-
Haematologica Nov 2012Modern chemotherapy regimens and supportive care have produced remarkable improvements in the overall survival of patients with hematologic malignancies. However, the... (Review)
Review
Modern chemotherapy regimens and supportive care have produced remarkable improvements in the overall survival of patients with hematologic malignancies. However, the development of targeted small molecules, monoclonal antibodies, and biological therapies that demonstrate greater efficacy and lower toxicity remains highly desirable in hematology, and oncology in general. In the context of biological therapies, T-lymphocyte based treatments have enormous potential. Donor lymphocyte infusion in patients relapsed after allogeneic hematopoietic stem cell transplant pioneered the concept that T lymphocytes can effectively control tumor growth, and this was then followed by the development of cell culture strategies to generate T lymphocytes with selective activity against tumor cells. Over the past decade, it has become clear that the adoptive transfer of ex vivo expanded antigen-specific cytotoxic T lymphocytes promotes sustained antitumor effects in patients with virus-associated lymphomas, such as Epstein-Barr virus related post-transplant lymphomas and Hodgkin's lymphomas. Because of this compelling clinical evidence and the concomitant development of methodologies for robust gene transfer to human T lymphocytes, the field has rapidly evolved, offering new opportunities to extend T-cell based therapies. This review summarizes the most recent biological and clinical developments using genetically manipulated T cells for the treatment of hematologic malignancies.
Topics: Animals; Gene Transfer Techniques; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Lymphocyte Transfusion; T-Lymphocytes; Transplantation, Homologous
PubMed: 22929977
DOI: 10.3324/haematol.2012.064303 -
Transfusion Sep 2015Invasive Fusarium infection is relatively refractory to available antifungal agents. Invasive fusariosis (IF) occurs almost exclusively in the setting of profound... (Review)
Review
BACKGROUND
Invasive Fusarium infection is relatively refractory to available antifungal agents. Invasive fusariosis (IF) occurs almost exclusively in the setting of profound neutropenia and/or systemic corticosteroid use. Treatment guidelines for IF are not well established, including the role of granulocyte transfusions (GTs) to counter neutropenia.
STUDY DESIGN AND METHODS
We conducted a systematic review, identifying IF cases where GTs were used as adjunctive therapy to antifungal agents and also report a single-center case series detailing our experience (1996-2012) of all IF cases treated with antifungal agents and GTs. In the systematic review cases, GTs were predominantly collected from nonstimulated donors whereas, in the case series, they were universally derived from dexamethasone- and granulocyte-colony-stimulating factor-stimulated donors.
RESULTS
Twenty-three patients met inclusion criteria for the systematic review and 11 for the case series. Response rates after GTs were 30 and 91% in the review and case series, respectively. Survival to hospital discharge remained low at 30 and 45%, respectively. Ten patients in the systematic review and three in the case series failed to achieve hematopoietic recovery and none of these survived. In the case series, donor-stimulated GTs generated mean "same-day" neutrophil increments of 3.35 × 10(9) ± 1.24 × 10(9) /L and mean overall posttransfusion neutrophil increments of 2.46 × 10(9) ± 0.85 × 10(9) /L. Progressive decrements in neutrophil response to GTs in two cases were attributed to GT-related HLA alloimmunization.
CONCLUSION
In patients with IF, donor-stimulated GTs may contribute to high response rates by effectively bridging periods of neutropenia or marrow suppression. However, their utility in the absence of neutrophil recovery remains questionable.
Topics: Female; Fusariosis; Granulocytes; Humans; Leukocyte Transfusion; Male
PubMed: 25857209
DOI: 10.1111/trf.13099 -
Transplantation and Cellular Therapy May 2023Post-transplantation relapse of acute myeloid leukemia and myelodysplastic syndromes has a poor prognosis. Donor lymphocyte infusion (DLI) is one treatment approach....
A Multicenter Phase 2 Clinical Trial of 10-Day Decitabine, Dose-Escalated Donor Lymphocyte Infusion, and Ruxolitinib for Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndromes after Allogeneic Hematopoietic Cell Transplantation.
Post-transplantation relapse of acute myeloid leukemia and myelodysplastic syndromes has a poor prognosis. Donor lymphocyte infusion (DLI) is one treatment approach. However, efficacy is limited, and toxicity, mostly in the form of acute graft-versus-host disease (GVHD), is frequent. We tested a novel approach using 10-day decitabine, dose-escalated DLI, and ruxolitinib in a multicenter phase 2 trial aimed at increasing the efficacy of DLI and reducing its toxicity. Up to four 28-day cycles were administered. The primary endpoint was 6-month overall survival (OS). Of the 14 patients who started cycle 1, 13 received 1 DLI, 6 received 2 DLIs, and 1 received 3 4 DLIs. A preplanned interim analysis after enrolling 14 patients suggested futility, and the trial was closed to accrual. The final analysis showed a 6-month OS of 36% (95% confidence interval [CI], 18 to 72), a 1-year progression-free survival of 7% (95% CI, 1% to 47%), a 6-month cumulative incidence of grade II-IV acute GVHD of 57% (95% CI, 26% to 80%), and a 1-year nonrelapse mortality of 14% (95% CI, 2% to 38%). The combined modality treatment studied in this trial was ineffective and did not reduce DLI toxicity.
Topics: Humans; Decitabine; Lymphocyte Transfusion; Hematopoietic Stem Cell Transplantation; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Graft vs Host Disease; Lymphocytes
PubMed: 36804933
DOI: 10.1016/j.jtct.2023.02.010 -
The Cochrane Database of Systematic... Oct 2011Neonates have immature granulopoiesis, which frequently results in neutropenia after sepsis. Neutropaenic septic neonates have a higher mortality than non-neutropenic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Neonates have immature granulopoiesis, which frequently results in neutropenia after sepsis. Neutropaenic septic neonates have a higher mortality than non-neutropenic septic neonates. Therefore, granulocyte transfusion to septic neutropenic neonates may improve outcomes.
OBJECTIVES
The primary objective was to determine the effect of granulocyte or buffy coat transfusions as adjuncts to antibiotics, after confirmed or suspected sepsis in neutropenic neonates, on all-cause mortality during hospital stay and neurological outcome at ≥ year of age. Secondary objectives were to determine the effects of granulocyte transfusions on length of hospital stay in survivors to discharge, adverse effects and immunologic outcomes at ≥ year of age.
SEARCH STRATEGY
The Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE and CINAHL, proceedings of the PAS conferences and ongoing trials at clinicaltrials.gov and clinical-trials.com were searched in July 2011.
SELECTION CRITERIA
Studies where neutropenic neonates with suspected or confirmed sepsis were randomised or quasi-randomised to granulocyte or buffy coat transfusions at any dose or duration, and reporting any outcome of interest were included.
DATA COLLECTION AND ANALYSIS
Relative risk (RR) and risk difference (RD) with 95% confidence intervals using the fixed effects model were reported for dichotomous outcomes. Pre-specified subgroup analyses were performed.
MAIN RESULTS
Four trials were eligible for inclusion. Forty-four infants with sepsis and neutropenia were randomised in three trials to granulocyte transfusions or placebo/no transfusion. In another trial, 35 infants with sepsis and neutropenia on antibiotics were randomised to granulocyte transfusion or IVIG.When granulocyte transfusion was compared with placebo or no transfusion, there was no significant difference in 'all-cause mortality' (three trials; typical RR 0.89, 95% CI 0.43 to 1.86; typical RD -0.05, 95% CI -0.31 to 0.21).When granulocyte transfusion was compared with intravenous immunoglobulin (one trial), there was a reduction in 'all-cause mortality' of borderline statistical significance (RR 0.06, 95% CI 0.00 to 1.04; RD -0.34, 95% CI -0.60 to -0.09; NNT 2.7, 95% CI 1.6 to 9.1).Pulmonary complications were the only adverse effect reported in the trials that used buffy coat transfusions. None of the trials reported on neurological outcome at one year of age or later, length of hospital stay in survivors to discharge or immunological outcome at one year of age or later.
AUTHORS' CONCLUSIONS
Currently, there is inconclusive evidence from randomised controlled trials (RCTs) to support or refute the routine use of granulocyte transfusions in neutropenic, septic neonates. Researchers are encouraged to conduct adequately powered multi-centre trials of granulocyte transfusions in neutropenic septic neonates.
Topics: Granulocytes; Humans; Immunoglobulins, Intravenous; Infant, Newborn; Leukocyte Transfusion; Neutropenia; Randomized Controlled Trials as Topic; Sepsis
PubMed: 21975741
DOI: 10.1002/14651858.CD003956.pub2 -
Transplantation and Cellular Therapy Apr 2022In the context of T-cell depletion, failing to achieve full donor chimerism (FDC) entails higher risk of graft loss and disease relapse. Donor lymphocyte infusion (DLI)...
In the context of T-cell depletion, failing to achieve full donor chimerism (FDC) entails higher risk of graft loss and disease relapse. Donor lymphocyte infusion (DLI) is an adoptive immunotherapy for mixed chimerism (MC) or relapsed disease after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (HSCT). Nevertheless, little is known of factors associated with attaining FDC or disease remission. We carried out a retrospective study with 100 adult patients to identify patient and donor factors that can predict achievement of FDC and disease remission and describe complications after DLI. Indications for DLI were T-cell MC in 61 patients and relapsed disease in 39 patients. Forty patients (65.6%) with MC attained T-full donor chimerism (T-FDC), with higher responses seen in patients whose donors were female (81.5% versus 52.9%, P = .004) and cytomegalovirus negative (76.5% versus 52%, P = .004). However, only patients with younger donors (<30 years old) compared to older donors (94.4% versus 53.5%, P = .013) and those attaining unfractionated whole blood (UWB) FDC after DLI (76.6% versus 28.6%, P < .001) had a survival benefit and subsequently a better graft-versus-host disease (GvHD)-free/relapse-free survival. Nineteen of 39 patients (48.7%) with relapsed disease achieved remission after DLI. In this cohort, attaining T-FDC impacted favorably in disease control (76.7% versus 12.5%, P = .012) and improved survival (45.5% versus 12.5%, P = .007). In the whole population, the cumulative incidence of acute GvHD (aGvHD) at day 100 after DLI was 23%, and chronic GvHD (cGvHD) at 1 year after DLI was 22%. In the whole population, donor age was also a determining factor for aGvHD, because patients with younger donors had a lower incidence of aGvHD (8% versus 36%, P = .021). The cGvHD was more likely to occur in patients who converted to T-FDC (34% versus 10.3%, P = .025). Donor characteristics are increasingly considered when deciding approaches for HSCT. Donor age should be considered when planning HSCT, as well as doses and scheduling of DLI. As per our experience, this should be done alongside T/UWB chimerism to achieve the maximal clinical benefit with less associated toxicity. Selection of younger male donors from stem cell registries can minimize the risk of GvHD and improve survival.
Topics: Adult; Female; Hematologic Neoplasms; Humans; Immunotherapy, Adoptive; Lymphocyte Transfusion; Male; Neoplasm Recurrence, Local; Retrospective Studies; T-Lymphocytes; Transplantation, Homologous
PubMed: 35104660
DOI: 10.1016/j.jtct.2022.01.022 -
The Journal of Allergy and Clinical... Jan 2022Type 2 innate lymphoid cells (ILC2s) are relevant players in type 2 asthma. They initiate eosinophil infiltration and airway hyperreactivity (AHR) through cytokine...
BACKGROUND
Type 2 innate lymphoid cells (ILC2s) are relevant players in type 2 asthma. They initiate eosinophil infiltration and airway hyperreactivity (AHR) through cytokine secretion. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is an inhibitory receptor considered to be an immune checkpoint in different inflammatory diseases.
OBJECTIVE
Our aim here was to investigate the expression of LAIR-1 and assess its role in human and murine ILC2s.
METHODS
Wild-type and LAIR-1 knockout mice were intranasally challenged with IL-33, and pulmonary ILC2s were sorted to perform an ex vivo comparative study based on RNA sequencing and flow cytometry. We next studied the impact of LAIR-1 deficiency on AHR and lung inflammation by using knockout mice and adoptive transfer experiments in Rag2Il2rg mice. Knockdown antisense strategies and humanized mice were used to assess the role of LAIR-1 in human ILC2s.
RESULTS
We have demonstrated that LAIR-1 is inducible on activated ILC2s and downregulates cytokine secretion and effector function. LAIR-1 signaling in ILC2s was mediated via inhibitory pathways, including SHP1/PI3K/AKT, and LAIR-1 deficiency led to exacerbated ILC2-dependent AHR in IL-33 and Alternaria alternata models. In adoptive transfer experiments, we confirmed the LAIR-1-mediated regulation of ILC2s in vivo. Interestingly, LAIR-1 was expressed and inducible in human ILC2s, and knockdown approaches of Lair1 resulted in higher cytokine production. Finally, engagement of LAIR-1 by physiologic ligand C1q significantly reduced ILC2-dependent AHR in a humanized ILC2 murine model.
CONCLUSION
Our results unravel a novel regulatory axis in ILC2s with the capacity to reduce allergic AHR and lung inflammation.
Topics: Adoptive Transfer; Alternaria; Alternariosis; Animals; Cytokines; Female; Humans; Immunity, Innate; Interleukin-33; Lung; Lymphocyte Transfusion; Lymphocytes; Male; Mice, Inbred C57BL; Mice, Knockout; Pneumonia; Receptors, Immunologic; Respiratory Hypersensitivity; Mice
PubMed: 34144112
DOI: 10.1016/j.jaci.2021.05.042 -
Biology of Blood and Marrow... Mar 2015Although allogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach for many pediatric patients with hematologic malignancies and some nonmalignant... (Review)
Review
Although allogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach for many pediatric patients with hematologic malignancies and some nonmalignant disorders, some critical obstacles remain to be overcome, including relapse, engraftment failure, graft-versus-host disease (GVHD), and infection. Harnessing the immune system to induce a graft-versus-tumor effect or rapidly restore antiviral immunity through the use of donor lymphocyte infusion (DLI) has been remarkably successful in some settings. Unfortunately, however, the responses to DLI can be variable, and GVHD is common. Thus, manipulations to minimize GVHD while restoring antiviral immunity and enhancing the graft-versus-tumor effect are needed to improve outcomes after allogeneic HSCT. Cellular therapies, defined as treatment modalities in which hematopoietic or nonhematopoietic cells are used as therapeutic agents, offer this promise for improving outcomes post-HSCT. This review presents an overview of the field for pediatric cell therapies in the transplant setting and discusses how we can broaden applicability beyond phase I.
Topics: Adolescent; Allografts; Cell- and Tissue-Based Therapy; Child; Child, Preschool; Female; Graft Rejection; Graft vs Host Disease; Graft vs Tumor Effect; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lymphocyte Transfusion; Male
PubMed: 25064748
DOI: 10.1016/j.bbmt.2014.07.018 -
Clinical Transplants 1995Tacrolimus is a more potent and satisfactory immunosuppressant than CyA for combination therapy with prednisone. In randomized trials comparing the 2 drugs, the ability... (Comparative Study)
Comparative Study Review
Tacrolimus is a more potent and satisfactory immunosuppressant than CyA for combination therapy with prednisone. In randomized trials comparing the 2 drugs, the ability of tacrolimus to rescue intractably rejecting grafts on the competing CyA arm allowed equalization of patient and graft survival on both arms when the intent-to-treat analytic methodology was applied. The ability of tacrolimus to systematically rescue the treatment failures of CyA suggested, as a matter of common sense, that it is the preferred baseline drug for hepatic transplantation. This conclusion was supported by analysis of secondary end points, including the ability to prevent rejection. Hepatic-intestinal, multivisceral and isolated intestinal transplantation became feasible on a practical basis only after the advent of tacrolimus. Nevertheless, better management strategies must be devised before intestinal transplantation, alone or with other abdominal viscera, will meet its potential. One such strategy is based on the discovery of the presence of previously unsuspected, low-level donor leukocyte chimerism in long-surviving allograft recipients. We believe that this chimerism is the essential explanation for the feasibility of organ transplantation and a link to the acquired neonatal tolerance demonstrated by Billingham, Brent and Medawar (32). The hematolymphopoietic chimerism in organ recipients explains why weaning to a drug-free state in selected long-term survivors is frequently feasible and particularly if the allograft is a liver. Weaning should never be attempted without a stepwise protocol and careful monitoring of graft function. Recognition of the natural chimerism that develops after whole organ transplantation has led to efforts to augment it with perioperative donor BM infusion. This procedure has been shown to be free of significant complications (including GVHD) in all kinds of whole organ recipients, including those given intestine. The prospects of clinical xenotransplantation must be evaluated in the same context of chimerism as that delineated for allotransplantation with the discovery of spontaneous chimerism. Before addressing chimerism-related questions in xenotransplantation, the additional barrier of the complement activation syndromes that cause hyperacute rejection will have to be surmounted. Although measures to effectively transplant xenografts have so far eluded us, the availability of the more potent drug, tacrolimus, and recognition of the seminal basis of allograft (or xenograft) acceptance via chimerism has inserted an element of reality into the largely wishful thinking that has been evident in discussions about the future of xenotransplantation.
Topics: Adolescent; Adult; Bone Marrow Transplantation; Clinical Protocols; Cross-Over Studies; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Intestines; Leukocyte Transfusion; Liver Transplantation; Male; Middle Aged; Multicenter Studies as Topic; Pennsylvania; Prednisone; Randomized Controlled Trials as Topic; Reoperation; Survival Rate; Tacrolimus; Tissue Donors
PubMed: 8794262
DOI: No ID Found -
The Cochrane Database of Systematic... Jun 2015Despite modern antimicrobials and supportive therapy, bacterial and fungal infections are still major complications in people with prolonged disease-related or... (Meta-Analysis)
Meta-Analysis Review
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.
Topics: Adult; Anti-Bacterial Agents; Antifungal Agents; Bacterial Infections; Cause of Death; Child; Glucocorticoids; Granulocyte Colony-Stimulating Factor; Granulocytes; Humans; Leukocyte Disorders; Leukocyte Transfusion; Mycoses; Neutropenia; Randomized Controlled Trials as Topic
PubMed: 26118415
DOI: 10.1002/14651858.CD005341.pub3 -
BioMed Research International 2016This article reports the influence of an autologous leukocyte- and platelet-rich plasma (L-PRP) injection as a minimally invasive method on supporting wound healing...
This article reports the influence of an autologous leukocyte- and platelet-rich plasma (L-PRP) injection as a minimally invasive method on supporting wound healing processes after a mandibular odontogenic cystectomy and double mandibular fracture fixation. 113 patients were enrolled into a control group (received no L-PRP injection) and 102 patients were enrolled into an L-PRP group with an oral mucosa incision. 18 patients after a double mandibular fracture were operated on using 2 external submandibular approaches receiving no fluids in the right site (a control group) and an L-PRP injection in the left incision (L-PRP group). Clinical observations showed that the oral mucosa healed faster in patients treated with L-PRP, in comparison to cases where inductive biomaterial was not added. Pain at the L-PRP injection site was relieved within few hours after an operation in patients with double mandibular fractures. However, there were no differences observed in the progression of the healing process. L-PRP possesses inductive properties that could stimulate healing processes and it seems to be one of the most promising methods in the future for the treatment of soft tissue defects.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone Regeneration; Female; Fracture Fixation; Humans; Leukocyte Transfusion; Male; Middle Aged; Platelet-Rich Plasma; Postoperative Complications; Surgery, Oral; Wound Closure Techniques; Wound Healing
PubMed: 28097149
DOI: 10.1155/2016/7649206