukocyte-containing, buffy-coat-depleted, red blood cell group. The interaction tests in these subgroups showed significantly different reaction patterns in the leukocyte-containing, buffy-coat-depleted red blood cell group compared with leukocyte-depleted red blood cell group for interleukin-6 and interleukin-12. Multivariate analysis showed a high interleukin-6 concentration with multiple organ dysfunction syndrome and both high interleukin-6 and interleukin-10 concentrations with hospital mortality. CONCLUSIONS: Allogeneic leukocyte-containing blood transfusions compared with leukocyte-depleted blood transfusions induce dose-dependent significantly higher concentrations of proinflammatory mediators in the immediate postoperative period after cardiac surgery. High concentrations of interleukin-6 are strong predictors for development of multiple organ dysfunction syndrome, whereas both interleukin-6 and interleukin-10 are associated with hospital mortality. These findings suggest that leukocyte-containing red blood cells interfere with the balance between postoperative proinflammatory response, which may further affect the development of complications after cardiac surgery.

Immunotherapy with cytokine induced killer cells in solid and hematopoietic tumours: a pilot clinical trial.

BACKGROUND AND OBJECTIVES: CIK cells are a novel population of efficient immune effector cells with high antitumour activity mainly due to the high proliferation of CD3(+)CD56(+) cells, so may play a role in the development of new forms of adoptive cellular immunotherapy. We started a pilot clinical trial with autologous CIK cells in patients with refractory lymphoma and metastatic solid tumours. This study was aimed at determining the feasibility of generating a sufficient number of CIK cells in heavily pretreated patients and at assessing treatment toxicity. DESIGN AND METHODS: CIK cells were generated from peripheral blood mononuclear cells (MNC) and incubated in the presence of IFN-gamma followed by OKT3 and IL-2. Treatment schedule consisted of three cycles of CIK cells infusions at an interval of 3 weeks. RESULTS: At present 12 patients were enrolled: 6 advanced lymphomas, 5 metastatic kidney carcinoma and 1 hepatocellular carcinoma (HCC). The median number of transferred cells per patient was 28 x 10(9) (range, 6-61). Protocol adherence was excellent and the toxicity profile was favourable. After CIK cells infusion, the absolute median count of lymphocytes, CD3(+), CD8(+) and CD3(+)CD56(+) cells significantly increased in patient's peripheral blood. Clinical outcome appeared promising: three patients had complete response (CR) and two patients had stabilization of disease with a median follow-up of 33 months (range, 9-44). INTERPRETATIONS AND CONCLUSIONS: These preliminary data showed that adoptive immunotherapy with CIK cells is a safe therapy with some suggestion of efficacy that significantly enhances immune functions increasing absolute numbers of effector cells without side effects. If confirmed in larger scale studies, these promising results may have a favourable impact on conventional treatment strategy of malignancies.

Granulocyte transfusions in children and young adults: does the dose matter?

BACKGROUND: Granulocyte transfusions (GTs) may increase the absolute neutrophil count (ANC) before hematopoietic regeneration in neutropenic patients after chemotherapy or hematopoietic stem cell transplantation and support anti-infective immunity. PROCEDURE: We assessed efficacy and tolerability of 778 GTs in 70 treatment episodes of 49 children and 10 young adults [median age 6.28 y (range: 0.13 to 17.7 y) and 21 y (18.0 to 28.0), respectively] suffering from bacterial (n=55) and/or fungal (n=31) infections during neutropenia owing to conventional chemotherapy (n=14), hematopoietic stem cell transplantation conditioning (n=44), or the underlying disease (n=1). We analyzed the impact of body weight, organ dysfunction, neutrophil dose on ANC increment, infection elimination, and survival. RESULTS: The median day-5 ANC increment was 1460/microL, correlating to the administered dose. However, 28-day survival did not correlate to the neutrophil dose nor to the ANC increment, potentially owing to the high number of neutrophils transfused to all patients (median >6x10(9)/kg within 5 d). The 28-day survival probability of the total patient cohort was 0.72+/-0.06 and the 100-day survival was 0.52+/-0.07. Adverse reactions were rare including fever (< or =World Health Organization grade III, 14%), chills (3%), and mild pulmonary complications (1%). CONCLUSIONS: These data corroborate the empirical evidence that GT with sufficient cell doses and rapid availability are a feasible, well-tolerated supplemental means to fight severe infections in neutropenic patients.